Metallopeptidases mechanism

L. Zhu and N. M. Kostic, Toward artificial metallopeptidases mechanisms by which platinum(II) and palladium(II) complexes promote selective, fast hydrolysis of unactivated amide bonds in peptides, Inorganic Chemistry, vol. 31, no. 

The previous chapter offered a broad overview of peptidases and esterases in terms of their classification, localization, and some physiological roles. Mention was made of the classification of hydrolases based on a characteristic functionality in their catalytic site, namely serine hydrolases, cysteine hydrolases, aspartic hydrolases, and metallopeptidases. What was left for the present chapter, however, is a detailed presentation of their catalytic site and mechanisms. As such, this chapter serves as a logical link between the preceding overview and the following chapters, whose focus is on metabolic reactions. 

The active sites of ACE contain the sequence His-Glu-X-X-His, in which the histidines are considered to participate in Zn2+ binding and Glu in the catalytic mechanism. A third Zn2+ ligand is proposed to be a glutamic acid, and the fourth is the nucleophilic water molecule (62). This structural motif is present in a number of metallopeptidases,... 

D. S. Auld, Catalytic Mechanisms For Metallopeptidases, in Handbook of Proteol)hic Enzymes , eds. A. J. Barrett,... 

Matrix metalloproteases (MMP) are also inhibited by hydroxamic acids and/or thiols. Over 25 variants of these enzymes are known, and some are involved in diseases ranging from inflammation to metastatic cancer (108). MMPs contain a zinc ion in the active site and function through the metallopeptidases catalytic mechanism already discussed. However, subtle differences between enzymes enable selective inhibitors to be developed (109). Fig. 15.25 lists some of the reported MMP inhibitors that use carboxylic acid (52-53), a hydroxamic acid (54-55), or thiol groups (56)as metal chelators. 

There was carried out a screening of flavonoids, phenylacrylic acids and various hydroxylated phenyl acetic acids, urinary metabolites of flavonoids, against three metallopeptidases, containing Zn as cofactor, to study their mechanism of activity in vitro [77]. 

Thermolysin (TEN EC 3.4.24.28), a thermostable bacterial protease isolated from Bacillus thermoproteolyticus, has been studied as the prototype of zinc-metallopeptidases at a time where no crystal structure was available for this class of proteases [122]. Crystallographic analysis of a number of TLN/inhibitor complexes has allowed an understanding of the binding mode of these inhibitors and allowed the mechanism of action of this protease to be determined [122]. These seminal studies have greatly inspired the development of NEP inhibitors, given the close stmctural relationship between TEN and NEP [123]. To examine further the structural relationships between these two peptidases, various phosphinic peptides were prepared. One of these compounds (58, Table 1) exhibits a Ki value of 26 nM toward thermolysin and 22 nM toward NEP [124]. 

---