Enzymology of Amino Acid Conjugation Reactions

Amino acid conjugation is a route of metabolism for various xenobiotic carboxylic acids and bile acids; however, knowledge of the enzymology (e.g., multiplicity of enzymes, substrate selectivity, catalytic mechanism, and protein structure), polymorphisms, and gene regulation is not as advanced as the cytochromes P450 and uridine 5′-diphosphate (UDP)-glucuronosyltransferases. Mechanistically, amino acid conjugation is a coupled enzyme system involving a mitochondrial adenosine triphosphate (ATP)-dependent acid medium-chain acyl-CoA synthetase (ACSM), which catalyzes the formation of an acyl-CoA thioester, and an acyl-CoA:glycine N-acyltransferase (GLYAT) that links the acyl group to glycine. Conjugation of bile acids is extramitochondrial involving initially enzymes located in the endoplasmic reticulum, while conjugation of bile acid-CoAs involves a peroxisomal bile acid-CoA:amino acid N-acyltransferase (BAAT). Within mitochondria, amino acid conjugation terminates the biological reactivity of xenobiotic acyl-CoAs, whereas conjugation of bile acids increases aqueous solubility and promotes bile acid flow and intestinal absorption. For both pathways, the amino acid utilized is species dependent. In mammals, excretion is predominantly as either glycine or taurine conjugates. Amino acid conjugation is important in both health and disease. Manipulation of mitochondrial amino acid conjugation is used in the treatment of nonketotic hyperglycinemia and hyperammonemia, and failure to conjugate bile acids can lead to cholestasis and loss of absorption of fat and fat-soluble vitamins. This chapter reviews the enzymology, substrate and inhibitor profile, and factors that regulate the activity of ACSM, GLYAT, and BAAT.