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

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.

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

Inhibition of early steps of de novo fatty-acid biosynthesis by different xenobiotica

1991 ◽  
Vol 81 (2) ◽  
pp. 251-255
Author(s):  
Manfred Focke ◽  
Andrea Feld ◽  
Hartmut K. Lichtenthaler
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Biosynthesis ◽  
De Novo ◽  
Acid Biosynthesis

Development of 'S', 'N’ Heterocycles as Antimycobacterials Targeting Fatty Acid Biosynthesis

2019 ◽  
Vol 15 ◽  
Author(s):  
L. K. Dahiwade ◽  
S. R. Rochlani ◽  
P. B. Choudhari ◽  
R. P. Dhavale ◽  
H. N. Moreira
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Biosynthesis ◽  
Antimycobacterial Activity ◽  
Drug Candidate ◽  
Causative Organism ◽  
Present Communication ◽  
Acid Biosynthesis ◽  
Rational Development ◽  
After Cancer ◽  
Drug Resistant Strains

Background: Mycobacterium tuberculosis is a causative organism of tuberculosis, which is most deadly disease after cancer in a current decade. The development of multidrug and broadly drug- resistant strains making the tuberculosis problem more and more critical. In last 40 years, only one molecule is added to the treatment regimen. Generally, drug design and development programs are targeted proteins whose function is known to be essential to the bacterial cell. Objectives: Reported here are the development of 'S', 'N’ heterocycles as antimycobacterials targeting fatty acid biosynthesis. Material and Methods: In the present communication, rational development of anti-mycobacterial agent's targeting fatty acid biosynthesis has been done by integrating the pocket modelling and virtual analysis. Results: The identified potential 33 lead compounds were synthesized, characterized by physicochemical and spectroscopic methods like IR, NMR spectroscopy and further screened for antimycobacterial activity using isoniazid as standard. All the designed compounds have shown profound antimycobacterial activity. Conclusion: In this present communication, we found that 3c, 3f, 3l and 4k molecules had expressive desirable biological activity and specific interactions with fatty acids. Further optimization of these leads is necessary for the development of potential antimycobacterial drug candidate having less side effects.

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