Inhibition of glutamate carboxypeptidase II by phosphonamidothionate derivatives of glutamic acid.
A limited series of N-thiophosphonyl-glutamates were found to be inhibitors of the prostate-specific membrane antigen (PSMA) form of glutamate carboxypeptidase II. Comparative inhibitory profiles of an analogous O-thiophosphonyl-2-hydroxyglutarate revealed that the amido-linkage of the N-thiophosphonyl-glutamate provides a significant enhancement of inhibitory potency presumably due to significant hydrogen-bonding interactions with acceptor groups in the active-site of PSMA resulting in tighter binding. An analogous N-phosphonyl-glutamate exhibited significantly greater inhibitory potency than the parent N-thiophosphonyl-glutamate indicating that the sulfur ligand of the N-thiophosphonyl-glutamates is responsible for less favorable active-site interactions than oxygen, potentially due to steric crowding from the longer P-S bond or as a result of active-site metal substitution of Co(II) for Zn(II) arising from assay conditions.
Rodriguez
C E
CE
Department of Chemistry and Biochemistry, San Francisco State University, CA 94132, USA.
Lu
H
H
Martinez
A R
AR
Hu
Y
Y
Brunelle
A
A
Berkman
C E
CE
D000954:Antigens, Surface; D001665:Binding Sites; D001667:Binding, Competitive; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D043425:Glutamate Carboxypeptidase II; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D008297:Male; D063086:Organothiophosphates / Q000138:chemical synthesis / Q000494:pharmacology*; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors; D011485:Protein Binding; D013329:Structure-Activity Relationship
D000954:Antigens, Surface; D004791:Enzyme Inhibitors; D063086:Organothiophosphates; D018698:Glutamic Acid; D002268:Carboxypeptidases; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D017430:Prostate-Specific Antigen