Enzymatic reduction of alloxan by thioredoxin and NADPH-thioredoxin reductase.
Alloxan reacts with certain sulfhydryl groups either by chemical modification or reduction to dialuric acid. The effects of the drug on NADPH-thioredoxin oxidoreductase, EC 1.6.4.5] and thioredoxin-(SH)2, a ubiquitous thiol-dependent disulfide reductase system, are described. Alloxan was a direct substrate for a nearly homogenous preparation of calf thymus NADPH-thioredoxin reductase with an apparent Km of 330 microM and a Kcat of 1000 min-1 at pH 7.0 and 25 degrees C. Alloxan was not a substrate for the corresponding Escherichia coli NADPH-thioredoxin reductase. However, E. coli and calf thymus thioredoxin-(SH)2 both efficiently reduced alloxan. Thus, alloxan showed an apparent Km of 70 microM in the presence of 3.4 microM E. coli thioredoxin, 0.2 microM thioredoxin reductase, and 0.4 mM NADPH. The insulin disulfide reductase activity of the complete calf thymus thioredoxin system was inhibited by alloxan, as predicted from the reaction of the drug with both thioredoxin-(SH)2 and thioredoxin reductase. The toxic action of alloxan on animal cells, particularly the beta cells of pancreas, may be caused by rapid oxidation of cellular NADPH and generation of cytotoxic dialuric acid catalyzed by the thioredoxin system.
D000496:Alloxan / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism; D003553:Cystine / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013879:Thioredoxins / Q000037:antagonists & inhibitors / Q000378:metabolism*
D001426:Bacterial Proteins; D003553:Cystine; D013879:Thioredoxins; D009249:NADP; D000496:Alloxan; D009247:NADH, NADPH Oxidoreductases; D013880:Thioredoxin-Disulfide Reductase; D003545:Cysteine