Structural elucidation of the specificity of the antibacterial agent triclosan for malarial enoyl acyl carrier protein reductase

Remo Perozzo, Mack Kuo, Amar Bir Singh Sidhu, Jacob T. Valiyaveettil, Robert Bittman, William R. Jacobs, David A. Fidock, James C. Sacchettini

Research output: Contribution to journalArticle

182 Citations (Scopus)

Abstract

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 Cαs, 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.

Original languageEnglish (US)
Pages (from-to)13106-13114
Number of pages9
JournalJournal of Biological Chemistry
Volume277
Issue number15
DOIs
StatePublished - Apr 12 2002

Fingerprint

Triclosan
Acyl Carrier Protein
Oxidoreductases
NAD
Anti-Bacterial Agents
Parasites
Plasmodium falciparum
Apicoplasts
Fatty Acids
Brassica napus
Falciparum Malaria
Cloning
Organism Cloning
Elongation
Proteins
Genes
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Structural elucidation of the specificity of the antibacterial agent triclosan for malarial enoyl acyl carrier protein reductase. / Perozzo, Remo; Kuo, Mack; Sidhu, Amar Bir Singh; Valiyaveettil, Jacob T.; Bittman, Robert; Jacobs, William R.; Fidock, David A.; Sacchettini, James C.

In: Journal of Biological Chemistry, Vol. 277, No. 15, 12.04.2002, p. 13106-13114.

Research output: Contribution to journalArticle

Perozzo, Remo ; Kuo, Mack ; Sidhu, Amar Bir Singh ; Valiyaveettil, Jacob T. ; Bittman, Robert ; Jacobs, William R. ; Fidock, David A. ; Sacchettini, James C. / Structural elucidation of the specificity of the antibacterial agent triclosan for malarial enoyl acyl carrier protein reductase. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 15. pp. 13106-13114.
@article{e066cd0e3a6e45e9a3d1a9b866d6b1b7,
title = "Structural elucidation of the specificity of the antibacterial agent triclosan for malarial enoyl acyl carrier protein reductase",
abstract = "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 Cαs, 0.30 {\AA}). 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.",
author = "Remo Perozzo and Mack Kuo and Sidhu, {Amar Bir Singh} and Valiyaveettil, {Jacob T.} and Robert Bittman and Jacobs, {William R.} and Fidock, {David A.} and Sacchettini, {James C.}",
year = "2002",
month = "4",
day = "12",
doi = "10.1074/jbc.M112000200",
language = "English (US)",
volume = "277",
pages = "13106--13114",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "15",

}

TY - JOUR

T1 - Structural elucidation of the specificity of the antibacterial agent triclosan for malarial enoyl acyl carrier protein reductase

AU - Perozzo, Remo

AU - Kuo, Mack

AU - Sidhu, Amar Bir Singh

AU - Valiyaveettil, Jacob T.

AU - Bittman, Robert

AU - Jacobs, William R.

AU - Fidock, David A.

AU - Sacchettini, James C.

PY - 2002/4/12

Y1 - 2002/4/12

N2 - 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 Cαs, 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.

AB - 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 Cαs, 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.

UR - http://www.scopus.com/inward/record.url?scp=0037066782&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037066782&partnerID=8YFLogxK

U2 - 10.1074/jbc.M112000200

DO - 10.1074/jbc.M112000200

M3 - Article

C2 - 11792710

AN - SCOPUS:0037066782

VL - 277

SP - 13106

EP - 13114

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 15

ER -