The time course of the interaction of sheep liver cytoplasmic aldehyde dehydrogenase with 2,2'- and 4,4'-dithiodipyridine: a comparison with the action of disulfiram.
2,2'-Dithiodipyridine reacts rapidly with sheep liver cytoplasmic aldehyde dehydrogenase in the presence of NAD +, resulting in activation of the enzyme by 2 to 2.5-fold (when assayed in the usual way). This is followed by the slow loss of most of the enzyme activity during the next few hours at 25 degrees C. 2-Thiopyridone is displaced from the labeled enzyme at approximately the same rate as activity is lost. This is explained in terms of the initial modification of an enzymatic thiol group (giving activation) followed by the reaction of the labeled group with a second enzymatic thiol group, resulting in the formation of a disulfide bond and the inactivation of the enzyme. 4,4'-Dithiodipyridine reacts in a broadly similar way, although both the loss of label and loss of activity are faster and do not correlate with each other as well as for the 2,2' isomer. The results suggest that the dithiodipyridines act to produce the same enzymatic disulfide bond as has been shown to arise from the reaction of the enzyme with disulfiram (a drug used in alcoholism treatment). The implications of the results are discussed with reference to the proposed mechanism of action of aldehyde dehydrogenase. It is concluded that the thiol group initially modified by disulfiram is unlikely to be catalytically essential to the dehydrogenase action of the enzyme.
D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives / Q000494:pharmacology*; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D003593:Cytoplasm / Q000201:enzymology; D004220:Disulfides; D004221:Disulfiram / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D009243:NAD / Q000494:pharmacology; D011725:Pyridines / Q000378:metabolism* / Q000494:pharmacology*; D012756:Sheep
D004220:Disulfides; D011725:Pyridines; D009243:NAD; C001105:2,2'-dipyridyl disulfide; C007542:4,4'-dipyridyl disulfide; C042861:4-thiopyridine; D015082:2,2'-Dipyridyl; D000444:Aldehyde Dehydrogenase; C029347:2-thiopyridine; D004221:Disulfiram