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 language | English (US) |
|---|---|
| Pages (from-to) | 13106-13114 |
| Number of pages | 9 |
| Journal | Journal of Biological Chemistry |
| Volume | 277 |
| Issue number | 15 |
| DOIs | |
| State | Published - Apr 12 2002 |
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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 journal › Article
}
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.
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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 -