User:Dhaval Upadhyay/L-asparaginase II Salmonella/sandbox

From Proteopedia

Abstract

+Structure Analysis of Escherichia coli Asparaginase II

By Dominic Fiorentino, Shraddha Desai, Dhaval Upadhyay and Ahmed Abdelrahman

PDB#1IHD.

salmonella enterica serovar Typhimurium (S.Typhimurium) uses Asparagine II to evade the development of T cell-mediated adaptive immunity by interfering with T cell priming. Asparagine II had a direct inhibtory effect on the naïve Tcells from mouse, blocking the proliferation.[1] The complete structure of Asparaginase II of salmonella is not fully determined, although it is 95% homologous to L-asparaginase of Escherichia coli. L-asparaginase of E.coli, is a tetramer with two identical active domains A and C. L-asparaginase has been used for treatment of acute lymphoblastic leukemia. This model will display and further study the active site of chain A. the hydrogen bonds of the Helices (shown in light magenta) help in the overall stability of molecule.

It is speculated that The enzymatic activity of asparginase starts with a nucleophilic attack on the β-amide group of asparagines, leading to acyl-enzyme intermediate. Aspartate contacts number of polar side chains to anchor the substrate with the product. The main-chain nitrogen and the Oɣ of Thr89 form hydrogen bonds with the β-carboxyl group of aspartate. Thr 89(orange) is the most likely candidate as the nucleophile that attacks the aspartate. The only basic residue in the active site region that could influence the nucleophilic character of Thr89 is Lys162 (dark blue). The positions of Thr12 (yellow) stabilize the tetrahedral intermediate formed between Thr89 and its substrates. The hydrogen bonds between the nitrogen atom of aspartate and the adjacent amino acids facilitate the binding of the substrate and stabilization of the transition states. The oxygen of Ser58 (light blue) interacts with the hydrogen of the alpha-carboxyl group. Serine is another nucleophile candidate in the asparginase II enzymatic activity only if the aspartate is in an opposite orientation the asparagene substrate.

Reference

Swain Amy, et all. “Crystal structure of Escherichia coli L-asparaginase, an enzyme 

used in cancer therapy.” Proc. Natl. Acad. Sci. February 1993: 1474-1478. Print.

Introduction

The amino acid Thr89