Glutamate carboxypeptidase II

MH M28 M28.010 Glutamate carboxypeptidase II Diagnosis and assessment of prostatic carcinoma... 

Bacich D. J., Ramadan E., O Keefe D. S., Bukhari N., Wegorzewska I., Ojeifo O., Olszewski R., Wrenn C. C., Bzdega T., Wroblewska B., Heston W. D., and Neale J. H. (2002). Deletion ofthe glutamate carboxypeptidase II gene in mice reveals a second enzyme activity that hydrolyzes N-acetylaspartylglutamate. J. Neurochem. 83 20-29. 

Berger U. V., Luthi-Carter R., Passani L. A., Elkabes S., Black I., Konradi C., and Coyle J. T. (1999). Glutamate carboxypeptidase II is expressed by astrocytes in the adult rat nervous system. J. Comp. Neurol. 415 52-64. 

Luszczki J. J., Mohamed M., and Czuczwar S. J. (2006). 2-phosphonomethyl-pentanedioic acid (glutamate carboxypeptidase II inhibitor) increases threshold for electroconvulsions and enhances the antiseizure action of valproate against maximal electroshock-induced seizures in mice. Eur. J. Pharmacol. 531 66-73. 

Thomas AG, Wozniak KM, Tsukamoto T, Calvin D, Wu Y, et al. 2006. Glutamate carboxypeptidase II (NAALADase) inhibition as a novel therapeutic strategy. Adv Exp Med Biol 576 327-337 discussion 361—323. 

E., Wroblewski, J. T, Yamamoto, T, Bzdega, T, Wroblewska, B., Neale, J. H. Synthesis of urea-based inhibitors as active site probes of glutamate carboxypeptidase II efficacy as analgesic agents. J. Med. Chem. 2004, 47(7), 1729-1738. 

Glutamate carboxypeptidase II Glutathione S-transferase Glycoprotein hormones alpha chain GMCSF... 

Another contrast between the zinc proteases and the carbonic an-hydrases concerns the zinc coordination polyhedron. The carbonic an-hydrases ligate zinc via three histidine residues, whereas the zinc proteases ligate the metal ion through two histidine residues and a glutamate (bidentate in carboxypeptidase A, unidentate in thermolysin). Hence, the fourth ligand on each catalytic zinc ion, a solvent molecule, experiences enhanced electrostatic polarization in carbonic anhydrase II relative to carboxypeptidase A. Indeed, the zinc-bound solvent of carbonic anhydrase II is actually the hydroxide anion [via a proton transfer step mediated by His-64 (for a review see Silverman and Lindskog, 1988)]. 

One possible mechanism for the hydrolysis of peptides or esters by carboxypeptidase A involves two steps with an anhydride (acyl-enzyme) intermediate.418 In the first step, the zinc(II) activates the substrate carbonyl group towards nucleophilic attack by a glutamate residue, resulting in the production of a mixed anhydride (127). Breakdown of the anhydride intermediate is rate determining with some substrates.419 An understanding of the chemistry of metal ion effects in anhydride hydrolysis is therefore of fundamental importance in regard to the mechanism of action of the enzyme. Until recently there have been few studies of metal ion-catalysed anhydride solvolysis. 

Another strategy for biological amide hydrolysis is exemplified by carboxypeptidase A. The electrophilic stabilization of the T.I. is now imparted by a Zn(II) ion and a guanidinium side chain from arginine-127. A zinc-bound water acts as the nucleophile, which is enhanced by general-base catalysis from the glutamate-270 side chain... 

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