The catalytic role of water in the binding site of l,d-transpeptidase 2 within acylation mechanism: A QM/MM (ONIOM) modelling.

Abstract

Mycobacterium tuberculosis is the causative agent of Tuberculosis. Formation of 3 → 3 crosslinks in the peptidoglycan layer of M. tuberculosis is catalyzed by l,d-transpeptidases. These enzymes can confer resistance against classical β-lactams that inhibit enzymes that generate 4 → 3 peptidoglycan crosslinks. The focus of this study is to investigate the catalytic role of water molecules in the acylation mechanism of the β-lactam ring within two models; 4- and 6-membered ring systems using two-layered our Own N-layer integrated Molecular Mechanics ONIOM (B3LYP/6-311++G(2d,2p): AMBER) model. The obtained thermochemical parameters revealed that the 6-membered ring model best describes the inhibition mechanism of acylation which indicates the role of water in the preference of 6-membered ring reaction pathway. This finding is in accordance with experimental data for the rate-limiting step of cysteine protease with the same class of inhibitor and binding affinity for both inhibitors. As expected, the ΔG# results also reveal that the 6-membered ring reaction pathway is the most favourable. The electrostatic potential (ESP) and the natural bond orbital analysis (NBO) showed stronger interactions in 6-membered ring transition state (TS-6) mechanism involving water in the active site of the enzyme. This study could be helpful in the development of novel antibiotics against l,d-transpeptidase.

• Authors: Collins U Ibeji, Gideon F Tolufashe, Thandokuhle Ntombela, Thavendran Govender, Glenn E M Maguire, Gyanu Lamichhane, Hendrik G Kruger, Bahareh Honarparvar
• Journal: Tuberculosis (Edinburgh, Scotland) (Tuberculosis (Edinb)) Vol. 113 Pg. 222-230 (12 2018) ISSN: 1873-281X [Electronic] Scotland
• PMID: 30514506 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Anti-Bacterial Agents
• Bacterial Proteins
• Peptidoglycan
• Water
• Imipenem
• Peptidyl Transferases
• Meropenem

Topics

• Acylation
• Anti-Bacterial Agents (chemistry, metabolism, pharmacology)
• Bacterial Proteins (antagonists & inhibitors, chemistry, metabolism)
• Binding Sites
• Catalysis
• Catalytic Domain
• Imipenem (chemistry, metabolism, pharmacology)
• Kinetics
• Meropenem (chemistry, metabolism, pharmacology)
• Models, Molecular
• Molecular Structure
• Mycobacterium tuberculosis (drug effects, enzymology)
• Peptidoglycan (metabolism)
• Peptidyl Transferases (antagonists & inhibitors, chemistry, metabolism)
• Protein Binding
• Water (metabolism)