Role of the oxyanion binding site and subsites S1 and S2 in the catalysis of oligopeptidase B, a novel target for antimicrobial chemotherapy

Biochemistry
Tünde JuhászLászló Polgár

Abstract

Oligopeptidase B is a member of a novel serine peptidase family, found in Gram-negative bacteria and trypanosomes. The enzyme is involved in host cell invasion, and thus, it is an important target for drug design. Oligopeptidase B is specific for substrates with a pair of basic residues at positions P1 and P2. The sensitivity of substrates to high ionic strength suggests that the arginines interact with the carboxylate ions of the enzyme. On the basis of a three-dimensional model, two carboxyl dyads (Asp460 and Asp462 and Glu576 and Glu578) can be assigned as binding sites for arginines P1 and P2, respectively. The dyads are involved in several events: (i) substrate binding, (ii) substrate inhibition at high substrate concentrations (different inhibitory mechanisms were demonstrated with substrates bearing one and two arginine residues), (iii) enzyme activation at millimolar CaCl2 concentrations with substrates having one arginine, and (iv) interaction of Ca2+ with the dyads which simplified the complex pH dependence curves. Titration with a product-like inhibitor revealed the pK(a) of the carboxyl group that perturbed the pH-kcat/Km profiles. The OH group of Tyr452 is part of the oxyanion binding site, which stabilizes the tra...Continue Reading

References

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Citations

Jul 5, 2002·Journal of Molecular Biology·Ariel B LindnerDan S Tawfik
Dec 22, 2009·SAR and QSAR in Environmental Research·K KaszubaA Bunker
May 25, 2002·Journal of Bacteriology·Rory E MortyNorma W Andrews
Nov 22, 2007·Biochimie·Theresa H T CoetzerLaura E J Huson
Mar 29, 2013·Chemistry : a European Journal·Isaac N ArthurChristopher J Easton

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