The Molecular Basis of Folate Salvage in Plasmodium falciparum

Salcedo-Sora, J. Enrique; Ochong, Edwin; Beveridge, Susan Elizabeth; Johnson, David J.; Nzila, Alexis; Biagini, Giancarlo A.; Stocks, Paul A.; O’Neill, Paul M.; Krishna, Sanjeev; Bray, Patrick G.; Ward, Stephen A.

doi:10.1074/jbc.m111.286054

Cited by 46 publications

(34 citation statements)

References 63 publications

(118 reference statements)

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“…Based on several studies on folic acid transporters (Eudes et al, 2010; Klaus et al, 2005; Salcedo-Sora et al, 2011), we made an E. coli knockout strain BL21(DE3)Δ abgT Δ pabA that lacks the abgT gene (Hussein et al, 1998; Carter et al, 2007) to impede uptake of the catabolite p -aminobenzoyl-glutamate and pabA gene (Kaplan and Nichols, 1986) to impair intracellular synthesis of the metabolite PABA. We then transformed these double knockout cells with pET15bΩ mtrF , expressing N. gonorrhoeae mtrF , or the empty vector pET15b.…”

Section: Resultsmentioning

confidence: 99%

Structure and Function of Neisseria gonorrhoeae MtrF Illuminates a Class of Antimetabolite Efflux Pumps

Bolla

Kumar

et al. 2015

Cell Reports

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SUMMARY Neisseria gonorrhoeae is an obligate human pathogen and the causative agent of the sexually-transmitted disease gonorrhea. The control of this disease has been compromised by the increasing proportion of infections due to antibiotic-resistant strains, which are growing at an alarming rate. N. gonorrhoeae MtrF is an integral membrane protein, which belongs to the AbgT family of transporters for which no structural information is available. Here we describe the crystal structure of MtrF, revealing a dimeric molecule with architecture distinct from all other families of transporters. MtrF is a bowl-shaped dimer with a solvent-filled basin extending from the cytoplasm to halfway across the membrane bilayer. Each subunit of the transporter contains nine transmembrane helices and two hairpins, posing a plausible pathway for substrate transport. A combination of the crystal structure and biochemical functional assays suggests that MtrF is an antibiotic efflux pump, mediating bacterial resistance to sulfonamide antimetabolite drugs.

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Section: Resultsmentioning

confidence: 99%

Structure and Function of Neisseria gonorrhoeae MtrF Illuminates a Class of Antimetabolite Efflux Pumps

Bolla

Kumar

et al. 2015

Cell Reports

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“…Folate membrane transporters have been found in folate heterotrophs 24 and organisms with dual de novo folate biosynthesis and salvage capabilities [35][36][37] . The former are obviously not covered by the model assembled here.…”

Section: Methodsmentioning

confidence: 99%

“…Some single-celled eukaryotes (i.e. Apicomplexan such as malaria and toxoplasmosis parasites) 37 and plants can perform both biosynthesis as well as salvage of folate from environment mainly via the FBT family of transporters 38 . This extra layer of complexity is not included in our model.…”

Section: Methodsmentioning

confidence: 99%

A mathematical model of microbial folate biosynthesis and utilisation: implications for antifolate development

Salcedo-Sora

Auley

2016

Mol. BioSyst.

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The metabolic biochemistry of folate biosynthesis and utilisation has evolved into a complex network of reactions. Although this complexity represents challenges to the field of folate research it has also provided a renewed source for antimetabolite targets. A range of improved folate chemotherapy continues to be developed and applied particularly to cancer and chronic inflammatory diseases. However, new or better antifolates against infectious diseases remain much more elusive. In this paper we describe the assembly of a generic deterministic mathematical model of microbial folate metabolism. Our aim is to explore how a mathematical model could be used to explore the dynamics of this inherently complex set of biochemical reactions. Using the model it was found that: 1) a particular small set of folate intermediates are overrepresented, 2) inhibitory profiles can be quantified by the level of key folate products, 3) using the model to scan for the most effective combinatorial inhibitions of folate enzymes we identified specific targets which could complement current antifolates, and 4) the model substantiates the case for a substrate cycle in the folinic acid biosynthesis reaction. Our model is coded in the systems biology markup language and has been deposited in the BioModels Database (MODEL1511020000), this makes it accessible to the community as a whole.

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“…One of the major folates is tetrahydrofolate which is utilized in donating one-carbon units for thymidylate and purine nucleotide synthesis, conversion of homocysteine into methionine and interconversion of serine into glycine [2]. In addition to the role as a constituent of protein, it plays a major role in the synthesis of S-adenosylmethionine necessary for methylation of RNA, DNA, some neurotransmitter, phospholipid, and proteins like histones.…”

Section: Introductionmentioning

confidence: 99%

Structural Comparison of Prokaryotic and Eukaryotic Folate Transporters by Computational Approach

Agarwal

Jha

2018

Asian J Pharm Clin Res

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Objective: In silico approach has particularly drawn attention in providing a realistic representation needed to understand the fundamental molecular structure of a transporter. The importance of folate metabolism and role in the internalization of antifolates in eukaryotes have been studied extensively, but the structural study of folate transporters in Homo sapiens (HFT), Plasmodium falciparum (PFT), and Streptococcus sp. (SFT) is still lacking. This study was conducted to study and compare the structures of prokaryotic and eukaryotic folate transporters.Methods: HFT, PFT, and SFT were queried using blast and sequences were retrieved using National Center for Biotechnology and Information (NCBI) databases. This was superseded by structural and functional prediction of transporters. The structure has been generated using Swiss model which was visualized using PyMol and validated by Procheck and ERRAT analysis along with the values of different secondary structures mapping to diverse sections of the Ramachandran plot. The structural and functional comparison was performed by PROSO, ProFunc, TM Score, Porewalker, TMHMM, and Protscale.Result: All the parameters for structural comparison suggest that H. sapiens folate transporter is 16.67% and 17.72% identical to Plasmodium and Streptococcus whereas Plasmodium is 21.59% identical to Streptococcus. The evaluation of transmembrane helices and hydrophobicity resulted in the presence of 1, 4, and 12 membrane-spanning segments with predicted US, UDUD, and UDS as pore shape in Plasmodium, Streptococcus, and humans. Conclusion:Such folate receptors are the main targets for the specific conveyance of antifolates. The differences found between these species may offer possibilities for the development of new drugs in future.

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The Molecular Basis of Folate Salvage in Plasmodium falciparum

Cited by 46 publications

References 63 publications

Structure and Function of Neisseria gonorrhoeae MtrF Illuminates a Class of Antimetabolite Efflux Pumps

Structure and Function of Neisseria gonorrhoeae MtrF Illuminates a Class of Antimetabolite Efflux Pumps

A mathematical model of microbial folate biosynthesis and utilisation: implications for antifolate development

Structural Comparison of Prokaryotic and Eukaryotic Folate Transporters by Computational Approach

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