Mårdh G, Falchuk K H, Auld D S, Vallee B L
Proc Natl Acad Sci U S A. 1986 May;83(9):2836-40. doi: 10.1073/pnas.83.9.2836.
Testosterone and its physiologically active metabolite 5 alpha-dihydrotestosterone are selective, allosteric inhibitors of the gamma subunit-containing isozymes of class I human alcohol dehydrogenase (ADH) with apparent Ki values for testosterone at pH 7.4 between 3.5 and 16 X 10(-6) M. Testosterone inhibition is noncompetitive with respect to ethanol, NAD+, 1,10-phenanthroline, and 4-methylpyrazole, identifying a regulatory site distinct from the catalytic site. Testosterone does not inhibit the class I isozymes composed only of alpha and/or beta subunits and only weakly inhibits the class II and III isozymes. Importantly, none of these human ADH isozymes oxidize or reduce the steroids with the delta 4 double bond or 5 alpha configuration. The allosteric effect of testosterone, restricted to the gamma subunits of human ADH, suggests unique metabolic specificities and pathways for these isozymes, apart from all others. This inhibition may ultimately be critical to an identification of their function(s). Analogous considerations of other metabolic effectors might further lead to similar insights regarding the alpha and beta subunit-containing isozymes as well as the class II and III ADH.
睾酮及其生理活性代谢物5α-二氢睾酮是人类I类乙醇脱氢酶（ADH）含γ亚基同工酶的选择性变构抑制剂，在pH 7.4条件下，睾酮的表观Ki值在3.5至16×10⁻⁶ M之间。睾酮的抑制作用相对于乙醇、NAD⁺、1,10-菲咯啉和4-甲基吡唑而言是非竞争性的，这表明存在一个与催化位点不同的调节位点。睾酮不会抑制仅由α和/或β亚基组成的I类同工酶，对II类和III类同工酶的抑制作用也很弱。重要的是，这些人类ADH同工酶均不会氧化或还原具有δ4双键或5α构型的类固醇。睾酮的变构效应仅限于人类ADH的γ亚基，这表明这些同工酶具有独特的代谢特异性和途径，与其他同工酶不同。这种抑制作用最终可能对确定它们的功能至关重要。对其他代谢效应物进行类似的研究，可能会进一步对含α和β亚基的同工酶以及II类和III类ADH产生类似的见解。
