Serine proteases classification

Protease Classification. In order to rationally design an inhibitor for a protease it is first necessary to place it into one of four families of proteases (see Table V). For a new enzyme, a study of its inhibition profile with a series of general protease inhibitors is sufficient to classify it into one of the four families. The inhibitors usually used are diiso-propylphosphofluoridate (DFP) or phenylmethane sulfonyl fluoride (PMSF) for serine proteases, 1,10-phenanthroline for metalloproteases, thiol reagents such as iodoacetate or N-ethylmaleimide for thiol proteases, and pepstatin or diazo compounds such as diazoacetyl-norleucine methyl ester for carboxyl proteases. 

Proteases are classified according to their catalytic mechanism. There are serine, cysteine, aspartic, and metalloproteases. This classification is determined through reactivity toward inhibitors that act on particular amino acid residues in the active site region of the enzyme. The serine proteases are widely distributed among microbes. The enzymes have a reactive serine residue in the active site and are generally inhibited by DFP or PMSF. They... 

Lang, S.A., Kozyukov, A.V., Balakin, K.V., Skorenko, A.V., Ivashchenko, A.A. and Savchuk, N.P. (2002) Classification scheme for the design of serine protease targeted compound libraries. J Comput Aided Mol Design, 16, 803-807. 

Figure 19.16 Chemical depiction of the protease classification system showing both the metabolic machinery and the transition state that Is thought to be operative for each case. (A) represents both serine (X=0) and cysteine (X=S) proteases with each of these specific amino acids being Implicated, respectively. (B) exemplifies an aspartic protease with the latter playing a key catalytic function within the active site. (C) depicts the metallo proteases with Zn++ representing one of the most common. Suspected transition states / for each protease reaction are shown within brackets.

Peptidases or proteases are enzymes that hydrolyse peptide bonds [9]. Proteolytic enzymes can be classified in five classes on basis of their catalytic mechanism aspartic, metallo-, cysteine, threonine and serine peptidases, whereby the latter three follow the same basic mechanism (Scheme 7.3) [10], Another classification of peptidases on the basis of statistically significant similarities in amino acid sequences was presented by Rawlings et al. (MEROPS database) [11], Serine proteases (SP) alone cover approximately one-third of all known proteases, and can accelerate the peptide hydrolysis very efficiently 10 fold) [6,11,12], SPs also hydro-... 

Based on their sequence homology, disulfide connectivity, and cysteine location within the sequence and chemistry of the reactive site. Pis can be assigned to distinct families, as classified by Laskowski and Kato. Kunitz-type, Bowman—Birk-type, Potato type I and type II, and squash inhibitors are members of these families shown in Table 3. For inhibitors not falling into these classifications more families have been proposed. Pis can also be classified by their target/mode of action. Plants have been found to express Pis that target serine proteinases, cysteine proteinases, aspartic proteinases, and metallo-proteinases. Serine and cysteine protease inhibitors are the best-studied PIs. ... 

Classincation of the Proteases. The classification of the proteases is based on their mechanism of catalysis (4), The four primary classes of proteases are the serine, aspartic, cysteine, and metalloproteases (5). This classification is based on the primary functional group found in the en me s active site. There are likely to be other proteases eventually characterized which will not precisely fit into this categorization scheme and additional categories will be needed. One example of a potential new category is the ATP-dependent proteinases (6), a group of proteinases which require ATP for activity. 

Proteases are grossly subdivided into two major groups, such as exopeptidases and endopeptidases, depending on their site of action. Based on the functional group present at the active site, proteases are further classified into four prominent groups, such as serine, aspartic, cysteine, and metal-loproteases (Hartley, 1996). There are a few miscellaneous proteases that do not precisely fit into the standard classification and one of them is ATP-dependent proteases (Menon et al., 1987). The flow sheet for classification of peptide hydrolases is given in Figure 9.3. 

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