Metallocarboxypeptidase D

Carboxypeptidase D (CPD) is officially named “metallocarboxypeptidase D” to distinguish it from a serine carboxypeptidase also named carboxypeptidase D. The gene name CPD refers to the metallocarboxypeptidase described in this chapter. CPD is a member of the metallocarboxypeptidase M14B subfamily, also known as the N/E subfamily. CPD consists of multiple carboxypeptidase-like domains, followed by a transmembrane domain and a cytosolic tail. In vertebrates and most other species, CPD has three carboxypeptidase-like domains, of which domains 1 and 2 are enzymatically active, while domain 3 lacks critical active-site residues and is devoid of activity. Domains 1 and 2 cleave peptides with C-terminal basic residues, albeit with different efficiency at cleaving Lys and Arg residues and with different pH optima. Domain 1 is more active at neutral pH, while domain 2 is optimal at acidic pH. The enzyme is primarily located in the trans-Golgi network, cycles to the cell surface via the constitutive exocytic pathway, and returns to the Golgi via the endocytic pathway. CPD is active in all intracellular compartments as well as on the cell surface, with different contributions from the first and second domains due to the variable pH of these compartments. CPD is broadly distributed among tissues and functions in the processing of proteins that transit the secretory pathway, which are initially processed by furin and related endopeptidases. These endopeptidases cleave at sites containing basic residues, and CPD removes C-terminal Lys and Arg from the processing intermediates. In neuroendocrine tissues that produce peptide hormones and/or neuropeptides, CPD plays a minor role in their production, with the major role played by carboxypeptidase E. CPD expression levels have been correlated with cancer, and CPD inhibitors may potentially be useful antineoplastics.