Selective inhibition of acyl-CoA dehydrogenases by a metabolite of hypoglycin.
Extracts of liver mitochondria from donor rats given hypoglycin, the toxic amino acid from the ackee plant (Blighia sapida) showed drastically reduced levels of acyl-CoA dehydrogenase activity with butyryl-CoA as substrate. Activity with octanoyl- and palmitoyl-CoA was unaffected. Evidence that the active agent is methylenecyclopropylacetyl-CoA, a hypoglycin metabolite, was obtained by observing effects of the compound on a partially purified enzyme mixture prepared from rabbit liver. At 13 muM concentration, it strongly inhibited butyryl-CoA dehydrogenase (EC 1.3.99.2) with butyryl-CoA as substrate; it was far less effective with palmitoyl-CoA as substrate for the other similar enzymes present in the preparation. Unlike normal substrates of the acyl-CoA dehydrogenases, the compound itself, and not a reaction product, is inhibitory. The observed effect is consistent with quite general inhibition of fatty acid beta-oxidation by hypoglycin.
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D002087:Butyrates / Q000378:metabolism; D003065:Coenzyme A / Q000378:metabolism; D003521:Cyclopropanes / Q000494:pharmacology*; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D007700:Kinetics; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology*; D010088:Oxidoreductases / Q000378:metabolism*; D010169:Palmitic Acids; D010947:Plants, Toxic; D051381:Rats
D000596:Amino Acids; D002087:Butyrates; D003521:Cyclopropanes; D010169:Palmitic Acids; D010088:Oxidoreductases; D005969:Glutamate Dehydrogenase; D000409:Alanine; D003065:Coenzyme A