Methylerythritol phosphate pathway to isoprenoids: kinetic modeling and in silico enzyme inhibitions in Plasmodium falciparum.
FEBS Lett
; 587(17): 2806-17, 2013 Sep 02.
Article
en En
| MEDLINE
| ID: mdl-23816706
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.
Palabras clave
1-deoxy-d-xylulose 5-phosphate; 1-deoxy-d-xylulose 5-phosphate reductoisomerase; 1-deoxy-d-xylulose 5-phosphate synthase; 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate; 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate reductase; 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate synthase; 2-C-methyl-d-erythritol 2,4-cyclodiphosphate; 2-C-methyl-d-erythritol 2,4-cyclodiphosphate synthase; 2-phospho-4-(cytidine 5'-diphospho)-2-C-methyl-d-erythritol; 4-(cytidine 5'-diphospho)-2-C-methyl-d-erythritol; 4-(cytidine 5'-diphospho)-2-C-methyl-d-erythritol kinase; 4-(cytidine 5'-diphospho)-2-C-methyl-d-erythritol synthase; BLAST; BLAST-P; CCC; CDPME; CDPMEK; CDPMEP; CDPMES; DMAPP; DXP; DXR; DXS; Drug target; FCC; GAP; HMBPP; HMBPPR; HMBPPS; IPP; Isopentenyl pyrophosphate; Kinetic model; MECPP; MECPPS; MEP; Malaria; Metabolic control analysis; Methylerythritol phosphate (MEP); PDB; PSI-BLAST; PYR; SBML; basic local alignment search tool; concentration control coefficient; dimethylallyl diphosphate; flux control coefficient; glyceraldehyde 3-phosphate; methylerythritol phosphate; position-specific iterated BLAST; protein BLAST; protein data bank; pyruvate; system biology markup language
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Plasmodium falciparum
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Terpenos
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Simulación por Computador
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Eritritol
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Modelos Químicos
Idioma:
En
Revista:
FEBS Lett
Año:
2013
Tipo del documento:
Article
País de afiliación:
India