2c07

From Proteopedia

Revision as of 15:49, 5 November 2007

OXOACYL-ACP REDUCTASE OF PLASMODIUM FALCIPARUM

Overview

Type II fatty acid biosynthesis represents an attractive target for the, discovery of new antimalarial drugs. Previous studies have identified, malarial ENR (enoyl acyl-carrier-protein reductase, or FabI) as the target, for the antiseptic triclosan. In the present paper, we report the, biochemical properties and 1.5 A (1 A=0.1 nm) crystal structure of OAR, (3-oxoacyl acyl-carrier-protein reductase, or FabG), the second reductive, step in fatty acid biosynthesis and its inhibition by hexachlorophene., Under optimal conditions of pH and ionic strength, Plasmodium falciparum, OAR displays kinetic properties similar to those of OAR from bacteria or, plants. Activity with NADH is <3% of that with NADPH. Fluorescence, enhancement studies indicate that NADPH can bind to the free enzyme, consistent with kinetic and product inhibition studies suggesting a, steady-state ordered mechanism. The crystal structure reveals a tetramer, with a sulphate ion bound in the cofactor-binding site such that the side, chains of the catalytic triad of serine, tyrosine and lysine are aligned, in an active conformation, as previously observed in the Escherichia coli, OAR-NADP+ complex. A cluster of positively charged residues is positioned, at the entrance to the active site, consistent with the proposed, recognition site for the physiological substrate (3-oxoacyl-acyl-carrier, protein) in E. coli OAR. The antibacterial and anthelminthic agent, hexachlorophene is a potent inhibitor of OAR (IC50 2.05 microM) displaying, non-linear competitive inhibition with respect to NADPH. Hexachlorophene, (EC50 6.2 microM) and analogues such as bithionol also have antimalarial, activity in vitro, suggesting they might be useful leads for further, development.

About this Structure

2C07 is a Single protein structure of sequence from Plasmodium falciparum with SO4 as ligand. Active as [acyl-carrier-protein_reductase 3-oxoacyl-[acyl-carrier-protein] reductase], with EC number 1.1.1.100 Structure known Active Site: AC1. Full crystallographic information is available from OCA.

Reference

Kinetic, inhibition and structural studies on 3-oxoacyl-ACP reductase from Plasmodium falciparum, a key enzyme in fatty acid biosynthesis., Wickramasinghe SR, Inglis KA, Urch JE, Muller S, van Aalten DM, Fairlamb AH, Biochem J. 2006 Jan 15;393(Pt 2):447-57. PMID:16225460 [[Category: 3-oxoacyl-[acyl-carrier-protein] reductase]]

Page seeded by OCA on Mon Nov 5 17:54:28 2007