Cathepsin angiotensin

Chloride ions are known to be required for the activity of only a few enzymes — certain peptidases. These peptidases include angiotensin II (Bunning and Rior-dan, 1983,1987), an enzyme that participates in the regulation of salt metabolism, and the cathepstns. The cathepsins are located in lysosomes, organelles used for the hydrolysis of nutrients recently transported into the cell. 

Carboxypeptidase is a unique 34.5 kDa metalloproteinase which removes the carboxyl terminal residues from a range of peptides, including angiotensin, leu -enkephalin, kinetensin, neuromedin N and neurotensin (Goldstein etal., 1989, 1991 Bunnett etal., 1992). As carboxypeptidase is released together with chymase, cathepsin G and proteoglycan in a 400-500 kDa complex, it is likely to act in concert with the other enzymes to degrade proteins. 

Another type of enzyme, termed a dipeptidyl aminopeptidase, releases dipeptides rather than amino acids from the /V-terminus. Cathepsin C is one such enzyme and it will remove dipeptides consecutively from the /V-terminus of a peptide until either Lys or Arg becomes the /V-terminal amino acid or until Pro is in position 2 or 3 in the chain. Thus two dipeptides, Asp—Arg and Val—Tyr are cleaved from angiotensin II ... 

Dipeptidyl carboxypeptidases remove the C-terminal dipeptide intact and therefore are analogous to the dipeptidyl aminopeptidases such as cathepsin C. One such enzyme, angiotensin-converting enzyme, is important biologically for converting angiotensin I into the hypertensive angiotensin II (see Section 9.3). This enzyme does not hydrolyse bonds of the type X—Pro but will hydrolyse Pro—X bonds. The use of dipeptidyl carboxypeptidases for sequence determination would probably increase if pure enzymes were readily available commercially. 

Figure 8.10 Some bioisosteric replacements for carboxylic acids (top) (Carini, D.J., et al. Nonpeptide angiotensin II receptor antagonists The discovery of a series of A-(Biphenylmethyl) imidazoles as potent, orally active antihypertensives. J. Med. Chem. 1991, 34, 2525-2547), esters (middle) (Kim, K.S., et al. Discovery of aminothiazole inhibitors of cyclin-dependent kinase 2 Synthesis, X-ray crystallographic analysis, and biological activities. /. Med. Chem. 2002, 45, 3905-3927.), and amides (bottom) (Black, W.C., et al. Trifluoroethylamines as amide isosteres in inhibitors of cathepsin K. Bioorg. Med. Chem. Lett. 2005,15,4741 744.) The clinical candidate odanacatib (bottom right) incorporates a trifluoroethylamine amide isostere. (Gauthier, J.Y., et al. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg. Med. Chem. Lett. 2008,18,923-928.)...

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