Hypoglycin A: A Specific Inhibitor of Isovaleryl CoA Dehydrogenase

Abstract

Evidence is presented for the specific in vivo and in vitro inhibition of isovaleryl CoA dehydrogenation by hypoglycin A and its derivative, a-ketomethylenecyclopropylpropionic acid. a-MethylbutyrylCoA dehydrogenation was also impaired, but the degree of inhibition was much lower. Isobutyryl CoA dehydrogenation was not inhibited. 4-Pentenoic acid inhibited none of these reactions. It is concluded that isovaleryl CoA is dehydrogenated by a specific enzyme, isovaleryl CoA dehydrogenase, contrary to previous assumptions that it is dehydrogenated by green acyl CoA dehydrogenase. The present concept agrees with our previous findings in isovaleric acidemia, a genetic disorder in which a specific defect of isovaleryl CoA dehydrogenase was observed. It was also demonstrated that isovaleric acidemia can be induced in experimental animals by the administration of hypoglycin A. Furthermore, some symptoms of "the vomiting sickness of Jamaica" appear to be due to isovaleric acid accumulation secondary to the ingestion of hypoglycin A.Isovaleric acidemia is a genetic defect of leucine metabolism (1-4) in which isovaleric acid accumulates in blood in large amounts. Based on the biochemical findings in this hereditary disorder, we proposed that isovaleryl CoA is dehydrogenated by a specific enzyme, isovaleryl CoA dehydrogenase (1,3) and that this enzyme is deficient in patients with isovaleric acidemia ( Fig. 1). It was previously believed that isovaleryl CoA, butyryl CoA, and hexanoyl CoA were dehydrogenated by a single enzyme, acyl CoA dehydrogenase (5,6).It has subsequently been shown that oxidation of leucine is inhibited by hypoglycin A (7,8). In contrast, oxidation of valine and isoleucine are not significantly inhibited by this compound (8). However, the specific step in the pathway of leucine metabolism that is inhibited by hypoglycin A has not been precisely identified.Hypoglycin A is an unusual amino acid having the structure of a-aminomethylenecyclopropylpropionic acid (9). It has been extracted from unripe fruits of ackee grown in Jamaica and has been identified as the cause of the "vomiting sickness of Jamaica" (10). Extreme hypoglycemia (11) In vivo experimentsAmino acids were given by stomach tube 30 min after intramuscular injection of the inhibitor. The blood samples were drawn by heart puncture 150 min after injection of the inhibitor. Short chain fatty acid analyses were performed by gasliquid chromatography (GLC) (1).In vitro experiments Incubations were for 3 hr at 37°C. The tissues and the incubation medium were homogenized after acidification with 0.5 ml of 2 N H2SO4 and extracted with 20 vol of chloroform-methanol 2:1. The filtered extract was separated into two phases by mixing with 0.2 N NaOH (0.2 vol of the extract). Unlabeled carrier was added to the homogenate before extraction.Only the upper alkaline layer, which contains most of the water soluble salts of carboxylic acids and acidic conjugates, was analyzed. The steam-distillable fractions after acid hydrolysis were designated as total fr...

Production of the Features of Reye's Syndrome in Rats with 4-Pentenoic Acid

“…Tanaka et al (25)(26)(27) have shown that hypoglycin inhibits the enzyme isovaleryl-CoA dehydrogenase and probably also glutaryl-CoA dehydrogenase and in rats results in the excretion of isovaleric, glutaric, and several other unusual carboxylic acids. In this respect hypoglycin toxicity and probably Jamaican vomiting sickness differ from pentenoic acid toxicity and Reye's syndrome.…”

Isovaleryl-CoA Dehydrogenase Activity in Isovaleric Acidemia Fibroblasts Using an Improved Tritium Release Assay

“…Employing an inhibitor of several acyl-CoA dehydrogenases, MCPA-CoA (2,8,9), we developed an improved assay for isovaleryl-CoA dehydrogenase to accurately determine residual isovaleryl-CoA dehydrogenase activity in fibroblasts of patients with clinically severe and mild forms of isovaleric acidemia.…”

Rapid diagnosis of hypoglycin A intoxication in atypical myopathy of horses

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