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Cation induced differential effect on structural and functional properties of Mycobacterium tuberculosis α-Isopropylmalate synthase

BACKGROUND: α-isopropylmalate synthase (MtαIPMS), an enzyme that catalyzes the first committed step of the leucine biosynthetic pathway of Mycobacterium tuberculosis is a potential drug target for the anti-tuberculosis drugs. Cations induce differential effect of activation and inhibition of MtαIPMS...

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Autores principales: Singh, Kulwant, Bhakuni, Vinod
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1919377/
https://www.ncbi.nlm.nih.gov/pubmed/17577419
http://dx.doi.org/10.1186/1472-6807-7-39
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author Singh, Kulwant
Bhakuni, Vinod
author_facet Singh, Kulwant
Bhakuni, Vinod
author_sort Singh, Kulwant
collection PubMed
description BACKGROUND: α-isopropylmalate synthase (MtαIPMS), an enzyme that catalyzes the first committed step of the leucine biosynthetic pathway of Mycobacterium tuberculosis is a potential drug target for the anti-tuberculosis drugs. Cations induce differential effect of activation and inhibition of MtαIPMS. To date no concrete mechanism for such an opposite effect of similarly charged cations on the functional activity of enzyme has been presented. RESULTS: Effect of cations on the structure and function of the MtαIPMS has been studied in detail. The studies for the first time demonstrate that different cations interact specifically at different sites in the enzyme and modulate the enzyme structure differentially. The inhibitors Zn(2+ )and Cd(2+ )ions interact directly with the catalytic domain of the enzyme and induce unfolding/denaturation of the domain. The activator K(+ )also interacts with the catalytic TIM barrel domain however, it does not induce any significant effect on the enzyme structure. Studies with isolated catalytic TIM barrel domain showed that it can carry out the catalytic function on its own but probably requires the non-catalytic C-terminal domain for optimum functioning. An important observation was that divalent cations induce significant interaction between the regulatory and the catalytic domain of MtαIPMS thus inducing structural cooperativity in the enzyme. This divalent cation induced structural cooperativity might result in modulation of activity of the catalytic domain by regulatory domain. CONCLUSION: The studies for the first time demonstrate that different cations bind at different sites in the enzyme leading to their differential effects on the structure and functional activity of the enzyme.
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spelling pubmed-19193772007-07-14 Cation induced differential effect on structural and functional properties of Mycobacterium tuberculosis α-Isopropylmalate synthase Singh, Kulwant Bhakuni, Vinod BMC Struct Biol Research Article BACKGROUND: α-isopropylmalate synthase (MtαIPMS), an enzyme that catalyzes the first committed step of the leucine biosynthetic pathway of Mycobacterium tuberculosis is a potential drug target for the anti-tuberculosis drugs. Cations induce differential effect of activation and inhibition of MtαIPMS. To date no concrete mechanism for such an opposite effect of similarly charged cations on the functional activity of enzyme has been presented. RESULTS: Effect of cations on the structure and function of the MtαIPMS has been studied in detail. The studies for the first time demonstrate that different cations interact specifically at different sites in the enzyme and modulate the enzyme structure differentially. The inhibitors Zn(2+ )and Cd(2+ )ions interact directly with the catalytic domain of the enzyme and induce unfolding/denaturation of the domain. The activator K(+ )also interacts with the catalytic TIM barrel domain however, it does not induce any significant effect on the enzyme structure. Studies with isolated catalytic TIM barrel domain showed that it can carry out the catalytic function on its own but probably requires the non-catalytic C-terminal domain for optimum functioning. An important observation was that divalent cations induce significant interaction between the regulatory and the catalytic domain of MtαIPMS thus inducing structural cooperativity in the enzyme. This divalent cation induced structural cooperativity might result in modulation of activity of the catalytic domain by regulatory domain. CONCLUSION: The studies for the first time demonstrate that different cations bind at different sites in the enzyme leading to their differential effects on the structure and functional activity of the enzyme. BioMed Central 2007-06-19 /pmc/articles/PMC1919377/ /pubmed/17577419 http://dx.doi.org/10.1186/1472-6807-7-39 Text en Copyright © 2007 Singh and Bhakuni; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Singh, Kulwant
Bhakuni, Vinod
Cation induced differential effect on structural and functional properties of Mycobacterium tuberculosis α-Isopropylmalate synthase
title Cation induced differential effect on structural and functional properties of Mycobacterium tuberculosis α-Isopropylmalate synthase
title_full Cation induced differential effect on structural and functional properties of Mycobacterium tuberculosis α-Isopropylmalate synthase
title_fullStr Cation induced differential effect on structural and functional properties of Mycobacterium tuberculosis α-Isopropylmalate synthase
title_full_unstemmed Cation induced differential effect on structural and functional properties of Mycobacterium tuberculosis α-Isopropylmalate synthase
title_short Cation induced differential effect on structural and functional properties of Mycobacterium tuberculosis α-Isopropylmalate synthase
title_sort cation induced differential effect on structural and functional properties of mycobacterium tuberculosis α-isopropylmalate synthase
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1919377/
https://www.ncbi.nlm.nih.gov/pubmed/17577419
http://dx.doi.org/10.1186/1472-6807-7-39
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