Amino acid conjugation: contribution to the metabolism and toxicity of xenobiotic carboxylic acids.
Despite being the first conjugation reaction demonstrated in humans, amino acid conjugation as a route of metabolism of xenobiotic carboxylic acids is not well characterised. This is principally due to the small number and limited structural diversity of xenobiotic substrates for amino acid conjugation. Unlike CYP and uridine 5'-diphosphate glucuronosyltransferase, which are localised in the endoplasmic reticulum, the enzymes of amino acid conjugation reside in mitochondria. Unique among drug metabolism pathways, amino acid conjugation involves initial formation of a xenobiotic acyl-CoA thioester that is then conjugated principally with glycine in humans. However, formation of the xenobiotic acyl-CoA thioester does not always infer subsequent amino acid conjugation. Evidence is presented that in the absence of glycine conjugation substrates that form acyl-CoA thioesters perturb mitochondrial function. This review discusses literature on the enzymes involved and the concept that xenobiotic substrate selectivity provides a barrier to protect the metabolic integrity of the mitochondria.
Knights
Kathleen M
KM
Flinders University & Flinders Medical Center, Department of Clinical Pharmacology, Bedford Park, Adelaide 5042, Australia. kathie.knights@flinders.edu.au
Sykes
Matthew J
MJ
Miners
John O
JO
D000596:Amino Acids / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002264:Carboxylic Acids / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000139:chemically induced / Q000378:metabolism; D006801:Humans; D050217:Metabolic Detoxication, Phase II; D008928:Mitochondria / Q000201:enzymology; D024101:Mitochondrial Proteins / Q000378:metabolism; D015394:Molecular Structure; D015262:Xenobiotics / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism*
D000596:Amino Acids; D002264:Carboxylic Acids; D024101:Mitochondrial Proteins; D015262:Xenobiotics