Metallopro teases

The continuous increase of antibiotic resistance, including the emergence of multidrug resistance in common pathogens, has created an urgent need for antibiotics with novel mechanisms of action. PDF, an essential metallopro-tease that removes the V-formyl group of all newly synthesised bacterial... 

Hase, C.C. and Finkelstein, R.A., Bacterial extracellular zinc-containing metallopro-teases, Microbiol. Rev., 57, 823-837, 1993. 

Lammich S, Kojro E, Postina R, et al. Constitutive and regulated alpha-secretase cleavage of Alzheimer s amyloid precursor protein by a disintegrin metallopro-tease. Proc Natl Acad Sci USA 1999 96 3922-3927. 

Marimastat matrix metallopro teases competitive, active site inhibits many MMPs inhibits MMP 1,2,7,8,9 ICffl < 20 nM (50)... 

Liabakk, N., Talbot, 1., Smith, K., Wilkinson, K., and Balkwill, P. (1996). Matrix metallopro-tease 2 (MMP-2) and matrix metalloproteahie 9 (MMP-9) type IV collagenases in colorectal cancer, CaPiCer Rfs. 56,190-196. 

The zincin proteases remodel the stroma during development and around tissues that have been injured or stressed (Sects. 13.2.4). All proteases possess one of the three types of activities (a) (Sects. 13.2.5) that cut within a polypeptide (b) (Sects. 13.3.1) that cut at the C- orN-terminus and (c) peptidases that cut small polypeptides. The five structural classes of proteases are listed in Table 8.1 and the enzymatic activities of the various metallopro-tease classes and subclasses are listed in Table 8.2. 

In addition to hydrogen bonding, there are other important polar interactions in protein-ligand complexes such as coordinative bonds with metal ions. For example, hydroxamic acids and thiols bind strongly to the zinc ion in the active site of metalloproteases [49], This interaction appears to be the most important contribution to binding in many metallopro-tease-inhibitor complexes. 

Musso DL et al (2001) N-hydroxyformamide peptidomimetics as TACE/matrix metallopro-tease inhibitors oral activity via PI isobutyl substitution. Bioorg Med Chem Lett 11 (16) 2147—2151... 

Leucine aminopeptidase is interesting in that its active site contains two zinc atoms which together bind and activate the water molecule [74]. Despite this enzyme containing a dinuclear metal center at its active site, its mechanism, and specifically its mode of proton transfers reactions, appear to follow the general theme established by thermolysin and carboxypeptidase Adenosine deaminase and other members of the family of nucleoside and nucleotide deaminases utilize zinc-bound water as the catalytic nucleophile to displace ammonia from the 6-position of purines or the 4-position of pyrimidines and in all cases display inverse solvent deuterium isotope effects ranging from 0.3 to 0.8 on fec/Kni [75-80]. These effects are reminiscent of those observed for metallopro-teases and have their origins, like those of the proteases, in fractionation factors for the protons of the bound water that are less than one. 

AG3340 (Prinomastat), a selective inhibitor of matrix metalloproteases, also inhibits retinal neovascularization in an animal model (63). Subsequently, a Phase II, randomized, double-masked, placebo-controlled study of the matrix metallopro-tease inhibitor AG3340 in patients with subfoveal CNV associated with AMD was conducted. The outcome of this study, however, was not released and the company decided not to proceed with a Phase III trial. 

Murata, C. E., and Goldberg, D. E. (2003a). Plasmodium falciparum falcilysin a metallopro-tease with dual specificity. J. Biol. Chem. 278,38022-38028. 

Tauro, J. R., B.-S. Lee, S. S. Lateef, andR. A. Gemeinhart. 2008. Matrix metallopro tease selective peptide substrates cleavage within hydrogel matrices for cancer chemotherapy activation. Peptides 29 1965-73. 

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