scholarly journals The crystal structure of PfFabZ, the unique β-hydroxyacyl-ACP dehydratase involved in fatty acid biosynthesis of Plasmodium falciparum

2009 ◽  
Vol 14 (6) ◽  
pp. 1570-1580 ◽  
Author(s):  
Dirk Kostrewa ◽  
Fritz K. Winkler ◽  
Gerd Folkers ◽  
Leonardo Scapozza ◽  
Remo Perozzo
Keyword(s):  
Crystal Structure ◽  
Plasmodium Falciparum ◽  
Fatty Acid ◽  
Fatty Acid Biosynthesis ◽  
Acid Biosynthesis

scholarly journals Kinetic, inhibition and structural studies on 3-oxoacyl-ACP reductase from Plasmodium falciparum, a key enzyme in fatty acid biosynthesis

2005 ◽  
Vol 393 (2) ◽  
pp. 447-457 ◽  
Author(s):  
Sasala R. Wickramasinghe ◽  
Kirstine A. Inglis ◽  
Jonathan E. Urch ◽  
Sylke Müller ◽  
Daan M. F. van Aalten ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Plasmodium Falciparum ◽  
Fatty Acid ◽  
Fatty Acid Biosynthesis ◽  
Competitive Inhibition ◽  
Acyl Carrier Protein ◽  
Antimalarial Activity ◽  
Kinetic Properties ◽  
Carrier Protein ◽  
Acid Biosynthesis

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 Å (1 Å=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 μM) displaying non-linear competitive inhibition with respect to NADPH. Hexachlorophene (EC50 6.2 μM) and analogues such as bithionol also have antimalarial activity in vitro, suggesting they might be useful leads for further development.

scholarly journals Type II Fatty Acid Biosynthesis Is Essential for Plasmodium falciparum Sporozoite Development in the Midgut of Anopheles Mosquitoes

2013 ◽  
Vol 13 (5) ◽  
pp. 550-559 ◽  
Author(s):  
Ben C. L. van Schaijk ◽  
T. R. Santha Kumar ◽  
Martijn W. Vos ◽  
Adam Richman ◽  
Geert-Jan van Gemert ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Plasmodium Falciparum ◽  
Fatty Acid ◽  
Fatty Acid Biosynthesis ◽  
Blood Stage ◽  
Acid Biosynthesis ◽  
Asexual Blood Stage ◽  
Liver Stage ◽  
Content Type ◽  
Fas Ii

ABSTRACT The prodigious rate at which malaria parasites proliferate during asexual blood-stage replication, midgut sporozoite production, and intrahepatic development creates a substantial requirement for essential nutrients, including fatty acids that likely are necessary for parasite membrane formation. Plasmodium parasites obtain fatty acids either by scavenging from the vertebrate host and mosquito vector or by producing fatty acids de novo via the type two fatty acid biosynthesis pathway (FAS-II). Here, we study the FAS-II pathway in Plasmodium falciparum , the species responsible for the most lethal form of human malaria. Using antibodies, we find that the FAS-II enzyme FabI is expressed in mosquito midgut oocysts and sporozoites as well as liver-stage parasites but not during the blood stages. As expected, FabI colocalizes with the apicoplast-targeted acyl carrier protein, indicating that FabI functions in the apicoplast. We further analyze the FAS-II pathway in Plasmodium falciparum by assessing the functional consequences of deleting fabI and fabB/F . Targeted deletion or disruption of these genes in P. falciparum did not affect asexual blood-stage replication or the generation of midgut oocysts; however, subsequent sporozoite development was abolished. We conclude that the P. falciparum FAS-II pathway is essential for sporozoite development within the midgut oocyst. These findings reveal an important distinction from the rodent Plasmodium parasites P. berghei and P. yoelii , where the FAS-II pathway is known to be required for normal parasite progression through the liver stage but is not required for oocyst development in the Anopheles mosquito midgut.

scholarly journals Crystal structure of FabZ-ACP complex reveals a dynamic seesaw-like catalytic mechanism of dehydratase in fatty acid biosynthesis

Cell Research ◽  
2016 ◽  
Vol 26 (12) ◽  
pp. 1330-1344 ◽  
Author(s):  
Lin Zhang ◽  
Jianfeng Xiao ◽  
Jianrong Xu ◽  
Tianran Fu ◽  
Zhiwei Cao ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Fatty Acid ◽  
Catalytic Mechanism ◽  
Fatty Acid Biosynthesis ◽  
Acid Biosynthesis

The Crystal Structure ofBurkholderia cenocepaciaDfsA Provides Insights into Substrate Recognition and Quorum Sensing Fatty Acid Biosynthesis

Biochemistry ◽  
2016 ◽  
Vol 55 (23) ◽  
pp. 3241-3250 ◽  
Author(s):  
Francesca Spadaro ◽  
Viola C. Scoffone ◽  
Laurent R. Chiarelli ◽  
Marco Fumagalli ◽  
Silvia Buroni ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Fatty Acid ◽  
Quorum Sensing ◽  
Fatty Acid Biosynthesis ◽  
Substrate Recognition ◽  
Acid Biosynthesis

Crystal Structure of MabA from Mycobacterium tuberculosis, a Reductase involved in Long-chain Fatty Acid Biosynthesis

2002 ◽  
Vol 320 (2) ◽  
pp. 249-261 ◽  
Author(s):  
Martin Cohen-Gonsaud ◽  
Stéphanie Ducasse ◽  
Francois Hoh ◽  
Didier Zerbib ◽  
Gilles Labesse ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Mycobacterium Tuberculosis ◽  
Fatty Acid ◽  
Fatty Acid Biosynthesis ◽  
Chain Fatty Acid ◽  
Acid Biosynthesis ◽  
Long Chain Fatty Acid ◽  
Long Chain
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