Peptidases clans

In the C-terminal domain are five helices in a closed bundle. This characteristic fold is typical of thermolysin-like peptidases. Clan MC contains metallocarbox-ypeptidases which belong to only one family (M14) which is divided into the subfamilies A, B and C. Typical for this clan is that one zinc ion is tetrahedrally coordinated by a water molecule, two histidine and one glutamate residues. Clan MF includes aminopeptidases that require cocatalytic zinc ions for their enzymatic activity. The well-known leucyl aminopeptidase has a two-domain structure bearing the active site in the C-terminal domain. Whereas exopeptidases of clan MG require cocatalytic ions of cobalt or manganese, clan MH contains the third group of metallopeptidases that also require cocatalytic metal ions, but here these are all zinc ions. The third clan in which cocatalytic metal ions are necessary is clan MF with zinc or manganese. Only one catalytic zinc ion is required for peptidases of clans MA, MB, MC, MD and ME. 

All peptidases within a family will have a similar tertiary structure, and it is not uncommon for peptidases in one family to have a similar structure to peptidases in another family, even though there is no significant sequence similarity. Families of peptidases with similar structures and the same order of active site residues are included in the same clan. A clan name consists of two letters, the first representing the catalytic type as before, but with the extra letter P , and the second assigned sequentially. Unlike families, a clan may contain peptidases of more than one catalytic type. So far this has only been seen for peptidases with protein nucleophiles, and these clans are named with an initial P . Only three such clans are known. Clan PA includes peptidases with a chymotrypsin-like fold, which besides serine peptidases such as chymotrypsin... 

Clan Family Code Peptidase Pathology or pharmacology... 

Inhibitors which interact only with peptidases of one catalytic type include pepstatin (aspartic peptidases) E64 (cysteine peptidases from clan CA) diisopropyl fluorophosphates (DFP) and phenylmethane sulfonyl-fluoride (PMSF) (serine peptidases). Bestatin is a useful inhibitor of aminopeptidases. 

Rawlings, N. D. Barrett, A. J. Introduction serine peptidases and their clans. In Handbook of Proteolytic Enzymes, 2nd edition Barrett, A. J. Rawlings, N. D. Woessner, J. F., Eds. Elsevier Academic Press Amsterdam, Boston, Heidelberg, London, New York, Oxford, Paris, San Diego, San Francisco, Singapore, Sydney, Tokyo 2004, pp 1417-1439. 

Table 2.1. Examples of Clans and Families of Peptidases, with Focus on Eukaryotes (taken... 

The evolutionary classification has a rational basis, since, to date, the catalytic mechanisms for most peptidases have been established, and the elucidation of their amino acid sequences is progressing rapidly. This classification has the major advantage of fitting well with the catalytic types, but allows no prediction about the types of reaction being catalyzed. For example, some families contain endo- and exopeptidases, e.g., SB-S8, SC-S9 and CA-Cl. Other families exhibit a single type of specificity, e.g., all families in clan MB are endopeptidases, family MC-M14 is almost exclusively composed of carboxypeptidases, and family MF-M17 is composed of aminopeptidases. Furthermore, the same enzyme specificity can sometimes be found in more than one family, e.g., D-Ala-D-Ala carboxypeptidases are found in four different families (SE-S11, SE-S12, SE-S13, and MD-M15). 

A. J. Barrett, N. D. Rawlings, Families and Clans of Cysteine Peptidases , Perspect. Drug Discov. Design 1996, 6, 1-11. 

Barrett AJ, Rawlings ND. Families and clans of serine peptidases. Arch Biochem Biophys 1995 318 247-250. 

Several vital processes rely on clan PA peptidases. Chief among them are blood coagulation and the immune response, which involve cascades of sequential zymogen activation. In both systems, the chymotrypsin-fold peptidase domain is combined with one more associated protein domains, including apple, CUB, EGF, fibronectin, kringle, sushi, and von Willebrand factor domains. These protein domains are on the N-terminus as an extension of the propeptide segment of the peptidase. Such a trend of N-terminal-associated domains in the SIA peptidase family is common across all forms of life. The domain architecture pairs well with the zymogen activation mechanism, which liberates the proper N-terminus to enable catalytic activity. Often, the associated protein domains remain attached to... 

Clan SC peptidases are a/p hydrolase-fold enzymes that consist of parallel P-strands surrounded by a-helices. The a/p hydrolase-fold provides a versatile catalytic platform that, in addition to achieving proteolytic activity, can either act as an esterase, lipase, dehalogenase, haloperoxidase, lyase, or epoxide hydrolase (18). Six phylogenetically distinct families of clan SC are known, and oifly four of them have known structure. Catalytic amenability of the a/p hydrolase-fold may underlie why clan SC peptidases are the second largest family of serine peptidases in the human genome. Other mechanistic classes need not use the catalytic serine and instead use cysteine or glutamic acid (19). Clan SC peptidases present an identical geometry to the catalytic triad observed in clans PA and SB, yet this constellation is ordered differently in the polypeptide sequence. Substrate selectivity develops from the a-helices that surround the central P-sheet core. Within clan SC, carboxypeptidases from family SIO are unique for their ability to maintain... 

About 40 families of serine- and threonine-type peptidases can be distinguished on the basis of sequence comparison. However, only a few known families of threonine-dependent peptidases are included therein. By comparing the tertiary structures and the order of the catalytic residues in the sequence most of these families can be grouped into seven clans (cf. Table 12.5-2). 

Clan SC contains peptidases with the a/P hydrolase fold bearing the catalytic triad in the order Ser, Asp, His. This clan includes the families (characteristic member in parentheses) S9 (prolyl oligopeptidase), S10 (carboxypeptidase C), S15 (Xaa-Pro dipeptidyl -peptidase), S28 (lysosomal Pro-Xaa carboxypeptidase), S33 (prolyl amino-peptidase), and S37 (Streptomyces PS-10 peptidase). The characteristic catalytic dyad Ser, Lys of dan SE is represented by the motif Ser-Xaa-Xbb-Lys, and the fold consists of helices and an a + P sandwich. The families of this clan Sll (penicillin-binding protein 5), S12 (Streptomyces R61 D-Ala-D-Ala carboxypeptidase), S13 (penicillinbinding protein 4) are involved in the biosynthesis, turnover and lysis of bacterial cell walls. 

Table 12.5-2. Evolutionary classification of peptidases into families and clans based on primary and teriary structure.

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