Chemical and biochemical derivates of trans-3-methylglutaconyl CoA: A molecular labyrinth

trans-3-Methylglutaconyl (3MGC) CoA is a seemingly innocuous metabolic intermediate that, in human intermediary metabolism, appears only in the leucine catabolism pathway. However, in multiple pathophysiological conditions, it is now recognized that trans-3MGC CoA can be generated via an alternate biosynthetic route. In such cases, as well as rare inborn errors of metabolism in genes encoding leucine catabolism pathway enzymes, increased levels of trans-3MGC CoA trigger the formation of a series of chemical derivates that represent potential disease biomarkers. Trans-3MGC CoA is a relatively unstable chemical entity that is prone to isomerize to cis-3MGC CoA, which spontaneously undergoes an intramolecular cyclization reaction, forming 3MGC anhydride and free CoA. The anhydride is susceptible to hydrolysis, forming the organic acid, 3MGC acid, which is excreted in urine as a mixture of cis- and trans-diastereomers. Alternatively, the anhydride can react with lysine side chain amino groups, resulting in protein 3MGCylation. Another derivate of trans-3MGC CoA, 3-methylglutaryl (3MG) CoA, is apparently formed by enzyme-mediated reduction of the double bond in trans-3MGC CoA. Once formed, 3MG CoA has three potential fates, including cyclization to form the corresponding anhydride which can either be hydrolyzed to 3MG acid or react with lysine residues to 3MGylate protein substrates. Alternatively, 3MG CoA can react with l-carnitine, via carnitine acyltransferase, generating 3MG carnitine and free CoA as products. This acylcarnitine derivate of trans-3MGC CoA has gained attention recently as a readily detectable biomarker of mitochondrial dysfunction in a growing number of disease processes.