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).