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Flavensomycin, an Inhibitor of Enzyme Reactions Involving Hydrogen Transfer

^a Department of Plant Pathology, University of Illinois, Urbana, Illinois 61801

ABSTRACT

The antifungal antibiotic flavensomycin inhibited the oxidation of amino acids and of glucose by Penicillium oxalicum. The compound inhibited L-amino acid oxidase (EC 1.4.3.2) activity for L-leucine and L-phenylalanine, and also D-amino acid oxidase (EC 1.4.3.3) in the oxidation for DL-alanine. The addition of flavin adenine dinucleotide, which is a cofactor for this enzyme, antagonized the action of the antibiotic. Glucose oxidase (EC 1.1.3.4) was also inhibited. The antibiotic inhibited the reduced nicotinamide adenine dinucleotide (NADH₂) cytochrome c reductase (EC 1.6.2.1) as well as the much slower nonenzymatic reduction of this cytochrome by the nucleotide. Reduced cytochrome c was also oxidized nonenzymatically by flavensomycin. The antibiotic completely inhibited the action of rabbit muscle lactic dehydrogenase (EC 1.1.1.27) in promoting the reduction of pyruvate by NADH₂ but only slightly affected the reverse reaction. Alcohol dehydrogenase (EC 1.1.1.1) was also similarly inhibited. Flavensomycin prevented the reduction of nicotinamide adenine dinucleotide phosphate by isocitrate in the presence of isocitrate dehydrogenase (EC 1.1.1.42). The hexokinase (EC 2.7.1.1)-catalyzed phosphorylation of glucose, in which the adenosine triphosphate acts as a phosphate donor, was only slightly affected. Flavensomycin also inhibited the action of yeast lactate dehydrogenase (EC 1.1.2.3) on the reduction of cytochrome c. High concentrations of cytochrome c were antagonistic to this reaction. The results point to an interference with enzymatically controlled hydrogen or electron transfer as the mechanism of the antifungal activity of flavensomycin.

¹ Present address: Kaken Chemical Co., Ltd., Honkomagome, Bunkyo-ku, Tokyo, Japan.