STRUCTURE OF MEMBRANE GLUTAMATE CARBOXYPEPTIDASE

Membrane glutamate carboxypeptidase (mGCP) hydrolyses pteroylpoly-gamm a-glutamates, methotrexate tri-gamma-glutamate and N-acetyl-aspartyl-a lpha-glutamate. The enzyme is thought to be required for intestinal up take of folate, for the resistance of some tumours to methotrexate, an d for the metabolism of N-acetyl-aspartyl-glutamate, an abundant neuro peptide. It has recently been reported that mGCP is a protein also kno wn as prostate-specific membrane antigen, homologous with transferrin receptor. This allows us to predict the domain structure of mGCP. More over, we have been able to assign the catalytic domain of mGCP to pept idase family M28, which contains cocatalytic zinc metallopeptidases. O n the basis of the known structure of an aminopeptidase in family M28, we predict that Asp(377), Asp(387), Glu(425), Asp(453) and His(553) a re ligands of two atoms of zinc bound in the catalytic site of mGCP, a nd suggest that the aminopeptidases of Vibrio and Streptomyces can ser ve as valuable models in the design of inhibitors for this medically i mportant enzyme.