Enzymology of Mitochondrial Amino Acid Conjugation Reactions

Abstract

Metabolism for a variety of endo- and xenobiotic carboxylic acids via amino acid conjugation occurs in several mammalian species. However, current knowledge of the multiplicity of enzymes involved, substrate selectivity, catalytic mechanism, protein structure, polymorphisms, and gene regulation is limited. It is also unclear what role amino acid conjugation plays in complex diseases such as cancer. Mechanistically, amino acid conjugation is a coupled enzyme system involving a mitochondrial medium-chain acyl-CoA synthetase (ACSM) catalyzing the formation of an acyl-CoA thioester, followed by an acyl-CoA: glycine N-acyltransferase (GLYAT) that links the acyl group, predominantly in mammals, to glycine. Although six ACSMs have been identified, only ACSM2B have been shown to catalyze xenobiotic-CoA conjugation. It is postulated that ACSM2A might have the same substrate selectivity as ACSM2B due to the high amino acid identity. Similarly, six paralogues of GLYAT exist but only GLYAT and GLYATL1 have been shown to conjugate xenobiotic-CoAs. Both ACSM2 and GLYAT are highly conserved, indicating that deleterious alleles with a negative effect on enzyme activity, are found at low frequencies. Within mitochondria, amino acid conjugation terminates the biological reactivity of xenobiotic acyl-CoAs and restores CoA levels. This chapter reviews the enzymology, substrate, and inhibitor profile, and factors regulating the activity of ACSM and GLYAT. Additionally, attempts to manipulate amino acid conjugation are discussed in the context of diminishing toxicity in certain inborn errors of metabolism.