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Originally published In Press as doi:10.1074/jbc.M112000200 on January 15, 2002

J. Biol. Chem., Vol. 277, Issue 15, 13106-13114, April 12, 2002
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Structural Elucidation of the Specificity of the Antibacterial Agent Triclosan for Malarial Enoyl Acyl Carrier Protein Reductase*

Remo PerozzoDagger §, Mack KuoDagger , Amar bir Singh Sidhu, Jacob T. Valiyaveettil||, Robert Bittman||, William R. Jacobs Jr.**, David A. Fidock, and James C. SacchettiniDagger Dagger Dagger

From the Dagger  Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843-2128, the  Department of Microbiology and Immunology and the ** Howard Hughes Medical Institute, Albert Einstein College of Medicine, The Bronx, New York 10461, and the || Department of Chemistry and Biochemistry, Queens College of The City University of New York, Flushing, New York 11367-1597

The human malaria parasite Plasmodium falciparum synthesizes fatty acids using a type II pathway that is absent in humans. The final step in fatty acid elongation is catalyzed by enoyl acyl carrier protein reductase, a validated antimicrobial drug target. Here, we report the cloning and expression of the P. falciparum enoyl acyl carrier protein reductase gene, which encodes a 50-kDa protein (PfENR) predicted to target to the unique parasite apicoplast. Purified PfENR was crystallized, and its structure resolved as a binary complex with NADH, a ternary complex with triclosan and NAD+, and as ternary complexes bound to the triclosan analogs 1 and 2 with NADH. Novel structural features were identified in the PfENR binding loop region that most closely resembled bacterial homologs; elsewhere the protein was similar to ENR from the plant Brassica napus (root mean square for Calpha s, 0.30 Å). Triclosan and its analogs 1 and 2 killed multidrug-resistant strains of intra-erythrocytic P. falciparum parasites at sub to low micromolar concentrations in vitro. These data define the structural basis of triclosan binding to PfENR and will facilitate structure-based optimization of PfENR inhibitors.

* This work was supported by awards from the NIAID (National Institutes of Health Grant AI 43268) and the Robert A. Welch Foundation (to J. C. S.) and the Howard Hughes Medical Institute-Research Resources Program for Medical Schools (to D. A. F.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Current address: Dept. of Applied Biosciences, Swiss Federal Institute of Technology (ETH), Zurich CH-8057, Switzerland.

Dagger Dagger To whom correspondence should be addressed. Tel.: 979-862-7636; Fax: 979-862-7638; E-mail: sacchett@tamu.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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