2C07

Oxoacyl-ACP reductase of Plasmodium falciparum

2C07 の概要

• エントリーDOI: 10.2210/pdb2c07/pdb
• 分子名称: 3-OXOACYL-(ACYL-CARRIER PROTEIN) REDUCTASE, SULFATE ION (3 entities in total)
• 機能のキーワード: oxidoreductase, fabg, short-chain alcohol reductase, fatty acid biosynthesis, apicoplast, ketoacyl-acp reductase
• 由来する生物種: PLASMODIUM FALCIPARUM (MALARIA PARASITE)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 31630.92

構造登録者

Urch, J.E.,Wickramasinghe, S.R.,Inglis, K.A.,Muller, S.,Fairlamb, A.H.,van Aalten, D.M.F. (登録日: 2005-08-26, 公開日: 2005-10-20, 最終更新日: 2023-12-13)

主引用文献

Wickramasinghe, S.R.,Inglis, K.A.,Urch, J.E.,Muller, S.,Van Aalten, D.M.F.,Fairlamb, A.H.
Kinetic, Inhibition and Structural Studies on 3-Oxoacyl-Acp Reductase from Plasmodium Falciparum, a Key Enzyme in Fatty Acid Biosynthesis.
Biochem.J., 393:447-, 2006

PubMed Abstract: 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.

PubMed: 16225460
DOI: 10.1042/BJ20050832

実験手法

X-RAY DIFFRACTION (1.5 Å)