Effect of substrate binding loop mutations on the structure, kinetics, and inhibition of enoyl acyl carrier protein reductase from plasmodium falciparum

ABSTRACT The β-ketoacyl-acyl carrier protein synthases are members of the thiolase superfamily and are key regulators of bacterial fatty acid synthesis. As essential components of the bacterial lipid metabolic pathway, they are an attractive target for antibacterial drug discovery. We have determined the 1.3 Å resolution crystal structure of the β-ketoacyl-acyl carrier protein synthase II (FabF) from the pathogenic organism Streptococcus pneumoniae. The protein adopts a duplicated βαβαβαββ fold, which is characteristic of the thiolase superfamily. The two-fold pseudosymmetry is broken by the presence of distinct insertions in the two halves of the protein. These insertions have evolved to bind the specific substrates of this particular member of the thiolase superfamily. Docking of the pantetheine moiety of the substrate identifies the loop regions involved in substrate binding and indicates roles for specific, conserved residues in the substrate binding tunnel. The active site triad of this superfamily is present in spFabF as His 303, His 337, and Cys 164. Near the active site is an ion pair, Glu 346 and Lys 332, that is conserved in the condensing enzymes but is unusual in our structure in being stabilized by an Mg2+ ion which interacts with Glu 346. The active site histidines interact asymmetrically with Lys 332, whose positive charge is closer to His 303, and we propose a specific role for the lysine in polarizing the imidazole ring of this histidine. This asymmetry suggests that the two histidines have unequal roles in catalysis and provides new insights into the catalytic mechanisms of these enzymes.

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IN-SILICO SCREENING AGAINST ANTIMALARIAL TARGET PLASMODIUM FALCIPARUM ENOYL-ACYL CARRIER PROTEIN REDUCTASE

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2017.v10s5.23114 ◽

2017 ◽

Vol 10 (17) ◽

pp. 127

Author(s):

Berwi Fazri Pamudi ◽

Azizahwati Azizahwati ◽

Arry Yanuar

Keyword(s):

Plasmodium Falciparum ◽

Virtual Screening ◽

In Silico ◽

Acyl Carrier Protein ◽

Parasitic Infection ◽

Antimalarial Drugs ◽

Chemotherapeutic Agents ◽

Effective Vaccine ◽

Carrier Protein ◽

In Silico Screening

Objective: Malaria is a parasitic infection that causes worldwide health problems. The absence of an effective vaccine and Plasmodium strains that are resistant to antimalarial drugs emphasize the importance of developing new chemotherapeutic agents. The use of computers for in-silico screening, or virtual screening, is currently being developed as a method for discovering antimalarial drugs. One of the enzymes that can support the development of the malaria parasite is the Plasmodium falciparum enoyl-acyl carrier protein reductase (PfENR). Inhibition of these enzymes leads to Type II lipid biosynthesis inhibition on the parasite.Methods: This research investigates the use of virtual screening to find PfENR inhibitor candidates. A molecular docking method using GOLD software and the medicinal plants in Indonesia database will be used. This target has been optimized by the removal of residues and the addition of charge. Ligand is expected to be an inhibitor of PfENR.Results: In-silico screening, or virtual screening, found that the top five compounds with the highest GOLD score at trial are kaempferol 3-rhamnosyl- (1-3)-rhamnosyl-(1-6)-glucoside; cyanidin 3,5-di-(6-malonylglucoside); 8-hydroxyapigenin 8-(2’’, 4’’-disulfato glucuronide); epigallocatechin 3,5,-di- O-gallat; quercetin 3,4’-dimethyl ether 7-alpha-L-arabinofuranosyl-(1-6)-glucoside. They had GOLD scores of 94.73, 95.90, 86.46, 85.39, and 84.40, respectively.Conclusions: There are two candidate inhibitor compounds from tea (Camellia sinensis), which have potential for development as an antimalarial drug, which are kaempferol 3-rhamnosyl-(1-3)-rhamnosyl-(1-6)-glucoside and epigallocatechin 3,5,-di-O-gallate, with a GOLD score of 94.73 and 85.39, respectively.

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Molecular modeling studies, synthesis, and biological evaluation of Plasmodium falciparum enoyl-acyl carrier protein reductase (PfENR) inhibitors

Molecular Diversity ◽

10.1007/s11030-009-9141-0 ◽

2009 ◽

Vol 13 (4) ◽

pp. 501-517 ◽

Cited By ~ 13

Author(s):

Varun A. Morde ◽

Mushtaque S. Shaikh ◽

Raghuvir R. S. Pissurlenkar ◽

Evans C. Coutinho

Keyword(s):

Plasmodium Falciparum ◽

Molecular Modeling ◽

Acyl Carrier Protein ◽

Biological Evaluation ◽

Carrier Protein ◽

Modeling Studies ◽

Molecular Modeling Studies ◽

Synthesis And Biological Evaluation

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

Journal of Structural Biology ◽

10.1016/j.jsb.2011.07.018 ◽

2011 ◽

Vol 176 (2) ◽

pp. 238-249 ◽

Cited By ~ 19

Author(s):

Koustav Maity ◽

Bharat Somireddy Venkata ◽

Neha Kapoor ◽

Namita Surolia ◽

Avadhesha Surolia ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Acyl Carrier Protein ◽

Structural Basis ◽

Carrier Protein ◽

Inhibitory Mechanisms

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Analysis Docking Of Plasmodium Falciparum Enoyl Acyl Carrier Protein Reductase (Pfenr) With Organic Compunds From Virtual Screening Of Herbal Database

Acta Chimica Asiana ◽

10.29303/aca.v3i1.14 ◽

2020 ◽

Vol 3 (1) ◽

pp. 127

Author(s):

Nya Daniaty Malau ◽

St Fatimah Azzahra

Keyword(s):

Plasmodium Falciparum ◽

Virtual Screening ◽

In Silico ◽

Fatty Acid Biosynthesis ◽

Acyl Carrier Protein ◽

Chemotherapeutic Agents ◽

Effective Vaccine ◽

Carrier Protein ◽

Autodock Vina ◽

In Silico Screening

Malaria is one of problematic infectious diseases worldwide. The absence of an effective vaccine and the spread of drug resistant strains of Plasmodium clearly indicate the necessity for the deveploment of new chemotherapeutic agents. Recent method being developed is searching a new drug of antimalarial using in silico screening, or also known as virtual screening. One of enzyme target that important for growth of the malaria parasite is Plasmodium falciparum Enoyl Acyl Carrier Protein Reductase (PfENR). Inhibition of this enzyme cause the fatty acid biosynthesis type II will be terminated. In this research, in silico screening was performed using AUTODOCK VINA software to find inhibitor candidates of PfENR by using ligands from the database of Medicinal Plants in Indonesia. On the AUTODOCK VINA software moleculer docking experiments were performed between ligands and macromolecule target PfENR. This target that has been optimized with residue removal and charges addition. Ligand is expected to be the PfENR inhibitors.

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