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Coenzyme A biosynthesis: mechanisms of regulation, function and disease

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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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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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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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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