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Coenzyme A biosynthesis: mechanisms of regulation, function and disease

Nature Metabolism volume 6, pages 1008–1023 (2024)Cite this article

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Abstract

The tricarboxylic acid cycle, nutrient oxidation, histone acetylation and synthesis of lipids, glycans and haem all require the cofactor coenzyme A (CoA). Although the sources and regulation of the acyl groups carried by CoA for these processes are heavily studied, a key underlying question is less often considered: how is production of CoA itself controlled? Here, we discuss the many cellular roles of CoA and the regulatory mechanisms that govern its biosynthesis from cysteine, ATP and the essential nutrient pantothenate (vitamin B5), or from salvaged precursors in mammals. Metabolite feedback and signalling mechanisms involving acetyl-CoA, other acyl-CoAs, acyl-carnitines, MYC, p53, PPARα, PINK1 and insulin- and growth factor-stimulated PI3K–AKT signalling regulate the vitamin B5 transporter SLC5A6/SMVT and CoA biosynthesis enzymes PANK1, PANK2, PANK3, PANK4 and COASY. We also discuss methods for measuring CoA-related metabolites, compounds that target CoA biosynthesis and diseases caused by mutations in pathway enzymes including types of cataracts, cardiomyopathy and neurodegeneration (PKAN and COPAN).

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Fig. 1: Functions of CoA.
Fig. 2: The de novo CoA biosynthesis pathway.
Fig. 3: CoA degradation and salvage pathways.
Fig. 4: Metabolite-based regulation of CoA biosynthesis.
Fig. 5: Signalling-mediated regulation of CoA biosynthesis.

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References

  1. Robishaw, J. D. & Neely, J. R. Coenzyme A metabolism. Am. J. Physiol. 248, E1–E9 (1985).

    CAS  PubMed  Google Scholar 

  2. Trefely, S. et al. Quantitative subcellular acyl-CoA analysis reveals distinct nuclear metabolism and isoleucine-dependent histone propionylation. Mol. Cell 82, 447–462 (2022).

    Article  CAS  PubMed  Google Scholar 

  3. Pietrocola, F., Galluzzi, L., Pedro, J. M. B. -S., Madeo, F. & Kroemer, G. Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab. 21, 805–821 (2015).

    Article  CAS  PubMed  Google Scholar 

  4. Trefely, S., Lovell, C. D., Snyder, N. W. & Wellen, K. E. Compartmentalised acyl-CoA metabolism and roles in chromatin regulation. Mol. Metab. https://doi.org/10.1016/j.molmet.2020.01.005 (2020).

  5. Guertin, D. A. & Wellen, K. E. Acetyl-CoA metabolism in cancer. Nat. Rev. Cancer 23, 156–172 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wanders, R. J. A., Baes, M., Ribeiro, D., Ferdinandusse, S. & Waterham, H. R. The physiological functions of human peroxisomes. Physiol. Rev. 103, 957–1024 (2023).

    Article  CAS  PubMed  Google Scholar 

  7. Paiva, P. et al. Animal fatty acid synthase: a chemical nanofactory. Chem. Rev. 121, 9502–9553 (2021).

    Article  CAS  PubMed  Google Scholar 

  8. Nowinski, S. M., Vranken, J. G. V., Dove, K. K. & Rutter, J. Impact of mitochondrial fatty acid synthesis on mitochondrial biogenesis. Curr. Biol. 28, R1212–R1219 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Juarez, D. & Fruman, D. A. Targeting the mevalonate pathway in cancer. Trends Cancer 7, 525–540 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Paneque, A., Fortus, H., Zheng, J., Werlen, G. & Jacinto, E. The hexosamine biosynthesis pathway: regulation and function. Genes 14, 933 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yien, Y. Y. & Perfetto, M. Regulation of heme synthesis by mitochondrial homeostasis proteins. Front. Cell Dev. Biol. 10, 895521 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Wang, Z. A. & Cole, P. A. The chemical biology of reversible lysine post-translational modifications. Cell Chem. Biol. 27, 953–969 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Resh, M. D. Fatty acylation of proteins: the long and the short of it. Prog. Lipid Res. 63, 120–131 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gamage, S. T., Manage, S. A. H., Chu, T. T. & Meier, J. L. Cytidine acetylation across the tree of life. Acc. Chem. Res. 57, 338–348 (2024).

    Article  Google Scholar 

  15. Beld, J., Sonnenschein, E. C., Vickery, C. R., Noel, J. P. & Burkart, M. D. The phosphopantetheinyl transferases: catalysis of a post-translational modification crucial for life. Nat. Prod. Rep. 31, 61–108 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chen, N., Liu, Y., Li, Y. & Wang, C. Chemical proteomic profiling of protein 4′‐phosphopantetheinylation in mammalian cells. Angew. Chem. Int. Ed. Engl. 132, 16203–16209 (2020).

    Article  Google Scholar 

  17. Tsybovsky, Y., Sereda, V., Golczak, M., Krupenko, N. I. & Krupenko, S. A. Structure of putative tumor suppressor ALDH1L1. Commun. Biol. 5, 3 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Drozak, J., Veiga‐da‐Cunha, M., Kadziolka, B. & Schaftingen, E. V. Vertebrate Acyl CoA synthetase family member 4 (ACSF4‐U26) is a β‐alanine‐activating enzyme homologous to bacterial non‐ribosomal peptide synthetase. FEBS J. 281, 1585–1597 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. Tossounian, M. -A. et al. Profiling the site of protein CoAlation and coenzyme A stabilization interactions. Antioxidants 11, 1362 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tsuchiya, Y. et al. Covalent Aurora A regulation by the metabolic integrator coenzyme A. Redox Biology https://doi.org/10.1016/j.redox.2019.101318 (2019).

  21. Lim, D. C. et al. Redox priming promotes Aurora A activation during mitosis. Sci. Signal. 13, eabb6707 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Baković, J. et al. A key metabolic integrator, coenzyme A, modulates the activity of peroxiredoxin 5 via covalent modification. Mol. Cell. Biochem. 461, 91–102 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Yu, B. Y. K. et al. Regulation of metastasis suppressor NME1 by a key metabolic cofactor coenzyme A. Redox Biol. 44, 101978 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gout, I. Coenzyme A, protein CoAlation and redox regulation in mammalian cells. Biochem Soc. Trans. 46, 721–728 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gowda, G. A. N., Abell, L. & Tian, R. Extending the scope of 1H NMR spectroscopy for the analysis of cellular coenzyme A and acetyl coenzyme A. Anal. Chem. 91, 2464–2471 (2019).

    Article  PubMed Central  Google Scholar 

  26. Atomi, H., Tomita, H., Ishibashi, T., Yokooji, Y. & Imanaka, T. CoA biosynthesis in archaea. Biochem Soc. Trans. 41, 427–431 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Leonardi, R. & Jackowski, S. Biosynthesis of pantothenic acid and coenzyme A. EcoSal Plus https://doi.org/10.1128/ecosalplus.3.6.3.4 (2007).

  28. Stein, E. D. & Diamond, J. M. Do dietary levels of pantothenic acid regulate its intestinal uptake in mice? J. Nutr. 119, 1973–1983 (1989).

    Article  CAS  PubMed  Google Scholar 

  29. Naquet, P., Kerr, E. W., Vickers, S. D. & Leonardi, R. Regulation of coenzyme A levels by degradation: the ‘ins and outs.’ Prog. Lipid Res. https://doi.org/10.1016/j.plipres.2020.101028. (2020).

  30. Prasad, P. D. et al. Molecular and functional characterization of the intestinal Na+-dependent multivitamin transporter. Arch. Biochem. Biophys. 366, 95–106 (1999).

    Article  CAS  PubMed  Google Scholar 

  31. Quick, M. & Shi, L. The sodium/multivitamin transporter: a multipotent system with therapeutic implications. Vitam. Horm. 98, 63–100 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sabui, S. et al. Biotin and pantothenic acid oversupplementation to conditional SLC5A6 KO mice prevents the development of intestinal mucosal abnormalities and growth defects. Am. J. Physiol. 315, C73–C79 (2018).

    Article  CAS  Google Scholar 

  33. Pourcel, L. et al. Transient vitamin B5 starving improves mammalian cell homeostasis and protein production. Metab. Eng. 60, 77–86 (2020).

    Article  CAS  PubMed  Google Scholar 

  34. Cantor, J. R. et al. Physiologic medium rewires cellular metabolism and reveals uric acid as an endogenous inhibitor of UMP synthase. Cell 169, 258–272 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Reibel, D. K., Wyse, B. W., Berkich, D. A., Palko, W. M. & Neely, J. R. Effects of diabetes and fasting on pantothenic acid metabolism in rats. Am. J. Physiol. 240, E597–E601 (1981).

    CAS  PubMed  Google Scholar 

  36. Reibel, D. K., Wyse, B. W., Berkich, D. A. & Neely, J. R. Coenzyme A metabolism in pantothenic acid-deficient rats. J. Nutr. 112, 1144–1150 (1982).

    Article  CAS  PubMed  Google Scholar 

  37. Jackowski, S. & Rock, C. O. Regulation of coenzyme A biosynthesis. J. Bacteriol. 148, 926–932 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rock, C. O., Calder, R. B., Karim, M. A. & Jackowski, S. Pantothenate kinase regulation of the intracellular concentration of coenzyme A. J. Biol. Chem. 275, 1377–1383 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Yao, J., Subramanian, C., Rock, C. O. & Jackowski, S. Human pantothenate kinase 4 is a pseudo‐pantothenate kinase. Protein Sci. 28, 1031–1047 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhang, Y. -M. et al. Chemical knockout of pantothenate kinase reveals the metabolic and genetic program responsible for hepatic coenzyme A homeostasis. Chem. Biol. 14, 291–302 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Zhou, B. et al. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat. Genet. 28, 345–349 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Rock, C. O., Karim, M. A., Zhang, Y. -M. & Jackowski, S. The murine pantothenate kinase (Pank1) gene encodes two differentially regulated pantothenate kinase isozymes. Gene 291, 35–43 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Zhang, Y. -M., Rock, C. O. & Jackowski, S. Feedback regulation of murine pantothenate kinase 3 by coenzyme A and coenzyme A thioesters. J. Biol. Chem. 280, 32594–32601 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Hong, B. S. et al. Crystal structures of human pantothenate kinases. Insights into allosteric regulation and mutations linked to a neurodegeneration disorder. J. Biol. Chem. 282, 27984–27993 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Kotzbauer, P. T., Truax, A. C., Trojanowski, J. Q. & Lee, V. M. -Y. Altered neuronal mitochondrial coenzyme A synthesis in neurodegeneration with brain iron accumulation caused by abnormal processing, stability, and catalytic activity of mutant pantothenate kinase 2. J. Neurosci. 25, 689–698 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Daugherty, M. et al. Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics. J. Biol. Chem. 277, 21431–21439 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Mostert, K. J. et al. The coenzyme A level modulator hopantenate (HoPan) inhibits phosphopantotenoylcysteine synthetase activity. ACS Chem. Biol. 16, 2401–2414 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Manoj, N., Strauss, E., Begley, T. P. & Ealick, S. E. Structure of human phosphopantothenoylcysteine synthetase at 2.3 Å resolution. Structure 11, 927–936 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Iuso, A. et al. Mutations in PPCS, encoding phosphopantothenoylcysteine synthetase, cause autosomal-recessive dilated cardiomyopathy. Am. J. Hum. Genet. 102, 1018–1030 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Strauss, E., Zhai, H., Brand, L. A., McLafferty, F. W. & Begley, T. P. Mechanistic studies on phosphopantothenoylcysteine decarboxylase: Trapping of an enethiolate intermediate with a mechanism-based inactivating agent. Biochemistry 43, 15520–15533 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Manoj, N. & Ealick, S. E. Unusual space-group pseudosymmetry in crystals of human phosphopantothenoylcysteine decarboxylase. Acta Crystallogr. D Biol. Crystallogr. https://doi.org/10.1107/s0907444903016214 (2023).

  52. Bravo‐Alonso, I. et al. Pathogenic variants of the coenzyme A biosynthesis‐associated enzyme phosphopantothenoylcysteine decarboxylase cause autosomal‐recessive dilated cardiomyopathy. J. Inherit. Metab. Dis. 46, 261–272 (2023).

    Article  PubMed  Google Scholar 

  53. Aghajanian, S. & Worrall, D. M. Identification and characterization of the gene encoding the human phosphopantetheine adenylyltransferase and dephospho-CoA kinase bifunctional enzyme (CoA synthase). Biochem. J. 365, 13–18 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Dusi, S. et al. Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation. Am. J. Hum. Genet. 94, 11–22 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Xue, L. et al. Probing coenzyme A homeostasis with semisynthetic biosensors. Nat. Chem. Biol. https://doi.org/10.1038/s41589-022-01172-7 (2022).

  56. Dibble, C. C. et al. PI3K drives the de novo synthesis of coenzyme A from vitamin B5. Nature https://doi.org/10.1038/s41586-022-04984-8 (2022).

  57. Huang, L. et al. A family of metal-dependent phosphatases implicated in metabolite damage-control. Nat. Chem. Biol. 12, 621–627 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Leonardi, R. et al. Modulation of pantothenate kinase 3 activity by small molecules that interact with the substrate/allosteric regulatory domain. Chem. Biol. 17, 892–902 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Li, X. et al. Pantothenate kinase 4 governs lens epithelial fibrosis by negatively regulating pyruvate kinase M2-related glycolysis. Aging Dis. 14, 1834–1852 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Leonardi, R., Rehg, J. E., Rock, C. O. & Jackowski, S. Pantothenate kinase 1 is required to support the metabolic transition from the fed to the fasted state. PLoS ONE 5, e11107 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Sun, M. et al. A novel mutation of PANK4 causes autosomal dominant congenital posterior cataract. Hum. Mutat. 40, 380–391 (2019).

    Article  CAS  PubMed  Google Scholar 

  62. Kuo, Y. -M. et al. Deficiency of pantothenate kinase 2 (Pank2) in mice leads to retinal degeneration and azoospermia. Hum. Mol. Genet. 14, 49–57 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Garcia, M., Leonardi, R., Zhang, Y. -M., Rehg, J. E. & Jackowski, S. Germline deletion of pantothenate kinases 1 and 2 reveals the key roles for CoA in postnatal metabolism. PLoS ONE 7, e40871 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Jeong, S. Y. et al. 4′‐Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN. EMBO Mol. Med. 11, e10489 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. DiMeo, I. et al. Neuronal Ablation of CoA synthase causes motor deficits, iron dyshomeostasis, and mitochondrial dysfunctions in a CoPAN mouse model. Int. J. Mol. Sci. 21, 9707 (2020).

    Article  CAS  Google Scholar 

  66. Mignani, L., Gnutti, B., Zizioli, D. & Finazzi, D. Coenzyme a biochemistry: from neurodevelopment to neurodegeneration. Brain Sci. 11, 1031 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hayflick, S. J., Jeong, S. Y. & Sibon, O. C. M. PKAN pathogenesis and treatment. Mol. Genet. Metab. 137, 283–291 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Munshi, M. I., Yao, S. J. & Mamoun, C. B. Redesigning therapies for pantothenate kinase-associated neurodegeneration. J. Biol. Chem. https://doi.org/10.1016/j.jbc.2022.101577 (2022).

  69. Vickers, S. D. et al. NUDT7 regulates total hepatic CoA levels and the composition of the intestinal bile acid pool in male mice fed a Western diet. J. Biol. Chem. 299, 102745 (2023).

    Article  CAS  PubMed  Google Scholar 

  70. Shumar, S. A. et al. Nudt19 is a renal CoA diphosphohydrolase with biochemical and regulatory properties that are distinct from the hepatic Nudt7 isoform. J. Biol. Chem. 293, 4134–4148 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kerr, E. W., Shumar, S. A. & Leonardi, R. Nudt8 is a novel CoA diphosphohydrolase that resides in the mitochondria. FEBS Lett. 593, 1133–1143 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Gasmi, L. & McLennan, A. G. The mouse Nudt7 gene encodes a peroxisomal nudix hydrolase specific for coenzyme A and its derivatives. Biochem. J. 357, 33–38 (2001).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Bond, L. M. et al. Fitm2 is required for ER homeostasis and normal function of murine liver. J. Biol. Chem. 299, 103022 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hunt, M. C., Tillander, V. & Alexson, S. E. H. Regulation of peroxisomal lipid metabolism: the role of acyl-CoA and coenzyme A metabolizing enzymes. Biochimie 98, 45–55 (2014).

    Article  CAS  PubMed  Google Scholar 

  75. Srinivasan, B. et al. Extracellular 4′-phosphopantetheine is a source for intracellular coenzyme A synthesis. Nat. Chem. Biol. 11, 784–792 (2015).

    Article  CAS  PubMed  Google Scholar 

  76. Bartucci, R., Salvati, A., Olinga, P. & Boersma, Y. L. Vanin 1: its physiological function and role in diseases. Int. J. Mol. Sci. 20, 3891 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Giessner, C. et al. Vnn1 pantetheinase limits the Warburg effect and sarcoma growth by rescuing mitochondrial activity. Life Sci. Alliance 1, e201800073 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Millet, V. et al. Harnessing the Vnn1 pantetheinase pathway boosts short chain fatty acids production and mucosal protection in colitis. Gut 72, 1115–1128 (2023).

    Article  CAS  PubMed  Google Scholar 

  79. Shurubor, Y. I. et al. Determination of coenzyme A and acetyl-coenzyme A in biological samples using HPLC with UV detection. Molecules 22, 1388 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Yu, Y. et al. Coenzyme A precursors flow from mother to zygote and from microbiome to host. Mol. Cell https://doi.org/10.1016/j.molcel.2022.05.006 (2022).

  81. Jackowski, S. Proposed therapies for pantothenate-kinase-associated neurodegeneration. J. Exp. Neurosci. 13, 1179069519851118 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Williamson, J. R. & Corkey, B. E. Assay of citric acid cycle intermediates and related compounds—update with tissue metabolite levels and intracellular distribution. Methods Enzymol. 55, 200–222 (1979).

    Article  CAS  PubMed  Google Scholar 

  83. Idell-Wenger, J. A., Grotyohann, L. W. & Neely, J. R. Coenzyme A and carnitine distribution in normal and ischemic hearts. J. Biol. Chem. 253, 4310–4318 (1978).

    Article  CAS  PubMed  Google Scholar 

  84. Broekhoven, A. V., Peeters, M. -C., Debeer, L. J. & Mannaerts, G. P. Subcellular distribution of coenzyme A: evidence for a separate coenzyme a pool in peroxisomes. Biochem. Biophys. Res. Commun. 100, 305–312 (1981).

    Article  PubMed  Google Scholar 

  85. Horie, S., Isobe, M. & Suga, T. Changes in CoA pools in hepatic peroxisomes of the rat, under various conditions. J. Biochem. 99, 1345–1352 (1986).

    Article  CAS  PubMed  Google Scholar 

  86. Chen, W. W., Freinkman, E., Wang, T., Birsoy, K. & Sabatini, D. M. Absolute quantification of matrix metabolites reveals the dynamics of mitochondrial metabolism. Cell 166, 1324–1337 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Alfonso-Pecchio, A., Garcia, M., Leonardi, R. & Jackowski, S. Compartmentalization of mammalian pantothenate kinases. PLoS ONE 7, e49509 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Ramaswamy, G., Karim, M. A., Murti, K. G. & Jackowski, S. PPARalpha controls the intracellular coenzyme A concentration via regulation of PANK1alpha gene expression. J. Lipid Res. 45, 17–31 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Hörtnagel, K., Prokisch, H. & Meitinger, T. An isoform of hPANK2, deficient in pantothenate kinase-associated neurodegeneration, localizes to mitochondria. Hum. Mol. Genet. 12, 321–327 (2003).

    Article  PubMed  Google Scholar 

  90. Johnson, M. A. et al. Mitochondrial localization of human PANK2 and hypotheses of secondary iron accumulation in pantothenate kinase‐associated neurodegeneration. Ann. N. Y. Acad. Sci. 1012, 282–298 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Zhang, Y. -M., Rock, C. O. & Jackowski, S. Biochemical properties of human pantothenate kinase 2 isoforms and mutations linked to pantothenate kinase-associated neurodegeneration. J. Biol. Chem. 281, 107–114 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Leonardi, R., Zhang, Y. -M., Lykidis, A., Rock, C. O. & Jackowski, S. Localization and regulation of mouse pantothenate kinase 2. FEBS Lett. 581, 4639–4644 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Brunetti, D. et al. Pantothenate kinase-associated neurodegeneration: altered mitochondria membrane potential and defective respiration in Pank2 knock-out mouse model. Hum. Mol. Genet. 21, 5294–5305 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Werning, M. et al. PKAN neurodegeneration and residual PANK2 activities in patient erythrocytes. Ann. Clin. Transl. Neurol. 7, 1340–1351 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Zhyvoloup, A. et al. Subcellular localization and regulation of coenzyme A synthase. J. Biol. Chem. 278, 50316–50321 (2003).

    Article  CAS  PubMed  Google Scholar 

  96. Skrede, S. & Halvorsen, O. Mitochondrial pantetheinephosphate adenylyltransferase and dephospho‐CoA kinase. Eur. J. Biochem. 131, 57–63 (1983).

    Article  CAS  PubMed  Google Scholar 

  97. Tahiliani, A. G. & Neely, J. R. Mitochondrial synthesis of coenzyme a is on the external surface. J. Mol. Cell. Cardiol. 19, 1161–1167 (1987).

    Article  CAS  PubMed  Google Scholar 

  98. Skrede, S. & Halvorsen, O. Mitochondrial biosynthesis of coenzyme A. Biochem. Biophys. Res. Commun. 91, 1536–1542 (1979).

    Article  CAS  PubMed  Google Scholar 

  99. Rhee, H. -W. et al. Proteomic mapping of mitochondria in living cells via spatially restricted enzymatic tagging. Science 339, 1328–1331 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Fiermonte, G., Paradies, E., Todisco, S., Marobbio, C. M. T. & Palmieri, F. A novel member of solute carrier family 25 (SLC25A42) is a transporter of coenzyme A and adenosine 3′5′-diphosphate in human mitochondria. J. Biol. Chem. 284, 18152–18159 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Prohl, C. et al. 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 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Vozza, A. et al. Biochemical characterization of a new mitochondrial transporter of dephosphocoenzyme A in Drosophila melanogaster. Biochim. Biophys. Acta Bioenerg. 1858, 137–146 (2017).

    Article  CAS  PubMed  Google Scholar 

  103. Agrimi, G., Russo, A., Scarcia, P. & Palmieri, F. The human gene SLC25A17 encodes a peroxisomal transporter of coenzyme A, FAD and NAD+. Biochem. J. 443, 241–247 (2012).

    Article  CAS  PubMed  Google Scholar 

  104. VanVeldhoven, P. P. et al. Slc25a17 gene trapped mice: PMP34 plays a role in the peroxisomal degradation of phytanic and pristanic acid. Front. Cell Dev. Biol. 8, 144 (2020).

    Article  Google Scholar 

  105. Abiko, Y., Ashida, S. -I. & Shimizu, M. Purification and properties of d-pantothenate kinase from rat liver. Biochim. Biophys. Acta 268, 364–372 (1972).

    Article  CAS  PubMed  Google Scholar 

  106. Karasawa, T., Yoshida, K., Furukawa, K. & Hosoki, K. Feedback inhibition of pantothenate kinase by coenzyme A and possible role of the enzyme for the regulation of cellular coenzyme A level. J. Biochem. 71, 1065–1067 (1972).

    Article  CAS  PubMed  Google Scholar 

  107. Shimizu, S., Kubo, K., Morioka, H., Tani, Y. & Ogata, K. Some aspects of the enzyme activities involved in coenzyme A biosynthesis in various microorganisms. Agric. Biol. Chem. 38, 1015–1021 (1974).

    Article  CAS  Google Scholar 

  108. Robishaw, J. D., Berkich, D. & Neely, J. R. Rate-limiting step and control of coenzyme A synthesis in cardiac muscle. J. Biol. Chem. 257, 10967–10972 (1982).

    Article  CAS  PubMed  Google Scholar 

  109. Voltti, H., Savolainen, M. J., Jauhonen, V. P. & Hassinen, I. E. Clofibrate-induced increase in coenzyme A concentration in rat tissues. Biochem. J. 182, 95–102 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Smith, C. M. The effect of metabolic state on incorporation of [14C]pantothenate into CoA in rat liver and heart. J. Nutr. 5, 863–873 (1978).

    Article  Google Scholar 

  111. Smith, C. M. & Savage, C. R. Regulation of coenzyme A biosynthesis by glucagon and glucocorticoid in adult rat liver parenchymal cells. Biochem. J. 188, 175–184 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Rock, C. O., Park, H. -W. & Jackowski, S. Role of feedback regulation of pantothenate kinase (CoaA) in control of coenzyme A levels in Escherichia coli. J. Bacteriol. 185, 3410–3415 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Fisher, M. N., Robishaw, J. D. & Neely, J. R. The properties and regulation of pantothenate kinase from rat heart. J. Biol. Chem. 260, 15745–15751 (1985).

    Article  CAS  PubMed  Google Scholar 

  114. Vallari, D. S., Jackowski, S. & Rock, C. O. Regulation of pantothenate kinase by coenzyme A and its thioesters. J. Biol. Chem. 262, 2468–2471 (1987).

    Article  CAS  PubMed  Google Scholar 

  115. Halvorsen, O. & Skrede, S. Regulation of the biosynthesis of CoA at the level of pantothenate kinase. Eur. J. Biochem. 124, 211–215 (1982).

    Article  CAS  PubMed  Google Scholar 

  116. Subramanian, C. et al. Allosteric regulation of mammalian pantothenate kinase. J. Biol. Chem. 291, 22302–22314 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Leonardi, R., Rock, C. O., Jackowski, S. & Zhang, Y. -M. Activation of human mitochondrial pantothenate kinase 2 by palmitoylcarnitine. Proc. Natl Acad. Sci. USA 104, 1494–1499 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Robishaw, J. D. & Neely, J. R. Pantothenate kinase and control of CoA synthesis in heart. Am. J. Physiol. 246, H532–H541 (1984).

    CAS  PubMed  Google Scholar 

  119. Levy, M. J. et al. A systems chemoproteomic analysis of Acyl-CoA/protein interaction networks. Cell Chem. Biol. 27, 322–333 (2020).

    Article  CAS  PubMed  Google Scholar 

  120. Dansie, L. E. et al. Physiological roles of the pantothenate kinases. Biochem. Soc. Trans. 42, 1033–1036 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Tubbs, P. & Garland, P. Variations in tissue contents of coenzyme A thio esters and possible metabolic implications. Biochem. J. 93, 550–557 (1964).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Williamson, J. R., Herczeg, B., Coles, H. & Danish, R. Studies on the ketogenic effect of glucagon in intact rat liver. Biochem Biophys. Res Commun. 24, 437–442 (1966).

    Article  CAS  PubMed  Google Scholar 

  123. Reibel, D. K., Wyse, B. W., Berkich, D. A. & Neely, J. R. Regulation of coenzyme A synthesis in heart muscle: effects of diabetes and fasting. Am. J. Physiol. 240, H606–H611 (1981).

    CAS  PubMed  Google Scholar 

  124. Smith, C. M., Cano, M. L. & Potyraj, J. The relationship between metabolic state and total CoA content of rat liver and heart. J. Nutr. 108, 854–862 (1978).

    Article  CAS  PubMed  Google Scholar 

  125. Lund, H., Stakkestad, J. A. & Skrede, S. Effects of thyroid state and fasting on the concentrations of CoA and malonyl-CoA in rat liver. Biochim. Biophys. Acta 876, 685–687 (1986).

    Article  CAS  PubMed  Google Scholar 

  126. Beinlich, C. J., Robishaw, J. D. & Neely, J. R. Metabolism of pantothenic acid in hearts of diabetic rats. J. Mol. Cell. Cardiol. 21, 641–649 (1989).

    Article  CAS  PubMed  Google Scholar 

  127. Kreuzaler, P. et al. Vitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer. Nat. Metab. https://doi.org/10.1038/s42255-023-00915-7 (2023).

  128. Humpton, T. J. & Vousden, K. H. Regulation of cellular metabolism and hypoxia by p53. Cold Spring Harb. Perspect. Med. 6, a026146 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Wang, S. -J. et al. p53-Dependent regulation of metabolic function through transcriptional activation of pantothenate kinase-1 gene. Cell Cycle 12, 753–761 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Jiang, L. et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature 520, 57–62 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Yang, L. et al. P53/PANK1/miR‐107 signalling pathway spans the gap between metabolic reprogramming and insulin resistance induced by high‐fat diet. J. Cell. Mol. Med. 24, 3611–3624 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Leu, J. I. -J., Murphy, M. E. & George, D. L. Mechanistic basis for impaired ferroptosis in cells expressing the African-centric S47 variant of p53. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.1821277116 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Chang, G. S. et al. A comprehensive and high-resolution genome-wide response of p53 to stress. Cell Rep. 8, 514–527 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Böhlig, L., Friedrich, M. & Engeland, K. p53 activates the PANK1/miRNA-107 gene leading to downregulation of CDK6 and p130 cell cycle proteins. Nucleic Acids Res. 39, 440–453 (2011).

    Article  PubMed  Google Scholar 

  135. Savolainen, M. J., Jauhonen, V. P. & Hassinen, I. E. Effects of clofibrate on ethanol-induced modifications in liver and adipose tissue metabolism: role of hepatic redox state and hormonal mechanisms. Biochem. Pharmacol. 26, 425–431 (1977).

    Article  CAS  PubMed  Google Scholar 

  136. Halvorsen, O. Effects of hypolipidemic drugs on hepatic CoA. Biochem. Pharmacol. 32, 1126–1128 (1983).

    Article  CAS  PubMed  Google Scholar 

  137. Skrede, S. & Halvorsen, O. Increased biosynthesis of CoA in the liver of rats treated with clofibrate. Eur. J. Biochem. 98, 223–229 (1979).

    Article  CAS  PubMed  Google Scholar 

  138. Miyazawa, S., Sakurai, T., Imura, M. & Hashimoto, T. Effects of ethyl p-chlorophenoxyisobutyrate on carbohydrate and fatty acid metabolism in rat liver. J. Biochem. 78, 1171–1176 (1975).

    Article  CAS  PubMed  Google Scholar 

  139. Polster, B. J., Yoon, M. Y. & Hayflick, S. J. Characterization of the human PANK2 promoter. Gene 465, 53–60 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Huang, Y. et al. Pantothenate kinase 2 interacts with PINK1 to regulate mitochondrial quality control via acetyl-CoA metabolism. Nat. Commun. 13, 2412 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Hoxhaj, G. & Manning, B. D. The PI3K–AKT network at the interface of oncogenic signalling and cancer metabolism. Nat. Rev. Cancer 20, 74–88 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Lambrechts, R. A. et al. CoA‐dependent activation of mitochondrial acyl carrier protein links four neurodegenerative diseases. EMBO Mol. Med. 11, e10488 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Leonardi, R., Rock, C. O. & Jackowski, S. Pank1 deletion in leptin-deficient mice reduces hyperglycaemia and hyperinsulinaemia and modifies global metabolism without affecting insulin resistance. Diabetologia 57, 1466–1475 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Breus, O., Panasyuk, G., Gout, I. T., Filonenko, V. & Nemazanyy, I. CoA synthase is in complex with p85alphaPI3K and affects PI3K signaling pathway. Biochem Biophys. Res. Commun. 385, 581–585 (2009).

    Article  CAS  PubMed  Google Scholar 

  145. Ferrandon, S. et al. CoA synthase (COASY) mediates radiation resistance via PI3K signaling in rectal cancer. Cancer Res. 80, 334–346 (2020).

    Article  CAS  PubMed  Google Scholar 

  146. Nemazanyy, I. et al. 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 (2004).

    Article  CAS  PubMed  Google Scholar 

  147. Arif, A., Jia, J., Willard, B., Li, X. & Fox, P. L. Multisite phosphorylation of S6K1 directs a kinase phospho-code that determines substrate selection. Mol. Cell 73, 446–457 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Breus, O., Panasyuk, G., Gout, I. T., Filonenko, V. & Nemazanyy, I. CoA synthase is phosphorylated on tyrosines in mammalian cells, interacts with and is dephosphorylated by Shp2PTP. Mol. Cell. Biochem. 335, 195–202 (2010).

    Article  CAS  PubMed  Google Scholar 

  149. Gudkova, D. et al. EDC4 interacts with and regulates the dephospho-CoA kinase activity of CoA synthase. FEBS Lett. 586, 3590–3595 (2012).

    Article  CAS  PubMed  Google Scholar 

  150. Baković, J. et al. Regulation of the CoA biosynthetic complex assembly in mammalian cells. Int. J. Mol. Sci. 22, 1131 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Bishop, T. R. et al. Acetyl-CoA biosynthesis drives resistance to histone acetyltransferase inhibition. Nat. Chem. Biol. https://doi.org/10.1038/s41589-023-01320-7 (2023).

  152. Crawford, M. C. et al. Comparative analysis of drug-like EP300/CREBBP acetyltransferase inhibitors. ACS Chem. Biol. https://doi.org/10.1101/2023.05.15.540887 (2023).

  153. Vella, V. et al. Kinome‐wide synthetic lethal screen identifies PANK4 as a modulator of temozolomide resistance in Glioblastoma. Adv. Sci. https://doi.org/10.1002/advs.202306027 (2024).

  154. Thakur, N. et al. Rational design of novel therapies for pantothenate kinase–associated neurodegeneration. Mov. Disord. 36, 2005–2016 (2021).

    Article  CAS  PubMed  Google Scholar 

  155. Sharma, L. K. et al. A therapeutic approach to pantothenate kinase associated neurodegeneration. Nat. Commun. 9, 4399 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Subramanian, C., Yao, J., Frank, M. W., Rock, C. O. & Jackowski, S. A pantothenate kinase-deficient mouse model reveals a gene expression program associated with brain coenzyme A reduction. Biochim. Biophys. Acta Mol. Basis Dis. https://doi.org/10.1016/j.bbadis.2020.165663. (2020).

  157. van Dijk, T. et al. Biallelic loss of function variants in COASY cause prenatal onset pontocerebellar hypoplasia, microcephaly, and arthrogryposis. Eur. J. Hum. Genet. 26, 1752–1758 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Mian, S. A. et al. Vitamin B5 and succinyl-CoA improve ineffective erythropoiesis in SF3B1-mutated myelodysplasia. Sci. Transl. Med. 15, eabn5135 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Zheng, Y. et al. COASY variant as a new genetic cause of riboflavin-responsive lipid storage myopathy. Cell Discov. 10, 25 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Tsuchiya, Y., Pham, U. & Gout, I. Methods for measuring CoA and CoA derivatives in biological samples. Biochem Soc. Trans. 42, 1107–1111 (2014).

    Article  CAS  PubMed  Google Scholar 

  161. Frank, M. W., Subramanian, C., Rock, C. O. & Jackowski, S. Quantification of coenzyme A in cells and tissues. J. Vis. Exp. https://doi.org/10.3791/60182 (2019).

  162. Goosen, R. & Strauss, E. Simultaneous quantification of coenzyme A and its salvage pathway intermediates in in vitro and whole cell-sourced samples. RSC Adv. 7, 19717–19724 (2017).

    Article  CAS  Google Scholar 

  163. Basu, S. S., Mesaros, C., Gelhaus, S. L. & Blair, I. A. Stable isotope labeling by essential nutrients in cell culture for preparation of labeled coenzyme A and its thioesters. Anal. Chem. 83, 1363–1369 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Snyder, N. W., Basu, S. S., Zhou, Z., Worth, A. J. & Blair, I. A. Stable isotope dilution liquid chromatography/mass spectrometry analysis of cellular and tissue medium- and long-chain acyl-coenzyme A thioesters. Rapid Commun. Mass Spectrom. 28, 1840–1848 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Yuan, M. et al. Ex vivo and in vivo stable isotope labelling of central carbon metabolism and related pathways with analysis by LC–MS/MS. Nat. Protoc. 14, 313–330 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Magnes, C., Sinner, F. M., Regittnig, W. & Pieber, T. R. LC/MS/MS method for quantitative determination of long-chain fatty acyl-CoAs. Anal. Chem. 77, 2889–2894 (2005).

    Article  CAS  PubMed  Google Scholar 

  167. Jones, A. E. et al. A single LC–MS/MS analysis to quantify CoA biosynthetic intermediates and short-chain acyl CoAs. Metabolites 11, 468 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Williamson, J. R. & Corkey, B. E. Assays of intermediates of the citric acid cycle and related compounds by fluorometric enzyme methods. Methods Enzymol. 13, 434–513 (1969).

    Article  CAS  Google Scholar 

  169. Sharma, L. K. et al. A high-throughput screen reveals new small-molecule activators and inhibitors of pantothenate kinases. J. Med. Chem. 58, 1563–1568 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Moolman, W. J. A., Villiers, Mde & Strauss, E. Recent advances in targeting coenzyme A biosynthesis and utilization for antimicrobial drug development. Biochem. Soc. Trans. 42, 1080–1086 (2014).

    Article  CAS  PubMed  Google Scholar 

  171. Schalkwijk, J. et al. Antimalarial pantothenamide metabolites target acetyl–coenzyme A biosynthesis in Plasmodium falciparum. Sci. Transl. Med. 11, eaas9917 (2019).

    Article  CAS  PubMed  Google Scholar 

  172. Gihaz, S. et al. High-resolution crystal structure and chemical screening reveal pantothenate kinase as a new target for antifungal development. Structure 30, 1494–1507 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Subramanian, C. et al. Pantothenate kinase activation restores brain coenzyme A in a mouse model of pantothenate kinase associated neurodegeneration. J. Pharmacol. Exp. Ther. https://doi.org/10.1124/jpet.123.001919 (2023).

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Acknowledgements

This work was supported by the following grants: V Foundation V Scholar Grant V2019-009 (to C.C.D.), NIH/NCI F31-CA254169 (to S.A.B.) and NIH/NIGMS R35-GM149229 (to P.A. Cole in support of S.E.D.-C.). We thank K.E. Wellen and N.W. Snyder for the helpful discussion of their data, our peer reviewers for their expert feedback, and our primary editor for his guidance and patience. We express our appreciation and respect for Charles O. Rock, a pioneer in the fields of CoA and lipid metabolism who passed away in 2023.

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  1. Department of Pathology, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Samuel A. Barritt & Christian C. Dibble

  2. Department of Medicine, Department of Biological Chemistry and Molecular Pharmacology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Sarah E. DuBois-Coyne

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  1. Samuel A. Barritt
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Conceptualization: S.A.B. and C.C.D. Writing, figure construction and editing: S.A.B., S.E.D.-C. and C.C.D.

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Correspondence to Christian C. Dibble.

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Nature Metabolism thanks Charles Rock and Ivan Gout for their contribution to the peer review of this work. Primary Handling Editor: Alfredo Gimenez-Cassina, in collaboration with the Nature Metabolism team.

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Barritt, S.A., DuBois-Coyne, S.E. & Dibble, C.C. Coenzyme A biosynthesis: mechanisms of regulation, function and disease. Nat Metab 6, 1008–1023 (2024). https://doi.org/10.1038/s42255-024-01059-y

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