Oct 17, 1982 - T5ANG-LEE,. M. Y. W.,. BYRNES, J. J., DOWMEY,. K. M., AND. So,. A. G.: Mechanism of inhibition of deoxyribonucleic acid synthesis by. 1-/3-D-.
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VoL 34, No.3 Printed in U.S.A.
REVIEWS
1982 by The American
Society
for Pharmacology
and Experimental
Therapeutice
Pharmacological and Biochemical Aspects S-Adenosylhomocysteine and S-Adenosylhomocysteine Hydrolase PER Department
I. II.
III.
ofPharmacology,
University
MAGNE
ofBergen,
of *
UELAND
MFH.bygget,
N.5016
Haukeland
Sykehus,
Bergen,
Norway
223
Introduction Pharmacological properties of S-adenosylhomocysteine A. Introductory data B. S-Adenosylhomocysteine C. Analogues of S-adenosylhomocysteine 1. 5’-Deoxy-5’-isobutyl thioadenosme 2. Sinefungin 3. S-Tubercidinylhomocysteine S-Adenosythomocysteine hydrolase A. Enzyme catalysis-interaction between substrates B. Catalytic mechanism C. Role in intermediary metabolism D. Methods E. Distribution and tissue level
and
its analogues
224 224 225 225 226 228 229 229
and
enzyme.
229
230 230
231 233 233 233 233 234 234 234 235 235 236 236 236
1. Vertebrates 2.
and
Microorganisms
Subcellular Relation to adenine Properties 1. Physiochemical 2. Kinetic properties 3. Binding properties Gene localization
plants
3.
F. G.
H. Iv.
Substrates, A. B.
V. VI.
hydrolase
data
analogues
237
239 239 240
4. Various Biological Metabolites
function
analogues pharmacological
and
is dedicated 60th
anniversary,
properties
of 3-deazaadenosme
245 metabolism
245 246
Introduction
of methionine
triphosphate (28, 33, 54). review
237
nucleoside
Inborn errors of purine Summary and conclusion
of his
of S-adenosylhomocysteine
3-Deazaadenosme
adenosme methionine
occasion
inactivators
3.
transmethylation
This
and
237
enzymatic
*
proteins
1. 2’-Deoxyadenosine 2. 9-f-D-arabinofuranosyladenine
I. THE
binding
properties
inhibitors,
Introductory Adenosme
C. D.
analogue
S-adenosyl-L-methionine as
a methyl
requires
the
donor presence
in
(34).
AdoMet
seems
of
t
Abbreviations
used
(ATP) to form so-called active This compound was identified as to
Professor October
Tollak
B.
Sirnes
on
(AdoMet)t
S-adenosylhomocysteine;
to be the are:
AdoMet,
c3AdoHcy,
most
17, 1982. 223
Hcy, L-homocysterne; deoxycoformycin;
ara-A, ara-AHcy,
mocysteine;
3-deazaadenosine.
c3Ado,
versatile
in 1952
methyldonor
S-Adenosyhnethionine;
AdoHcy,
S-3-deazaadenosylhomocysteine;
SIBA, 5’..deoxy-5’-isobutyl thioadenosine; homocysteme; MTA, 5’-deoxy-5’-methyltluoadenosme;
the
by Cantom
c7AdoHcy,
S-tubercidinylAdo, adenosme;
9-f1-n-arabinofuranosylademne; S-(5’-(9-arabinofuranosyladenyl))-L-ho-
dCF,
2’-
224
in
UELAND
mammalian
folic (204)
systems,
whereas
5-methyltetrahydro-
acid (274), methylcobalamine function as methyl donors
Many
low
molecular
strates These
for AdoMet-dependent include catechols (117),
tamine
(72),
interest
has
serotonin phospholipids,
in various
cellular
processes
ture and methylated
function by
(143). specific
Methylation
involved ribosomal
in
serve
transmethylases norepinephrine and
devoted
membrane
the level
compounds
(191)
been
AdoMet.
only
weight
tryptamine
recently which
has
related
of
as
(239). methylation
sub-
been
assigned
Much of
and
ribonucleic
acids
of protein DNA from
mRNA are requiring
has
not
differentiation suggested.
into boxyl
been
established,
(235), Incorporation
and
but
carcinogenesis of methyl
at the sources
a relation
methyltransferases
(173,
Carboxymethylation processes methylation
174,
213;
like
chemotaxis of cellular
seems
(241, 301, formation
(AdoHcy) demonstrated hibition AdoHcy studied in rat
from of was
the liver.
extended inhibitory methylases
by others, showing of a number of
transmethylases
three have
214). in
114,
and
hydrolase. last few
159,
have
nearly
the
same
is a potent trans172,
192,
217,
AdoHcy often Km values for sites of most
or higher
affinity
for
AdoHcy than AdoMet. In the early papers on AdoHcy levels in tissues, the cellular content of this metabolite was probably overestimated (84, 147, 243) because of a rapid increase in the concentration the animal in tissues indicates
of AdoHcy in tissues following death of (152, 152a). Determination of AdoHcy content involving rapid processing of tissue samples that the AdoHcy level is about 0.5 to 30 nmol/
action gation of
AdoHcy
is an
section properties
in
search carried
analogues synthetic
for inhibiout along
2) inhibitors perturb biologof AdoHcy; may be adenosine
for AdoHcy
syntheana-
hydrolase.
describes
the
biological
of AdoHcy and analogues studied
its anain most
is followed by a review of the literaand physiological role of AdoHcy
hydrolase inhibitors
agents
a
posare
analogues of AdoHcy of these compounds are
article
properties on the
may
has stimulated the of AdoHcy hydrolase.
be
potential
the of
investiSome
chemotherapeutic
of AdoHcy hydrolase with naturally occurring metabolites
strates
for
the
of the adenosine
concept of analogues
enzyme.
a review serving These
synis
on the pharmacology as inactivators or sub-
data
are
discussed
AdoHcy hydrolase as with cytotoxic effects.
on the possible role of AdoHcy hydrolase pathology of some diseases of impaired
in light
a target Finally,
for data
in the molecular purine catabolism
presented.
II.
biological
that
The been
has
of this
together with analogues
methylases,
possibility
thereby influby Deguchi
points to the these reactions
agents.
AdoHcy cell from
The interaction compounds and
A.
to the
dem-
reactions
phenomena, inhibiting
described, of adenosine
are
first
This area of research has expanded during years, and basic knowledge on the mechanism
these
g in most organs of mammals, and that the AdoMet content is 5-10 times higher (103b, 152, 152a, 252, 253). This relationship between the cellular content of AdoHcy and AdoMet, and the reported Ki/Km values of transpoints
was
transmethylation
as substrates part
of AdoHcy into potent
agents. thetic
metabolic
L-homocystelne. S-adenosytho-
which
1) Several and some
and pharmacological logues, with emphasis
of phosphatidylcholine was later confirmed
157,
the
ofcertain transmethylases; of AdoHcy hydrolase may by blocking the degradation active intact
first
detail. This ture on the
152a,
by
and enzyme
3.3.1.1),
active methylation
serving
The was (37). In-
of
potent inhibitors or inactivators ical methylation 3) biologically sized in the
(76,
liver by de la Haba and Cantoni in 1959 of this enzyme may play a critical role
different lines. been synthesized,
by who
228, 255, 320). The inhibitor constants for equal or are lower than the corresponding AdoMet; this indicates that the catalytic
(EC
liver
transmethyla-
is relieved
of biological compounds
ref.
transmethylation Gibson et a!. (107),
that AdoHcy AdoMet-dependent
perfused
AdoMet-dependent
involvement
pharmacologically tors of biological
has been compared with (15). is the subject of recent
by
enzymatic synthesis This observation
in rat activity
of elevated
of transmethylademonstrated both
180), isolated (252, 253).
AdoHcy
hydrolase
onstrated (68). The
The
(15, 207). Thus, offer great util-
upon transmethylation and Scarano in 1953
of by
in vivo.
exerts an inhibunder normal con-
conditions
inhibition has been
conversion of AdoHcy to adenosine The reaction is catalyzed by the
S-adenosyl-L-homocysteine
AdoMet-dependent first reported
67,
inhibition reactions
logues of
64,
The
AdoHcy
under
cells (164, 177, in whole animals
and carprotein a role
However,
of AdoHcy, by AdoHcy
wide variety sibility that
319).
AdoMet by Cantoni
(61,
see
to play
and secretion components may
ity in biological regulation, and phosphorylation in this respect The biochemistry of AdoMet reviews The
for review,
of proteins
in intact 154) and
to growth,
glutamyl, by specific
154).
transmethylation
whether transmethylases
in controlling tissue levels of AdoHcy and ence methyl-transfer reactions, as suggested and Barchas (67) for the biogenic amines.
(27, 63) has been groups from AdoMet
lysyl, arginyl, histidyl, aspartyl, groups of proteins is catalyzed
(152,
mocysteine
is probably
synthesis different
questioned on most
cellular content tion reactions
tion
struc-
contains methylated bases (316), and enzymes catalyzing the incorporation of methyl groups into DNA have been described (71, 265). The role of methylation of eukaryotic DNA
ditions
a role
to membrane
ofAdoMet-dependent
It has been itory effect
(318). (219), his-
to
Both tRNA transmethylases
regulation (242, 261).
inhibitor
(188), and betaine in a few instances.
Pharmacological
Properties
Adenosyihomocysteine Introductory
and
of S-
Its Analogues
Data
Transmethylation phenomena
reactions related
are to
involved the
in
development
various of
225
S-ADENOSYLHOMOCYSTEINE
pathological of tRNA
processes. Abnormal methylation patterns been described in various tumors and in transformed by oncogenic DNA and RNA viruses
cells (8,
26,
have
190,
203).
Viral
and
eukaryotic
cellular
mRNA
methylated nucleosides (220, 261), and the term7G residue is necessary for the efficient binding of mRNA to ribosomes (29). Methylation of the 5’-capstructure in viral mRNA seems to be an essential reaction for the virus replication in the host cell (161). A decreased rate of AdoHcy metabolism has been observed in cells contain minal
infected
with
Rous
sarcoma
virus
above suggest that inhibition tions may affect processes replication, virus transformation malignant
(222).
The
data
cited
of transmethylation reacsuch as virus growth and of cells, and growth of
B. S-Adenosylhomocysteine
stimulated fibroblasts
of transmethylation resection I). In contrast to itself is a rather ineffeccatacholamines in neumethylation in phyto-
lymphocytes
(305).
(45)
Furthermore,
and
AdoHcy
chick has
no
effect on oncogenic transformation of chick embryo fibroblasts (236). The inefficiency ofexogenous AdoHcy in cellular systems has been explained by rapid metabolism of this compound by intact cells (66, 236). An additional explanation is offered by the fact that extracellular AdoHcy does not cross the cell membrane as an intact molecule. This statement is based on the following observations.
creted
Radioactive
AdoHcy
injected
into
rats
is ex-
in the
and only proteins
urine as S-adenosyl-y-thio-a-ketobutyrate, small amounts are incorporated (78). Similar results were obtained
into
cellular
when radioactive AdoHcy was injected intravenously into dogs. Only trace amounts of radioactivity could be detected in nucleic acids or proteins of tissues, and essentially all of the urinary radioactivity was associated with AdoHcy (309). These data show that AdoHcy is not taken up by cells and is not available for intracellular AdoHcy hydrolase. This conclusion is in accordance with the finding that AdoHcy is not taken up by isolated rat hepatocytes as an intact molecule. However, extracellular AdoHcy is hydrolyzed hydrolase AdoHcy
to adenosine
and
L-homocysteine
leaking out of the binds to acceptor(s)
by AdoHcy
hepatocytes. on
the
In addition, cell
surface
(1).
hepatoplasma membranes from rat liver has shown that AdoHcy specifically binds to a heterogenous population of sites with an apparent Kd of 0.4 to 0.7 M (289). Phospholipid methyltransferase of the plasma membrane does not totally account for these acceptors for AdoHcy This statement is based on competition studies with AdoHcy analogues and is supported by the Characterization cytes and purified
of these
acceptors
of isolated
.
observation
acceptors pmol/106
that
on
AdoHcy
the
binding
capacity
of
the
AdoHcy
the surface of rat hepatocytes (about 12 cells) is high relative to the low specific activity
(289). The for AdoHcy
localized investigation.
physiologand their
to the
membrane
an effect
sedative and anticonvulsive properties in cat (96, 99). This observation suggests of AdoHcy on the central nervous system, and
has
related
the
has
rabbit,
rat,
been
and
to effects
of catecholamines ity
exists
and
in vivo
on the
of AdoHcy
binding
of AdoHcy
Small
in the
was
hippocampus.
It was
suggested on
that
the
phospholipid
from
observed
from binding
A similar
for phospholipid
by
compound. in vitro
to membranes were
possibil-
mediated
the parent demonstrated
variations
observed
reside
metabolism
the
are
binding of AdoHcy to membranes of the rat brain, and the highest
found
(95a).
effects
rather than et al. (94) have
cortex.
bution may
these
metabolites Fonlupt
cerebral
of AdoHcy
(10, 93, 97, 98). However,
that
AdoHcy Recently,
was
AdoHcy is a potent inhibitor actions in cell free systems (see analogues of AdoHcy, AdoHcy tive inhibitor of methylation of roblastoma cells (197), and tRNA embryo
relation to methyltransferases are subjects for further
in vitro regions
cells.
hemagglutinin
of phospholipid methyltransferase ical role of membrane acceptors
rat
for
the
different activity
regional
distri-
methyltransferase
binding
sites
for AdoHcy
methyltransferase
localized
in the membrane (95, 95a). The possibility of an anticonvulsant action of AdoHcy is supported by the data provided by Schatz and coworkera. The convulsant L-methlonme d,l-sulfoximine (MSO) (194a)
decreases
as AdoMet)
the (249).
by administration and
in methylation protein
content
of AdoHcy
(as well
AdoHcy
in vivo
of cerebral
of adenosine
in a decrease lipid
cerebral Elevation
and homocysteine of histamine and
carboxymethylation
(252,
results
phospho253)
and
prevents MSO-induced increase in methylation and protects against MSO seizures (254). Finally, the anticonvulsants, dilantin and phenobarbital, increase the cerebral content of AdoHcy, and upon administration of partly
phenobarbital ylation was
a slight observed
C. Analogues
Many moiety,
reduction (254).
in protein
carboxymeth-
of S-Adenosylhomocysteine
analogues acid
amino
synthesized
(15,
of AdoHcy, modified in the portion, or purine ring, have
sugar been
17, 18, 22, 25, 46, 58, 60, 62, 139-141,
308).
The purpose of these efforts is to obtain information on the structural requirements for binding of AdoHcy to various transmethylases, to provide analogues specific for certain methylases and compounds that resist metabolic degradation. Many AdoHcy analogues have been tested as inhibitors of catechol 0-methyltransferase, phenylethanolamine
hydroxyindole
(13, 15, 17, 18, 22-25, tRNA methyltransferase, (21,
41, 89,
histamine
N-methyltransferase,
methyltransferase,
142,
185,
N-
0-methyltransferase
58, 60, 62, 141) protein methylation, and mRNA methyltransferase 237,
238,
305).
Some
general
conclu-
on data from various small and some macromolecule methyltransferases. Methyltransferases show strict structural requirements for AdoHcy. The following groups seem to be essential for the binding of AdoHcy to several methyltransferases: the terminal amino group, the sulfur atom in the thioether linkage, the 6-amino sions have been drawn molecule methyltransferases
based
226
UELAND
group of adenine, and the ribose moiety. Most modifications in the ribose residue result in almost complete loss of activity, whereas modifications in the adenine ring have given compounds (S-3-deazaadenosythomocysteine and 5-tubercidinyl-homocysteine), hibitors of methyltransferases ceptions
to these
example, mRNA mRNA
tive
which
(14).
general
rules
have
been
protein carboxymethyltransferase, (guanine-7-)-methyltransferase,
(nucleoside-2’-)methyltransferase to sulfur modified analogues
Furthermore, ring are weak
the structural methylases different are being to obtain inhibition
various
analogues
are
However,
potent
in-
several
ex-
reported.
and are very
of AdoHcy modified
For virion
virion
(19,
in the
sensi227).
adenine
inhibitors ofthese enzymes (19, 227). Thus, requirements for the inhibition of transby AdoHcy analogues seem to be somewhat
from one enzyme to another. Continuing efforts made to synthesize new analogues of AdoHcy
compounds that may allow for differential of methyltransferases (15, 154a, 308). The effects of AdoHcy analogues in various biological systems have been studied to a certain extent. Some of these compounds have antiviral and growth inhibitory effects (15, 185, 237, 267). The biological properties of well characterized analogues will be reviewed in the following paragraphs. shown in figure 1. 1. 5’-Deoxy-5’-isobutyl
Their
structural
formulas
are
thioadenosine. 5’-Deoxy-5’-isobutyl thioadenosine (SIBA) was synthesized by Hildesheim and coworkers in 1971 (140). The compound is an antiviral agent in various systems. SIBA is an inhibitor of cell transformation by Rous sarcoma virus (236) and mouse sarcoma virus (237), and a particularly potent inhibitor of multiplication of mouse mammary tumor virus transformed cells (275). A single injection of 1 mg of SIBA prolongs (by 42%) the survival time of mice infected also
and
with
Friends
virus
(237).
inhibits the multiplication this effect is associated with
synthesis
and
methylation
Furthermore,
of Herpes virus reduction in viral
ofviral
mRNA
(161).
influenza
Inhibition demonstrated
virus
transport factors.
Polyoma
in
the
presence
blastogenesis of
SIBA
(12),
has
been
and
this
effect ylation effects
may be related to the possible role of transmethreactions in blast formation (260). Antiparasitic of SIBA have been demonstrated against Plasmodium falciparum in vitro (277). Potential oncostatic properties of SIBA are indicated by the finding that this compound inhibits the plating efficiency of cells transformed
by methylcholanthrene
(237).
A structural analogue of SIBA, 3-deaza-SIBA, is a noncompetitive inhibitor of AdoHcy hydrolase (49) and inhibits phospholipid methylation in intact cells (65). This compound has antiviral effects against Rous sarcoma virus, Gross murine leukemia virus (49), Herpes
compounds
structurally
unrelated
to
SIBA.
A
membrane factor interacting with SIBA has been postulated to explain the effect on cellular transport (223). SIBA exerts essentially no inhibitory effect on AdoHcy acceptors and phospholipid methyltransferase of rat liver plasma membranes (245, 289). Thus, there is no obvious reason to suggest that SIBA exerts its effect on cellular
SIBA
(237).
of mitogen-induced
sugar,
type I, protein
virus replication in mouse embryo fibroblasts and nucleic acid methylation in infected cells are inhibited at relatively low concentrations of SIBA (232). Finally, SIBA also exerts antiviral effects against Epstein-Barr virus and
virus, and the RNA type C virus (11). It also possesses antimalaria effects (278). Data on the molecular effects of SIBA are accumulating, and it seems that this compound may induce various metabolic derangements in the intact cell. These effects are not limited to perturbation of transmethylation reactions, but also include effects on cellular transport and on metabolism of methylthioadenosine and cyclic AMP. SIBA is a relatively weak inhibitor of transmethylases in cell free systems (186, 232, 236, 305). The inhibitor constant of SIBA for protein methylase I is 100 to 600 M (41, 186), and higher than 1000 M for tRNA transmethylase (186, 280, 304), protein methylase II (209), protein methylase III (304), and DNA transmethylase (9). In contrast, inhibition of methylation can be demonstrated in intact cells (232, 306). For example, whereas SIBA does not inhibit phospholipid methyltransferase in purified rat liver plasma membranes and microsomes (245, 247), inhibition of phospholipid methylation in isolat,ed rat hepatocytes is observed (247). The synthesis of AdoHcy hydrolase is suppressed in cells cultivated in the presence of SIBA, and this compound is a weak inhibitor of isolated AdoHcy hydrolase (222). Only a slight or no increase in cellular content of AdoHcy in hepatocytes (247) or lymphocytes (326) exposed to SIBA could be demonstrated. A remarkable property of SIBA (but not sinefungin) is its inhibitory effect on cellular uptake of nucleosides and
by
a direct
interaction
with
these
membrane
The possibility that SIBA influences membrane function is supported by the recent observation that SIBA increases the cyclic AMP content and stimulates adenylate cyclase in Xenopus laeuis oocytes (256). No effect on cyclic AMP synthesis and adenylate cyclase in mouse lymphocytes could be demonstrated. However, in these cells, SIBA is an inhibitor of phosphodiesterase and thereby AMP response of intact cells
adenylate
cyclase
physiologically
active
(322).
This
the
low Km cyclic potentiates the to several activators
effect
concentrations
was of the
AMP cyclic of
observed drug
at
(322).
SIBA is a good substrate for the methylthioadenosine (MTA) cleavage enzyme from sarcoma 180 cells (244), and MTA phospharylase from human placenta (39) and Lupinus luteus seeds (120), and MTA nucleosidase isolated These
from the observations
bacterium suggest
Calderiella that SIBA
acidophilia may interfere
(40). with
the metabolism of MTA. In isolated rat hepatocytes, SIBA induces accumulation of MTA, which is associated with a pronounced export of this compound into the extracellular medium (246). The fact that SIBA is a
227
S-ADENOSYLHOMOCYSTEINE
NH2 H2N
H3
r1
N
HOOC HO S-Adenosyl
OH
L-methionine
-
(AdoMet)
H2N\ CH-CH
-CH
HOOC’
2
-S-CH 2
N
N
HOOH
S-AdenosyL-L-homocysteine
(AdoHcy)
NH2
NH2 H2N
,CH-CH2S
CH-CH /
CH3
HOOC HO
5’- Deoxy-
t1JH2
CH2
2-CH2-CH-#{231}H
OH
HO
5’-.isobutyt-thioadenosine (SI
OH
Sinefungin
BA)
NH2 H2N
NH2
NH2 H2N C H-C H2-CH2-CH-CH
“CH-CH2-CH2-
/
HOOC
cj::)
5-
HOOC HO
OH
HO S-Tubercidinyl
A 914 SC
OH
-L-homocysteine (c7AdoHcy)
FIG.
1. Chemical
structure
of S-adenosyl-L-methionine,
S-adenosylhomocysteine,
substrate and inhibitor of MTA phosphorylase suggests that SIBA may cause various metabolic derangements in the intact cells, including effects on polyamine biosynthesis and production of methylthio groups essential for cell division. It may also induce formation of large amounts of adenine (from SIBA) leading to cellular depletion of 5-phosphoribosyl-1-pyrophosphate (237). An inhibitory effect of SIBA on the biosynthesis of polyaxnines is indicated by the finding that this compound decreases the spermidine content in transformed mouse fibroblasts. However, in a cell free system, SIBA is a more potent inhibitor of spermine synthase than of spermidine synthase. Cell growth cannot be restored to normal levels by the addition of spermidine, suggesting
that
and
SIBA
has
some
S-adenosylhomocysteine
other
inhibitory
proliferation (218). Some of the biological perhaps be considered MTA
is converted
biological from MTA
extract involves
to
effects in the methionine
analogues.
actions
toward
exerted by SIBA should light of the finding that by
intact
(314a). Biosynthesis of the conversion of MTA
ylthionbose-1-phosphate ylase. The conversion tions where the carbons
cellular
cells
and
in
methiomne to 5’-meth-
catalyzed by MTA phosphoris followed by a sequence of reacof the ribose portion, the carbon
and hydrogens of the methyl group, and the sulfur of MTA are all incorporated into methonine. This pathway may provide a significant synthesis of cellular methionine (314a). Inhibition of this salvage pathway for methionine
228
UELAND
biosynthesis by blocking the MTA tion in the presence of SIBA, may biological effects of SIBA, including ical methylation as well as inhibition
phosphorylase reaccontribute to some inhibition of biologof polyamine syn-
thesis. The
uptake
recently transport
of SIBA
into
chick
been studied by system composed
component could system is inhibited
be
Enouf et of a high
is metabolized
and
adenine
the
compound
has
high affinity with an intact
In chick
is metabolized
embryo
SIBA
is
along
two
pathways,
injected and widely
into rats distributed
enzymes by using
phosphorylase,
of SIBA
nucleoside
and
The
of SIBA deficient in
a
of the
chick
are
activity very
embryo
(115). potent
serves
fibroblasts
by
Rous
and its metabolite, of transformation sarcoma
virus,
of but
A9145C is quite toxic at active concentrations (237, 304). Polyoma virus replication in mouse embryo fibroblasts is inhibited at nontoxic levels of sinefungin whereas cytotoxic concentrations are required for the inhibition of mouse sarcoma virus and mouse mammary tumor virus (237). Vaccinia virus plaque formation in mouse L-cells seems to be especially sensitive to sinefungin and A9145C, (10 tiM) the
and is inhibited at low, nontoxic of these compounds (229).
Antiparasitic inhibition
at a low inhibition
concentrations
activity of sinefungin is demonstrated of Plasmodium falciparum grown
concentration of
growth
of sinefungin of
Trypanosoma
(0.3
.tM) cruzi
Leshmania tropica (185). Preliminary experiments show that sinefungin tumor growth in vivo in mice, but the survival
to suggest biological
transmethylation
by in vitro
(278),
and
(237)
and
that effects
reactions.
these analogues of by inhibiting cellu-
Sinefungin
is a more
po-
and protein fibroblasts than methylation in
whole
A9145C
cells
(305).
tremely potent methyltransferase as compared 229). Sinefungrn AdoMet-dependent
Both
inhibitors with
sinefungin
and
are
ex-
of virion mRNA (guanine-7-)K1 values in the nanomolar range,
with K for AdoHcy of about 1 M (227, and A9145C are also inhibitors of various transmethylases catalyzing the
methylation of biogenic amines (103). AdoMet:protein 0-methyltransferase
and
phospho-
lipid methyltransferase(s) have been assigned a role in cellular processes such as chemotaxis and secretion (15). The former enzyme is strongly inhibited by sinefungin and A9145C (16, 19, relatively insensitive
201) whereas the to these AdoHcy
latter enzyme is analogues (245).
Thus, these ing the role
may be valuable 0-methyltransferase
tools for studyin chemotaxis
compounds of protein
secretion
Among nefungin
(16). the many synthetic is the most potent from
grown
in
the
analogues inhibitor
of AdoHcy, of 24-sterol-C-
Saccharomyces
presence
of
si-
cerevisiae.
sineftmgin
revealed
a
dramatic increase in zymosterol, the substrate of this enzyme, and a concomitant decrease in the level of ergosterol, which is the product of this methyltransferase (194). These data suggest that inhibition of AdoMetdependent transmethylation contributes to the antifungal
properties of this agent (194). Recent data provided by Pugh
suggest cellular
that sinefungin processes other
methylation AdoHcy
and
Borchardt
and A9145C may exert than AdoMet-dependent
(227) effects on trans-
reactions. These compounds, various synthetic AdoHcy analogues
and
stimulate viral guanylyl transferase viral RNA synthesis. These effects antiviral properties of sinefungin Cellular disposition been studied in detail.
of sinefungin Both agents
but
activity and may contribute and A9145C. and A9145C are inactive
not tested, inhibit to the
has not as inhib-
itors of protein carboxymethyltransferase in intact synaptosomes, but are potent inhibitors of the enzyme in lysed synaptosomes and of isolated enzyme. Lack of effect could not be explained by extensive metabolism of these compounds (19). Likewise, sinefungin inhibits phospholipid (245), These sinefungin
inhibits time of
(201). These possible on-
tent inhibitor of tRNA methyltransferase methylase I and III from chick embryo AdoHcy (304), and inhibits the tRNA
Yeast
phosphorylase, which to form 5’-deoxy-5’-S-
Sinefungin inhibitors
reasonable exert their
methyltransferase
compound
2. Sinefungin. Sinefungin is a “carba-analogue” of AdoHcy where the thio-ether is replaced by an aminosubstituted methylene unit (fig. 1). This compound (A9145) was isolated from Streptomycesgriseolus at Lilly Research Laboratories (121), and was shown to possess antifungal A9145C,
it seems AdoHcy
and
substrate catalyzes
5’-deoxy-5’-S-isobu-
latter
as a substrate for purine nucleoside condenses it with hypoxanthine isobutylthioinosine (171a).
several embryo
phosphorylase,
SIBA is not MTA phosphorylase to adenine
mice, the to various
and by chick
in the metabolism human cell lines
purine
tylthioribose-1-phosphate.
or
i.e. or hyadenine
and
is extensively metabolized, in addition to those formed can be demonstrated (183).
or adenosine deamiase. adenosine deaminase. conversion
and by a com-
fibroblasts,
to 5’-deoxy-S’-S-isobutylthioinosine 5’-deoxy-5’-S-isobutylthionbose
The role of various been evaluated
MTA
The
increased of the
costatic properties of sinefungin and related compounds. In contrast to SIBA, sinefungin and A9145C are very potent inhibitors of some transmethylases in vitro. Thus,
lar
to 5’-deoxy-5’-isobutylthionbose
(184). When SIBA compound is rapidly organs. metabolites fibroblasts,
has
at the 5’-S-side chain, SIBA may enter cells naturally occurring
in prokaryots.
deamination drolysis to
fibroblasts
a!. (88). A mixed and a low affinity
demonstrated. SIBA analogues
by
adenosine residue, modified by S-adenosylmethinone. carrier system transporting pounds. SIBA
embryo
the tumor-bearing animals is not data should stimulate investigation
methylation
in
but is ineffective findings might and
related
determining their The biological
rat
liver
plasma
membranes
in intact rat hepatocytes (247). suggest that cellular transport of compounds
effectiveness properties
is an important
in vivo of sinefungin
(19). and
factor its metab-
229
S-ADENOSYLHOMOCYSTEINE
olite
should
stimulate
carba-analogues fulness
further
efforts
of AdoHcy,
and
as chemotherapeutic
to synthesize
to
agents
evaluate
their
new
AdoHcy
use-
the equilibrium defined by the
(308).
(68).
3. S- Tubercidinylhomocysteine. S-Tubercidinylhomocysteine (c7AdoHcy) is the 7-deaza-analogue of AdoHcy, which was synthesized to obtain a transmethylase inhibitor ical
resisting properties
metabolic of this
degradation compound
some detail by Coward 166, 197, 238). c7AdoHcy catalyzing
the
tamine
(18,
(58, 59). The biologhave been studied in
and coworkers inhibits various
methylation 58),
and
of biogenic is
a
potent
his-
osine
and
tRNA
methyltrans-
ferase castle
is a potent inhibitor (guarnne-7)-methyltransfer-
but virus
between vs. the
the AdoHcy Newcastle
mRNA
(nucleoside-2’)-methyltransferase
vivo 238)
is a weak inhibitor (227). This finding
methylation are also
ues
obtained
on the (227).
cytoplasmic c7AdoHcy.
AdoHcy
is also
for
a potent
and
biogenic effective
amines and RNA in this respect
AdoHcy
(45,
fact
that
165,
166,
same
This
is not
in
potent the
(245, 289). In for AdoMet than the val-
enzymes
(59).
has
cells, natural
and
been
explained
metabolized
of
hibits the patocytes pared
(66),
investigation
by cells
Such extra-
cell membrane general statecompletely in-
phospholipid methylation in isolated rat he(247). Radioactive c7AdoHcy has been preand
this
compound
of cellular
may
transport
investigation will and intracellular
probably metabolism
precaution should be taken from binding of c7AdoHcy
be
useful
of AdoHcy not
for
to distinguish to acceptors
cellular on the
S-Adenosylhomocysteine Catalysis-Interaction
AdoHcy of AdoHcy
hydrolase catalyzes to adenosine and
concentration micromolar
between
of range,
the
substrates the
reaction
is
higher favors
termed sequestration physiological role sion of adenosine adenosine enzyme
hydrolysis When the than
in
with AdoHcy by168, 293). A fraction
the of
bound adenosine slowly (293)
by
liver is adenine certain
cannot incubation
be
of AdoHcy
to inosine catalyzed This phenomenon
rat liver (168). with a suicide
by
under synthesis
conditions of and hydrol-
(294).
from
the inactive sine-enzyme
by adenhas been
of adenosine to indicate a possible of this process (272, 298). The converto adenine and the sequestration of
concentrations
hydrolase
zyme
sulfate (128) or ethanol AdoHcy hydrolase is
can also be demonstrated catalysis, i.e. both during
human
of adenosine
inactivate
lymphocytes,
placenta
The kinetics mechanism complex complex
and
is formed from a reversible adeno(310). The inactivation of the en-
adenosine
kinetics
AdoHcy (137),
of inactivation are consistent (137, 168), which implies that
and
the
sequestration
are probably related phenomena, strated at low enzyme concentration concentration, respectively (294). a stable complex with adenosine The
Substrates
synthesis
complex (50, 128,
(2). not
of adenosine
binding
hydrolase by Jakubowski
of adenosine
which are and high Thus, enzyme is enzymaticaily to and
from
demonenzyme forming mac-
formation
plant has been and Guranowski
of stud(163).
The enzyme, which is a dimer, binds two molecules of adenosine. The binding of the first molecule is rapid whereas binding of the second molecule is a slow process. This suggests negative cooperativity among binding sites. The enzyme-adenosine complex reacts slowly to form adenine, ribose, and active enzyme. Thus, in contrast to mammalian AdoHcy hydrolase, adenosine does not inactivate the enzyme. The half-life of the newly formed complex
the reversible L-homocysteine.
a stable tissues
sodium dodecyl complexed with
adenine by AdoHcy med in some detail
uptake cell sur-
can aden-
zyme with Adenosine
by but
Hydrolase
A. Enzyme and Enzyme
inhibitors
catalysis of either
but en-
tive.
face.
ifi.
299).
potent
the enzyme by removal
is
(68).
forms various
the
analogues.
be obscured of c7AdoHcy,
M (68,
are
and
(272). Tightly (128) or dissociates
High
(66), and is not a substrate for AdoHcy hydrolase (52). Furthermore, whereas AdoHcy is not taken up by cells as an intact molecule (1, 78, 309), it has been suggested that some analogues of AdoHcy cross the to reach their target enzyme (279). This ment holds for c7AdoHcy, which nearly
10_6
by
of the enzyme with excess unlabelled adenosine, dissociates readily upon boiling or treatment of the
ysis
is more congener,
by whole
expressed K,,,1, which
L-homocysteine
available for deamination osine deaminase (272).
inhibiAdoHcy
of methylation
in intact than its
197).
c7AdoHcy
the
inhibitor
conditions released
mRNA (165, Among various
most
precisely reaction,
of adenosine tightly bound to the enzyme from converted to adenine or a substance liberating (50, 272, 297), and this reaction is reversible under
vaccinia virus The vaccinia and
more of the
reaction, hydrolysis
or L-homocysteine
Adenosine drolase from
of New-
(227)
c7AdoHcy is the methyltransferase(s)
with
protein
enzyme from differences
to plasma membrane from rat liver the inhibitor constants of c7AdoHcy transmethylases are often lower
c7AdoHcy
the
of this suggests
site virus
of Novikoff sensitive to
AdoHcy analogues, tor ofphospholipid binding general, dependent
binding disease
and
amines
(59)
ase (228) vaccinia
adenosine
of the hydrolytic be directed toward
of
be
[Ado] X [Hcy] [AdoHcy]
=
165,
inhibitor
and
Both
can
constant equation:
(45, 58, 59, transmethylases
carboxymethyltransferase (59, 281). c7AdoHcy disease viron mRNA
K
This
is short,
whereas
the
old
complex
dissociates
slowly (163). liver AdoHcy
Similar data hydrolase
have been obtained with (272), but comparable
data
mammalian
enzyme
for the
Kinetic
studies
and
gel filtration
are
not
mouse kinetic
available.
experiments
indicate
230
UELAND
that AdoHcy forms a long-lived hydrolase from mouse liver. This
complex complex
life
finding
of 5 to 10 minutes
be related hydrolase, sine B.
(294).
This
to the finding that but is less potent
AdoHcy in this
with AdoHcy shows a halfshould
C. Role AdoHcy
perhaps
inactivates respect than
purified adeno-
abolic
These workers mogeneity from enzyme contains in the catalytic is based on
mechanism by Palmer
of AdoHcy and Abeles
hydrolase (215, 216).
cycle. A mechanism oxidation/reduction or AdoHcy, of NAD/NADH.
the substrate activates tates the elimination
is suggested, C-3’ of the
at
with
the C-4’ proton, of C-5’ substituent
explanation
for
3’-Ketonucleosides the purine base
the
of
are
of
known
other
in
It
should
teine also
(EC
formed
be
hydrolytic
direction
are
metabolized
rapidly reaction
2.7.1.20)
that
AdoHcy hydrolysis
(100). is L-homocysof AdoHcy
may (50,
and this reaction is catalyzed by two 5-methyltetrahydrofolate:L-homocysteine (EC 2.1.1.13) or betaine:L-homocys-
mulating
in
the
AdoHcy
hydrolase
AdoHcy,
and
(EC to form
intact
cell, is
the
the
enzymatic
catalyzed
by
toward
synthesis
of
of AdoHcy
is
degradation
Ade
H’\4 HO
OH
OOH
E-B
E-BH
OOH
ENADH
ENADH
Ad.
Ad.
Ad.
#{149} H2O
o
HO-CH2 C=/Ol,H
Hcy-SH.
E-B
OOH
e E-BH
ENADH
HO-CH2
H
HO
0 OH
E-B
Ade
=Adenne
j
Hcy
=
mechanism
0 OH
o,C?HCH2.CH2 NH3
OH
E-B
Base
E’NAD=NAD the
2. Catalytic
H
E#{149}NADH
Ad.
E#{149}NAD FIG.
H
E-NADH
H’\4’H E-B
o
HO-CH2 H
of S-adenosylhomocysteine
(AdoHcy)
at active tightly enzyme
hydrolase
site bound
[modified
to from
Palmer
and
accu-
reaction
Hcy_S-CH2,oJ
ENAD’
en-
2.1.1.5.). L-Homocysteine cystathionine. This reac-
directed
Ade HcyS_CH2,oJ
is
pathway in vertebrates leading L-Homocysteine is converted to
5-methyltransferase reacts with serine
Ade
E-B
as
as a cellular
tion is catalyzed by the enzyme cystathionine-$-synthase (EC 4.2.1.22) (205). When adenosine or L-homocystelne or both are
(216).
-
of AdoHcy the reaction A), the met-
from
noted
metabolic (36).
L-methiomne, zymes, i.e. methyltransferase
to spontaneously
HcY-S-CH2,,o.,J
the
hydrolysis Although section III
hydrolase
kinase
product
the only known to L-homocystelne
to aden-
ademne
of adenosine
teine.
NAD. Following to give 3’-keto,4’reacts with water
formation
the
L-homocystelne
cell (57, 66, 68, 84). role of the AdoHcy
The
and thus facili(OH-group of
to form 3’-ketoadenosine, which is then reduced osine (fig. 2). Oxidation of the nucleoside to 3’-ketonucleoside
is probably and
action
or homocysteinyl group of AdoHcy). HydrolAdoHcy thus involves oxidation of 3’-hydroxyl
group of AdoHcy by enzyme bound oxidation, L-homocysteine is eliminated 5’-dehydroadenosine. This compound
272,294). liberate
which ribose
a concomitant The oxidation
catalyzes
source of adenosine in various tissues has not been evaluated. It has been suggested that AdoHcy may be a site of production of adenosine in the mammalian heart (258). Adenosine is metabolized along two pathways, i.e. deamination to inosine catalyzed by adenosine deaminase (EC 3.5.4.4.) or phoshorylation to AMP through the
used AdoHcy hydrolase purified to hobeef liver as the source of enzyme. The tightly bound NAD, which participates
residue of adenosine reduction/oxidation
an
flow
in the The
Mechanism
Data on the catalytic have been provided
offer
hydrolase
adenosine
Catalytic
Metabolism
to adenosine and L-homocystelne. favors synthesis of AdoHcy (see
(168).
adenosine ysis of
in Intermediary
Abeles
(215)].
231
S-ADENOSYLHOMOCYSTEINE
inhibited. obtained
High cellular by supplementing
homocysteine,
even
of enzymes onstrated cells, whole
without
metabolizing with cultured
isolated animals
In
level of AdoHcy can exogenous adenosine
liver
has
adenosine
adenosine. (164, 177,
of
deaminase
heart
rat,
(75, are
not
fact
the
cellular
level
low
relative
to
(76,
154),
enzymatic
and
of
Explanations
in
the intact hydrolase. observations:
concentrated sues
binds
able
for
crude tightly
in-
heart
is ex-
the
of
be In
of
should be macological
for
L-homocysteine
The
existence
has been adenosine
of a cellular suggested (75). is compartment-
extract
various
from
and
mammalian
hydrolase
further
and
of magnitude
and for
AdoHcy (152, the metabolism
indicated osine
by the in the
curs
both
of
that
synthesis
the
by compounds enzyme (286,
sequestration
of adenof
of this
bound to same order
the
that
resists
high levels of extracellular adenosine similar conclusion has been reached hearts of the dog and the rat (210a).
catalytic the amount
site of
AdoHcy as the
mobilization
bound This
amount (295).
of
Adenosine in adenosine (116). It was tion and
to AdoHcy may obscure cellular
hydrolase the
adenosine,
transport
by
at
least
neuroblastoma
the
extracellular effect decreases
AdoHcy aden-
liberates of in
adetotal
hepatocytes cells
kinase has been studied recently observed that the intracellular
of adenosine exceeds that this concentrative
by
deaminase (295). A from studies with Thus, a substantial
readily determination
deficient by Green concentra-
concentration, as the
to
The
by
suggests
and/or
binding
other
of the
fact
of
intracelluthat
adeno-
hydrolase has (101) and by of lipolysis
extracellular,
free
of intracellular
taken and
into account physiological
fraction
of
adenosine
bound to AdoHcy hydrolase or other general, intracellular sequestration when effects
may
proteins (258). of adenosine
relating the of adenosine
phar(100)
to the concentrations of this nucleoside in tissues. A similar reasoning can be made for AdoHcy. AdoHcy complexed with AdoHcy hydrolase may not exert its inhibitory effect (294). In addition, cellular
on AdoMet-dependent AdoHcy may be tightly
components
(289).
Cellular
transmethylases bound to other
compartmentation
AdoHcy has in fact been suggested as an the finding that the tissue level of AdoHcy ciently high to entirely block some important reactions
of
explanation of seems suffitransmeth-
(85).
Conversion of adenosine to adenine is a side-reaction catalyzed by AdoHcy hydrolase (294, 297). The reaction can also be demonstrated under conditions of enzymatic synthesis and hydrolysis of AdoHcy (294), but is rather
inefficient
titatively statement human
in
mainly from of polyamine The the
vitro.
main
summarized
source by the cells
cleavage synthesis points
metabolism
Furthermore,
are formed unlikely that
important is supported lymphoblastoid
only
the
of cellular adenine. recent observation at least, adenine
role
purines
small
from adenosine in rat this reaction is a quan-
of methylthioadenosine, (170). on
of in figure
a product
of AdoHcy
and
sulfur
This that, in derives
hydrolase compounds
in are
3.
D. Methods The
enzyme
activity
either in the synthetic urement of AdoHcy
of AdoHcy
either as DL-homocystelne cysteine thiolactone (77). tage that the equilibrium synthesis of AdoHcy, L-homocysterne) are a source
in the presence L-Homocysteine
is assayed
data
of adenosine is present
or is prepared from L-homoThis assay carries the advanof the enzyme catalysis favors
and the available
of adenosine to erroneous
hydrolase
or hydrolytic direction. The meassynthesis is performed by incubation
of the enzyme preparation and L-homocysteine (68).
Deamination con-
author
a saturable
with AdoHcy and Sollevi is a regulator
the
A portion
amounts of adenine liver (76). It seems is
fraction of adenosine may be complexed with hydrolase in intact cells. It should be noted that a fraction of endogenous osine nine.
oc-
AdoHcy
complex
intracellular of magnitude
is attributed nucleoside.
ylation
(6)
found to form a stable hydrolase in isolated
formation
adenosine
in same
hydrolase
hydrolysis
interacting with 295). In hepatocytes,
adenosine is of the of cellular
The
Fur-
of these data intact cell is
AdoHcy
has been AdoHcy
rat.
(298).
of adenosine
relevance in the
and
adenosine intracellular
avail-
hydrolase is of the
level
of purified
of the
endogenous hydrolase
tissue
253). The adenosine
findings
during
hepatocytes
amount
252,
presence
(294). Recently complex with blocked of the
as the
tis-
is not
degradation
thermore, the cellular level of AdoHcy mouse liver is about 10 1M (298), which order
point
the interaction with is based on the folof adenosine added to
to AdoHcy
increases.
explained
in adipose tissues, but most of the adenosine content in tissues is probably bound to intracellular proteins (101). Likewise, the vasodilatatory effect of adenosine in the
(179)
Km
be
sine forms a stable complex been stressed by Fredholm Schlitz et al. (258). Adenosine
of homocysteine
cell through This statement A fraction
deamination
may
of the
L-homocystelne.
alized AdoHcy lowing
of adenosine
this
in light
the
pool of bound L-homocysteine The possibility exists that
of
to these
that
apparent
readily
AdoHcy hydrolase (about 160 .&M) (75). These data to a role of AdoHcy hydrolase in the disposition endogenous
in
synthesis
centration
adenosine to AdoHcy hydrolase lar components (116). The physiological implication
dem(125)
even in the absence conditions of inhibited
76).
findings
tremely
and
the
inhibition
This has been 180) and isolated
been demonstrated homocysteine, under
teresting that
pharamcological
perfused liver (252, 253).
isolated
AdoHcy exogenous
thus be and/or
substrates as radioactive
in crude when
tissue the
activity
(adenosine and compounds. extract
may
is measured
be
232
UELAND
10
AdoMet
cysteine
L-methionine
/ R
,ATP cystathionine 1
Hcy
R-CH3
AdoHcy
AdoHcy
hydrolase
410
AdoHcy
S-Adenosyl-L
AdoMet
S -Adenosyl
Ado
Adenosine
Hcy
L-homocysteine
R
methyl
FIG.
3. Role
of
adenosine
tightly
betaine:
adenosine
The original described by
RNA
Ado
etc.)
in
intermediary
kinase
(3),
hydrolase
metabolism. adenosine
(7),
S-methyltransferase
in the synthetic direction circumvented by inclusion itors (110) in the incubation
AMP
(I. e. proteins,
DNA,
to AdoHcy
L-homOcySterne
methionine
-
Adenine
hydrolase
(2),
bound
-homocysteine L
-
acceptor
AdoHcy
deaminase)
inosine
,
phospholipids.
(adenosine
2
AdoMet-dependent
5’-monophosphate
cystathionine-$-synthase
(9),
(8),
ATP:L-methionine
(167). This problem of adenosine deaminase mixture (167).
method for the assay ofAdoHcy de la Haba and Cantoni (68),
methyltransferases
nucleotidase
(4),
(5),
adenosine
release
methyltransferase
labeled in the adenosyl-moiety from labeled adenosine as
catalyst
from inosine chromatography
(68,
by
249,
column (299).
299).
with
is synthesized AdoHcy hy-
AdoHcy
is separated
(234), paper (249), The assay developed
or thin-layer by Schatz
measuring the disappearance of free suithydryl groups of L-homocysteine. This method is rapid, but L-homocysteine is oxidized when oxygen is present (68). The assay cannot be performed in the presence of reducing agents, which have been found to stabilize the enzyme (168, 288).
et al. (250) is based on the separation of AdoHcy from metabolites by high-pressure liquid chromatography. Trewyn and Kerr (280) have described a procedure the synthesis of S-adenosyl-L-[2(n)-3H]homocysteine from S-adenosyl-L-[2(n)-3H]methionine. The reaction
The
catalyzed
double
Harris AdoHcy, Other
isotope
developed
by
Finkelstein
(91) measures the formation which is isolated by column radiochemical
assays
involve separation chromatography thin-layer
have
chromatography but
The
are
developed,
134,
radioisotope
rather
and
of radioactive chromatography.
271),
AdoHcy
which
from AdoHcy electrophoresis
(119,
(234).
sensitivity,
been
of adenosine (175), low-voltage
chromatography high
assay
by or
techniques
paper (167), column offer
laborious.
osine, and tors of the is therefore osine
formed
to a lesser hydrolytic included (68).
degree L-homocystelne, reaction, and adenosine in the assay mixture Hydrolysis
of AdoHcy
are inhibideaminase to trap adencatalyzed
by
AdoHcy hydrolase is the only pathway for the degradation of AdoHcy in crude extracts from mammalian tissues (250), and the measurement of the hydrolysis of AdoHcy is therefore not obscured by metabolism of AdoHcy by other enzymes. This makes the assay suitable for the determination of enzyme activity in crude extract (282, 290).
by
glycine
is used
and unreacted dextran-coated
N-methyltransferase.
as
a substrate
AdoHcy charcoal.
its for is
Radioactive
for
AdoHcy
is removed This assay
hydrolase,
by adsorption procedure combines
to
high sensitivity and ease of operation (280). A rapid spectrophotometric assay for the measurement of AdoHcy hydrolysis has been developed recently. The procedure is based on monitoring the formation of uric acid
Measurement of the enzyme catalysis in the hydrolytic direction is performed by incubating the enzyme in the presence of AdoHcy. The products of the reaction, aden-
(6), and
(10).
AdoHcy enzymatically drolase
synthesis, is based on
aminohydrolase
adenosine
uptake
5-methyltetrahydrofolat.e:L-homocysteine
S-adenosyltransferase
can be inhib-
(1),
adenosine
from
AdoHcy
in the
system, by recording the (257, 282). The formation also the basis in polyacrylamide
for
out
rapidly
inactivated
in
of a coupled
absorbance of uric
at acid
activity staining gels (282).
The optimal conditions hydrolase from isolated worked
presence
the
for rat
author’s by
factors
292 from
of AdoHcy
in
the
nm is
hydrolase
the extraction hepatocytes laboratory.
enzyme to 295 AdoHcy
of AdoHcy have been The
extract
enzyme
is
(probably
adenosine or a derivative thereof) and this can be prevented by extraction of the hepatocytes in ice-cold buffer that contains homocysteine, dithiothreitol, and phosphate (125). AdoHcy hydrolase has been purified to apparent ho,
mogeneity
from
mouse
(291),
bovine
(215),
calf
(234),
and
S-ADENOSYLHOMOcYSTEINE rat
(102,
bovine
168)
liver;
adrenal
purification (80, 81, 102,
form. AdoHcy homogeneity
enzyme al. (234)
has
zyme kidney;
by
activity was intermediate
brain with
and data
the
highest in in spleen
mouse tissues published rat, highest activity was adrenal
lase,
i.e.
the the
also the
dog,
and
(309).
in heart, 91, 250).
demonstrated precaution
high
testes, AdoHcy
by the high (92). Small
are observed between (30, 249). There may be AdoHcy hydrolase mogenate human
liver
The
pig the
distribution
(290),
levels
of AdoHcy
tissues
are
(137), and
intestine of deamination
40%
values and
of
adenosine
spleen, and can also be the rat when of adenosine
deaminase in enzyme activity
different
of the
regions
rat
cific high
species specific
brain
variations activity
is 20 times heart of the
higher than dog (257).
in in ho-
of AdoHcy
hydrolase
cells
(136), (125).
These
data,
in mouse
liver
the The has
been
252,
is in
reported
253).
The
met-
should
be
related
of AdoHcy of AdoHcy hydrolase
to
and
drolase activity hypophysectomy,
to in
activity,
under
the
The
spe-
whereas
a decrease rat prostate AdoHcy hydrolase
a
thy-
in specific and testes activity
decrease severely, but is restored of testosterone (189). AdoHcy hy-
adrenals of the but dexamethazone
in AdoHy
the the
in animals fed estradiol injections
with
enzyme activity (315). In rat liver, pyridoxine deficiency
increase
to be factors.
increases and enzyme
that
to parallel
(84). seems
hormonal
of the enzyme diet. Hydrocortisone increased
finding
seems
hydrolase in rat liver
of nutritional
in slightly
the
in tissues
hydrolase
rat
decreases does not
leads
activity,
after restore
to a moderate
which
seems
to be
associated with a block in the utilization of AdoHcy (86). The level of the enzyme in the brain and liver of the rat does not fluctuate significantly during the life span (84, 152).
and plants. Knowledge hydrolase in microorganisms
2. Microorganisms occurrence of AdoHcy is mainly
based
(309). No bacteria The degradation AdoHcy
on the
possess of AdoHcy
nucleosidase
work
of Walker
on
and
the and
Duerre
AdoHcy hydrolase activity. in bacteria is catalyzed by
(73)
and
S-ribosylhomocysteine
cleavage enzyme (198). The former enzyme has been purified from Escherichia coli, and has a specific activity which is about 1000 times greater than that of AdoHcy hydrolase (36, 73). This points to the importance of
teracting with AdoHcy hydrolase, may be nontoxic antibactenal agents (36). AdoHcy hydrolase has been found in various kinds of yeast (74, 79) and in plants (309), and has been purified
be
the The with (298).
of
purified to same order of the enzyme
calculated
(152,
This
level
(169),
also
concentration concentration
10 M.
tissue
the
roughly
removal
together
can
of 1 to
309),
can
en(128),
hydrolase
based on the ability complex with adenosine. method are in accordance of enzyme activity
The specific activity of AdoHcy hydrolase homogeneity from various tissues is of the magnitude (81, 102, 216, 234, 299). Thus,
tis-
The
fibroblasts
suggest that AdoHcy in animal tissues. AdoHcy hydrolase
may reflect examined.
value
in human
investigated. in human placenta
erythrocytes
leukemia
the
activities
298,
tissues
as the
AdoHcy
roxine treatment is associated activity (91). In hormone-depleted after hypophysectomy, the
plants
activity in crude extract the enzyme in the tissue
(6) and
activity protein
result
the
for low
level of adenosine variations in the
determined by a method enzyme to form a stable results obtained with this those based on measurement
hydrolase
for
range
specific
91, 250,
in most
of magnitude
has been reported after administration
hydro-
20 to
prostate, activity
considerable activity. The
with those cited above, is ubiquitously distributed The tissue level of
AdoHcy
and in
low
(84, 91, 250). In the and pancreas. Kidney
muscle, hydrolase
has not been systematically has been demonstrated
lymphoblasts liver
en-
of the rat liver is 5 times the activity found in (290). Furthermore, the activity in the heart
of the guinea determined for sues zyme
rabbit
are largely in accordance of the enzyme in rat and
in these
in the small is taken to prevent
catalyzed this tissue
order
influence
The
the liver, pancreas, and testis; and
values for liver and pancreas. Intermediate enzyme activity are reported for brain,
activities lung (84,
same
on the (84,
enzyme
to be in the
the
suggestion
hydrolase
rat,
Duerre
by others in the liver
contain
activities
of this
tissue level AdoHcy
and
heart. These findings on the occurrence
and
6-mercap8-(3-aminopropyl-
chicken,
Walker
on data tissues
abolic implications of this relationship between AdoHcy hydrolase and its substrates (see section III C) probably apply to other tissues than mouse and rat liver. This
to apparent that involve
of AdoHcy
Based
various
be calculated
Level
distribution
from
investigated
(298). from
concentration
methods of the
liver has been done the enzyme in pure
and
10 M
in extract
The
concentration
Tissue
The
tissues
(43)
about
(251);
(119).
on Sepharose-bound
and
in various
brain
seeds
been purified by procedures
liver
D-nboside (168).
1. Vertebrates.
rat
plant
from calf to obtain
chromatography
E. Distribution
(128);
and
involve conventional 234, 251, 291). Crystallization
hydrolase from rat
topurine 9 amino)adenosine
was
placenta
(80, 81);
procedures 168, 215,
partially purified by Richards et
affinity
human
cortex
233
that
from
of AdoHcy specific
in
inhibitors
bacteria.
It
of AdoHcy
Saccharomyces
cerevisiae
has
been
suggested
nucleosidase,
(175)
not
leaves
in-
of spinach
beet (226), and to apparent homogenity from yellow lupin seed (119). 3. Subcellular. Few data exist on the subcellular localization of AdoHcy hydrolase (100). Finkeistein and Harri.s (91) reported that the postmicrosomal supernatant of the rat liver contains almost all of the AdoHcy synthase activity,
but
of of
nuclear fraction. liver is localized
to
activity
a substantial
recovered
amount
AdoHcy exclusively in
the
is recovered
in
the
hydrolase in the
in human and rat cytosol fraction. The
nuclear
fraction
could
be
ex-
234
UELAND
plained by contamination of this fraction with soluble proteins (290). Likewise, AdoHcy hydrolase in the rat brain (30, 251) and the heart from various species (257) is a soluble protein. AdoHcy hydrolase can be demonstrated in the rat brain synaptosomes agreement with the fact that these cytoplasmic constituents (313).
(30), structures
which
is in contain
molecular
size
properties
ofthe
these enzyme
A
to Adenine
cyclic
protein
AMP
kinase
Chambaut
binding
activity
et
by papers
Analogue
al.
in
protein was
1971
on similar
Binding not
associated
demonstrated (44).
proteins
This
in rat report
from
other
ing embryos of Drosophila melanogaster and human erythrocytes (181, 317), mouse and bovine tissues (268), bovine adrenal Trypanosomagambiense (311), Jerusalem zome tissues (104), cow, dog (211, 212), and and bovine (312) binding proteins
and porcine have a
200,000 and/or sediment 284, 291, 317). Adenosine cyclic AMP site (80, 156, and
Corbin
binding tissues. remained
(268)
and Kredich proteins from are
with
has
been
by
followed
sources,
includ-
(284), rabbit liver (291), rat cortex (80), artichoke rhirat (87) heart,
as 95 (44, 80, 87, 104, 181, 268, binds to a site distinct from the 181, 268, 284, 291, 317). Sudgen the
name
proteins role of Hershfield
(134) demonstrated human placenta,
associated
finding
liver
was
(206) kidney. Most of these molecular weight of about
suggested
protein for such The physiological unknown until
with
hydrolase for the
and
binding spleen
activity.
cyclic
on an affinity
This
AMP-adenosine adreadeare
identical
have
AdoHcy
hydrolase.
Near
et
al.
(206)
to an inactive form isolation procedure.
proenzymes be
markedly sent lism.
from
various
scribed synthase cyclic This
binding by
Olsson activity. AMP-adenosine protein
has
proteins
from
cow
and
dog
heart
de-
et al. (211, 212) possess no AdoHcy Endrizzi et al. (87) have isolated a binding protein from rat heart. a molecular
weight
and
subunit
com-
position similar to those reported for AdoHcy hydrolase from other mammalian tissues. The binding protein can be separated from AdoHcy hydrolase by affinity chromatography (87). These data should perhaps be interpreted different naturally
in light of the finding sources is inactivated occurring
deoxyadenosine (132, and adenine nucleotides hydrolase from mouse
purines,
that
AdoHcy hydrolase from in the presence of various
which
include
137), AdoHcy (168), (288, 299). Treatment liver with ATP does
adenosine,
2’-
inosine (131), of AdoHcy not affect the
with
for
physiochemical
or during the of enzymatwhich hydrolase,
activity
of AdoHcy
and which
hydrolase,
involved
are or
should
adenosine
properties
enzymes
such
converted
may
in purine
its
differ repremetabotissues
G. Properties 1. Physiochemical
properties.
Most
data
on
the
phy-
hydrolase are rather to homogeneity from a molecular weight of coefficient of about
is composed of four subunits of 45,000 to 48,000 (81, 102, 128, 215, 216, 234, 251, 268, 291, 296). In
contrast, the adenine analogue binding protein from rabbit erythrocytes (Mr 240,000 and subunit Mr of 48,000) (317) and AdoHcy hydrolase from calfliver (Mr 237,000 and subunit Mr of 50,000-60,000) (234) seem to be proteins of slightly higher subunit composition.
This method reproducibility
for example (31, 32). The
of the
Binding proteins for cyclic AMP in mammalian is the subject of a recent review article (82).
G), and this glyceraldehyde adenosine
hydrolase
proteins
those
AdoHcy from mouse
be another enzyme, dehydrogenase
of AdoHcy
other
proteins hydrolase
binding proteins, related to AdoHcy
Binding with
that
behavior
either in the intact cell However, the existence
devoid
derivatives,
binding
binding proteins, resembling those identical to this en-
AdoHcy
adenosine closely
considered.
altered
binding
represent
ically inactive phylogenetically
the unlikely
analogue properties probably
inactive
may
described a 130,000 molecular weight protein from porcine kidney with binding characteristics that resemble those of adenine analogue binding proteins. The molecular weight of this protein is lower than the molecular weight of mammalian AdoHcy hydrolase (see section III protein may 3-phosphate
with
changes It is not
column.
Enzymatically
95, and daltons
binding protein from mouse liver (271) and bovine nal cortex (81). The question stifi remains whether nine analogue binding proteins from other sources to
associated
293).
siochemical properties of AdoHcy consistent. The enzyme purified various mammalian tissues has 180,000 to 190,000, a sedimentation
from rat and bovine this class of proteins (128) and Hershfield
that adenosine lymphoblasts,
AdoHcy
confirmed
adenine-analogue
are
but
(288,
In conclusion, adenine which show physiochemical of AdoHcy hydrolase, are properties
Proteins
enzyme,
enzyme
changes
zyme. F. Relation
of the
molecular
hydrolase, purified liver, bovine liver,
weight to apparent and bovine
in the same laboratory, tion on a HPLC gel
has been permeation
enzymes
exactly
eluted
with
these
sources
has
exactly
the enzymes are analyzed amide gel electrophoresis decylsulfate two bands These data of AdoHcy
same
the
liver,
and
enzymes rat (102) bound
same
by in the
retention
Stokes
discontinous presence
time and from
radius.
When
polyacrylof sodium do-
under conditions favoring high resolution, of equal density can be distinguished (81). are consistent with a molecular composition hydrolase given by the symbol a,82.
bound Abeles has
later
tightly cycle
NAD was first (215, 216) for the been
confirmed
from calf liver (234), human and mouse (288) liver. About per
to gel ifitraThese three
by high resolution AdoHcy hydrolase
AdoHcy hydrolase contains which participates in the catalytic B). Enzyme Palmer and
different
homogeneity adrenal cortex
subjected column.
the
is characterized (233). Thus,
(81).
and
mol
of enzyme
subunit
bound NAD (see section III
demonstrated enzyme from by
others
placenta 1 mol (102,
for (128),
of NAD
128,
216,
by beef the and is 234,
235
S-ADENOSYLHOMOCYSTEINE
288).
The isoelectric point of AdoHcy hydrolase from (291), rat (102, 168), calf (234) and bovine (81) liver, bovine adrenal cortex (81), and rat brain (251) is in the range from pH 5.35 to pH 6.0. The enzyme purified to homogeneity from yellow lupin
results
mouse
for adenosine was obtained (167), been confirmed with homogenous
and
(168).
on
seeds
malian
(119)
shows
physiochemical
properties
that
differ
AdoHcy hydrolase. The plant enzyme has a molecular weight of 110,000, and is composed of two identical subunits of 55,000 daltons. The isoelectric point of this enzyme is 4.9, which is lower than that of mammalian AdoHcy hydrolase. The data reviewed above, suggest that mammalian AdoHcy hydrolase from different sources shows nearly no variations with respect to molecular size, subunit composition, and charge. However, two isoelectric focusing variants have been observed in calf liver with p1 values of5.8 and 6.0 (234). Two enzymes can be separated in extract from bovine adrenal cortex by DEAE-cellulose chromatography. The predominating form focuses at pH 5.35, which is the same isoelectric point as that observed for the enzyme from bovine liver (81). The mouse liver enzyme focuses at pH 5.7 (81). The bovine enzymes can also be separated from the mouse liver enzyme by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate (81). Thus, AdoHcy hydrolase may exist as isoenzyme forms, or the enzyme is modified to various degrees during extraction and purification. Comparative enzymology on AdoHcy hydrolase should be carried out with the view to explain different pharmacological remarkedly
from
spouses
of tissues
those
of mammalian
to inhibitors
of AdoHcy
hydrolase
(35,
36). The kinetic properties of AdoHcy of some controversy. Walker and that Km for adenosine of the rat liver enzyme was 1.5 mM. This value has later been corrected to 0.66 mM by the same authors (152). These data are somewhat in variance with those obtained by Finkelstein and Harris (91), who reported a Km value of 0.25 mM for adenosine of the rat liver enzyme. Kajander et al. (167) using the same assay procedure and source of enzyme as Walker and Duerre, could not reproduce the 2. Kineticproperties. hydrolase are a matter Duerre (309) reported
TABLE Physiochemical
and
kineticproperties
of these
authors.
Rather
AdoHcy
from to
tM
60 .tM
Beef
liver
Mouse
liver
Yellow
lupin
seeds
Calf liver
the
Km
may,
cation
of the
presence
216,
234,
data
251,
271,
lupin
enzyme
48,000
192,000
4
48,000
185,000
4 2
be
explained
by
modifi-
kinetic
enzyme
for adenosine
and 12 zM, respectively for the enzyme from
Rat
brain
180,000
4 4
Rat Rat
liver
220,000
5
liver
188,000
4
185,000
4 4
placenta
Bovine
adrenal
Bovine
liver
190,000
cortex
185,000
the
in vitro.
and
(119). The spinach beet
of
AdoHcy tissues.
purified
from
are
2.3 iM
AdoHcy
corresponding are 13 iM and
values 41 M
(226).
The
physiochemical
hydrolase ble
from
and various
kinetic
properties
sources
are
of AdoHcy
summarized
in
ta-
1.
3. Binding binding factor osine These
(K = ligands
protein logues
0.1
seem
adenosine
site the
shows AMP
to
strict
different
and
(291,
293).
AdoHcy
adenine
0.3
tM).
on
the
requirements,
to be less
cyclic
restrictive.
to AdoHcy characteristics that for the erythrocyte AMP
hydrolase
analogue
=
studies with 77 anaconcluded that the
seems
from mouse liver shows identical to those reported
and
AMP aden-
both sites
structural
site
of adenosine
hydrolase are almost protein
bind
on inhibition Olsson (210)
cyclic
binding
(287)
to
(317). Based of adenosine,
whereas The
The adenosine-cycic rabbit erythrocytes binds zM) and cyclic AMP (Ki
properties.
from
from
binding
mouse
proteins
liver
from
1 hydrolase
purified
to homogeneity
from
various
sources References
45,000-46,500 55,000 50,000-60,000
AdoHcy
M
pM
45
10.5
Hcy mM
(317) 5.7
0.2
4.9 5.8
2.3 420
0.75 12.0
(215,
216)
0.15
(81, 271, 291, 296, 299)
4.6
(119)
63
(234)
6.0 Human
The
isolation. Furthermore, may be critical for the
of the homogenous seeds
Ado
5
4
299).
exist on the kinetic properties from sources other than mammalian
values
Km
yellow
at least, during
factor(s)
of the
Few hydrolase The
partly enzyme
of some
behavior
M
240,000
110,000
for
of
p1
237,000
values
K,, for
M,
erythrocytes
(102,
properties
hydrolase
ofS-adenosylhomocysteine
No.
Rabbit
data
AdoHcy hydrolase purified to homogeneity from mouse liver, bovine adrenal cortex, and bovine liver have been compared in the same laboratory. Exactly the same Km values for adenosine (0.2 ,M) and AdoHcy (0.75 tM) were obtained for these enzymes (81). Thus, different kinetic properties reported for AdoHcy kinetic
Subunits Source
value of 0.7 tM this value has later enzyme for rat liver Km
purified to homogeneity from mamhave been reported, i.e. Km values for 0.2 1M to 420 M, and for AdoHcy from
tissues
0.75
apparent
inconsistent
hydrolase
adenosine
An
0.5
48,000 47,000 47,000
5.6
(128)
36.6 0.90
(251)
6.6
0.6
5.7
1.05
45,000-46,000
5.35
0.2
0.75
(80,
45,000-46,000
5.35
0.2
0.75
(81)
15.2
0.06
(168)
0.155
(102) 81)
rat
236
UELAND
and bovine other than
tissue (268) also bind adenine cyclic AMP. Whereas adenine
the adenosine both the cyclic
site only, AMP, AMP and the
binding
capacity
of the
process
termed
activation,
tides
(287,
292).
dissociation
cyclic
This
ADP, adenosine
AMP
process
by is
or polymerization
and
site
induced
nucleotides
interacts
not
with
ATP bind to site (287). The
is increased adenine
by a nucleo-
associated
of the
enzyme (288, NAD (288), but
synthesis
mouse
and
liver
hydrolysis
enzyme
of AdoHcy
(299).
The
effects
Gene
by the
of
corn-
(303).
It
Francke
(133a),
using
human-Chinese
is suggested
that
the
occurrence
genes coding for these two enzymes on the mosome may have evolutionary sigificance. deaminase
catalyzes
the
catabolism
deoxyadenosine and thereby AdoHcy hydrolase activity 1).
Furthermore,
pro-
eukaryots, eukaryotic enzyme. have occurred after AdoHcy hydrolase binds
adenine
of
the
same chroAdenosine
of adenosine
and
2’-
deaminase
occurs
both
in
whereas AdoHcy hydrolase is an Evolution of AdoHcy hydrolase may adenosine deaminase. The fact that forms a stable complex with adenonucleotides,
and
contains
tightly
NAD (see sections III A, III G 3 and III G 1) points to the possibility that evolution of the AdoHcy hydrolase gene involves recombination of part of the adenosine for NAD
deaminase gene with a DNA sequence coding and adenine nucleotide binding domain(s)
Substrates,
Inhibitors,
and
S-Adenosylhomocysteine A. Introductory Ademne strated by lowed sides
studies
hamster
of
Inactivators Hydrolase
Data toxicity Aranow
by the are toxic
to mammalian in 1961 (5).
observation to cells and
cells was first This discovery
that several are effective
adenine antitumor
demon-
was
fol-
nucleoand/or
found
in
adenosine
the
nucleoside.
with
mouse
cells
toxicity interferes
(193)
resistant
low
cells
levels
point
adenosine. adenosine
that adenosine However, cells pynmidine
starvaor mutual concentrais toxic to
in adenine phosphoribosyltransferase toxicity is enhanced by L-homocysteine
and is associated and inhibition toxicity The
is
and
of adenosine by that
of exogenous uridine (180) kinase, are sensitive to high (138). Likewise, adenine
deficient Adenosine
(138).
requires
conclusion (160)
fibroblasts
with
are orga-
toxicity
to adenosine-induced
tion by addition loss of adenosine tions of adenosine
various
This
is prevented by uridine suggests with pyrimidine synthesis.
with increased cellular of cellular methylation
to AdoHcy
hydrolase
(134). role of AdoHcy
hydrolase
cells
drolase.
Under
reaction
is directed
presence
toward
adenosine
in adenosine
deficient
where
the
toxicity with
mutant
in AdoHcy
AdoHcy
synthesis
of exogenous
for
et al. (171)
partially
conditions
levels of AdoHcy (111, 180). These
as a target
by Kamatani
has been evaluated murine lymphoid
of AdoHcy,
homocysteine
hy-
hydrolase
and
i.e. in high
con-
centration of adenosine, the mutant cells accumulate less AdoHcy and are less sensitive to the toxic effect of the drug combination than the parent cells. In contrast, a low concentration of adenosine alone, which is expected to exert only an inhibitory effect on AdoHcy hydrolase leading to an accumulation of AdoHcy derived from
AdoMet,
higher
levels
cells compared equally sensitive
induces
to the to the
parent growth
osine. Thus, in the toxic effect
the murine lymphoblasts of high concentrations
combination
with
(182),
which
to
be
of the (300).
is required of stimulated
nucleoside, Incubation
only in
to be mediated
by
causes of dATP
for
a dramatic that may
against
(but not adenoduring the first
in phytohemagglutinin-stimulated been suggested that catalyzing
analogue
effective
(39). 2’-Deoxyadenosine [3H]leucine incorporation
kinase
mutant lines are of aden-
at least, of adenosine
adenosine
particularly
2’-deoxyadenosine
(273).
cell effect
is a cytotoxic seems
It has
DNA
in the
cells. Both inhibitory
seems
day of blastogenesis lymphocytes (285).
deoxyadenosine lular levels
of AdoHcy
homocysteine
AdoHcy (171). 2’-Deoxyadenosine lymphocytes sine) inhibits
(133a). IV.
of
pyrazomycin compounds
kinase and resistant to growth inhibition The observation by Ishii and Green (160)
the
creates conditions favoring (see sections III A and IV B
adenosine
and
sine, bound
Chinese
made
hybrids and monoclonal antibodies to human AdoHcy hydrolase, have localized the gene for AdoHcy hydrolase to chromosome 20. The gene for adenosine deaminase has also been mapped to this chromsome
phosphorylation based on
9-
N6-methylad-
ribonucleoside), Some of these
naturally occurring nucleosides nisms (269). It has been suggested that
data
and
aristerornycin),
291) con-
Localization
Hershfleld hamster cell
(± (purine (3).
(269),
pounds on enzyme catalysis parallels their inhibitory effect on adenosine binding (287), thus indicating that the adenosine binding site may be identical to the catalytic site (299). This possibility is supported by the finding that AdoHcy inhibits the adenosine binding to AdoHcy hydrolase from human placenta (128). H.
of adenosine nebularin and tubercidin
with
catalyzed these
analogue enosine,
or dissociation of enzyme bound forinational changes in the protein structure occurs as judged by altered reactivity of SH-groups (296). The observation that the so-called activation of the cyclic AMP site is associated with loss of catalytic activity (288) points to the possibility that this process is related to partial denaturation of the enzyme. Adenine and adenine nucleotides competitively inhibit the
antiviral agents. These compounds include 3’-deoxyadenosine (cordycepin) (162), 2’,3’-dideoxyadenosine (69), f3-D-arabinofuranosyladenine (ara-A) (162), 9-$-D-xylofuranosyladenine (83, 122), formycin (108), carbocycic
the
the
enzyme
phosphorylation
producing lymphocytes elevation inhibit the
cytotoxicity with
2’-
of intracelsynthesis of
237
S-ADENOSYLHOMOCYSTEINE
The
antibiotic,
properties,
ara-A,
and
peutic
agent
has
in
have
been
which some
is an inhibitor DNA polymerases
suggested
ara-A
degradation cal
replication mechanism
proposed
and
analogues,
including
tubercidine, of nuclear 266).
recent
ara-A
to inhibition
of potent tight
inhibitors
binding
the
conversion
by
alcohol
analogue of (EHNA) potentiate the bi-
of ara-A
deami-
deaminase the inactive
to
adenosine
deaminase
inhibitors
Irreversible
re-
useful
inactivation
This
observation
shows
enzyme
is protected
AdoHcy,
but
later
kinetics against
and
of
confirmed
‘(cat
saturability.
inactivation
not by homocysteine or
been
mechanism
by
(132).
The adenosine
These
data
of inactivation
of
AdoHcy hydrolase by 2-deoxyadenosine (310). A mechanism of action of 2’-deoxyadenosine based on knowledge of the catalytic mechanism of the enzyme has been provided by Abeles et al. (2). The inactivation of homogenous nied
AdoHcy by conversion
hydrolase
from
bovine
of 2’-deoxyadenosine
liver
The
shows
enzyme
Id-
similari-
in a cell-free
system.
DNA
mac-
causes
cel-
inhibits nbonucleotide of deoxynucleotide
synthesis.
This
is not
also
2’-Deoxyadenosine
in adenosine of AdoHcy
A human
lympho-
kinase accumuto inactivation of
is explained kinase hydrolase.
resub-
by accumulation
deficient The
of
cells, leading role of dATP
to ac-
cumulation and AdoHcy hydrolase inactivation in cellular toxicity was evaluated by supplementing the cellular medium with deoxynucleosides. It was concluded that inactivation
of AdoHcy
cumulation sine (135).
not
to the
et al. (202) acute T-cell
treated with the 2’-deoxycoformycin. gives
hydrolase
contribute
increased adenosine,
as well
toxicity
as
dATP
reported on a 13-year-old lymphoblastic leukemia
potent
boy with who was
adenosine deaminase Inhibition of adenosine
plasma
levels
ac-
of 2’-deoxyadeno-
inhibitor, deaminase
of 2’-deoxyadenosine,
accumulation
of dATP
in
but
lymphoblasts
and nearly total inhibition of lymphoblast drolase. The patient died 3 days after the discontinued, and postmortem examination
in accumulation
this
effect. This case tigation of the possible
AdoHcy hytherapy was revealed
and
irreversible reduction of enzyme bound NAD. The authors suggest that 2’-deoxyadenosine is oxidized to 3’-
of AdoHcy
may
agents
ara-A vator
and 2’-deoxyadenosine. of AdoHcy hydrolase
zyme
is
also of the
by
protected of its
other enzyme,
been
proposed,
against substrates,
purines such
inactivation adenosine
interacting as adenine,
of 2’-deoxyadenosine.
The with
is associated
(132)
inactivator of The kinetic are similar for
by ara-A and AdoHcy,
with AMP,
the
catalytic
and
ADP
of AdoHcy
resembles
enzyme
in leu-
ara-A is a suicide inacti(132). The mouse liver en-
of inactivation which
to inveswith
Hershfield
showed that ara-A is even a more potent AdoHcy hydrolase than 2’-deoxyadenosine. characteristics of the inactivation process
presence
contribute
report should stimulate the use of compounds interfering
AdoHcy metabolism as chemotherapeutic kemia. 2. 9-f3-D-Arabinofuranosyladenine.
A mechanism
is accompa-
to adenine
process
(136)
137).
complete absence of leukemic cells in all organs. It was suggested that lysis of T lymphoblasts is mediated by 2’deoxyadenosine (202). Inactivation of AdoHcy hydrolase
from other sources (2, 50, 137). 2’tightly to the enzyme. The inac-
first-order
a suicide
has
for
hydrolase.
Mitchell refractory
hydrolase by 2’-deoxyadenosine was first demby Hershfleld (132) for the enzyme from human
tivation
and
as
(135).
adenosine protection
resulting
2’-Deoxyadenosine.
for AdoHcy hydrolase Deoxyadenosine binds
suggest
have
analogues
in cells
intracellular
of CIATP that leads to depletion
required
AdoHcy
(111).
Analogues
lymphoblasts.
of the
(135,
blastoid cell line deficient in adenosine lates less dATP, but it is also resistant
2’-deoxy-
are
of this
kinetics
lular build-up ductase and strates
of adenosine
inhibitor,
newed the interest in adenosine chemotherapeutic agents.
AdoHcy onstrated
the
process
inactivate
probably because of protection of the enzyme by accumulating in the cells in the presence of 2’-
xylofurano-
effect
in culture
inactivation
to
erythrocytes
tivated, AdoHcy
9-$-D-arabinofuranosythypoxanthine, and shown to enhance the effects of ara-A in several cell systems and in vivo (42). Likewise, these inhibitors also block the degradation of adenosine, 2’deoxyadenosine, cordycepin and xylofuranosyladenine, and they potentiate the biological effects of these agents
1.
with
shown
human
fate (2).
the
metabolite, have been
B. Adenosine
of the
3’-
enzyme
fraction
and formycin in intact cells
ological effects of adenosine analogues that nated by this enzyme. For example, adenosine
Potent
lymphoblasts
The
the
to NADH. The is unknown
been
has in intact
NAD. and
is irreversibly reduced moiety of 2’-deoxyadenosine
human
ties
bound
adenine,
A small
effects and mechanisms has been stimulated
coformycin (dCF), and the aliphatic adenine, erythro-9-(2-hydroxy-3-nonyl)adenine (109). Adenosine deaminase inhibitors
(109).
by enzyme eliminates
rat
adenosine anand various
is without
biological analogues
as the
block
NAD sugar
netics
of biologi-
cordycepin,
2’-Deoxyadenosine
such
inhibitors
block
bound of the
and
that
from
may
8-azaadenosine, RNA methylation
development
deaminase
lead
showing
hydrolase
derivative
2’-Deoxyadenosine AdoHcy hydrolase
and into
(283). A nuof ara-A was
(281),
keto
deoxyadenosine
Investigation of the of action of adenosine the
that
of
reductase incorporation
of biological methylation by been demonstrated. Adenosine
syladenine, are inhibitors (111-113,
effects
to ara-ATP,
(281).
Inhibition alogues has
adenosine
Kerr
keto-2’-deoxyadenosine
antiviral
chemothera-
biological
of AdoHcy
of AdoHcy
methylation
an
of DNA of action
and
inhibitor
workers
The
ribonucleotide (42), and the
by Trewyn
These
and as
to its conversion of
the
is a potent
liver.
(42).
attributed
DNA may inhibit cleotide independent
oncostatic
evaluated
humans
ara-A
first
has
been
the
tight
inactivation binding
the but
site (123).
hydrolase
mechanism
irreversible
in
of ara-A
has of action of the (123),
238
UELAND
conversion of bound ara-A to adenine, and reduction of enzyme bound NAD to NADH (124, 130, 133). The formation of adenine is kinetically closely related to reduction
of
involves rivative
enzymatic by NAD,
the
NAD
preceeding
(124).
The
oxidation as described paragraph.
mechanism
suggested
of ara-A to its 3’-keto-defor 2’-deoxyadenosine in However,
in the
presence
of
L-homocysteine, S-(5’-(9-arabinofuranosyladenyl)-L-homocysteine (ara-AHcy) is formed at a rate that is about one half of the rate of inactivation, and the velocity of the inactivation process is reduced accordingly. It is concluded that reduction of NAD and formation of adenine result from an abortive catalytic cycle, and the enzyme entering a complete cycle leading to formation of ara-AHcy, is not inactivated (124). Inactivation of AdoHcy hydrolase by ara-A in intact cells, such as human rocytes (136), mouse
lymphoblasts plasmacytoma
(137), cells,
human mouse
erythL-cells,
and
half-maximal
rate
of inactivation
thermore, hibitors inactivation
by
AdoHcy
the exert
or
possibly
observation essentially suggests
other
that
deamination
major factor limiting the short-term AdoHcy hydrolase. The inactivation to a massive build-up ticularly pronounced
of ara-A
and
ara-A
in the
hepatocytes.
On
the
other
hand, the reactivation is markedly inhibited by the adenosine deaminase inhibitor, dCF, c3Ado, and, to a lesser degree, by homocysteine. Inhibitor of protein synthesis and inosine were without effect. These data form the basis of the hypothesis that the reactivation mechanism is enhanced under cellular conditions favoring hydrolysis of AdoHcy. Alternatively, the ara-A-AdoHcy hydrolase complex is continuously reactivated and the reactivated enzyme is trapped by forming an inactive complex with
hydrolase
injection
of the
fact
that
naturally
adenosine, AdoHcy (137, (132) are inactivators of may protect the enzyme the enzyme to an inactive between tight binding of (section III C), and the This possibility should be
in various
with
in most
ara-A
plus
served
a
is associated with export of AdoHcy into the extracellular medium (125). A process leading to reactivation of AdoHcy hydrolase in intact cells exposed to ara-A has been described (126). The reactivation is associated with a pronounced fall in the cellular content of AdoHcy. Reactivation of AdoHcy hydrolase in intact hepatocytes is stimulated by supplementing the extracellular medium with adenosine deaminase, which induces a decrease in the amount of adenosine
in light
nucleosides, such as 168), and 2’-deoxyadenosine AdoHcy hydrolase. This process against metabolites converting form. It seems that a relation adenosine to AdoHcy hydrolase reactivation process may exist.
restored
which is parand the accu-
mulation
substrates
ara-A
organs
is
of mice
rapidly
treated
inactivated,
and
tissues
within
8 to 10 hours.
The
increase
in enzyme activity is not affected by cycloheximide and is partly inhibited by dCF. Inhibition of the reactivation process by dCF correlates with a massive accumulation of AdoHcy in organs of mice treated by injection with
effect of ara-A on of the enzyme leads
of cellular AdoHcy, in the hepatocytes,
are
in these tissues. Especially high obtained in the liver and kidney. In the absence of an adenosine deaminase inhibitor the enzyme activity gradually recovers and is nearly fully
inof
is not
which
AdoHcy accumulates concentrations are
Fur-
deaminase the kinetics
analogues,
be considered
AdoHcy
at nearly
metabolites.
that adenosine no effect on
probably occurring
by
the same level of ara-A. It is concluded that ara-A readily gains access to intracellular AdoHcy hydrolase. However, in contrast to cell-free systems the inactivation of intracellular AdoHcy hydrolase does not proceed to completion, in that 2% to 3% of the AdoHcy hydrolase activity in rat hepatocytes and some cultured cells is not inactivated. This is explained by protection of the intracellular enzyme
or adenosine
of adenosine deaminase (126). The observation that both dCF and c3Ado inhibit the reactivation process suggests that these compounds may potentiate the effect of ara-A on biological methylation in vivo (126). The existence of a cellular process reactivating intracellular AdoHcy hydrolase inactivated by ara-A should
investigated.
human chronic leukemia cells, and isolated cells of rat liver (125) has been demonstrated. The inactivation process shows kinetic characteristics resembling those observed in cell-free systems, i.e. first order kinetics, saturability,
adenosine
dCF,
after
whereas
only
a slight
injection
with
ara-A
port those Thus, dCF
obtained enhances
with the
isolated effect
metabolism
by blocking
the
increase
alone.
was
These
ob-
data
sup-
cells in suspension. of ara-A on AdoHcy
reactivation
of AdoHcy
hy-
drolase in vivo. In addition, increased tissue levels of adenosine induced by dCF may also contribute to this effect (127). An essential question related to the duration of the inhibition of AdoHcy catabolism in the presence of araA is the turnover of intracellular AdoHcy hydrolase. No investigation has been devoted to this subject. Preliminary studies in the author’s laboratory indicate that the half-life of the enzyme is more than 12 hours in tissues of mice. However, precaution should be taken when meas-
uring the half-life of toxic inhibitors may
cause
the
of AdoHcy hydrolase of protein synthesis. accumulation
of metabolites
AdoHcy hydrolase. AdoHcy hydrolase inactivation lation have been demonstrated tients 240).
receiving
The
cessation incapable
reactivation
ara-A
enzyme
of the
enzyme
activity
for
is partly
of the treatment of protein synthesis,
(240).
intracellular also observed fluctuations
during
therapy
inactivating
and AdoHcy in erythrocytes
treatment
activity
enzyme activity was but there are marked
in the presence These compounds
virus
infection
restored As
this may enzyme.
accumufrom pa-
erythrocytes be explained
after are by
Suppression
in mononuclear with partial in
(129,
9 days
these
of cells,
return
cells
of (240).
239
s-ADEN0sYLH0M0cYsTEINE AdoHcy accumulation leading to inhibition of cellular methylation may account for the antiviral properties (129, 240) as well as some side effects of ara-A. Recent studies with the ara-A analogue, 9-f3-D-arabinofuranosyl-2-fluoroadenine (2-F-ara-A) have shed some doubt on the role of AdoHcy hydrolase as a mediator of the cytotoxic effects of these compounds. 2-F-ara-A, a nucleoside that is resistant to deamination, has cytotoxic effects against cultured cells comparable to that of ara-A plus dCF. The nucleoside triphosphate derivatives of both nucleosides are potent inhibitors of DNA polymerase and ribonucleotide reductase, but 2-F-ara-A is a weak inactivator of AdoHcy hydrolase. Furthermore, cells that have lost their capacity to phosphorylate these cornpounds are resistant to them. These data indicate that the cytotoxic effects of ara-A and 2-F-ara-A are related to inhibition of DNA synthesis (312a). 3. 3-Deazaadenosine. Chiang et al. (52) tested 43 an-
lated
alogues
erythroleukemic
of
AdoHcy
sugar, 5’-thioether substrates and was
found
that
(c3AdoHcy)
is
c3AdoHcy
c3Ado
with
synthetic
direction.
rat
and data
biological
(see section 4. Various
injections
the
for
and
cAdo
for
the
cells
properties
of
of c3Ado
analogues.
Biosynthesis
from demonstrated
was
of S-
N6-methyladenoby Hoffman This observation
from mouse liver. by others by using intact cells enzyme (118). S-N6-Methyladenosylin the
liver
of mice
S-N6-methyladenosine is
a
potent
mRNA
methylation (228) and tRNA 279); this suggests that administration adenosine may block RNA methylation nucleosides
(325)
treated
with
(148).
N6-Methyl-
inhibitor
of
methylation of
viral
(185a, Ne-methyl-
in vivo
structurally
(148). resemble
the
inactivation
induced
IV B, 1 and
2), reversibility
induced
inactivation
the
enzyme
be
into
mice
the
causes
liver
(151).
an
mouse
plementing derivatives.
cells
the cellular In both the
AdoMet-level increases of AdoMet-dependent
tion The
dialdehyde
phospholipid
by sup-
indicating inhibition reactions (149). hydrolase
and
carboxymethyla-
in mouse L-cells (20). antiviral agent,
and
9-((S)-2,3-dihydroxypropyl)-
adenine ((S)-DHPA) is an aliphatic nucleoside analogue, which was found by Votruba and Holy (307) to be an inhibitor of isolated AdoHcy hydrolase from rat liver. The same workers have studied the interaction of allphatic
adenine
derivatives
aliphatic
chain,
containing
so-called
hydroxyl
eritadenines,
groups with
rat
in liver
AdoHcy hydrolase. Among these compounds, D-eritadenine is a potent inhibitor and inactivator of the enzyme (307a).
It was proposed by these agents
exerted
of AdoHcy Numerous
catabolism nucleoside
substrates,
inhibitors,
lase
(50,
c3Ado,
118,
137,
that some may be
of the biological effects mediated by inhibition
(307, 307a). analogues and
307,
have
inactivators
325).
lesser
degree,
formycin
In addition
are
inhibitor
inactivator
of the
range, effective
A, which
is followed
omycin),
pyrazomycin,
whereas (118).
good
and
for
to the
a
iso-
of the corresponding has been demonstrated is a particularly potent enzyme,
c3Ado and Carbocyclic
ofAdoHcy been reported AdoHcy
as
hydro-
and,
substrates
purified
by carbocycic
tested
to adenosine
nebularine,
lated enzyme (118), and formation AdoHcy analogues in intact cells (118, 325). Carbocycic adenosine the nanomolar osine are less
been
of AdoHcy
2-aza-3-deazaadenosine,
of purified
sine, c3Ado, and N6-methyladenosine, are potent competitive inhibitors of the enzyme with K values three orders of magnitude less than Km (150). The inactivation of AdoHcy hydrolase by adenosine dialdehyde and re-
markedly
AdoHcy
tent
adeno-
increases
of
in Friend
inactivates
to function
nucleosides
content level
methylation
inhibitors,
of
of
phosphate
AdoHcy
AdoHcy
by 50%; thus transmethylation
known
enzyme,
not
medium with these adenosine intact liver and in the cells, the
weak
the
in the the
elevation has
for
section
by dialysis
(but
increase
Furthermore,
duces a marked 2-Chloro-adenosine
derivatives
2’-deox-
(see
demonstrated
Tris-buffer
competitive
as substrates
and
in vitro
of the adenosine-dialdehyde-
can
against
by ara-A
process
the proposed intermediate in the catalytic cycle of AdoHcy hydrolase, i.e. 3’-keto-adenosine (see section III B, fig. 2). These compounds were therefore tested as inhibitors of the enzyme (150). The penodate-oxidized derivatives of nonsubstrate nucleosides are relatively whereas
of affinity-
buffer). It is suggested that an amino acid residue at the catalytic site, possibly a lysinyl residue, forms a Schiff base adduct with the adenosine dialdehyde (20). Injection ofperiodate-oxidized derivatives of adenosine
inhibits
in these
characteristics
are directed
is an irreversible
Adenosine
investigation
kinetic
and
yadenosine
in the the
reagents,
Whereas
c3Ado;
is about
shows
toward the active site of the enzyme. Adenosine dialdehyde binds tightly to the enzyme, and both the binding and the inactivation are prevented in the presence of adenosine and AdoHcy. Furthermore, the time-dependent inactivation shows saturability and seems to occur via a unimolecular reaction.
the
adenosylhomocysteine
Periodate-oxidized
(52).
enzyme
is formed
basis
pharmacological
is formed
of
as It
enzyme
for the
Kmvalue
IV C). nucleoside
homocysteine
the
L-homocysteine
c3AdoHcy
form
and
homogenous
purine,
adenosine, and is about 1.26 Vmax for adenosine (234). c3Ado induces in the content of AdoHcy in isolated
N-methyladenosythomocysteine sine and homocysteine (148) in crude extract has been confirmed.
and
to
for
substrate
The
for
the
substrate
as a good
same as the Km times higher than a drastic increase These
the
acid portion hydrolase.
S-3-deazaadenosyl-L-homocysteine
a good
hepatocytes,
in
and amino of AdoHcy
is hydrolyzed
serves
(52).
modifications
linkage, inhibitors
compounds
labeling
with
in intact to be hydrolase
adenosine
2-amino-6-chloro-purine
K
8-aminoadenadenosine
in in-
cells (118). a more pothan
ara-
(± aristerriboside,
nebularin, 2-chloro-ara-A, and 2’-deoxyadenosine in the order mentioned (50). These analogues inactivate the enzyme according to first order kinetics, and are classified
240
UELAND
as type
A analogues,
B analogues that
which
are
(as for example
show
a curvilinear
Cordycepin
distinguished
from
class
the properties (see sections
adenosine-5’-carboxamide)
inactivation
(50).
(203a)
and
the
be
carbocycic
analogue of c3Ado, 3-deaza-C-Ado (203b), were synthesized. Ara-3-deazaadenine is a mediocre inhibitor of AdoHcy hydrolase and reveals only moderate antiviral properties against herpes simplex type 1 virus (203a). In contrast, the results obtained with 3-deaza-C-Ado are more promising. This compound is not subjected to
(130).
tive
The observation that cordycepin is an inactivator of AdoHcy hydrolase raises the possibility that interference with RNA metabolism and the cytotoxic effects observed in the presence of this compound stem from blocking the degradation of AdoHcy. However, cordycepin is not a potent inactivator of AdoHcy hydrolase (137), and this
accumulation in intact cells. The compound properties at noncytotoxic concentrations results obtained with 3-deaza-C-Ado suggest
compound
active
AdoHcy
is an
ara-3-deazaadenine
adenosine might
C)
inactivator of observation shows that inactivation of AdoHcy hydrolase by adenosine analogues does not in all instances involve oxidation of the 3’-hydroxyl group of the ribose residue. Inactivation of AdoHcy hydrolase by some analogues is not associated with reduction or loss of enzyme bound NAD isolated
(3’-deoxyadenosine)
combined,
of ara-A, c3Ado, and carbocycic IV B, 2, 3, and 4 and IV
hydrolase
does
not
(50,
induce
an
137).
This
accumulation
of AdoHcy
in WI-L2 cells (111). Experimental data provided by Glazer and Hartman (111) and Kredich (176) indicate that the inhibitory effect of cordycepin on the methylation of nuclear RNA is not mediated by AdoHcy hydrolase. Cordycepin is metabolized to the 3’-deoxyanalogue ofAdoMet in the intact cell (176, 321), which may in turn be responsible for the inhibition of nucleic acid methylation. Similar
ladenine. ylation
tion
results This
are
in murine
ladenine
with
of AdoMet
is not
adenosine
with
9-$-D-xylofuranosy-
analogue
inhibits
erythroleukemia
is associated
analogues
obtained
adenosine
and
and
deficient
meth-
the
inhibi-
cells
metabolized
to its AdoMet
hydrolase,
AdoHcy
small
analogues.
The latter two compounds may interfere with methyltransfer reactions (103a). Several analogues of adenosine were tested by Zimmerman et al. (325) with respect to their ability to increase the AdoHcy level or be metabolized to their corresponding S-nucleosidylhomocysteine derivatives in mouse lymphocytes. It was concluded that base modified adenosine
analogues
such
as
c3Ado,
2-aminoadenosine,
N6-methyladenosine, formycin A, N6-hydroxy-adenosine, purine ribonucleoside, and 8-aza-adenosine are condensed with L-homocysteine to form their corresponding AdoHcy (ara-A, nine)
analogue. Ribo-modifled adenosine 2’-deoxyadenosine, 5’-deoxyadenosine, function
as
inhibitors
of AdoHcy
analogues and adehydrolase,
detectable amounts of the corresponding logues are not formed (325).
and
AdoHcy
ana-
The concept of AdoHcy hydrolase cal target for the development agents (52, 132) has been exploited
as a pharmacologiof chemotherapeutic recently by Montgom-
ery
the
and
coworkers
(203a,
b). With
view
that
and
compete-
induces
AdoHcy
has antiviral (203b). The that knowl-
edge on the structure-activity action between adenosine
relationship of the inter analogues and AdoHcy hydro-
lase
for the
may
be of great
In conclusion, or substrates
for
these induce high with L-homocystelne cleosidylhomocysteine fects
value
synthesis
of biologically
purines.
of
some
many adenosine analogues are inhibitors isolated AdoHcy hydrolase. Some cellular
adenosine
analogues
of AdoHcy
of
levels of AdoHcy and condense to form the corresponding S-nuderivatives. Thus, biological efmay
be
related
inhibition of transmethylation reactions. The of adenosine analogues as substrates, inhibitors,
C. Biological
and
accumulate
and
is an effective
hydrolase,
hydrolase
are
summarized
to
functions and inin table
and
Pharmacological
Properties
of 3-
Deazaadenosine
amounts of the xylofuranosyl analogue of AdoHcy. These data indicate that this adenosine analogue is phosphorylated to the corresponding triphosphate, which is further
of AdoHcy
2.
9-fl-D-Xylofuranosy-
of AdoHcy
or phosphorylation,
inhibitor
activators
RNA
of xylofuranosyl
AdoHcy.
a substrate
kinase
cells,
accumulation
deamination
some
C3Ado is both a substrate and an inhibitor of isolated AdoHcy hydrolase. When injected into rats, c3Ado increases the tissue level of AdoHcy and AdoMet and causes a marked appearance of c3AdoHcy. These biochemical changes are associated with a decrease in the AdoMet/AdoHcy ratio and perturbation ofvarious transmethylation
reactions,
ylation Some
reduction
decreased
of lipids (48). tissue differences
in the
level
of cre-
urintry excretion of 3acid and reduction in meth-
in the
response
to c3Ado
have
been observed. There is a 10-fold increase in the AdoHcy level in rat spleen and no alteration in the AdoMet level. In the heart, lung, and kidney of the rat, c3Ado induces no increase in the cellular content of AdoHcy and AdoMet, and only trace amounts of c3AdoHcy are formed. The tissue level of AdoHcy, AdoMet, and c3AdoHcy is high in the rat liver, whereas in the liver of hamster there is no increase in AdoHcy content, but the concentration of AdoMet increases and c3AdoHcy is formed (179). The differential response of various tissues to c3Ado has been related to different Km/Ki of AdoHcy hydrolase
of
i.e.
atinine in the liver, methoxy-4-hydroxymandelic
from
various
Evaluation
of the
tool for the tions requires
investigation knowledge
sources
use
(35).
of c3Ado
as a pharmacological
of biological methylation of effects and reactions
reacof this
241
S-ADENOSYLHOMOCYSTEINE TABLE Adenosine
analogues
Name
as substrates,
Chemical
inhibitors
structure
2
or inactivators
Substrate
of S-adenosylhomocysteine
Inhibitor
Inactivator
hydrolase
References
NH
NL 1+)
4+4
4+4
+4+
+4+
4.4+
+
4+
(+)
++
+
(+)
4
(4)
O.118,1i7,168,32)
AdenOsi ne
Base -modified
adenosine
anal
ogues -
HOH2C
(4)
50,52,118,234,325)
N
3-Deazaadenosine
cx3
HOH2f
-“N
2-Aza-3-deaza-
0
118)
adenosine HO
OH H N
K, I,, HOH2C Nebularin
(50,118,325)
NH2 J4(LN HOH2C 4
Form ycin
H
HOH2C
6
N-Methyladenosine
I HO
CH3
I
0
+
exposed
to
0.1
mM
c3Ado.
synthesis and be demonstrated
Radioactive
(50,118,148.325)
OH
compound in systems not related to the AdoHcy hydrolase reaction. c3Ado is neither a substrate nor an inhibitor of adenosine deaminase (158) or adenosine kinase (199). No effect on DNA and protein effect on RNA synthesis can
(50,118,325)
only
a slight in cells
c3Ado
is not
incorporated
into nucleic acids (7). c3Ado is a weak of adenylate cyclase from human fibroblasts and neuroblastoma cells (48), and increases only slightly the cyclic AMP level in human and rabbit neutrophils (327). However, Zimmerman et al. (323) have reported inhibitor
recently
that
lymphocytes
incubated
with
micromolar
242
UELAND TABLE
Name
Chemical
siructure
2-Continued
Substrate
Inhibitor
Inactivator
References
NH2 8- Aza-adenosi
ne HOH2C
+
(4)
(4)
(+)
(50,118.325)
kcZ HO
Pyrazomy
+
OH
cm HOH2C
C
+4
(50,118)
OH
2-Chioro-
4+9.
(50,325)
4+1’
125.130,132,133,
adenosine
Sugar-modified
adenosine
analogues NH2’ JN
HOH2?
N: (
Adenine arabinosi de
(JAristeromycin
(4)
of adenylate
cyclase
activity
(323). Likewise, c3Ado, alone or in combination with homocysteine, increases the cyclic AMP level in rat hepatocytes exposed to hormones. The effect could be explained by inhibition of cyclic AMP degradation by high level of c3AdoHcy and AdoHcy accumulating in these
The
cells
(248).
enzymatic
synthesis
123,
124,
4+4+
+4+
(50,
118)
H
concentrations of c3Ado (or adenosine) in a medium supplemented with homocysteine accumulate supramillimolar concentrations of c3AdoHcy (or AdoHcy). These cells exhibit an increased (5- to 40-fold) cyclic AMP response to prostaglandin E, adenosine, 2-chloroadenosine, isoproterenol, and cholera toxin. These effects have been explained by inhibition of cyclic AMP phosphodiamplification
118,
HOH2C
HO
and
50,
136,137,281,325)
(+)
esterase
+4
of phosphatidylcholine
from
phosphatidylethanolamine
toward
inhibition
(143)
by
c3Ado
(48,
is particularly
154).
The
sensitive
conversion
involves three stepwise methyl transfer reactions seem to be catalyzed by two AdoMet-dependent yltransferases
(143).
lated to membrane ping of fl-adrenergic number of available of benzodiazepines
Various
biological
phenomena
that methre-
function and structure, such as coureceptors to adenylate cyclase, the $-adrenergic binding sites, binding to its receptors, ATPase activity, leukocyte chemotaxis, histamine release from mast cells, and lymphocyte mitogenesis seem to depend on phospholipid methylation (143, 145). Inhibition of phospholipid methylation by c3Ado is associated with inhibition of histamine release induced by concanavalin A in rat mastcells (144) and immunoglobulin E mediated hista-
243
S-ADENOSYLHOMOCYSTEINE TABLE
Name
Chemical
structure
2-Continued
Substrate
Inhibitor
Inactivator
References
NH2
-Deoxyadenosine
HOH2
N
C
N
+
2,50,
118.
132,135,
1(6,137,325)
HO
9-(S)-( 2.3 -dihydroxy propyl )adenine
-
+4
(307)
0H CH2OH
+++
HO
D-Erit adeni ne
+++
(307a)
HO COOH
NH2
Adenosine dialdehyde
HOH2C
N”
CHO Base
and
sugar-modified
+++
(20,149,150,151)
+4+
CHO analogues NH2
ara-3-dsaZO-
HOH2C
+
(203a:
ad.nine
HO
NH2
HOH2C Carbocyclic
,
I?J
(+)
+4+
21) 3b)
3- deazaadenosine HO
OH
mine release, arachidonic acid release in rat leukemic basophils (64a, 65), and chemotactic response of human monocytes (225). Furthermore, c3Ado also decreases the number of $-adrenergic receptors on HeLa cells (143).
Phospholipid methylation and the biological processes are inhibited by concentrations of c3Ado at which nucleic acid and protein methylation are not affected (143). The effect of c3Ado on phospholipid biosynthesis in
244
UELAND
the
liver
Chiang
from
rat
and
et al. (51).
hamster
The
phosphatidylethanolamine
duced
when
is associated
choline
into
with
in the
findings
have
patocytes
(53)
and
remains
macrophage
or
itory
re-
hamster.
the
total
constant
made
in vitro
macrophages
and
The biosynthesis may become
by
The
incorporation
and
liver
been
is drastically
rat and
increased
It seems that phosphatidylcholine choline, the so-called Kennedy ation of phosphatidylethanolamine lated. choline
liver
into
phosphatidylcholine,
of phospholipids
ilar
is injected
investigated
of phospholipids
in the
c3Ado
inhibition
was
methylation
of
amount (51).
with
Sim-
cultured
neutrophils
he(224).
synthesis via CDPpathway, and N-methylare mutually regu-
of phosphatidylcholine de-repressed upon
via perturbation
CDPof
but
cell
effect not
c3AdoHcy
in
is not
formed
broken
human
blood
a valuable methylation a potent
suggestion
is supported
AdoHcy rather tion of neutrophil
by
in
vitro
data
showing
that
c3AdoHcy is an effective competitive inhibitor of phospholipid methylation in cell-free systems (53, 245). c3Ado is an inhibitor of phospholipid methylation in human platelets (155, 263). Stimulation of the platelets with agonists such as epinephrine, ADP, or thrombin decrease phospholipid methylation (262). The interpretation of these data from experiments with platelets is complicated by the finding that 3-deaza(±)aristeromycin, which inhibits phospholipid methylation in platelets, does not affect ulatory agents Differentiation
aggregation or secretion (53). of fibroblasts to fat
c3Ado. This nucleoside may possible role of phospholipid by
methyl
transfer
c3Ado response
reactions
is stimulated
be a tool for studying the methylation and other
in cellular
obesity
(47).
rapidly and reversibly, the synaptic retinal neurons and muscle fibers in A role of biological methylation in neurois also indicated by the finding that low
concentrations
of c3Ado
zation-dependent by
substantially
neurotransmitter
pheochromocytoma (230).
cells
by stim-
inhibits, between
culture (276). transmission
tiated
induced
cells,
the
and
simultaneous
However,
no
strict
enhance
release that
the
addition correlation
depolari-
from effect
of
cultured is poten-
homocysteine
between
inhibition
of phospholipid methylation or protein carboxymethylation and enhancement of transmitter release could be demonstrated. The small increase in cyclic AMP levels induced by c3Ado in these cells does not account for the effect on cellular exocytosis (231). These data from pheochromocytoma cells add a cautionary note to the use of c3Ado as a specific transmethylation inhibitor. Inhibition
was
demonstrated
chemotaxis seems to
This
ofchemotaxis
by
by c3Ado be mediated
conclusion
is based
of rabbit
O’Dea
et al.
neutrophils
(208).
by c3Ado Inhibition of
in a mouse macrophage by c3AdoHcy, and not
on the observation
that
affected
with
AdoMet
and
homocysteine.
is
metabolic
that
and
The
the
inhibition
by
similar
levels
and the inhibition of homocysteine
neutrophil functions carboxymethylation curves
for
of
inhibiof lymwith the
neu-
is more pronounced in the (324). Whereas inhibition of
roughly correlates (327), the disparity of c3Ado
mediated cytolysis and suggests the involvement in cytolysis (327). An
for
is associated
described
L-
curves
cellular
c3Ado
to those
of
response
increased
cytolysis events
c3Ado is lectin-
presence
dose
be
c3AdoHcy,
than c3AdoHcy is responsible functions (327). The inhibition
phocyte-mediated
response
by of the
suggests
may between
of AdoHcy,
enhanced
Comparison effects
trophils, presence
270).
relationship
buildup
in is
is also function of
c3Ado
cytolysis.
cellular
In
responsive
(187,
that
the
neutrophil-mediated
for these
from
suggested
studying
cells.
accumulate and c3AdoHcy
reactions and leukocyte functions. inhibitor of neutrophil chemotaxis
is associated and
for
Furthermore, these
mouse macrophages the phagocytic
is not
inhib-
AdoHcy
from
preparation
et al. (324) tool
to the
c3Ado.
c3AdoHcy to c3Ado,
by whereas
monocytes
Zimmerman
of phospholipid
This
cell
cells (3a). Phagocytosis inhibited by c3Ado,
to
in sonicates
synthesized
in
sensitive accumulates
response
AdoHcy and sensitive
inhibitors
(51).
is not
contrast, both intact macrophages
dependent
in vivo
which
on chemotaxis,
c3AdoHcy
phospholipid methylation by c3Ado (51, 53). In hamster liver administration of c3Ado induces the appearance of c3AdoHcy and the tissue level of AdoHcy remains essentially unaffected (48); this suggests that c3AdoHcy and AdoHcy are about equally effective as methylation
line,
of c3Ado
for
with inhibition between the
inhibition
of dose
of lymphocyte-
inhibition of carboxymethylation of other methylation reactions elevated level of cyclic AMP
is
inhibitory to lymphocyte-mediated cytolysis. Thus, the increase in cellular level of cyclic AMP induced by c3Ado may contribute to its effect on lymphocyte function (326). c3Ado totoxicity
(plus homocysteine of natural kifier
where methylation and nucleic acid, that
of phospholipids, is inhibited (153).
phospholipid
activation) cells (153). Investigation
thiolactone) (NK) cells
methylation
plays
a role into
the
inhibits the at concentrations
but not of protein The authors suggest
(and
phospholipase
in the recognition antiviral
stimulated by the observation inhibit virus replication (see
properties
the
bryn cells is inhibited exhibits antiviral activity virus, from (11).
cell line AdoHcy.
virus (11).
another
has
simian
virus
40,
by and
of Rous
of chick of Sindbis
stomatitis (49) in chick
c3Ado. Furthermore, against Herpes simplex RNA
type
was
of AdoHcy Bader et al.
reproduction
vesicular virus
of NK
of c3Ado
transformation The reproduction
embryo cells by this virus. virus, Newcastle disease virus, (7), and Gross murine leukemia
A2
function
that analogues section II C).
(7) reported that c3Ado inhibits sarcoma virus and malignant
cy-
C virus
virus emc3Ado type 1
isolated
cultured human acute myelogenous leukemia cells The oncogenic transformation induced by simian 40 and RNA type C virus is also inhibited by c3Ado Recently, Trager et al. (278) have shown that c3Ado antimalarial activity against Plasmodium falci-
245
s-ADEN08YLH0M0cYsTEINE
parum
in
useful
culture.
findings
These
chemotherapeutic
In conclusion, adenosine
agent
c3Ado
analogue
seems
that
point
in the
to
via
the
among the many effects be related to inhibition
exerted by c3Ado, of methylation, and
as
be questioned.
c3Ado
are
mediated
products ety
The
of this
of biological
some may not the specificity
inhibitor
exists
that
observed
with
of this diseases.
investigation of human
some
effects
of
metabolic wide van-
c3Ado
should
stim-
compound
as
a drug
to the
naturally
substrates
occurring
of AdoHcy purines
lites affect AdoHcy hydrolase, 5’-Deoxy-5’-methylthioadenosine formed from AdoMet during
and
at least
hydrolase,
other
cleotides is observed with half-maximal possibility more,
the
account lase
synthesis of the polyamines, and spermine (314), is an inactivator of AdoHcy hydrolase from human placenta, lymphoblasts (137), and erythrocytes (90). The inactivation of the enzyme by MTA obeys first order kinetics, shows satur-
on this regulation
ability
with
more,
the
to MTA,
adenosine
and
tive-site-directed ported for
AdoHcy
other
and
is irreversible.
against
(90).
These
mechanism adenosine
Further-
inactivation
data
suggest
of action analogues
by an
ac-
of MTA, as re(137). However,
MTA is a less potent inactivator than 2’-deoxyadenosine (90, 137), and it remains to be established whether cellular effects of MTA (218, 302) are related to inactivation of AdoHcy hydrolase. Adenine is a competitive inhibitor of AdoHcy hydrolase
from
enzyme
mouse
from
(251).
In
liver
(299)
human
addition,
and
an
lymphoblasts adenine
inhibitor
(134)
induces
of
and
a time
rat
the
brain
dependent,
reversible inactivation of the mouse liver enzyme (288, 299). The inactivation is partly inhibited by the presence of inorganic phosphate (288). The effect of adenine on AdoHcy hydrolase is in agreement with the finding that adenine
increases
lymphoblasts ever, high
the
cellular
(178) and concentrations
level
of AdoHcy
mouse lymphocytes of adenine are
elevate the cellular level of AdoHcy. This may be explained by rapid metabolism of adenine by cells or by insensitivity of the intracellular enzyme toward adenine. Thus, the physiological implication of the effect of adenine on AdoHcy hydrolase remains to be defined. Adenine nucleotides (AMP, ADP, and ATP) bind to
AdoHcy
hydrolase
tively
inhibit
These
metabolites
tion
of the
the purified
from enzyme
also enzyme
mouse
liver,
catalysis
induce
and (see
an
in vitro
also section
irreversible (288,
299).
an
in
response adenine
of nu-
of phosphate, (288). Thus the of AdoHcy
considered.
data
hy-
Furtherbe
taken
on AdoHcy
into hydro-
effect of AdoMet inconsistent. The
on the enzyme from with the observation
inhibitor
of the
rat
brain
calf liver (52) is that AdoMet is a enzyme
(251).
Fur-
AdoHcy hydrolase and the inhibitor
K)
for
for
AdoMet
observation, of AdoHcy induces
human
in that Km for adenosine
The
product
Km
dependent
in-
(131).
This
is a substrate liver, plants
reaction
reaction,
is very
1000
for inosine is about and Vmax iS 40 times
been demonstrated reactions, but this
Based
AdoMet in the was suggested
phosphate
In addition, inosine purified from beef
of the
AdoHcy.
role of activity
hydrolase isolated from human inhibition of the enzyme in intact and lymphoblastoid cells (131) has
placenta
cient than
equals
a possible hydrolase
a reversible,
of AdoHcy Moderate erythrocytes
been demonstrated. AdoHcy hydrolase and
on AdoHcy hydrolase finding of no inhibitory
it has been reported that liver is inhibited by AdoMet,
Inosine
times
smaller
for (36), ineffi-
higher (36, 130).
S-inosylhomocysteine,
to be an inhibitor
compound
has
of methyl
is a relatively
transfer
weak
inhibi-
tor compared to AdoHcy and several other AdoHcy analogues (14, 58, 60, 320). Zimmerman et al. (325) have reported that S-inosylhomocysteine is formed in intact mouse lymphocytes exposed to exogeneous inosine. The possible
effects
of
S-inosylhomocysteine
cellular functions under normal tions deserve further attention.
V. Inborn
in human
(325). Howrequired to
the and
should
in vitro
to the
are
(288).
activation placenta. human
is protected
be
of phosphate
comparing
Data on the seem somewhat
(281).
respect
on
as a modulator should
counter-
points
nucleotides
at low concentrations effect at 2 to 5 mM
presence
constant product
are
which
phosphate to adenine
in vivo
when
enzyme
(288), of the
of phosphate activity
thermore, from rat
metabo-
in vitro. (MTA), a
of the
phosphate
possibility that the effect vitro phenomenon. The effect of inorganic purified AdoHcy hydrolase
spermidine,
enzyme
inactivation
inorganic
competitive
addition
various
and by
effect of AdoMet not in agreement
D. Metabolites
In
inhibition
drolase
should
by hitherto unrecognized compound. Nevertheless, the
effects
ulate further for treatment
hydrolase
methylation. c3Ado the regulation and reactions. However,
a transmethylase
possibility
a
stable
AdoHcy
of biological for studying methylation
compound
as
acted
to be a metabolically
acts
reaction as an inhibitor may be a useful tool physiological role of
of this
c3Ado
future.
formation
and
pathological
of Purine
Errors
in condi-
Metabolism
Some defects of purine metabolism are associated with immunodeficiency disease. Severe combined immunodeficiency disease is a uniformly fatal inherited disorder characterized by failure of development of specific cel-
lular
and
humoral
demonstrated ciency in certain 195)
immunity. in 1972 individuals
Giblett
and
adenosine with this
coworkers deaminase disease.
(105, defiAnother
competiIII G).
inherited immunodeficiency disease with defects in cellular immunity and relatively normal humoral immunity has later been shown by Giblett and coworkers (106) to
inactiva-
be
Both
the
linked
patients
to nucleoside with
the
phosphorylase
neurological
disease,
deficiency.
Some
Lesch-Nyhan
syn-
246
UELAND
drome, have subtle abnormalities tion (4). The disease is associated salvage enzyme, hypoxanthine-guanine transferase.
Furthermore,
an
adenine phosphoribosyltransferase found in erythrocytes from disease
(259).
The
of B-lymphocyte with
pathogenesis
of purmne
high
level
activity afflicted
patients of these
of
has been with this
abnormalities
of adenosine
deaminase
has
the
concentration
urine,
of AdoHcy
should be Preliminary
orders. been
published
(199a),
but
further
the
synthetic
(264).
The
is increased
phate
and
most
abundant
these
concentration (200), but
deoxyadenosine
5’-diphosphate
nucleotides
patients
in
(55, 56, 70). The
metabolism
(38)
of ATP deoxyadenosine
indicates
in the seem
the
abnormal
Data
cited
in section
mechanism
for
interference
IV point the
toxic
to be the from
deoxynucleotide
with
DNA
thesis (55). However, Simmonds et al. (264) that 2’-deoxyadenosine may be a metabolite proliferating cells of lymphoid origin. dent
erythtnphos-
erythrocytes
syn-
suggested toxic
to
to a nucleotide-indepeneffect
of adenosine
and
2-
deoxyadenosine. AdoHcy hydrolase seems to be a target enzyme for these metabolites (132). Hershfield et al. (136) demonstrated deficiency of AdoHcy hydrolase in the erythrocytes of three adenosine deaminase-deficient patients,
thereby
indicating
a
secondary
inactivation
of
AdoHcy
hydrolase. This observation was confirmed by and Fox (169), who also found low AdoHcy hydrolase activity in erythrocytes from patients with purine nucleoside phosphorylase deficiency, and from patients lacking hypoxanthine-guanine phosphoribosyltransferase. Besides 2’-deoxyadenosine, no compounds known to accumulate in these metabolic disorders were found by these workers to inactivate AdoHcy hydrolase in extracts from erythrocytes. Furthermore, the enzyme shows a normal half-life in Lesch-Nyhan syndrome (169). However, inosine inactivates AdoHcy hydrolase in the presence of phosphate. This finding may offer an explanation for the AdoHcy hydrolase deficiency in purine nucleoside phosphorylase and hypoxanthine-guanine Kaminska
phosphoribosyltransferase-deficient
A lymphoblastoid cell a patient with adenosine These contain
cells
adenosine
(131).
has been established from deaminase deficiency disease. deaminase (ADA-cells), and AdoHcy hydrolase activity in
line
60% of the deaminase positive lymphoblastoid cells (ADA+ cells). Cells from relatives of the patient are partially deficient in adenosine deaminase, but have normal AdoHcy hydrolase activity. The ADA-cells are more sensitive to the inhibitory effect of exogenous 2’deoxyadenosine on AdoHcy hydrolase, cell growth, and immunoglobulin production than the ADA+ cells (283a). These data favor a role of AdoHcy hydrolase in the adenosine
about
lack
patients
disease.
VI.
e.g.
with these dishas recently
data
value
Summary
should
be
of urinary
pro-
AdoHcy
Conclusion
and
The product of the AdoMet-dependent tion reactions, AdoHcy, is a potent inhibitor of a number of transmethylases analogues
material,
in patients on this subject
vided to clarify the diagnostic level in immunodeficiencies.
urine
in biological
determined data
encouraged the investigation of the role of purine metabolism in immunofunction. Immunodeficiency disease and defects of purine metabolism are subjects of recent reviews (146, 196, 303). An increased level of adenosine in plasma has been reported in patients with adenosine deaminase deficiency (136, 200), and 2’-deoxyadenosine was demonstrated in rocytes
deficiency
As a consequence of a secondary inactivation of AdoHcy hydrolase in certain immunodeficiency diseases,
phosphoribosyl-
abnormally
discovery
func-
lack
of AdoHcy
are
transmethylanegative feedback in vitro. Some effective
inhibitors
of
certain methylation reactions, and these compounds may exhibit antivirus and oncostatic properties. Inhibition of biological methylation is also observed in the presence of adenosine analogues, which may serve as inhibitors or substrates the basis
for AdoHcy of the concept
hydrolase. of AdoHcy
This observation forms hydrolase as a target
for adenosine analogues with cytotoxic effects. Perturbation of biological methylation may contribute to the antiviral and oncostatic properties of some adenosine analogues.
AdoHcy
for the
design
hydrolase
Acknowledgments. were
The
supported
Science
by
and
Nordisk author
the
script
and
many
workers
valuable in
this
assistance
R.
suggestions, field
of
for
Mona
for
and and
having
for
Cancer, fond.
read
to thankfully
the
The manu-
acknowledge in
is highly
article
Fighting
manuscripts
Haldorsen
this Council
Langfeldts
for
providing
future.
in
Research
Society
Scheline
enzyme
in the
referenced
Medisinaldepot
Ronald
a useful
Norwegian
Norwegian
Norsk
to thank
the
be
agents studies
from
Humanities,
offering
secretarial
author’s
grants
Insulinfond, wishes
may
of chemotherapeutic
The
press.
appreciated.
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