CHAPTER 6

Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham

Garrett and Grisham, Biochemistry, Third Edition

Essential Question • What principles underlie the integration of catabolism and energy production with anabolism and energy consumption? How is metabolism integrated in complex organisms with multiple organ systems?


Outline • Can Systems Analysis Simplify the Complexity of Metabolism? • What Underlying Principle Relates ATP Coupling to the Thermodynamics of Metabolism? • Can Cellular Energy Status Be Quantified? • How Is Metabolism Integrated in a Multicellular Organism?


27.1 – Can Systems Analysis Simplify the Complexity of Metabolism?

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Catabolic and anabolic pathways, occurring simultaneously, must act as a regulated, orderly, responsive whole See Figure 27.1 - catabolism, anabolism and macromolecular synthesis Just a few intermediates connect major systems sugar-Ps, alpha-keto acids, CoA derivs, and PEP ATP & NADPH couple catabolism & anabolism Phototrophs also have photosynthesis and CO2 fixation systems Garrett and Grisham, Biochemistry, Third Edition

Figure 27.1 Block diagram of intermediary metabolism.


27.2 – What Underlying Principle Relates ATP Coupling to the Thermodynamics of Metabolism? Three types of stoichiometry in biological systems • Reaction stoichiometry - the number of each kind of atom in a reaction • Obligate coupling stoichiometry - the required coupling of electron carriers • Evolved coupling stoichiometry - the number of ATP molecules that pathways have evolved to consume or produce - a number that is a compromise, as we shall see Garrett and Grisham, Biochemistry, Third Edition

The Significance of 38 ATPs The "ATP stoichiometry" has a large effect on the Keq of a reaction • Consider glucose oxidation (page 932) • If 38 ATP are produced, cellular ∆G is -967 kJ/mol and Keq = 10170, a very large number! • If ∆G = 0, 58 ATP could be made, but the reaction would come to equilibrium with only half as much glucose oxidized as we could have had • So the number of 38 is a compromise!


Nature of the ATP Equivalent A different perspective • ∆G for ATP hydrolysis says that at equilibrium the concentrations of ADP and Pi should be vastly greater than that of ATP • However, a cell where this is true is dead • Kinetic controls over catabolic pathways ensure that the [ATP]/[ADP][Pi] ratio stays very high • This allows ATP hydrolysis to serve as the driving force for nearly all biochemical processes Garrett and Grisham, Biochemistry, Third Edition

Significance of large Keq The more ATP obtained, the lower the equilibrium constant, and the higher the level of glucose required • If [glucose] is below this value, it won't be effectively utilized • Large Keq means that this threshold level of glucose will be be very low • Large Keq also means that the reaction will be far from equilibrium and can thus be regulated Garrett and Grisham, Biochemistry, Third Edition

The ATP Equivalent

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What is the "coupling coefficient" for ATP produced or consumed? Coupling coefficient is the moles of ATP produced or consumed per mole of substrate converted (or product formed) Cellular oxidation of glucose has a coupling coefficient of 30-38 (depending on cell type) Hexokinase has a coupling coefficient of -1 Pyruvate kinase (in glycolysis) has a coupling coefficient of +1 Garrett and Grisham, Biochemistry, Third Edition

The ATP Value of NADH vs NADPH • The ATP value of NADH is 2.5-3 • The ATP value of NADPH is higher • NADPH carries electrons from catabolic pathways to biosynthetic processes • [NADPH]>[NADP+] so NADPH/NADP+ is a better e- donating system than NADH/NAD+ • So NADPH is worth 3.5-4 ATP! Garrett and Grisham, Biochemistry, Third Edition

Unidirectionality of Pathways A "secret" role of ATP in metabolism • Both directions of any pair of opposing pathways must be favorable, so that allosteric effectors can control the direction effectively • The ATP coupling coefficient for any such sequence has evolved so that the overall equilibrium for the conversion is highly favorable


27.3 – Can Cellular Energy Status Be Quantified? • • • •

‘Energy Charge’ Adenylates provide phosphoryl groups to drive thermodynamically unfavorable reactions Energy charge is an index of how fully charged adenylates are with phosphoric anhydrides If [ATP] is high, E.C.→1.0 If [ATP] is low, E.C.→ 0 Garrett and Grisham, Biochemistry, Third Edition

Figure 27.2 Relative concentrations of AMP, ADP, and ATP as a function of energy charge. (This graph was constructed assuming that the adenylate kinase reaction is at equilibrium and that ∆G°' for the reaction is -473 J/mol; Keq = 1.2.)


Figure 27.3 Responses of regulatory enzymes to variation in energy charge. Enzymes in catabolic pathways have as their ultimate metabolic purpose the regeneration of ATP from ADP. Such enzymes show an R pattern of response to energy charge. Enzymes in biosynthetic pathways utilize ATP to drive anabolic reactions; these enzymes follow the U curve in response to energy charge.


Figure 27.4 The oscillation of energy charge (E.C.) about a steady-state value as a consequence of the offsetting influences of R and U processes on the production and consumption of ATP. As E.C. increases, the rates of R reactions decline, but U reactions go faster. ATP is consumed, and E.C. drops. Below the point of intersection, R processes are more active and U processes are slower, so E.C. recovers. Energy

charge oscillates about a steady-state value determined by the intersection point of the R and U curves.


27.4 – How Is Metabolism Integrated in a Multicellular Organism?


Figure 27.5 Metabolic relationships among the major human organs: brain, muscle, heart, adipose tissue, and liver.


Fueling the Brain • Brain has very high metabolism but has no fuel reserves • This means brain needs a constant supply of glucose • In fasting conditions, brain can use βhydroxybutyrate (from fatty acids), converting it to acetyl-CoA in TCA • This allows brain to use fat as fuel!


Figure 27.6 The structure of β-hydroxybutyrate and its conversion to acetyl-CoA for combustion in the citric acid cycle.


Creatine Kinase in Muscle • Muscles must be prepared for rapid provision of energy • Creatine kinase and phosphocreatine act as a buffer system, providing additional ATP for contraction • Glycogen provides additional energy, releasing glucose for glycolysis • Glycolysis rapidly lowers pH, causing muscle fatigue Garrett and Grisham, Biochemistry, Third Edition

Figure 27.7 Phosphocreatine serves as a reservoir of ATP-synthesizing potential. When ADP accumulates as a consequence of ATP hydrolysis, creatine kinase catalyzes the formation of ATP at the expense of phosphocreatine. During periods of rest, when ATP levels are restored by oxidative phosphorylation, creatine kinase acts in reverse to restore the phosphocreatine supply.


Muscle Protein Degradation • During fasting or high activity, amino acids are degraded to pyruvate, which can be transaminated to alanine • Alanine circulates to liver, where it is converted back to pyruvate - food for gluconeogenesis • This is a fuel of last resort for the fasting or exhausted organism


Figure 27.8 The transamination of pyruvate to alanine by glutamate:alanine aminotransferase.


Figure 27.9 Metabolic conversions of glucose-6-phosphate in the liver.
