Zn-metalloproteases

Several Zn metalloproteases play an important role in A 3 turnover in the CNS [156]. Insulin degrading enzyme (IDE), neprilysin (NEP), endothelin-converting enzyme, angiotensin-converting enzyme, thimet oligopeptidase and MMPs have all demonstrated A 3 cleavage activity in vitro and/or in vivo [156]. Numerous studies have examined in great detail how Zn modulates the protease activity of these enzymes [157]. Unfortunately, little is known... 

One of the most powerful derivatization techniques of Pi position was presented in 2003 by Makaritis et al. They prepared phosphinic pseudodipeptide precursors bearing a propargyl group in their Pi side chain (42) and saw that these molecules can serve as excellent dipolarophiles in 1,3-dipolar cycloadditions with in situ-prepared nitrile oxides (Scheme 21) [74], This approach can be easily applied in both solid phase and solution s5mtheses, and has been successfully used in the discovery of selective inhibitors of several Zn-metalloproteases [38, 84, 92, 103, 104]. 

Although native PDFs utilise Fe rather than Zn, the PDF metal-binding site is still very representative of a traditional zinc-metalloprotease [57], containing a conserved HEXXH motif. Crystal structures of the Fe ", Ni ", ... 

Metalloprotease inhibitors - also known as metalloproteases or zinc proteases - are proteolytic enzymes of which the activity depends on metal ions, normally bound Zn -. Examples of metalloproteases are the pancreatic enzymes carboxypeptidase A and B, elastase, the well-characterized bacterial enzyme thermolysin and the collagenase family (found in both bacterial and mammalian cells, fibroblast collagenase, neutrophil elastase, gelatinase). 

Figure 5-2. Typical conservation patterns of three protein classes. Residues invariant or conserved in more than 80% ofthe sequences are printed on a black or grey background, respectively. A Mainly nonpolar conservation in the UBA domain, a small protein domain that interacts preferentially with ubiquitin1781. B Invariant polar active site residues in the phospholipase D family1291. C Nearly invariant metal-binding residues in the HtpX/Ste24 family of Zn-containing metalloproteases.

Fig. 2. Catalytic motifs of thermolysin-like metalloproteases (a) a H2O chelates Zn + as part of the catalytic motif, (b) no H2O participate in the catalytic motif (modified from Auld, 1997, and Pelmenschikov Siegbahn, 2002, respecively).

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