Structural basis for the functional and inhibitory mechanisms of beta-hydroxyacyl-acyl carrier protein dehydratase (FabZ) of Plasmodium falciparum

Maity, Koustav and Venkata, Bharat Somireddy and Kapoor, Neha and Surolia, Namita and Surolia, Avadhesha and Suguna, Kaza (2011) Structural basis for the functional and inhibitory mechanisms of beta-hydroxyacyl-acyl carrier protein dehydratase (FabZ) of Plasmodium falciparum. In: Journal of Structural Biology, 176 (2). pp. 238-249.

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Abstract

The beta-hydroxyacyl-acyl carrier protein dehydratase of Plasmodium falciparum (PfFabZ) catalyzes the third and important reaction of the fatty acid elongation cycle. The crystal structure of PfFabZ is available in hexameric (active) and dimeric (inactive) forms. However, PfFabZ has not been crystallized with any bound inhibitors until now. We have designed a new condition to crystallize PfFabZ with its inhibitors bound in the active site, and determined the crystal structures of four of these complexes. This is the first report on any FabZ enzyme with active site inhibitors that interact directly with the catalytic residues. Inhibitor binding not only stabilized the substrate binding loop but also revealed that the substrate binding tunnel has an overall shape of ``U''. In the crystal structures, residue Phe169 located in the middle of the tunnel was found to be in two different conformations, open and closed. Thus, Phe169, merely by changing its side chain conformation, appears to be controlling the length of the tunnel to make it suitable for accommodating longer substrates. The volume of the substrate binding tunnel is determined by the sequence as well as by the conformation of the substrate binding loop region and varies between organisms for accommodating fatty acids of different chain lengths. This report on the crystal structures of the complexes of PfFabZ provides the structural basis of the inhibitory mechanism of the enzyme that could be used to improve the potency of inhibitors against an important component of fatty acid synthesis common to many infectious organisms. (C) 2011 Elsevier Inc. All rights reserved.

Item Type:	Journal Article
Publication:	Journal of Structural Biology
Publisher:	Elsevier Science
Additional Information:	Copyright of this article belongs to Elsevier Science.
Keywords:	Fatty acid biosynthesis;beta-hydroxyacyl ACP dehydratase; Active site inhibitor complex;Substrate binding tunnel; Plasmodium falciparum;X-ray crystallography
Department/Centre:	Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited:	04 Nov 2011 09:37
Last Modified:	04 Nov 2011 09:37
URI:	http://eprints.iisc.ac.in/id/eprint/41817

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