CARBOXYPEPTIDASE INHIBITORS

CARBOXYPEPTIDASE INHIBITORS act against various members of carboxypeptidase enzyme family that cleave the C-terminal residue from oligopeptides or from proteins. They can be divided into classes on the basis of their functional characteristics. These classes are dealt with separately in terms of their alternate names, notable substrates and inhibitors. Most of these are thought to correspond to the metalloproteinase class of enzyme. There are a number of enzymes of special interest in relation to their neuropeptidase actions.

Dipeptidyl carboxypeptidase A (EC 3.4.15.1; angiotensin-converting enzyme; ACE; kininase II) is a much-studied zinc-metalloproteinase, cleaving the last two carboxyterminal residues of peptides. It has a wide distribution and is found in a membrane-bound form, notably on vascular endothelial cells and in plasma. Notable substrates include angiotensin I (converted to an active product, angiotensin II), bradykinin, cholecystokinin, gastrin, leucine-enkephalin, methione-enkephalin, LH-RH, neurotensin and substance P. Inhibitors include the large family of ACE inhibitors used in therapeutics as antihypertensives. Examples in clinical use include captopril, cilazapril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril and trandolapril. ACE inhibitors can be administered clinically as prodrugs that are converted to the active molecule in vivo, e.g. enalapril to enalaprilat, and ramipril to ramiprilat. See ACE INHIBITORS.

Carboxypeptidase H (EC 3.4.27.10; carboxypeptidase H; enkephalin convertase) is not fully characterized, and may be a metalloproteinase. Substrates of this enzyme, found in cell membranes and secretory vesicles, include enkephalins, bradykinin and ATRIAL NATRIURETIC peptide. Two mercapto inhibitors used are MERGETPA (MGTA) and GEMSA, but they are not very selective.

Carboxypeptidase N (EC 3.4.17.3; kininase I; arginase carboxypeptidase) is a zinc-metalloproteinase. Notable substrates of this soluble enzyme include: bradykinin (to form [desArg9]-BK, active at B1 bradykinin receptors), enkephalins and atrial natriuretic peptide. An inhibitor used is MERGETPA, but it is not very selective.

Carboxypeptidase P (EC 3.4.17.-; prolylcarboxypeptidase; angiotensinase C) is not fully characterized, and may be a metalloproteinase. Notable substrates of this plasma membrane enzyme include enterostatin. Inhibitors include EDTA and o-phenanthroline.