The stereospecific suicide inhibition of human melanoma thioredoxin reductase by 13-cis-retinoic acid.
13-cis retinoic acid has been shown to be a stereospecific suicide inhibitor of thioredoxin reductase purified from human melanoma tissue. All trans retinoic acid does not inhibit this enzyme. The covalent addition of 13-cis retinoic acid to the thiolate active site of thioredoxin reductase produces a thioether enzyme-inhibitor complex. This has been established by a kinetic analysis and by active site labeling with 3H-13 cis retinoic acid. A mechanism involving Michael addition of the thiolate group in the active site of thioredoxin reductase to the 13-cis double bond of enzyme-bound inhibitor has been proposed. This reaction may be important in the human epidermis because thioredoxin reductase has been shown to be a major antioxidant catalyst in human keratinocytes, melanocytes, melanoma cells, and in human skin as well as in melanoma tissues.
Schallreuter
K U
KU
Department of Dermatology, University of Hamburg, FRG.
Wood
J M
JM
D002478:Cells, Cultured; D003600:Cytosol / Q000201:enzymology; D004817:Epidermis / Q000201:enzymology; D006801:Humans; D015474:Isotretinoin / Q000494:pharmacology*; D007700:Kinetics; D008545:Melanoma / Q000201:enzymology*; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D012878:Skin Neoplasms / Q000201:enzymology; D013237:Stereoisomerism; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*
D009247:NADH, NADPH Oxidoreductases; D013880:Thioredoxin-Disulfide Reductase; D015474:Isotretinoin