Metallocarboxypeptidases: Emerging Drug Targets in Biomedicine

Abstract

Metallocarboxypeptidases (MCPs) are commonly regarded as exopeptidases that actively participate in the digestion of proteins and peptides. In the recent years, however, novel MCPs comprising a wide range of physiological roles have been found in different mammalian extra-pancreatic tissues and fluids. Among them, CPU, also known as thrombin-activatable fibrinolysis inhibitor (TAFI), has been shown to cleave C-terminal Lys residues from partially degraded fibrin, acting as inhibitor of clot fibrinolysis and therefore constituting an important drug target for thrombolytic therapies. Other MCPs such as CPE, CPN, CPM, and CPD function as pro-hormone and neuropeptide processors and display several structural differences with the pancreatic-like enzymes. In addition, important advances have been made in the discovery and characterization of new endogenous and exogenous proteinaceous inhibitors; the structural determination of their complexes with several MCPs has revealed novel binding modes. Finally, the use of MCPs in antibody-directed enzyme pro-drug therapy (ADEPT) has proved to be an efficient approach for the delivery of lethal levels of chemotherapeutic drugs specifically at tumor tissues. Taken together, these recent developments may help to understand potential biomedical implications of MCPs. Future perspectives for the regulation of these enzymes through the use of more selective and potent inhibitors are also discussed in this review and combined with earlier observations in the field.

CCP1/Nna1 functions in protein turnover in mouse brain: Implications for cell death inPurkinje cell degenerationmice

“…1). While aminopeptidases are thought to contribute to intracellular peptide degradation, the dogma in the field is that carboxypeptidases are not involved, despite the im-portant role that carboxypeptidases play in degradation of peptides in the intestine and other extracellular compartments (2)(3)(4).…”

A novel subfamily of mouse cytosolic carboxypeptidases

“…Carboxypeptidases (CPs) perform a large number of functions throughout the body, ranging from the digestion of food to the biosynthesis of peptides that function in intercellular signaling (1). Most CPs are present in the secretory pathway of various cell types, functioning either within the cell by processing molecules that are secreted or functioning after secretion by processing extracellular peptides and proteins.…”

Plasticity in the Oxidative Folding Pathway of the High Affinity Nerita Versicolor Carboxypeptidase Inhibitor (NvCI)

“…Several MCPs have been linked to human diseases, such as cancer, alzheimer disease, type 2 diabetes, acute pancreatitis and pancreas cancer, fibrinolysis and inflammation. Consequently, MCPs and their strong, small protein inhibitors have been of considerable medical interest as potential drug targets or effectors 27, 28 . The study of folding/unfolding pathways allows to gain insight into the essential elements that confer foldability and stability to MCPs inhibitors and is prerequisite for their production, minimization and redesign for biomedical and biotechnological purposes.…”