Document Detail

Mutational analysis of the triclosan-binding region of enoyl-ACP (acyl-carrier protein) reductase from Plasmodium falciparum.
MedLine Citation:
PMID:  15139852     Owner:  NLM     Status:  MEDLINE    
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.
Mili Kapoor; Jayashree Gopalakrishnapai; Namita Surolia; Avadhesha Surolia
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Biochemical journal     Volume:  381     ISSN:  1470-8728     ISO Abbreviation:  Biochem. J.     Publication Date:  2004 Aug 
Date Detail:
Created Date:  2004-07-23     Completed Date:  2004-12-10     Revised Date:  2013-06-09    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  England    
Other Details:
Languages:  eng     Pagination:  735-41     Citation Subset:  IM    
Molecular Biophysics Unit, Indian Institute of Science, Bangalore-560012, India.
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MeSH Terms
Amino Acid Sequence
Binding Sites / genetics
Chromatography, Gel / methods
Circular Dichroism / methods
Electrophoresis, Polyacrylamide Gel / methods
Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
Molecular Sequence Data
Mutagenesis, Site-Directed / genetics*
NAD / metabolism
Oxidoreductases / antagonists & inhibitors,  chemistry,  genetics*,  metabolism*
Plasmodium falciparum / enzymology*,  genetics
Protein Structure, Quaternary / genetics
Triclosan / chemistry,  metabolism*
Reg. No./Substance:
3380-34-5/Triclosan; 53-84-9/NAD; EC 1.-/Oxidoreductases; EC Reductase (NADH)

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