Inactivation of gamma-glutamylcysteine synthetase by SAPH-3 disulfide: role of the histaminyl moiety.
Certain disulfide analogues of cystamine were prepared and evaluated for the ability to inhibit gamma-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in glutathione synthesis. The compound SAPH-3 disulfide (2a) was found to be the most effective inactivator of GCS reported to date. Studies of structural analogues of 2a indicate that the histamine moiety plays a significant role in enzyme inactivation. Substitution of methyl groups on the carbon atoms adjacent to both sulfur atoms of the disulfide drastically decreases inhibitory action, probably due to a steric repulsion near the sulfur atom at the enzyme active site.
Schor
N F
NF
Department of Pediatrics, School of Pharmacy, University of Pittsburgh, PA 15213.
Cheng
B
B
Siuda
J F
JF
D000818:Animals; D004220:Disulfides / Q000138:chemical synthesis / Q000494:pharmacology*; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D004220:Disulfides; D011725:Pyridines; D005721:Glutamate-Cysteine Ligase