β‐Ketoacyl‐ACP synthase I/II from <i>Plasmodium falciparum</i> (PfFabB/F)—Is it B or F?

Sharma, Shilpi; Sharma, Shailendra Kumar; Surolia, Namita; Surolia, Avadhesha

doi:10.1002/iub.205

Cited by 9 publications

(6 citation statements)

References 29 publications

(22 reference statements)

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“…This step is however bypassed in the very first elongation cycle, where FabH instead performs the equivalent condensation reaction. The P. falciparum and T. gondii FabB/F possess sequence features consistent with apicoplast targeting, and the activity of PfFabB/F has been demonstrated by complementation [137] and in vitro assay [66,70]. Although PfFabB/F shares sequence similarity with both FabB and FabF ␤-ketoacyl-ACP synthases, the enzyme is most similar to FabF in activity [137], and its structure has correspondingly been modeled on the FabF of cyanobacteria [138].…”

Section: ˇ-Ketoacyl-acp Synthase I/ii (Fabb/f)mentioning

confidence: 95%

Fatty acid metabolism in the Plasmodium apicoplast: Drugs, doubts and knockouts

Shears

Botté

McFadden

2015

Molecular and Biochemical Parasitology

104

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The malaria parasite Plasmodium possesses a relict, non-photosynthetic plastid known as the apicoplast. The apicoplast is essential for parasite survival, and harbors several plant-like metabolic pathways including a type II fatty acid synthesis (FASII) pathway. The FASII pathway was discovered in 1998, and much of the early research in the field pursued it as a therapeutic drug target. These studies identified a range of compounds with activity against bloodstage parasites and led to the localization and characterization of most enzymes in the pathway. However, when genetic studies revealed FASII was dispensable in bloodstage parasites, it effectively discounted the pathway as a therapeutic drug target, and suggested these compounds instead interfered with other processes. Interest in FASII then shifted toward its disruption for malaria prophylaxis and vaccine development, with experiments in rodent malaria models identifying a crucial role for the pathway in the parasite's transition from the liver to the blood. Unexpectedly however, the human malaria parasite P. falciparum was recently found to differ from rodent models and require FASII for mosquito stage development. This requirement blocked the production of the FASII-deficient forms that might be used as a genetically attenuated parasite vaccine, suggesting the pathway was also unsuitable as a vaccine target. This review discusses how perception of FASII has changed over time, and presents key findings about each enzyme in the pathway to identify remaining questions and opportunities for malaria control.

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Section: ˇ-Ketoacyl-acp Synthase I/ii (Fabb/f)mentioning

confidence: 95%

Fatty acid metabolism in the Plasmodium apicoplast: Drugs, doubts and knockouts

Shears

Botté

McFadden

2015

Molecular and Biochemical Parasitology

104

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“…That PFF1275c is a FabF rather than a FabB orthologue was recently deduced from complementation studies of E. coli mutants. 104 The validity of the system as a target requires that it is active and essential in a life stage that is relevant for a chemotherapeutic treatment, i.e., during the erythrocytic stage. The activity of FASII has been studied using T. gondii as a working model, although this model did not fully reflect the situation in P. falciparum as T. gondii contains an apicoplast FASII and a cytosolic FASI, whereas the malaria parasite only contains a plastid FASII.…”

Section: Is Fasii a Valid Target?mentioning

confidence: 99%

Plasmodium falciparum Apicoplast Drugs: Targets or Off-Targets?

et al. 2011

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“…Sharma, et al. (45) reported that enzymes involved in condensing play an important role in fatty acid composition of organism. Morgan‐Kiss, et al.…”

Section: β‐Ketoacyl‐acp Synthase I/ii (Pffabb/f)mentioning

confidence: 99%

“…E. coli has two isoforms for the elongation condensing enzymes (FabB and FabF) whereas Plasmodium has only one isoform. Sharma, et al (45) reported that enzymes involved in condensing play an important role in fatty acid composition of organism. Morgan-Kiss, et al (46) reported that the genome of Lactococcus lactis encodes a single long chain 3-ketoacyl-acyl carrier protein synthase.…”

Section: B-ketoacyl-acp Synthase I ⁄ Ii (Pffabb ⁄ F)mentioning

confidence: 99%

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Antimalarial Drugs and Drug Targets Specific to Fatty Acid Metabolic Pathway of Plasmodium falciparum

Qidwai

Khan²

2012

Chem Biol Drug Des

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Plasmodium falciparum, a causitive agent of malaria, is the third most prevalent factor for mortility in the world. Falciparum malaria is an example of evolutionary and balancing selection. Because of mutation and natural selection, the parasite has developed resistance to most of the existing drugs. Under such circumstances, there is a growing need to develop new molecular targets in P. falciparum. A four membrane bound organelles called apicoplast, very much similar to that of chloroplast of plants, have been found in parasite. Therefore, the proteins involved in metabolic pathways of apicoplasts are important drug targets. Among the pathways in apicoplast, fatty acid biosynthetic pathway is the most important metabolic pathway in P. falciparum. Several studies have explored the role of different proteins involved in this pathway and antimalarial compounds against this target. In this review, we have studied the role of different proteins in fatty acid metabolism and designing, synthesis and evaluation of compounds against the targets identified in fatty acid metabolic pathway. Malaria is the global health problem and causes worldwide morbidity and mortality. Approximately, 300-500 million clinical cases and one million deaths caused per year worldwide due to malaria (1). Four Plasmodium species (P. vivax, P. ovale, P. malariae, and P. falciparum) are responsible for human malaria. Out of these, P. falciparum species causes most fatal form of malaria. This parasite has a plastid like organelle called as apicoplast. Resistance to known antimalarial and the lack of an effective vaccine have created an urgent need to discover new biologically active compounds. A four-membrane plastid organelle, the apicoplast is present in many apicomplexan parasites including P. falciparum, and apicoplast is believed to have arisen through endosymbiosis of an algal cell that had previously incorporated a cyanobacterium (2). The sequencing of the P. falciparum genome coupled with a detailed analysis of the proteins of known function, which were targeted to the apicoplast, allowed the construction of an apicoplast specific metabolic map (3). Several metabolic pathways exist in apicoplast, differing significantly from those found in the human host, based on its prokaryotic origin and has been considered as potential drug target for new therapeutics (4). Fatty acid biosynthetic pathway is the most important pathway in apicoplast. Most eukaryotes have type I fatty acid synthase (FAS) enzymes, which are large multifunctional enzymes composed of one or two polypeptides. Malaria parasites of the genus Plasmodium do not contain FAS and rely instead on a type II fatty acid synthase (FAS II) for the de novo production of fatty acids. Seven proteins found in the P. falciparum genome comprise a dissociated FAS II (5). The FAS II of P. falciparum is composed of six discrete enzymes, and the acyl carrier protein (ACP) serves to shuttle the nascent fatty acid among the enzymes of pathway. The apicoplast of parasite is the site for FAS II biosyn...

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β‐Ketoacyl‐ACP synthase I/II from Plasmodium falciparum (PfFabB/F)—Is it B or F?

Cited by 9 publications

References 29 publications

Fatty acid metabolism in the Plasmodium apicoplast: Drugs, doubts and knockouts

Fatty acid metabolism in the Plasmodium apicoplast: Drugs, doubts and knockouts

Plasmodium falciparum Apicoplast Drugs: Targets or Off-Targets?

Antimalarial Drugs and Drug Targets Specific to Fatty Acid Metabolic Pathway of Plasmodium falciparum

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