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| - | [[Image:2c07.gif|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_2c07| PDB=2c07 | SCENE= }} | | {{STRUCTURE_2c07| PDB=2c07 | SCENE= }} |
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| - | '''OXOACYL-ACP REDUCTASE OF PLASMODIUM FALCIPARUM'''
| + | ===OXOACYL-ACP REDUCTASE OF PLASMODIUM FALCIPARUM=== |
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| - | ==Overview==
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| - | 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.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_16225460}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 16225460 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_16225460}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Oxidoreductase]] | | [[Category: Oxidoreductase]] |
| | [[Category: Short-chain alcohol reductase]] | | [[Category: Short-chain alcohol reductase]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 21:02:46 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 04:39:53 2008'' |
Revision as of 01:39, 29 July 2008
Template:STRUCTURE 2c07
OXOACYL-ACP REDUCTASE OF PLASMODIUM FALCIPARUM
Template:ABSTRACT PUBMED 16225460
About this Structure
2C07 is a Single protein structure of sequence from Plasmodium falciparum. 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
Page seeded by OCA on Tue Jul 29 04:39:53 2008
