Melanocytotoxicity and the mechanism of activation of gamma-L-glutaminyl-4-hydroxybenzene.
gamma-L-Glutaminyl-4-hydroxybenzene is converted by the tyrosinase of the common mushroom, Agaricus bisporus, to the toxic, dormancy-inducing metabolite 2-hydroxy-4-imino-2,5-cyclohexadiene-1-one. Hydroxylation of gamma-L-glutaminyl-4-hydroxybenzene by mammalian tyrosinase was monitored by determining tritium water release from gamma-L-glutaminyl-[3,5-(3)H[4-hydroxybenzene and occurred at only 25% of the rate found with tyrosine. The dihydroxy product of the hydroxylation reaction, gamma-L-glutaminyl-3,4-dihydroxybenzene, was not oxidized by the mammalian enzyme. Therefore, oxidation of gamma-L-glutaminyl-4-hydroxybenzene to sulfhydryl-reactive quinones by mammalian tyrosinase is an unlikely explanation for the hair depigmentation and inhibition of melanocarcinoma growth observed following administration of this compound. Cleavage of gamma-L-glutaminyl-4-hydroxybenzene by gamma-glutamyl transpeptidase releasing p-aminophenol was demonstrated. p-Aminophenol was an active depigmenting and melanocytotoxic compound. N2-Methyl-gamma-L-glutaminyl-4-hydroxybenzene was synthesized, differing from gamma-L-glutaminyl-4-hydroxybenzene only by the presence of a methylated amide linkage. This chemical modification resulted in a compound resistant to cleavage by gamma-glutamyl transpeptidase and lacking in melanocytotoxic activity. gamma-Glutamyl transpeptidase cleavage is proposed as the route for transformation of gamma-L-glutaminyl-4-hydroxybenzene into an active inhibitor of melanocytes.
D000627:Aminophenols / Q000378:metabolism; D000818:Animals; D002417:Cattle; D004789:Enzyme Activation; D005973:Glutamine / Q000031:analogs & derivatives* / Q000378:metabolism; D006900:Hydroxylation; D007980:Levodopa / Q000378:metabolism; D008544:Melanocytes / Q000201:enzymology*; D008545:Melanoma / Q000201:enzymology; D051379:Mice; D014442:Monophenol Monooxygenase / Q000378:metabolism; D014316:Tritium; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D000627:Aminophenols; D005973:Glutamine; D014316:Tritium; C001298:gamma-L-glutaminyl-4-hydroxybenzene; D007980:Levodopa; C012171:agaridoxin; C027359:N(2)-methyl-gamma-L-glutaminyl-4-hydroxybenzene; D014442:Monophenol Monooxygenase; D005723:gamma-Glutamyltransferase