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.

Identification of Novel Genes That Modify Phenotypes Induced by Alzheimer's β-Amyloid Overexpression in Drosophila

“…In our studies we have identified carboxypeptidase D, which belongs to a family of enzymes that proteolytically process peptides in the secretory pathway (Arolas et al 2007), as a modifier of Ab toxicity. Previous reports have identified carboxypeptidase B as an enzyme that may degrade Ab intracellularly (Matsumoto et al 2001) by processing its carboxy terminus (Hamazaki 1998).…”

Characterization of Carboxypeptidase A6, an Extracellular Matrix Peptidase

“…It appears that the limiting factor in this cleavage is the removal of Leu 10 , as extremely small amounts of angiotensin 1-9 are detected relative to the amount of angiotensin II (i.e. angiotensin [1][2][3][4][5][6][7][8]. Thus, removal of His 9 appears to proceed faster than removal of Leu 10 .…”

“…All metallo-CPs have structurally similar CP domains. In addition to the CP domain, all A/B members contain an N-terminal propeptide that is necessary for folding and is cleaved off upon enzyme activation (1,4). The majority of A/B and N/E enzymes are secreted and function outside of the cell.…”

Fibroblast growth factor-1 (FGF-1) promotes adipogenesis by downregulation of carboxypeptidase A4 (CPA4) – a negative regulator of adipogenesis implicated in the modulation of local and systemic insulin sensitivity

“…They play key roles in processes including the degradation of proteins within the digestive tract as well as in the biosynthesis of peptide hormones and neuropeptides (Sapio and Fricker 2014). Hence there is considerable interest in defining the distinct roles of the carboxypeptidases, which are recognized as potential drug targets (Arolas et al 2007). Indeed, elevated CPA4 expression has been linked with increased aggressiveness of cancers including prostate cancer and non-small lung cell cancer (Sun et al 2016, Witte et al 2000).…”