Identification, characterization, and inhibition of Plasmodium falciparum β-hydroxyacyl-acyl carrier protein dehydratase (FabZ)

Sharma, Shailendra Kumar ; Kapoor, Mili ; Ramya, T. N. C. ; Kumar, Sanjay ; Kumar, Gyanendra ; Modak, Rahul ; Sharma, Shilpi ; Surolia, Namita ; Surolia, Avadhesha (2003) Identification, characterization, and inhibition of Plasmodium falciparum β-hydroxyacyl-acyl carrier protein dehydratase (FabZ) Journal of Biological Chemistry, 278 (46). pp. 45661-45671. ISSN 0021-9258

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Official URL: http://www.jbc.org/content/278/46/45661.short

Related URL: http://dx.doi.org/10.1074/jbc.M304283200

Abstract

The emergence of drug-resistant forms of Plasmodium falciparum emphasizes the need to develop new antimalarials. In this context, the fatty acid biosynthesis (FAS) pathway of the malarial parasite has recently received a lot of attention. Due to differences in the fatty acid biosynthesis systems of Plasmodium and man, this pathway is a good target for the development of new and selective therapeutic drugs directed against malaria. In continuation of these efforts we report cloning and overexpression of P. falciparum β-hydroxyacyl-acyl carrier protein (ACP) dehydratase (PffabZ) gene that codes for a 17-kDa protein. The enzyme catalyzes the dehydration of β-hydroxyacyl-ACP to trans-2-acyl-ACP, the third step in the elongation phase of the FAS cycle. It has a Km of 199 μM and kcat/Km of 80.4 M−1 s−1 for the substrate analog β-hydroxybutyryl-CoA but utilizes crotonoyl-CoA, the product of the reaction, more efficiently (Km=86 μM, kcat/Km=220 M−1 s−1). More importantly, we also identify inhibitors (NAS-91 and NAS-21) for the enzyme. Both the inhibitors prevented the binding of crotonoyl-CoA to PfFabZ in a competitive fashion. Indeed these inhibitors compromised the growth of P. falciparum in cultures and inhibited the parasite fatty acid synthesis pathway both in cell-free extracts as well as in situ. We modeled the structure of PfFabZ using Escherichia coli β-hydroxydecanoyl thioester dehydratase (EcFabA) as a template. We also modeled the inhibitor complexes of PfFabZ to elucidate the mode of binding of these compounds to FabZ. The discovery of the inhibitors of FabZ, reported for the first time against any member of this family of enzymes, essential to the type II FAS pathway opens up new avenues for treating a number of infectious diseases including malaria.

Item Type:Article
Source:Copyright of this article belongs to The American Society for Biochemistry and Molecular Biology.
ID Code:55213
Deposited On:18 Aug 2011 12:06
Last Modified:03 Oct 2011 14:03

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