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Methylerythritol phosphate pathway to isoprenoids: kinetic modeling and in silico enzyme inhibitions in Plasmodium falciparum.
FEBS Lett. 2013 Sep 02; 587(17):2806-17.FL

Abstract

The methylerythritol phosphate (MEP) pathway of Plasmodium falciparum (P. falciparum) has become an attractive target for anti-malarial drug discovery. This study describes a kinetic model of this pathway, its use in validating 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR) as drug target from the systemic perspective, and additional target identification, using metabolic control analysis and in silico inhibition studies. In addition to DXR, 1-deoxy-d-xylulose 5-phosphate synthase (DXS) can be targeted because it is the first enzyme of the pathway and has the highest flux control coefficient followed by that of DXR. In silico inhibition of both enzymes caused large decrement in the pathway flux. An added advantage of targeting DXS is its influence on vitamin B1 and B6 biosynthesis. Two more potential targets, 2-C-methyl-d-erythritol 2,4-cyclodiphosphate synthase and 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate synthase, were also identified. Their inhibition caused large accumulation of their substrates causing instability of the system. This study demonstrates that both types of enzyme targets, one acting via flux reduction and the other by metabolite accumulation, exist in P. falciparum MEP pathway. These groups of targets can be exploited for independent anti-malarial drugs.

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Authors+Show Affiliations

Singh VK
School of Computational & Integrative Sciences, Jawaharlal Nehru University, New Delhi, India. viveksingh.nov@gmail.com
Ghosh I
No affiliation info available

MeSH

Aldose-Ketose IsomerasesAlgorithmsBiosynthetic PathwaysComputer SimulationEnzyme InhibitorsEnzymesErythritolEscherichia coliEscherichia coli ProteinsKineticsModels, BiologicalModels, ChemicalMultienzyme ComplexesOxidoreductasesPhosphorus-Oxygen LyasesPhosphotransferases (Alcohol Group Acceptor)Plasmodium falciparumProtozoan ProteinsTerpenesTransferases

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23816706

Citation

Singh, Vivek Kumar, and Indira Ghosh. "Methylerythritol Phosphate Pathway to Isoprenoids: Kinetic Modeling and in Silico Enzyme Inhibitions in Plasmodium Falciparum." FEBS Letters, vol. 587, no. 17, 2013, pp. 2806-17.
Singh VK, Ghosh I. Methylerythritol phosphate pathway to isoprenoids: kinetic modeling and in silico enzyme inhibitions in Plasmodium falciparum. FEBS Lett. 2013;587(17):2806-17.
Singh, V. K., & Ghosh, I. (2013). Methylerythritol phosphate pathway to isoprenoids: kinetic modeling and in silico enzyme inhibitions in Plasmodium falciparum. FEBS Letters, 587(17), 2806-17. https://doi.org/10.1016/j.febslet.2013.06.024
Singh VK, Ghosh I. Methylerythritol Phosphate Pathway to Isoprenoids: Kinetic Modeling and in Silico Enzyme Inhibitions in Plasmodium Falciparum. FEBS Lett. 2013 Sep 2;587(17):2806-17. PubMed PMID: 23816706.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Methylerythritol phosphate pathway to isoprenoids: kinetic modeling and in silico enzyme inhibitions in Plasmodium falciparum. AU - Singh,Vivek Kumar, AU - Ghosh,Indira, Y1 - 2013/06/28/ PY - 2013/05/27/received PY - 2013/06/14/revised PY - 2013/06/17/accepted PY - 2013/7/3/entrez PY - 2013/7/3/pubmed PY - 2013/10/29/medline KW - 1-deoxy-d-xylulose 5-phosphate KW - 1-deoxy-d-xylulose 5-phosphate reductoisomerase KW - 1-deoxy-d-xylulose 5-phosphate synthase KW - 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate KW - 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate reductase KW - 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate synthase KW - 2-C-methyl-d-erythritol 2,4-cyclodiphosphate KW - 2-C-methyl-d-erythritol 2,4-cyclodiphosphate synthase KW - 2-phospho-4-(cytidine 5′-diphospho)-2-C-methyl-d-erythritol KW - 4-(cytidine 5′-diphospho)-2-C-methyl-d-erythritol KW - 4-(cytidine 5′-diphospho)-2-C-methyl-d-erythritol kinase KW - 4-(cytidine 5′-diphospho)-2-C-methyl-d-erythritol synthase KW - BLAST KW - BLAST-P KW - CCC KW - CDPME KW - CDPMEK KW - CDPMEP KW - CDPMES KW - DMAPP KW - DXP KW - DXR KW - DXS KW - Drug target KW - FCC KW - GAP KW - HMBPP KW - HMBPPR KW - HMBPPS KW - IPP KW - Isopentenyl pyrophosphate KW - Kinetic model KW - MECPP KW - MECPPS KW - MEP KW - Malaria KW - Metabolic control analysis KW - Methylerythritol phosphate (MEP) KW - PDB KW - PSI-BLAST KW - PYR KW - SBML KW - basic local alignment search tool KW - concentration control coefficient KW - dimethylallyl diphosphate KW - flux control coefficient KW - glyceraldehyde 3-phosphate KW - methylerythritol phosphate KW - position-specific iterated BLAST KW - protein BLAST KW - protein data bank KW - pyruvate KW - system biology markup language SP - 2806 EP - 17 JF - FEBS letters JO - FEBS Lett VL - 587 IS - 17 N2 - The methylerythritol phosphate (MEP) pathway of Plasmodium falciparum (P. falciparum) has become an attractive target for anti-malarial drug discovery. This study describes a kinetic model of this pathway, its use in validating 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR) as drug target from the systemic perspective, and additional target identification, using metabolic control analysis and in silico inhibition studies. In addition to DXR, 1-deoxy-d-xylulose 5-phosphate synthase (DXS) can be targeted because it is the first enzyme of the pathway and has the highest flux control coefficient followed by that of DXR. In silico inhibition of both enzymes caused large decrement in the pathway flux. An added advantage of targeting DXS is its influence on vitamin B1 and B6 biosynthesis. Two more potential targets, 2-C-methyl-d-erythritol 2,4-cyclodiphosphate synthase and 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate synthase, were also identified. Their inhibition caused large accumulation of their substrates causing instability of the system. This study demonstrates that both types of enzyme targets, one acting via flux reduction and the other by metabolite accumulation, exist in P. falciparum MEP pathway. These groups of targets can be exploited for independent anti-malarial drugs. SN - 1873-3468 UR - https://www.unboundmedicine.com/medline/citation/23816706/Methylerythritol_phosphate_pathway_to_isoprenoids:_kinetic_modeling_and_in_silico_enzyme_inhibitions_in_Plasmodium_falciparum_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-5793(13)00482-1 DB - PRIME DP - Unbound Medicine ER -
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