Signalling functions of coenzyme A and its derivatives in ... - CiteSeerX

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Signalling functions of coenzyme A and its derivatives in mammalian cells Hongorzul Davaapil*, Yugo Tsuchiya* and Ivan Gout*1 *Institute of Structural and Molecular Biology, University College London, Gower Street, London WC1E 6BT, U.K.

Abstract In all living organisms, CoA (coenzyme A) is synthesized in a highly conserved process that requires pantothenic acid (vitamin B5 ), cysteine and ATP. CoA is uniquely designed to function as an acyl group carrier and a carbonyl-activating group in diverse biochemical reactions. The role of CoA and its thioester derivatives, including acetyl-CoA, malonyl-CoA and HMG-CoA (3-hydroxy-3-methylglutaryl-CoA), in the regulation of cellular metabolism has been extensively studied and documented. The main purpose of the present review is to summarize current knowledge on extracellular and intracellular signalling functions of CoA/CoA thioesters and to speculate on future developments in this area of research.

Introduction CoA is a ubiquitous and obligatory cofactor that is produced in all living organisms by a highly conserved pathway involving five enzymatic steps requiring pantothenic acid (vitamin B5 ), cysteine and ATP [1]. The unique structure of CoA allows it to function as a master acyl group carrier and carbonyl-activating group [2], resulting in a diverse range of metabolically active thioester derivatives, including acetyl-CoA, malonyl-CoA and HMG-CoA (3-hydroxy-3methylglutaryl-CoA) (Figure 1). The levels of CoA and its derivatives in mammalian cells and tissues are tightly regulated by various extracellular stimuli, including nutrients, hormones and cellular metabolites. It has been demonstrated that the total level of CoA is reduced in response to insulin, glucose, fatty acids and pyruvate, whereas glucagon and glucocorticoids have an opposite effect [3,4]. The changes in the level of CoA occur with fasting, re-feeding and several pathological conditions, such as diabetes, cancer and cardiac hypertrophy [2]. Moreover, the ratio between CoA and its thioester derivatives is important for cellular homoeostasis. The subcellular distribution of CoA in mammalian cells reflects the variety of processes in which it is implicated. The concentration of CoA in mitochondria and peroxisomes is estimated to be in the range 2–5 mM and 0.7 mM respectively. The level of cytosolic CoA is significantly lower, ranging from 0.05 mM to 0.14 mM [5,6]. CoA is regarded as a coenzyme of metabolic integration. CoA and its derivatives are implicated in the catabolism of proteins, carbohydrates and lipids via metabolic reactions that allow the energy from food to be released in the form of acetyl-CoA. CoA/CoA derivatives are key components in Key words: cellular function, coenzyme A (CoA), mammalian cell, signalling pathway. Abbreviations: CaMBD, calmodulin-binding domain; CaMKII, Ca2 + /calmodulin-dependent protein kinase II; CoASSG, CoA–glutathione disulfide; GPCR, G-protein coupled receptor; HAT, histone acetyltransferase; KATP channel, ATP-sensitive K + channel; LC-acyl-CoA, long-chain acylCoA; LPC, lysophosphatidylcholine; PKC, protein kinase C; SUR1, sulfonylurea receptor type 1; VSMC, vascular smooth muscle cell. 1 To whom correspondence should be addressed (email [email protected]).

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the tricarboxylic acid cycle and diverse anabolic processes, including biosynthesis of lipids, amino acids, ketone bodies, cholesterol and steroid hormones, and neurotransmitter acetylcholine [7–10]. In contrast with the overwhelming number of publications on the importance of CoA/CoA derivatives in cellular metabolism, their role in the regulation of signalling proteins and signal transduction pathways has not been adequately addressed. It is the aim of the present review to summarize current knowledge and to discuss future perspectives and challenges in understanding signalling functions of CoA/CoA thioesters.

Extracellular functions of CoA/CoA thioesters If CoA and its derivatives have the potential to function as extracellular signalling molecules, there are two logical questions to address: (i) how are CoA/CoA derivatives released into the extracellular space; and (ii) what is the nature of cellular receptors which can bind CoA/CoA derivatives in a specific mode and activate signalling pathways controlling cellular functions. To our knowledge, it is the established view that CoA and its derivatives are large charged molecules which do not cross the plasma membrane of viable cells. Taking into account that the ADP moiety is an integral part of CoA, it is appropriate to discuss in brief the huge amount of research into extracellular signalling by ATP and other purine nucleotides. Extracellular functions of ATP were revealed for the first time nearly ¨ 100 years ago, when Drury and Szent-Gyorgyi [11] reported that extracellular purines were responsible for a dilatation of coronary vessels. Since that time, specific receptors for purines have been discovered, the modes of ATP release into the extracellular space identified and signalling mechanisms to various cellular processes defined. It is now well-established that the release of intracellular ATP and other purines can occur through cytolysis, exocytosis and active transport Biochem. Soc. Trans. (2014) 42, 1056–1062; doi:10.1042/BST20140146

Coenzyme A and Its Derivatives in Cellular Metabolism and Disease

Figure 1 Chemical structures of CoA and key derivatives HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA.

Figure 2 The role of CoA and its thioesters in extracellular and extracellular signalling. aPKC, atypical PKC; nPKC, novel PKC.

[12]. There is evidence that ATP is released from damaged cells and blood platelets during conditions such as heart attack, hypertension and artherosclerosis [13]. Taking into account that CoA/CoA derivatives are present in appreciable amounts in mammalian cells and tissues, especially in heart and liver [2], one might expect that these metabolites can be released into the extracellular space following cell membrane damage or cell death and modulate the function of cell-surface receptors. Exocytosis of intracellular CoA/CoA thioesters may represent one of the physiological modes of release, which is well documented for ATP, ADP and other purines

in neuronal and non-neuronal cells in response to certain physiological stimuli [12]. It has been known for a long time that some secretory vesicles contain, in addition to catecholamine neurotransmitters, large quantities of ATP [14]. The release of ATP by vascular endothelial cells under conditions of high shear stress has also been characterized [15,16]. To our knowledge, the presence of CoA and its derivatives in exocytotic vesicles has not been reported so far. The ability of the ATP-binding cassette proteins, including CFTR (cystic fibrosis transmembrane conductance regulator), to transport ATP into the extracellular space has  C The

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been reported [17,18]. To date, no studies have been published describing the active transport of CoA/acyl-CoA out of mammalian cells. In the literature, there are thousands of papers describing the structure, binding specificities, activation modes and downstream signalling of purinergic receptors [19]. In contrast, a handful of papers have been published to date on extracellular signalling by CoA/acyl-CoA implicated mainly in the regulation of platelet aggregation and vasoconstriction [20–23].

Regulation of platelet aggregation by CoA and its thioesters The first report describing signalling function of CoA/acylCoA was published by Lin et al. in 1976 [20]. The authors investigated the effects of CoA and a range of LC-acyl-CoAs (long-chain acyl-CoAs) on platelet function. A significant inhibition of platelet aggregation in response to ADP, collagen and epinephrine was observed in the presence of palmitoylCoA and other LC-acyl-CoAs. Notably, the inhibitory effect of LC-acyl-CoAs was more pronounced than that of free CoA. Furthermore, the inhibition of platelet aggregation induced by LC-acyl-CoAs was reversed by the addition of excess ADP. Later, in 1988, Lascu et al. [21] reported the inhibition of ADP- and thrombin-induced platelet aggregation by LCacyl-CoAs. The logic of this study was based on two facts: (i) phospholipid composition is significantly altered in the process of platelet activation, including the release of arachidonic acid from phosphatidylcholine and phosphatidylinositol as well as the production of LPC (lysophosphatidylcholine) and diacylglycerol [24–26]; (ii) fatty acids are incorporated into platelet phospholipids by the CoA-mediated metabolic pathway and acyl-CoA functions as a donor of acyl groups for LPC [27]. Therefore the authors anticipated that CoA and acyl-CoA may influence platelet function. Indeed, LC-acylCoA esters, oleoyl-CoA, linoleoyl-CoA and arachidonoylCoA were shown to produce a concentration-dependent inhibition of ADP-induced platelet aggregation. Purified preparations of platelets obtained from healthy donors were used in these studies. Furthermore, arachidonic acid-induced aggregation of platelets was also inhibited, but not the slower aggregation caused by the potent tumour promoter PMA. Notably, much higher concentrations of CoA and longer incubations with platelets were required to obtain inhibition of ADP- or thrombin-induced aggregation. As non-esterified (‘free’) fatty acids had no effect on platelet aggregation, even at a very high concentration, the authors speculated that: (i) both CoA and acyl components of LC-acyl-CoAs are required for mediating the inhibitory effect on platelet activation induced by ADP and thrombin; (ii) the inhibitory effect of LCacyl-CoAs on platelet aggregation is possibly mediated via enzymes or receptors (such as P2Y receptors) involved in the activation mechanism. A few years later, Coddou et al. [22] investigated the effect of hypolipidemic drug metabolites of CoA (nafenopin-CoA and ciprofibroyl-CoA) on the function of P2Y1 receptors  C The

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expressed in Xenopus laevis oocytes. In the course of their study, they found that nafenopin-CoA and ciprofibroylCoA, as well as palmitoyl-CoA, effectively antagonized the effect of ATP on Cl − currents mediated by P2Y1 receptors in oocytes. CoA and acetyl-CoA were shown to be less effective. In addition, nafenopin-CoA and ciprofibroyl-CoA showed little or no antagonism at P2Y2 , P2X2 , P2X4 and two 5HT (5-hydroxytryptamine) receptors. On the basis of these findings, the authors speculated that LC-acyl-CoAs have the potential to interact directly with the P2Y1 receptor through a mechanism that involves both the CoA group and the acyl tail, where the ADP moiety may occupy the ATP-binding pocket and the hydrophobic tail may bind to a groove adjacent to the ligand-binding pocket. Purinergic GPCRs (G-protein coupled receptors) found on the membranes of platelets can be stimulated by nucleotides to cause aggregation [28]. Manolopoulos et al. [23] hypothesized that CoA/acyl-CoAs may have an antagonistic role in regulating GPCR activation in the process of platelet activation. The authors performed a detailed investigation of the effects of CoA and several acyl-CoAs on platelet function by measuring platelet shape change using light scattering and Ca2 + mobilization and VASP (vasodilator-stimulated phosphoprotein) phosphorylation by flow cytometry. The inhibition of ADP-induced platelet aggregation by acyl-CoAs was concentration-dependent and most effective with compounds containing saturated acyl groups of 16–18 carbons in length. In addition, it was demonstrated that unsaturated LC-acyl-CoA and CoA are less effective inhibitors of ADP-induced platelet aggregation, indicating that the hydrophobic moiety and its composition are critical for efficient inhibition. Since LC-acyl-CoA compounds inhibited platelet aggregation induced by ADP, but not other agonists, the role of P2Y1 receptors in mediating the inhibitory effect was investigated. In this context, the effect of P2Y1 and P2Y2 antagonists MRS-2179 and ARC69931 was examined on ADP-induced platelet aggregation in the presence or absence of LC-acyl-CoA compounds. These studies revealed that the palmitoyl-CoA inhibitory effect is mainly mediated via P2Y1 receptors. In addition, a partial antagonism was also observed via P2Y12 receptors with no involvement of P2X1 receptors.

CoA–glutathione heterodimer enhances vasoconstriction Another instance of CoA acting as an extracellular signalling molecule is in the context of vasoconstriction [29]. VSMCs (vascular smooth muscle cells) participate in the contraction and relaxation of vascular smooth muscle. They are most notably found lining arteries. Cardiovascular disorders, such as hypertension, are caused by excessive vasoconstriction due to an increase in volume and proliferation of VSMCs [30]. ATP and ADP are known stimulators of DNA synthesis and cell proliferation in cultured VSMCs, and these cellular effects are mediated via P2 purinergic receptors [31]. In a search for a parathyroid-derived vasoconstrictive factor, Jankowski et al. [29] isolated and identified CoASSG

Coenzyme A and Its Derivatives in Cellular Metabolism and Disease

(CoA–glutathione disulfide). In their study, they showed that in addition to ATP and ADP, synthesized and purified CoASSG can act as a renal vasoconstrictor by increasing the proliferation of VSMCs in a dose-dependent manner. In contrast, glutathionate on its own had no effect on VSMC proliferation. Notably, CoASSG-induced proliferation of VSMCs was significantly inhibited by purinergic receptor antagonists DMPX [3,7-dimethyl-1-(2propargyl)xanthine] and PPADS (pyridoxal-phosphate-6azophenyl-2 ,4 -disulfonic acid), indicating that the proliferative effect of CoASSG is enabled via signalling pathways mediated by P2 receptors. There are several reasons that CoA may act in concert with ATP after injury. First, the effect of CoA on vasoconstriction is in contrast with the antagonistic function of LC-acylCoA in platelet function, where the CoA derivatives inhibit the function mediated by ATP and ADP. ATP is released in large amounts from platelets and damaged cells in conditions such as ischaemia and hypertension, and affects a variety of processes, including both platelet function and vasoconstriction [13]. In the context of injury, CoA is presumably released alongside ATP from damaged cells and enhances ATP’s role in vasoconstriction. This is possibly to avoid excessive blood loss during injury. Meanwhile, it also acts as a competitive inhibitor of platelet aggregation, perhaps preventing the formation of excessive blood clots. Hence CoA may fine-tune the function of ATP during injury, maintaining balance between blood loss and clots. Secondly, CoA may subsequently be degraded after release to its constituent molecules, which would then be utilized.

CoA/CoA thioesters as intracellular signalling molecules A diverse range of intracellular proteins have been found to interact with and to be regulated by CoA and its derivatives. Most of them are implicated in metabolic pathways where CoA/acyl-CoAs function as substrates or regulators of enzymatic reactions. Studies of the regulation of intracellular signalling by CoA/CoA derivatives are infrequent and not always followed up to advance the knowledge. In the present review, we discuss some of these regulatory interactions and their relevance in the regulation of signal transduction pathways and cellular functions.

Regulation of insulin release via the ATP-sensitive K + channel Glucose-induced insulin secretion is linked to the metabolic state of the pancreatic β-cells and signal transduction pathways. The KATP channel (ATP-sensitive K + channel) couples glucose metabolism to electrical activity and insulin secretion in β-cells [32]. Intracellular ATP and ADP are known to inhibit or stimulate channel activity respectively. Under high-energy conditions, when the ATP/ADP ratio is high, the KATP channel is inhibited, leading to depolarization and activation of voltage-dependent Ca2 + channels, and

insulin secretion. Larsson et al. [33] demonstrated that total CoA and LC-acyl-CoA levels increase significantly in response to prolonged exposure of cells to non-esterified fatty acids [33]. In addition, LC-acyl-CoA esters were found to induce a rapid and potent opening of KATP channels and to counteract the blocking effect of ATP. The induction of KATP channels by LC-CoA esters requires the presence of both the fatty acid tail and the CoA moiety. It was also shown that the ideal activators are C14–C18 saturated or unsaturated LC-acyl CoA molecules, whereas no stimulatory effect was observed with fatty acids alone, CoA or short-chain CoA esters. The KATP channel is a complex of the pore-forming Kir6.2 and SUR1 (sulfonylurea receptor type 1) [34]. The inhibitory effect of ATP on the KATP channel is mediated by specific association with Kir6.2, whereas sulfonylurea and ADP interact with SUR1 [35]. Larsson et al. [33] confirmed the activation of the KATP channel by LC-acyl-CoA and found that Kir6.2 possesses an intrinsic LC-acyl-CoA stimulatory site. Interestingly, the site of interaction for LC-acyl-CoA esters was found to be different from that of ATP. Moreover, mutational analysis of Kir6.2 revealed that Lys332 is critical for its interaction with LC-acyl-CoA, as the K332A mutant is not stimulated by LC-acyl-CoA [36]. On the basis of these findings, the authors proposed that the binding of LCacyl-CoA esters to the pore-forming subunit may induce a conformational change which allows the pore to remain open for longer periods of time. Indeed, elevated LC-acylCoA levels have been described in obese individuals, or those suffering from Type 2 diabetes who have impaired glucosestimulated insulin secretion, reinforcing the non-canonical metabolic role of acyl-CoAs [37,38].

Regulation of protein kinases by CoA/acyl-CoAs It has been reported that CoA and its derivatives associate with and regulate the activity of several protein kinases implicated in signal transduction. Low-micromolar concentrations of LC-acyl-CoAs were shown to strongly inhibit the activity of PKC (protein kinase C) purified from bovine neutrophils [39]. The authors noted that the inhibitory effect of LC-acyl CoAs was strongest with chain lengths of 16 to 20 carbons. Notably, palmitic acid and free CoA did not exhibit any inhibitory effect even at very high concentrations, indicating that the integrity of the LC-acyl-CoA is required for inhibition. The authors proposed that the acyl chain moiety of LC-acyl-CoA interacts with the lipid regulatory domain of PKC in the same manner as activating lipids, such as diacylglycerol and phosphatidylserine, whereas the CoA moiety mediates specific interactions with the ATPbinding site. Therefore double occupancy of both the lipid domain and the ATP-binding site of PKC by LC-acylCoAs is required for specific inhibition of the enzyme. In a more recent study, Yaney et al. [40] found that LCacyl-CoAs differentially regulate the activity of different PKC class isoforms. The authors observed that the activity of atypical PKC was strongly activated by myristoylCoA, palmitoyl-CoA and oleoyl-CoA. In contrast,  C The

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myristoyl-CoA and oleoyl-CoA caused inhibition of novel PKC, whereas palmitoyl-CoA only had a weak stimulatory effect, highlighting the diversity of LC-acyl-CoAs as potential allosteric regulators. The role of CoA in the regulation of apoptosis in Xenopus laevis oocytes mediated by specific activation of CaMKII (Ca2 + /calmodulin-dependent protein kinase II) has been reported recently [41]. CaMKII is regulated by the Ca2 + /calmodulin complex and functions in many signalling cascades ranging from learning and memory to the exit from mitosis [42,43]. The activation of CaMKII involves the autophosphorylation at Thr286 induced by Ca2 + /calmodulin binding [44]. It is known that phosphorylation of caspase 2 by CaMKII inhibits apoptosis of vertebrate oocytes in response to nutrient deprivation [45]. The authors found that when CoA was added to purified Xenopus CaMKII and caspase 2, there was increased phosphorylation of caspase 2. MD and mutational studies revealed that a patch of positively charged residues (Lys292 , Arg296 and Lys300 ) in the CaMBD (calmodulin-binding domain) mediates specific interaction with CoA. It was hypothesized that the binding of CoA to CaMBD increases the local conformational flexibility of the protein, facilitating its interaction with Ca2 + /calmodulin, subsequent activation and downstream signalling. CaMKII activation by CoA was independent of an increase in cytosolic Ca2 + , suggesting the involvement of a novel non-canonical pathway. One drawback of this study is that high (millimolar) non-physiological concentrations of CoA were used to demonstrate the activation of CaMKII and phosphorylation of caspase 2. The concentration of cytosolic CoA in cells and tissues is significantly lower and ranges between 0.02 and 0.14 mM. Furthermore, the concentration of total shortchain acyl-CoA in Xenopus embryo extracts is in the low-micromolar range and the CoA/acetyl-CoA ratio does not change significantly at earlier stages of embryonic development [46].

Role of CoA thioesters in post-translational modifications of proteins The function of CoA esters as the acyl group donors for protein modifications has been studied extensively. In the last decade, the landscape of reversible lysine modifications by small acyl groups, known as acylation, has significantly expanded [47–49]. Protein lysine acylation is mediated by acyltransferases, commonly known as HATs (histone acetyltransferases). Although HATs were initially thought to catalyse the transfer of acetyl groups, it has been shown recently that they are also capable of transferring other short-chain acyl groups, such as acetyl, malonyl, butyryl, propionyl and glutaryl, to lysine residues from acyl-CoAs [49,50]. These reversible modifications neutralize the positive charge of lysine residues and modulate protein function in diverse ways, including subcellular localization, stability, enzymatic activity and the formation of regulatory complexes. Protein lysine acetylation was discovered nearly half a century ago and has been regarded  C The

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for many years as a key regulatory mechanism in chromatin remodelling and gene expression. Recent advances in MS have revealed thousands of acetylated proteins involved in diverse cellular processes, including chromatin remodelling and transcription, cytoskeletal rearrangement, metabolic regulation and cell signalling. In addition to lysine acetylation, studies from various laboratories have recently revealed malonylation, butyrylation, propionylation, succinylation and glutarylation of lysine residues in a diverse range of cellular proteins, including those implicated in signalling pathways [48,49,51–53]. The physiological relevance of these modifications remains to be elucidated.

Conclusion and future prospects In summary, a more thorough investigation is required to shed light on one of the least studied aspects of CoA function, namely extracellular and intracellular signalling. In particular, it will be important to determine whether CoA/CoA esters can be released from viable cells of different types in a regulated manner. In this regard, the detection of CoA/CoA esters in platelet granules and synaptic vesicles is of importance. There are over 500 members of the family of GPCRs and endogenous ligands for more than 100 receptors remain unknown. It is plausible to speculate that CoA or its derivatives may function in the extracellular space as specific ligands for some of these ‘orphan’ receptors. Molecular docking, MD (molecular dynamics) simulation, and a range of biochemical and biophysical studies may facilitate these tasks. Future studies should also uncover the relative contribution of CoA/CoA derivatives to the regulation of signal transduction pathways mediated by direct interaction and modulation of signalling proteins. Further insights into the role of CoA/CoA esters in regulating diverse signalling pathways may prove beneficial to develop therapies that specifically target human pathologies with dysregulation of CoA biosynthesis or CoA thioester homoeostasis.

Funding Research was supported by the University College London Business (UCLB) proof-of-concept (PoC) funding [UCLB grant numbers PoC11-018 and PoC-13-014]. H.D. is supported by a Medical Research Council Ph.D. scholarship.

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53 Xie, Z., Dai, J., Dai, L., Tan, M., Cheng, Z., Wu, Y., Boeke, J.D. and Zhao, Y. (2012) Lysine succinylation and lysine malonylation in histones. Mol. Cell. Proteomics 11, 100–107 CrossRef PubMed

Received 21 May 2014 doi:10.1042/BST20140146