Structure of membrane glutamate carboxypeptidase.
Membrane glutamate carboxypeptidase (mGCP) hydrolyses pteroylpoly-gamma-glutamates, methotrexate tri-gamma-glutamate and N-acetyl-aspartyl-alpha-glutamate. The enzyme is thought to be required for intestinal uptake of folate, for the resistance of some tumours to methotrexate, and for the metabolism of N-acetyl-aspartyl-glutamate, an abundant neuropeptide. It has recently been reported that mGCP is a protein also known as prostate-specific membrane antigen, homologous with transferrin receptor. This allows us to predict the domain structure of mGCP. Moreover, we have been able to assign the catalytic domain of mGCP to peptidase family M28, which contains cocatalytic zinc metallopeptidases. On the basis of the known structure of an aminopeptidase in family M28, we predict that Asp377, Asp387, Glu425, Asp453 and His553 are ligands of two atoms of zinc bound in the catalytic site of mGCP, and suggest that the aminopeptidases of Vibrio and Streptomyces can serve as valuable models in the design of inhibitors for this medically important enzyme.
Rawlings
N D
ND
Department of Immunology, The Babraham Institute, Cambridge, UK.
Barrett
A J
AJ
D000595:Amino Acid Sequence; D001665:Binding Sites; D002268:Carboxypeptidases / Q000737:chemistry*; D002462:Cell Membrane / Q000201:enzymology; D006801:Humans; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011990:Receptors, Transferrin / Q000737:chemistry; D016415:Sequence Alignment
D011990:Receptors, Transferrin; D002268:Carboxypeptidases; C026134:glutamate carboxypeptidase