Knights Kathleen M, Sykes Matthew J, Miners John O
Flinders University & Flinders Medical Center, Department of Clinical Pharmacology, Bedford Park, Adelaide 5042, Australia.
Expert Opin Drug Metab Toxicol. 2007 Apr;3(2):159-68. doi: 10.1517/17425255.3.2.159.
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.
尽管氨基酸结合反应是在人体中首次被证实的结合反应，但作为外源性羧酸代谢途径的氨基酸结合作用尚未得到充分表征。这主要是由于用于氨基酸结合的外源性底物数量少且结构多样性有限。与定位于内质网的细胞色素P450（CYP）和尿苷5'-二磷酸葡萄糖醛酸基转移酶不同，氨基酸结合酶存在于线粒体中。在药物代谢途径中，氨基酸结合作用独树一帜，它涉及外源性酰基辅酶A硫酯的初始形成，然后在人体中主要与甘氨酸结合。然而，外源性酰基辅酶A硫酯的形成并不总是意味着随后会发生氨基酸结合。有证据表明，在缺乏甘氨酸结合底物的情况下，形成酰基辅酶A硫酯的外源性物质会扰乱线粒体功能。本综述讨论了相关酶的文献以及外源性底物选择性为保护线粒体代谢完整性提供屏障这一概念。
