Proteases families

The nonstructural region of the precursor, harboring the viral replication machinery, is cut into its mature components in a maturation reaction in which two viral proteases (NS2-pro and NS3/4A-pro) cooperate. Site-directed mutagenesis of an other wise infectious cDNA has shown that both HCV-encoded proteases are necessary for viral infectivity, but most of the attention has so far been focused on one of them a member of the serine protease family (EC 3.4.21) located in the N-terminal region of the viral NS3 protein. 

The outstanding inclusion ability and the carboxylic functions of host I raised the idea of co-erystallizing it with imidazole (Im) which, due to its versatile nature 114), is one of the frequently used components in enzyme active sites, generally presented by histidine. Formally, a system made of imidazole and an acid component may mimic two essential components of the so-called catalytic triad of the serine protease family of enzymes the acid function of Aspl02 and the imidazole nucleus of His57 115) (trypsin sequence numbering). The third (albeit essential) component of the triad corresponding to the alcohol function of Seri 95 was not considered in this attempt. This family of enzymes is of prime importance in metabolitic processes. 

Scallan, M.J., Raj, B.K.M., Calvo, B., Garin-Chesa, P., Sanz-Moncasi, M.P., Healey, J.H., Old, L.J. and Rettig, W.J. (1994) Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblast of epithelial cancers. Proceedings of the National Academy of Sciences ofthe United States of America, 91, 5657-5661. 

CysPc Calpain-like thiol protease family E(MF)B 1(1) 14(14) ... 

The situation with the domain families of the ubiquitin-mediated pathway contrasts with the domain families that function in animal and plant programmed cell death, or apoptosis. As reviewed elsewhere (Ara-vind et al., 1999b), a few domains in eukaryotic apoptotic proteins have prokaryotic homologs, including the cysteine protease family of caspases... 

In A. vinelandii, C-terminal cleavage occurs in crude extracts after restoration of nickel and requires hours rather than minutes, as is the case in vivo. It does not require de novo protein synthesis and surprisingly is not redox or O2 sensitive. Also, it is not inhibited by well-established inhibitors of metallo- or serine protease families (Menon and Robson 1994). 

Proteins can be classed into groups based on their overall 3-D shapes, known as protein folds (O Figure 22-la). In general, proteins that have similar functions have similar folds. This means that if you are the proud parent of an unknown protein whose structure is solved, it may be possible to make educated guesses as to the function of the protein based on its overall fold. There are a number of well-known exceptions to this [notably, the serine protease family, subtilisin and trypsin/chymotrypsin (Hartley, 1979)], but the... 

Mercaptoacyl pharmacophore library. Zinc metalloproteases are inhibited by small molecules that contain mercaptans (thiols -CH2SH), carboxylic acids (-CO2H), and hydroxamic acids (-CONHOH). These functional groups chelate the active-site metal disrupting normal enzyme function. The angiotensinconverting enzyme (ACE) inhibitor Captopril is an example of a thiol-based metalloprotease inhibitor. Thiols, carboxylic acids, and hydroxamic acids are consequently affirmed pharmacophores for this protease family. A historical example of a pharmacophore-... 

A second example of protease inhibitor design that properly illustrates the peptide scaffold-based approach is that of thrombin inhibitors. Work with these compounds led to the identification of highly potent, selective, and in vivo-effective lead compounds. A member of the serine protease family, thrombin cleaves a number of substrates (e.g., fibrinogen) and activates its platelet receptor (a G-protein-coupled receptor) by proteolysis of the extracellular N-terminal domain which results in self-activation (for a review see Reference 66). Initial lead inhibitors of thrombin were substrate-based, including the fibrinogen P3-Pi Phe-Pro-Arg sequence [67] and simple Arg derivatives such as Tos-Arg-OMe [68]. 

Trypsin, chymotrypsin, and elastase—three members of the serine protease family—catalyze the hydrolysis of proteins at internal peptide bonds adjacent to different types of amino acids. Trypsin prefers lysine or arginine residues chymotrypsin, aromatic side chains and elastase, small, nonpolar residues. Carboxypeptidases A and B, which are not serine proteases, cut the peptide bond at the carboxyl-terminal end of the chain. Carboxypeptidase A preferentially removes aromatic residues carboxypeptidase B, basic residues. (Illustration copyright by Irving Geis. Reprinted by permission.)... 

Sorimachi, H., Ohmi, S., Emori, Y., Kawasaki, H., Saido, T., Ohno, S., Minami, Y., Suzuki, K., 1990, A novel member of the calcium-dependent cysteine protease family, Biol. Chem. Hoppe Seyler., 371, 171-6... 

From a structural point of view, kallikreins belong to the serine protease family of enzymes. The essential features of serine proteases that are preserved in the kallikreins can be summarized as follows only one serine residue of the protein is catalytically active two residues, a histidine and an... 

Characterization of HIV-1 protease as a member of the aspartic acid protease family provided the rationale for most of the efforts to design inhibitors (Kohl et al, 1988 Krausslich et al., 1988 Navia et al., 1989 Pearl and Taylor, 1987). Previous efforts to develop therapeutically useful inhibitors of the mechanistically related enzyme renin had demonstrated that potent inhibitors could be prepared by replacing the scissile amide bond of a substrate analogue with a nonhydrolyzable isostere to mimic the tetrahedral intermediate or transition state involved in amide hydrolysis (Greenlee, 1990). Although several dipeptide isosteres have been used to successfully generate highly potent HIV-1 protease inhibitors, a relatively small number have resulted in compounds that reached clinical development. 

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