Isocitrate lyase of Mycobacterium tuberculosis is inhibited by quercetin through binding at N-terminus

Harish Shukla; Vikash Kumar; Amit Kumar Singh; Shivangi Rastogi; Shaheb Raj Khan; Mohammad Imran Siddiqi; Manju Yasoda Krishnan; Md Sohail Akhtar

doi:10.1016/j.ijbiomac.2015.04.005

Isocitrate lyase of Mycobacterium tuberculosis is inhibited by quercetin through binding at N-terminus

Int J Biol Macromol. 2015:78:137-41. doi: 10.1016/j.ijbiomac.2015.04.005. Epub 2015 Apr 11.

Authors

Harish Shukla¹, Vikash Kumar¹, Amit Kumar Singh¹, Shivangi Rastogi², Shaheb Raj Khan², Mohammad Imran Siddiqi³, Manju Yasoda Krishnan⁴, Md Sohail Akhtar⁵

Affiliations

¹ Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow 226 031, India.
² Microbiology Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow 226 031, India.
³ Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow 226 031, India; Academy of Scientific and Innovative Research, Chennai 600 113, India.
⁴ Microbiology Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow 226 031, India; Academy of Scientific and Innovative Research, Chennai 600 113, India.
⁵ Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow 226 031, India; Academy of Scientific and Innovative Research, Chennai 600 113, India. Electronic address: sohail@cdri.res.in.

PMID: 25869309
DOI: 10.1016/j.ijbiomac.2015.04.005

Abstract

Combating tuberculosis requires new therapeutic strategies that not only target the actively dividing bacilli but also the dormant bacilli during persistent infection. Isocitrate lyase (ICL) is a key enzyme of the glyoxylate shunt, crucial for the survival of bacteria in macrophages and mice. MtbICL is considered as one of the potential and attractive drug targets against persistent infection. We report the inhibition of MtbICL by quercetin with IC50 of 3.57 μM. In addition, quercetin strongly inhibited the growth of Mtb H37Rv utilizing acetate, rather than glucose as the sole carbon source, suggesting the inhibition of glyoxylate shunt. Quercetin binds at the N-terminus of MtbICL (Kd - 6.68 μM).

Keywords: Docking; Glyoxylate shunt; Isocitrate lyase; Mycobacteria; Quercetin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Isocitrate Lyase / antagonists & inhibitors
Isocitrate Lyase / chemistry*
Models, Molecular
Molecular Conformation
Mycobacterium tuberculosis / enzymology*
Protein Binding
Protein Interaction Domains and Motifs*
Quercetin / chemistry*
Quercetin / pharmacology

Substances

Enzyme Inhibitors
Quercetin
Isocitrate Lyase