PDBsum entry 3f4b

Oxidoreductase

PDB id: 3f4b

Contents

Protein chains

284 a.a. *

Ligands

NAD ×4

TCL ×4

Waters ×264

* Residue conservation analysis

PDB id:

3f4b

Name:

Oxidoreductase

Title:

Crystal structure of plasmodium berghei enoyl-acyl-carrier-protein reductase with triclosan

Structure:

Enoyl-acyl carrier protein reductase. Chain: a, b, c, d. Fragment: unp residues 75 to 396. Engineered: yes

Source:

Plasmodium berghei. Organism_taxid: 5821. Gene: pbfabi. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.49Å R-factor: 0.184 R-free: 0.254

Authors:

J.C.Sacchettini,H.-C.Tsai

Key ref:

M.Yu et al. (2008). The fatty acid biosynthesis enzyme FabI plays a key role in the development of liver-stage malarial parasites. Cell Host Microbe, 4, 567-578. PubMed id: 19064257

Date:

31-Oct-08 Release date: 02-Mar-10

Protein chains

Q6TEI5  (Q6TEI5_PLABE) -  Enoyl-acyl carrier protein reductase from Plasmodium berghei

Seq: 396 a.a.

Struc: 284 a.a.

Enzyme reactions

• Enzyme class: E.C.1.3.1.9 - enoyl-[acyl-carrier-protein] reductase (NADH).
• Reaction: a 2,3-saturated acyl-[ACP] + NAD⁺ = a (2E)-enoyl-[ACP] + NADH + H⁺

2,3-saturated acyl-[ACP] + NAD(+) (Bound ligand (Het Group name = NAD) corresponds exactly) = (2E)-enoyl-[ACP] + NADH + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

Cell Host Microbe 4:567-578 (2008)

PubMed id: 19064257

The fatty acid biosynthesis enzyme FabI plays a key role in the development of liver-stage malarial parasites.

M.Yu, T.R.Kumar, L.J.Nkrumah, A.Coppi, S.Retzlaff, C.D.Li, B.J.Kelly, P.A.Moura, V.Lakshmanan, J.S.Freundlich, J.C.Valderramos, C.Vilcheze, M.Siedner, J.H.Tsai, B.Falkard, A.B.Sidhu, L.A.Purcell, P.Gratraud, L.Kremer, A.P.Waters, G.Schiehser, D.P.Jacobus, C.J.Janse, A.Ager, W.R.Jacobs, J.C.Sacchettini, V.Heussler, P.Sinnis, D.A.Fidock.

ABSTRACT

The fatty acid synthesis type II pathway has received considerable interest as a candidate therapeutic target in Plasmodium falciparum asexual blood-stage infections. This apicoplast-resident pathway, distinct from the mammalian type I process, includes FabI. Here, we report synthetic chemistry and transfection studies concluding that Plasmodium FabI is not the target of the antimalarial activity of triclosan, an inhibitor of bacterial FabI. Disruption of fabI in P. falciparum or the rodent parasite P. berghei does not impede blood-stage growth. In contrast, mosquito-derived, FabI-deficient P. berghei sporozoites are markedly less infective for mice and typically fail to complete liver-stage development in vitro. This defect is characterized by an inability to form intrahepatic merosomes that normally initiate blood-stage infections. These data illuminate key differences between liver- and blood-stage parasites in their requirements for host versus de novo synthesized fatty acids, and create new prospects for stage-specific antimalarial interventions.