Inhibition of glutamate carboxypeptidase II by phosphonamidothionate derivatives of glutamic acid.

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Rodriguez CE, Lu H, Martinez AR, Hu Y, Brunelle A, Berkman CE

Inhibition of glutamate carboxypeptidase II by phosphonamidothionate derivatives of glutamic acid.

J Enzyme Inhib. 2001 Oct;16(4):359-65.

PubMed ID

11916141 [ View in PubMed

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Abstract

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.

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Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Glutamic acid	Glutamate carboxypeptidase 2	Protein	Humans	Unknown	Not Available	Details