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+ [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.
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Research Article|
July 27 2004
Mutational analysis of the triclosan-binding region of enoyl-ACP (acyl-carrier protein) reductase from Plasmodium falciparum
Mili KAPOOR;
Mili KAPOOR
*Molecular Biophysics Unit, Indian Institute of Science, Bangalore-560012, India
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Jayashree GOPALAKRISHNAPAI;
Jayashree GOPALAKRISHNAPAI
*Molecular Biophysics Unit, Indian Institute of Science, Bangalore-560012, India
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Namita SUROLIA;
Namita SUROLIA
1
†Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore, India
1To whom correspondence should be addressed (e-mail surolia@jncasr.ac.in).
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Avadhesha SUROLIA
Avadhesha SUROLIA
*Molecular Biophysics Unit, Indian Institute of Science, Bangalore-560012, India
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Publisher: Portland Press Ltd
Received:
February 26 2004
Revision Received:
April 26 2004
Accepted:
May 13 2004
Accepted Manuscript online:
May 13 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2004
Biochem J (2004) 381 (3): 735–741.
Article history
Received:
February 26 2004
Revision Received:
April 26 2004
Accepted:
May 13 2004
Accepted Manuscript online:
May 13 2004
Citation
Mili KAPOOR, Jayashree GOPALAKRISHNAPAI, Namita SUROLIA, Avadhesha SUROLIA; Mutational analysis of the triclosan-binding region of enoyl-ACP (acyl-carrier protein) reductase from Plasmodium falciparum. Biochem J 1 August 2004; 381 (3): 735–741. doi: https://doi.org/10.1042/BJ20040302
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