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Coenzyme A biosynthetic machinery in mammalian cells David Lopez Martinez*, Yugo Tsuchiya* and Ivan Gout*1 *Institute of Structural and Molecular Biology, University College London, Gower Street, London WC1E 6BT, U.K.

Abstract CoA (coenzyme A) is an essential cofactor in all living organisms. CoA and its thioester derivatives [acetyl-CoA, malonyl-CoA, HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) etc.] participate in diverse anabolic and catabolic pathways, allosteric regulatory interactions and the regulation of gene expression. The biosynthesis of CoA requires pantothenic acid, cysteine and ATP, and involves five enzymatic steps that are highly conserved from prokaryotes to eukaryotes. The intracellular levels of CoA and its derivatives change in response to extracellular stimuli, stresses and metabolites, and in human pathologies, such as cancer, metabolic disorders and neurodegeneration. In the present mini-review, we describe the current understanding of the CoA biosynthetic pathway, provide a detailed overview on expression and subcellular localization of enzymes implicated in CoA biosynthesis, their regulation and the potential to form multi-enzyme complexes for efficient and highly co-ordinated biosynthetic process.

Introduction CoA (coenzyme A) was discovered in 1947 and 6 years later the Nobel Prize was awarded to F. Lipmann for this discovery. Since that time, CoA and a diverse range of its thioester derivatives have been the focus of intense investigations, which uncovered their essential roles in various pathways of cellular metabolism, post-translational modifications, signal transduction and gene expression, and dysregulation in human pathologies [1]. The biochemistry of CoA biosynthesis was deciphered more than 30 years ago and shown to be universal in all branches of life. Subsequently, the importance of CoA/CoA derivatives was uncovered for diverse cellular functions. These include the biosynthesis of fatty acids, ketone bodies and cholesterol [malonylCoA and HMG-CoA (3-hydroxy-3-methylglutaryl-CoA)], amino acid metabolism (propionyl-CoA and succinylCoA), fatty acid oxidation (acyl-CoA and acetyl-CoA), biosynthesis of neurotransmitter acetylcholine (acetyl-CoA), and acetylation of histones and regulation of gene expression (acetyl-CoA) [1–3]. Molecular cloning of genes for the CoA biosynthetic pathway, initially in bacteria and then in yeast and mammals, has provided researchers with essential tools for bioinformatics and mutational studies, expression of recombinant proteins and structural analysis, examining Key words: coenzyme A (CoA), coenzyme A biosynthetic complex, regulation, signalling pathway. Abbreviations: CAB/Cab, CoA biosynthesis; CoA, coenzyme A; COASY/CoAsy, CoA synthase; CoA-SPC, CoA-synthesizing protein complex; CoQ, coenzyme Q; DPCK, dephospho-CoA kinase; EDC4, enhancer of mRNA-decapping protein 4; IMM, inner mitochondrial membrane; LEU5, leucine biosynthesis 5; NBIA, neurodegeneration with brain iron accumulation; OMM, outer mitochondrial membrane; PanK/PANK, pantothenate kinase; PI3K, phosphoinositide 3-kinase; PLA, proximity ligation assay; PPAT, 4 -phosphopantetheine adenylyltransferase; PPCDC, 4 phosphopantothenoylcysteine decarboxylase; PPCS, 4 -phosphopantothenoylcysteine synthase; Shp2PTP, Src homology 2 domain-containing protein tyrosine phosphatase; Vhs3, viable in a Hal3 Sit4 background. 1 To whom correspondence should be directed (email [email protected]).

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subcellular localization of CoA biosynthetic enzymes, generation of transgenic animal models. The association of the CoA biosynthetic pathway with neurodegeneration in the beginning of this century has given a new dimension to this field of research. Initially, inactivating mutations in PANK2 (pantothenate kinase 2) [4,5] were linked to the NBIA (neurodegeneration with brain iron accumulation) disorder and, recently, COASY (CoA synthase) was also found to be a disease-associated gene in patients with NBIA [6]. In order for CoA to regulate such diverse cellular functions, its biosynthesis, CoA/CoA thioester ratio and degradation must be tightly regulated in different cellular compartments. There are several possibilities to consider for regulatory mechanisms, including (i) regulation of gene expression for the biosynthetic enzymes; (ii) post-translational modifications and activity regulation of CoA biosynthetic enzymes; (iii) changes in the compartmentalization; (iv) metabolic flux of CoA and its thioester derivatives; and (v) degradation of CoA [1].

Universal mechanism of CoA biosynthesis in all living cells CoA biosynthesis is highly conserved from prokaryotes to eukaryotes and proceeds in five enzymatic steps. It is initiated with pantothenate, which is more commonly known as vitamin B5. Plants, fungi and most bacteria can synthesize pantothenate de novo and only animals and some microbes need to obtain it from outside. Pantothenate is transported into cells through specific carriers such as a sodium co-transporter in bacteria, a hydrogen symporter in yeast or a sodium-dependent multivitamin transporter in the intestinal epithelium of mammals [1]. The first Biochem. Soc. Trans. (2014) 42, 1112–1117; doi:10.1042/BST20140124

Coenzyme A and Its Derivatives in Cellular Metabolism and Disease

Figure 1 Schematic diagram of a universal pathway for CoA biosynthesis and its key players in bacteria, yeast and mammals Dotted oval indicates components of the CoA-SPC described in yeast [12].

step in CoA biosynthesis is the phosphorylation of pantothenate by PanK. This step has been shown to be rate-limiting in most organisms and subjected to feedback regulation by CoA itself or its derivatives [7]. Generated 4 -phosphopantothenate is then condensed with cysteine at the expense of ATP (or CTP in bacteria) to yield 4 -phosphopantothenoylcysteine in a reaction catalysed by PPCS (4 -phosphopantothenoylcysteine synthase). Afterwards, PPCDC (4 -phosphopantothenoylcysteine decarboxylase) catalyses the decarboxylation of to generate 4 4 -phosphopantothenoylcysteine phosphopantetheine. This is followed by a second ratelimiting reaction in the pathway, which is the transfer of the AMP moiety of ATP to form dephospho-CoA by PPAT (4 -phosphopantetheine adenylyltransferase). Finally, the enzyme DPCK (dephospho-CoA kinase) phosphorylates dephospho-CoA, producing CoA (Figure 1) [1]. Some of these enzymatic activities are carried out by bifunctional enzymes, such as PPCS and PPCDC in bacteria [1] or PPAT and DPCK that constitute a unique enzyme in mammals called COASY (Figure 1) [8].

CoA biosynthetic machinery in bacteria, yeast and mammalian cells In bacteria, the nomenclature for the biosynthetic enzymes is CoaA, CoaBC (bifunctional enzyme), CoaD and CoaE for each of the steps previously discussed and presented in Figure 1. Furthermore, there are at least three types of CoaA (PANK): type I, II and III. Type I is expressed in Escherichia coli and is efficiently inhibited by CoA. Type II is found in Staphylococcus aureus and shares some homology with the mammalian PANK. It is not inhibited by CoA or its derivatives, which might underpin its role in

regulating the response to oxidative stress in these bacteria. A novel type III enzyme, encoded by CoaX, is present in many pathogenic bacteria. It lacks inhibition by CoA and constitutes a potential molecular target for the development of novel antibiotics [1,9]. The bacterial enzymes usually show quaternary structure: CoaA is a homodimer, CoaBC is a homododecamer, and CoaD and CoAE are trimers [1], but they do not seem to associate in multienzyme complexes, directing CoA biosynthesis. However, in the yeast Saccharomyces cerevisiae there is mounting evidence for the formation of such a complex. The genes encoding the five biosynthetic enzymes in yeast CAB1–CAB5 (where CAB is CoA biosynthesis) follow the universal CoA biosynthetic pathway (Figure 1). The formation of a multienzyme complex was first described for an alternative pathway to Cab1– Cab5, where ATP was transferred to pantothenate before phosphorylation [10]. Nevertheless, this alternative model was not subsequently confirmed because the CAB genes are essential for the cell and the E. coli gene CoaBC can individually complement Cab-null mutants, supporting the existence of a unique universal pathway for the synthesis of CoA. The next advance in the theory of a multienzyme complex for CoA biosynthesis was the discovery of a heterotrimeric PPCDC in yeast [11]. Unlike mammals and plants where PPCDC is a homotrimeric enzyme, in yeast it was found to be a heterotrimeric complex of Cab3 and two other related proteins Hal3 [also known as Sis2 (SIt4 suppressor)] and Vhs3 (viable in a Hal3 Sit4 background). In this complex, Hal3 and Vhs3 not only provide an essential catalytic residue for the PPCDC activity of Cab3, but also inhibit two protein phosphatases (Ppz1 and Ppz2), which are implicated in saline tolerance and cell-cycle progression [11]. This study presents one of the first examples of a potential cross-talk between CoA biosynthesis and  C The

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regulatory signalling pathways. Later, Olzhausen et al. [12] found that Cab3 was at the core of a much bigger complex, a CoA-SPC (CoA-synthesizing protein complex). They found that Cab3 and Cab5 co-fractionated in a gel-filtration assay as part of a complex of approximately 330 kDa and Cab3 was also able to interact with the other enzymes of the biosynthetic complex, except Cab1 [12]. Therefore Cab3 can be considered a protein scaffold for the CoA-SPC and the interaction with Cab1 may function as a regulatory event in the pathway. The identification of the CoA-SPC is the first evidence of the existence of a CoA biosynthetic complex and further studies are required to examine its composition and functionality in response to various stimuli and stresses. To our knowledge, there are no published studies to date describing the existence of a CoA biosynthetic complex in mammals. However, gel-filtration chromatography of rat brain extracts showed that CoAsy is eluted in two separate peaks: the lower molecular range peak of 60–150 kDa, possibly representing uncomplexed CoAsy, and a highmolecular-mass peak in the range of 450 kDa, where CoAsy may exist in complex with other cellular proteins, including those implicated in CoA biosynthesis [13]. Furthermore, specific interaction between the first and last enzymes of the CoA biosynthetic pathway, PanK1β and CoAsy, was demonstrated by PLA (proximity ligation assay), an antibody-based technique that allows detection of proteins ´ in close proximity in situ [14] (D. Lopez, unpublished work). In the literature, genetic and biochemical studies provide the evidence that enzymes implicated in the biosynthesis of another important cellular cofactor, CoQ (coenzyme Q), exist in a multi-subunit complex in yeast [15,16]. In contrast with CoA biosynthetic enzymes, all CoQ polypeptides possess a potential mitochondrial-targeting sequence, and fractionation studies revealed that they are associated with the matrix side of the IMM (inner mitochondrial membrane). It has been proposed that Coq2, which possesses six putative membrane-spanning motifs, may function as a scaffold for the formation of the CoQ biosynthetic complex [16]. Notably, it remains to be determined whether a multienzyme CoQ complex such as observed in yeast is also formed in mammalian cells. Subcellular localization of CoA biosynthetic enzymes in mammalian cells has been a matter of debate and intensive investigation in the last decade. The main efforts have been focused on studying the localization of two rate-limiting enzymes, PanK and CoAsy [7,8]. A comprehensive analysis on the compartmentalization of the PanK isoforms has revealed a complex pattern of their subcellular distribution in mitochondria, nucleus and clathrin-coated vesicles [17]. PanK1α is exclusively localized in the nucleus, whereas PanK1β exhibits cytosolic localization and association with clathrin-coated vesicles and recycling endosomes. Interestingly, human and mouse PanK2 isoforms showed different patterns of subcellular localization. Human PanK2, which possesses functional nuclear localization and export signals at the N-terminal regulatory region, is observed in the nucleus and the mitochondria. In contrast, mouse PanK2  C The

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lacks both targeting sequences and is found exclusively in the cytosol [17]. The observed difference in the subcellular localization of human and mouse PanK2 may explain the lack of a neurodegenerative phenotype in the mouse knockout model of PanK2, whereas mutations in human PANK2 gene result in a progressive neurodegenerative disease [5]. Notably, the localization of mouse PanK2 is under debate, as detailed fractionation studies have recently revealed that it is localized in the IMM [6]. The discrepancy in the subcellular localization of mouse PanK2 can be explained by the fact that overexpressed and endogenous proteins were examined in the studies described above [6,17]. The PanK3 isoform is exclusively localized in the cytosol [17]. The data on the localization of CoAsy are also controversial. The PPAT and DPCK activities of CoAsy were reported in the cytosol [18], the OMM (outer mitochondrial membrane) [19] and in the mitochondrial matrix [20]. In mammalian cells, there is one gene for CoAsy which encodes three isoforms with alternative translation initiation codons [21]. CoAsyα shows ubiquitous expression, whereas CoAsyβ is primarily expressed in the brain. Both isoforms are predominantly localized to mitochondria, but their submitochondrial localization remains unclear. Zhyvoloup et al. [8] showed that CoAsyα possesses a hydrophobic sequence at its N-terminus that anchors this bifunctional enzyme to the OMM with both enzymatic domains facing the cytosol [8]. This finding is in agreement with a previously published study in which both enzymatic activities of CoAsy (PPAT and DPCK) were found to be located on the OMM. However, other studies revealed that CoAsy is mainly present in the matrix and probably anchored to the IMM [6,22]. These discrepancies could be explained by the presence of CoA splicing isoforms in different submitochondrial locations. Furthermore, nuclear and cytosolic localization of CoAsy have been recently observed in a panel of cell lines by confocal microscopy (V. Filonenko, unpublished work). The subcellular localization of CoAsyγ , which lacks the Nterminal membrane-targeting sequence and only possesses the DPCK domain, is currently unknown. In the human genome, the PPCS and PPCDC genes also exist as single copies [23]. Furthermore, the PPCDC activity was found exclusively in the cytosol [24]. It has been proposed that CoAsy, which possesses the membranelocalization motif, may function as a scaffold protein for the formation of the CoA biosynthetic complex [8].

Regulation of CoA biosynthesis by intracellular and extracellular stimuli and stresses The levels of CoA and its thioester derivatives are tightly regulated by various extracellular stimuli, including hormones of metabolic homoeostasis, nutrients, intracellular metabolites and stresses (Figure 2). It has long been known that fasting, glucagon and glucocorticoids, and treatment with hypolipidaemic drugs can increase the total level of CoA [25–29]. On the other hand, insulin, glucose, fatty acids and

Coenzyme A and Its Derivatives in Cellular Metabolism and Disease

Figure 2 Schematic diagram of the potential CoA biosynthetic complex in mammalian cells with negative and positive regulators

pyruvate were shown to decrease the level of intracellular CoA [18,30]. Changes in the level of CoA were also reported in several pathological conditions, such as diabetes, Reye’s syndrome, cancer, vitamin B12 deficiency and cardiac hypertrophy [4,25,28,31–34]. It has to be noted that most of these studies were carried out 20–30 years ago and there is a need to confirm and advance these original findings with the use of more sensitive assays and detection approaches, such as MS. The molecular mechanisms implicated in the regulation of intracellular level of CoA and the CoA/CoA derivatives ratio are not well understood. To date, most studies have been mainly focused on studying the regulation of two rate-limiting enzymes in CoA biosynthesis, PanK and CoAsy. From bacteria to mammalian cells, negative-feedback regulation of PanK, and hence CoA biosynthesis, by CoA, acetyl-CoA or acyl-CoA is a well-documented fact [1,7]. Taking into account that the intracellular levels of CoA/CoA derivatives levels are regulated by hormones, nutrients and intracellular metabolites, the research on the cross-talk between signal transduction pathways and CoA biosynthetic enzymes has been recently initiated. To date, mammalian CoAsy was found to be in complex with different proteins implicated in diverse signalling pathways, including ribosomal protein S6K1 (S6 kinase 1) [13], p85α regulatory subunit of PI3K (phosphoinositide 3-kinase) [35], tyrosine phosphatase Shp2PTP (Src homology 2 domain-containing protein tyrosine phosphatase) and tyrosine kinase Src [36], and EDC4 (enhancer of mRNA-decapping protein 4) [37]. Some of these interactions were shown to be modulated by serum starvation/stimulation and in response to stresses. Moreover, the activity and function of CoAsy was also found to be regulated by post-translational modifications. For example, tyrosine phosphorylation of CoAsy by members of the Src tyrosine kinase family was shown to be required for its interaction with p85α regulatory subunit of PI3K [35]. Moreover, tyrosine dephosphorylation of CoAsy by Shp2PTP in vitro results in the increase of its PPAT activity [36]. The interaction of CoAsy with EDC4, a central scaffold component of processing bodies, is regulated by growth

factors and is affected by cellular stresses [37]. EDC4 was also shown to strongly inhibit the dephospho-CoA kinase activity of CoAsy in vitro [37]. The importance and mechanisms of these interactions are not well understood, but part of the answer may lie in the regulation of the formation of a potential CoA biosynthetic complex. Consistent with this hypothesis, studies with PLA have shown that the interaction between PanK1β and CoAsy is significantly enhanced in response to ´ serum starvation and oxidative stress (D. Lopez, unpublished work). It is well known that the level of CoA is not uniform inside the cell and differs considerably depending on the compartment examined. Sequestered pools of CoA are found in peroxisomes and mitochondria where CoA concentrations are estimated to be 0.7 mM and 2.2–5.0 mM respectively. Cytosolic concentrations of CoA are much lower and range from 0.02 to 0.14 mM in various tissues and organs [26,38,39]. Sequestration of CoA in subcellular compartments suggests two options for its biosynthesis and transportation within the cell. The first option implies the existence of CoA biosynthetic machinery in cytosol, peroxisomes and mitochondria. If this is the case, all CoA biosynthetic enzymes, including PPCS and PPCDC, should be present in these subcellular compartments. In a second scenario, the CoA biosynthetic machinery assembles only in the cytosol in response to various extracellular stimuli and stresses, and synthesized CoA is then transported into various compartments in a regulated manner. Several laboratories reported CoA transport into mitochondria isolated from yeast and mammalian cells [40]. Interestingly, deletion of the yeast mitochondrial CoA transporter, LEU5 (leucine biosynthesis 5), resulted in a 15-fold reduction in mitochondrial CoA levels, but did not affect the cytosolic CoA content [41]. Expression of the human orthologue of yeast Leu5, the Graves’ disease protein, was shown to restore the level of mitochondrial CoA in yeast deficient for LEU5.

Conclusions and future perspectives Following molecular cloning of genes encoding CoA biosynthetic enzymes, the association of the CoA biosynthetic pathway with neurodegeneration and the realization of the pathway’s importance for antibacterial drug discovery, the field of CoA research is currently in a ‘renaissance’ period. It is important to keep the momentum and to advance various aspects of CoA research with new innovative ideas and by applying modern technologies/methodologies for accurate measurements of CoA/CoA derivatives levels in cells and cellular compartments, for monitoring the formation of the CoA biosynthetic complex, and for the development of novel cellular and animal models. On the topic of the present minireview, we envisage significant progress to be made in the next few years on the existence of the CoA biosynthetic complex in mammalian cells, its subcellular localization, and regulation by signalling pathways in response to extracellular stimuli, intracellular metabolites and stresses. The analysis  C The

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of gel-filtration elution profiles from cells and tissues, the application of PLA assay and FRET (fluorescent resonance energy transfer) technology may help to answer some of these questions.

Funding This work was supported by the BBSRC (Biotechnology and Biological Sciences Research Council) [grant number BB/L010410/1], UCLB (University College London Business) Proof of Concept funding [grant numbers UCLB PoC-11-018 and UCLB PoC-13-014]. David Lopez Martinez is supported by ‘la Caixa’ scholarship for postgraduate studies abroad.

References 1 Leonardi, R., Zhang, Y.-M., Rock, C.O. and Jackowski, S. (2005) Coenzyme A: back in action. Prog. Lipid Res. 44, 125–153 CrossRef PubMed 2 Kleinkauf, H. (2000) The role of 4 -phosphopantetheine in t’ biosynthesis of fatty acids, polyketides and peptides. Biofactors 11, 91–92 CrossRef PubMed 3 Begley, T.P., Kinsland, C. and Strauss, E. (2001) The biosynthesis of coenzyme A in bacteria. Vitam. Horm. 61, 157–171 CrossRef PubMed 4 Zhou, B., Westaway, S.K., Levinson, B., Johnson, M.A., Gitschier, J. and Hayflick, S.J. (2001) A novel pantothenate kinase gene (PANK2) is defective in Hallervorden–Spatz syndrome. Nat. Genet. 28, 345–349 CrossRef PubMed 5 Hortnagel, ¨ K., Prokisch, H. and Meitinger, T. (2003) An isoform of hPANK2, deficient in pantothenate kinase-associated neurodegeneration, localizes to mitochondria. Hum. Mol. Genet. 12, 321–327 CrossRef PubMed 6 Dusi, S., Valletta, L., Haack, T.B., Tsuchiya, Y., Venco, P., Pasqualato, S., Goffrini, P., Tigano, M., Demchenko, N., Wieland, T. et al. (2014) Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation. Am. J. Hum. Genet. 94, 11–22 CrossRef PubMed 7 Rock, C.O. (2000) Pantothenate kinase regulation of the intracellular concentration of coenzyme A. J. Biol. Chem. 275, 1377–1383 CrossRef PubMed 8 Zhyvoloup, A., Nemazanyy, I., Panasyuk, G., Valovka, T., Fenton, T., Rebholz, H., Wang, M.-L., Foxon, R., Lyzogubov, V., Usenko, V. et al. (2003) Subcellular localization and regulation of coenzyme A synthase. J. Biol. Chem. 278, 50316–50321 CrossRef PubMed 9 Yang, K., Eyobo, Y., Brand, L.A., Martynowski, D., Tomchick, D., Strauss, E. and Zhang, H. (2006) Crystal structure of a type III pantothenate kinase: insight into the mechanism of an essential coenzyme A biosynthetic enzyme universally distributed in bacteria. J. Bacteriol. 188, 5532–5540 CrossRef PubMed 10 Bucovaz, E.T., Macleod, R.M., Morrison, J.C. and Whybrew, W.D. (1997) The coenzyme A-synthesizing protein complex and its proposed role in CoA biosynthesis in bakers’ yeast. Biochimie 79, 787–798 CrossRef PubMed 11 Ruiz, A., Gonzalez, ´ A., Munoz, ˜ I., Serrano, R., Abrie, J.A., Strauss, E. and Arino, ˜ J. (2009) Moonlighting proteins Hal3 and Vhs3 form a heteromeric PPCDC with Ykl088w in yeast CoA biosynthesis. Nat. Chem. Biol. 5, 920–928 CrossRef PubMed 12 Olzhausen, J., Moritz, T., Neetz, T. and Schuller, ¨ H.-J. (2013) Molecular characterization of the heteromeric coenzyme A-synthesizing protein complex (CoA-SPC) in the yeast Saccharomyces cerevisiae. FEMS Yeast Res. 13, 565–573 CrossRef PubMed 13 Nemazanyy, I., Panasyuk, G., Zhyvoloup, A., Panayotou, G., Gout, I.T. and Filonenko, V. (2004) Specific interaction between S6K1 and CoA synthase: a potential link between the mTOR/S6K pathway, CoA biosynthesis and energy metabolism. FEBS Lett. 578, 357–362 CrossRef PubMed 14 Soderberg, ¨ O., Leuchowius, K.-J., Gullberg, M., Jarvius, M., Weibrecht, I., Larsson, L.-G. and Landegren, U. (2008) Characterizing proteins and their interactions in cells and tissues using the in situ proximity ligation assay. Methods 45, 227–232 CrossRef PubMed  C The

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15 Gin, P. and Clarke, C.F. (2005) Genetic evidence for a multi-subunit complex in coenzyme Q biosynthesis in yeast and the role of the Coq1 hexaprenyl diphosphate synthase. J. Biol. Chem. 280, 2676–2681 CrossRef PubMed 16 Laredj, L.N., Licitra, F. and Puccio, H.M. (2014) The molecular genetics of coenzyme Q biosynthesis in health and disease. Biochimie 100C, 78–87 CrossRef 17 Alfonso-Pecchio, A., Garcia, M., Leonardi, R. and Jackowski, S. (2012) Compartmentalization of mammalian pantothenate kinases. PLoS ONE 7 11, e49509 CrossRef PubMed 18 Robishaw, J.D., Berkich, D. and Neely, J.R. (1982) Rate-limiting step and control of coenzyme A synthesis in cardiac muscle. J. Biol. Chem. 257, 10967–10972 PubMed 19 Tahiliani, A.G. and Neely, J.R. (1987) Mitochondrial synthesis of coenzyme A is on the external surface. J. Mol. Cell. Cardiol. 19, 1161–1167 CrossRef PubMed 20 Skrede, S. and Halvorsen, O. (1979) Mitochondrial biosynthesis of coenzyme A. Biochem. Biophys. Res. Commun. 91, 1536–1542 CrossRef PubMed 21 Nemazanyy, I., Panasyuk, G., Breus, O., Zhyvoloup, A., Filonenko, V. and Gout, I.T. (2006) Identification of a novel CoA synthase isoform, which is primarily expressed in the brain. Biochem. Biophys. Res. Commun. 341, 995–1000 CrossRef PubMed 22 Rhee, H.-W., Zou, P., Udeshi, N.D., Martell, J.D., Mootha, V.K., Carr, S.A. and Ting, A.Y. (2013) Proteomic mapping of mitochondria in living cells via spatially restricted enzymatic tagging. Science 339, 1328–1331 CrossRef PubMed 23 Daugherty, M., Polanuyer, B., Farrell, M., Scholle, M., Lykidis, A., de Crecy-Lagard, ´ V. and Osterman, A. (2002) Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics. J. Biol. Chem. 277, 21431–21439 CrossRef PubMed 24 Scandurra, R., Barboni, E., Granata, F., Pensa, B. and Costa, M. (1974) Pantothenoylcysteine-4 -phosphate decarboxylase from horse liver. Eur. J. Biochem. 49, 1–9 CrossRef PubMed 25 Kerbey, A.L., Radcliffe, P.M. and Randle, P.J. (1977) Diabetes and the control of pyruvate dehydrogenase in rat heart mitochondria by concentration ratios of adenosine triphosphate/adenosine diphosphate, of reduced/oxidized nicotinamide-adenine dinucleotide and of acetyl-coenzyme A/coenzyme A. Biochem. J. 164, 509–519 PubMed 26 Horie, S., Isobe, M. and Suga, T. (1986) Changes in CoA pools in hepatic peroxisomes of the rat under various conditions. J. Biochem. 99, 1345–1352 PubMed 27 Berge, R.K., Aarsland, A., Bakke, O.M. and Farstad, M. (1983) Hepatic enzymes, CoASH and long-chain acyl-CoA in subcellular fractions as affected by drugs inducing peroxisomes and smooth endoplasmic reticulum. Int. J. Biochem. 15, 191–204 CrossRef PubMed 28 Reibel, D.K., Wyse, B.W., Berkich, D., a Palko, W.M. and Neely, J.R. (1981) Effects of diabetes and fasting on pantothenic acid metabolism in rats. Am. J. Physiol. 240, E597–601 PubMed 29 Smith, C.M. and Savage, C.R. (1980) Regulation of coenzyme A biosynthesis by glucagon and glucocorticoid in adult rat liver parenchymal cells. Biochem. J. 188, 175–84 PubMed 30 Berge, R.K., Hosøy, L.H. and Farstad, M.N. (1984) Influence of dietary status on liver palmitoyl-CoA hydrolase, peroxisomal enzymes, CoASH and long-chain acyl-CoA in rats. Int. J. Biochem. 16, 403–410 CrossRef PubMed 31 McAllister, R.A., Fixter, L.M. and Campbell, E.H. (1988) The effect of tumour growth on liver pantothenate, CoA, and fatty acid synthetase activity in the mouse. Br. J. Cancer 57, 83–86 CrossRef PubMed 32 Brass, E.P., Tahiliani, A.G., Allen, R.H. and Stabler, S.P. (1990) Coenzyme A metabolism in vitamin B-12-deficient rats. J. Nutr. 120, 290–297 PubMed 33 Corkey, B.E., Hale, D.E., Glennon, M.C., Kelley, R.I., Coates, P.M., Kilpatrick, L. and Stanley, C.A. (1988) Relationship between unusual hepatic acyl coenzyme A profiles and the pathogenesis of Reye syndrome. J. Clin. Invest. 82, 782–788 CrossRef PubMed 34 Reibel, D.K., Uboh, C.E. and Kent, R.L. (1983) Altered coenzyme A and carnitine metabolism in pressure-overload hypertrophied hearts. Am. J. Physiol. 244, H839–H843 PubMed 35 Breus, O., Panasyuk, G., Gout, I.T., Filonenko, V. and Nemazanyy, I. (2009) CoA Synthase is in complex with p85αPI3K and affects PI3K signaling pathway. Biochem. Biophys. Res. Commun. 385, 581–585 CrossRef PubMed 36 Breus, O., Panasyuk, G., Gout, I.T., Filonenko, V. and Nemazanyy, I. (2010) CoA Synthase is phosphorylated on tyrosines in mammalian cells, interacts with and is dephosphorylated by Shp2PTP. Mol. Cell. Biochem. 335, 195–202 CrossRef PubMed

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37 Gudkova, D., Panasyuk, G., Nemazanyy, I., Zhyvoloup, A., Monteil, P., Filonenko, V. and Gout, I. (2012) EDC4 interacts with and regulates the dephospho-CoA kinase activity of CoA synthase. FEBS Lett. 586, 3590–3595 CrossRef PubMed 38 Idell-Wenger, J.A., Grotyohann, L.W. and Neely, J.R. (1978) Coenzyme A and carnitine distribution in normal and ischemic hearts. J. Biol. Chem. 253, 4310–4318 PubMed 39 Williamson, J.R. and Corkey, B.E. (1979) Assay of citric acid cycle intermediates and related compounds: update with tissue metabolite levels and intracellular distribution. Methods Enzymol. 55, 200–222 CrossRef PubMed

40 Tahiliani, A.G. (1989) Dependence of mitochondrial coenzyme A uptake on the membrane electrical gradient. J. Biol. Chem. 264, 18426–18432 PubMed 41 Prohl, C., Pelzer, W., Diekert, K., Kmita, H., Bedekovics, T., Kispal, G. and Lill, R. (2001) The yeast mitochondrial carrier Leu5p and its human homologue Graves’ disease protein are required for accumulation of coenzyme A in the matrix. Mol. Cell. Biol. 21, 1089–1097 CrossRef PubMed

Received 30 April 2014 doi:10.1042/BST20140124

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Coenzyme A biosynthetic machinery in mammalian cells.

CoA (coenzyme A) is an essential cofactor in all living organisms. CoA and its thioester derivatives [acetyl-CoA, malonyl-CoA, HMG-CoA (3-hydroxy-3-me...
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