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Mutational analysis of the triclosan-binding region of enoyl-ACP reductase from Plasmodium falciparum

Kapoor, Mili and Gopalakrishnapai, Jayashree and Surolia, Namita and Surolia, Avadhesha (2004) Mutational analysis of the triclosan-binding region of enoyl-ACP reductase from Plasmodium falciparum. In: Biochemical Journal, 381 . pp. 735-741.

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Abstract

Triclosan, a known antibacterial, acts by inhibiting enoyl-ACP (acyl-carrier protein) reductase (ENR), a key enzyme of the type II fatty acid synthesis (FAS) system. Plasmodium falciparum, the human malaria-causing parasite, harbours the type II FAS; in contrast. its human host utilizes type I FAS. Due to this striking difference, ENR has emerged as an important target for the development of new antimalarials. Modelling studies, and the crystal structure of P.falciparum ENR, have highlighted the features of ternary complex formation between the enzyme, triclosan and $NAD^{\mathrm{+}}$ [Suguna. A. Surolia and N. Surolia (2001) Biochem. Biophys. Res. Commun. 283, 224-228;Perozzo, Kuo, Sidhu, Valiyaveettil, Bittman, Jacobs, Fidock, and Sacchettini (2002) J. Biol. Chem. 277, 13106-13114; and Swarnamukhi,Kapoor, N. Surolia, A. Surolia and Suguna (2003) PDB1UH5]. To address the issue of the importance of the residues involved in strong specific and stoichiometric binding of triclosan to P. falciparum ENR, we mutated the following residues: Ala-217, Asn-218, Met-281, and Phe-368.The affinity of all the mutants was reduced for triclosan as compared with the wild-type enzyme to different extents. The most significant mutation was A217V, which led to a greater than 7000-fold decrease in the binding affinity for triclosan as compared with wild-type PfENR.A217G showed only 10-fold reduction in the binding affinity. Thus,these studies point out significant differences in the triclosan-binding region of the P. falciparum enzyme from those of its bacterial counterparts.

Item Type: Journal Article
Additional Information: The copyright for this article belongs to Portland Press
Keywords: Enoyl-ACP reductase;FabI;triclosan;mutants;inhibitor; Fatty acid biosynthesis
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited: 25 Oct 2004
Last Modified: 19 Sep 2010 04:16
URI: http://eprints.iisc.ernet.in/id/eprint/2125

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