Methylerythritol phosphate pathway to isoprenoids: Kinetic modeling andin silicoenzyme inhibitions inPlasmodium falciparum

Abstract

a b s t r a c tThe 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.

Interactions between temperature and intercellular CO2 concentration in controlling leaf isoprene emission rates

“…Such a mechanism is required to explain how processes, such as photosynthesis, which affect the ATP balance of the chloroplast on the order of μ mol m −2 s −1 , control fluxes of isoprene, which occur on the order of nmol m −2 s −1 . Logically, reductions in the rate of ATP synthesis, even relatively large reductions, would continue to produce enough ATP to drive a metabolic flux, such as I s , that exists at rates 1000‐fold below that of the rate of ATP turnover (also see Singh & Ghosh , for evidence that chloroplast ATP availability is non‐limiting for MEP pathway activity across a broad range of environmental conditions).…”

Exploring Drug Targets in Isoprenoid Biosynthetic Pathway forPlasmodium falciparum

“…The metabolite 1-deoxy-D-xylulose-5-phosphate is not only an intermediate of the MEP pathway for the biosynthesis of isopentenyl diphosphate but is also involved in the biosynthesis of thiamin (vitamin B1) and pyridoxal (vitamin B6) in plants and many microorganisms. An added advantage of targeting 1-deoxy-D-xylulose-5-phosphate synthase is its influence on vitamins B1 and B6 biosynthesis in malaria parasite [14]. …”

Phage Display on the Anti‐infective Target 1‐Deoxy‐d‐xylulose‐5‐phosphate Synthase Leads to an Acceptor–Substrate Competitive Peptidic Inhibitor

“…The potential of DXS as a drug target is also underlined by its involvement in pyridoxal phosphate (vitamin B6) and thiamine (vitamin B1) biosynthesis in many bacteria, offering the opportunity to target three metabolic pathways at once. Furthermore, DXS possesses an important regulatory role for the flux of metabolites throughout the whole MEP pathway as shown recently …”

“…Furthermore, DXS possesses an important regulatory role for the flux of metabolites throughout the whole MEP pathway as shown recently. [19] Considering its crucial importance in bacterial metabolism, it is surprising that DXS is one of the least studied among the enzymeso ft he MEP pathway in terms of crystallography and inhibitord evelopment. In fact, there are just two crystal structures deposited in the PDB of the enzymei nc omplex with its cofactor ThDP (Escherichia coli,P DB ID:2 O1S, incomplete crystal structure; Deinococcus radiodurans,P DB ID:2 O1X).…”