Overview of coenzyme A metabolism and its role in cellular toxicity.
Coenzyme A (CoASH) has a clearly defined role as a cofactor for a number of oxidative and biosynthetic reactions in intermediary metabolism. Formation of acyl-CoA thioesters from organic carboxylic acids activates the acid for further biotransformation reactions and facilitates enzyme recognition. Xenobiotic carboxylic acids can also form CoA-thioesters, and the resulting acyl-CoA may contribute to the compound's toxicity. Generation of an unusual or poorly-metabolized acyl-CoA from a xenobiotic may lead to cellular metabolic dysfunction through several types of mechanisms including: (1) inhibition of key metabolic enzymes by the acyl-CoA; (2) sequestration of the total cellular CoA pool as the unusual acyl-CoA; (3) physical-chemical effects of the acyl-CoA; and (4) sequestration and depletion of carnitine as the acyl group is transformed from the acyl-CoA to form the corresponding acylcarnitine. Many of these toxicities are similar to sequelae observed in the inherited organic acidurias in which endogenously-generated acyl-CoAs accumulate secondary to an enzymopathy. Insights into the cellular mechanisms of xenobiotic acyl-CoA accumulation have been derived from model systems developed to understand organic acidemias, such as the methylmalonyl-CoA accumulation of the methylmalonic acidurias. The relevance of acyl-CoA accretion to human pathophysiology has now been well established, and identification of the relevant mechanism of toxicity can allow implementation of strategies to minimize the metabolic injury. Additionally, recognition of the potential for acyl-CoA mediated xenobiotic injury should result in improved rational drug design and earlier recognition of such toxicity when it develops.
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Department of Medicine, Case Western Reserve University, Cleveland, OH 44106-4981.
D000214:Acyl Coenzyme A / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D003065:Coenzyme A / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D008661:Metabolism, Inborn Errors / Q000378:metabolism*; D008764:Methylmalonic Acid / Q000652:urine; D015262:Xenobiotics / Q000378:metabolism / Q000633:toxicity*
D000214:Acyl Coenzyme A; D015262:Xenobiotics; D008764:Methylmalonic Acid; D003065:Coenzyme A