Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The 2C-methylerythritol 4-phosphate (MEP) pathway for the biosynthesis of isopentenyl pyrophosphate and its isomer dimethylallyl pyrophosphate, which are the precursors of isoprenoids, is present in plants, in the malaria parasite Plasmodium falciparum and in most eubacteria, including pathogenic agents. However, the MEP pathway is absent from fungi and animals, which have exclusively the mevalonic acid pathway. Given the characteristics of the MEP pathway, its enzymes represent potential targets for the generation of selective antibacterial, antimalarial and herbicidal molecules. We have focussed on the enzyme 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol kinase (CMK), which catalyses the fourth reaction step of the MEP pathway. A molecular dynamics simulation was carried out on the CMK dimer complex, and protein-protein interactions analysed, considering also water-mediated interactions between monomers. In order to find small molecules that bind to CMK and disrupt dimer formation, interactions observed in the dynamics trajectory were used to model a pharmacophore used in database searches. Using an intensity-fading matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry approach, one compound was found to interact with CMK. The data presented here indicate that a virtual screening approach can be used to identify candidate molecules that disrupt the CMK-CMK complex. This strategy can contribute to speeding up the discovery of new antimalarial, antibacterial, and herbicidal compounds.
J Mol Model 2009 Aug
PMID:Mimicking direct protein-protein and solvent-mediated interactions in the CDP-methylerythritol kinase homodimer: a pharmacophore-directed virtual screening approach. 1919 99

The first transcriptomes, expressed sequence tags (ESTs) in a leaf and root from Withania somnifera plant referenced in this report are the first of its kind. A cDNA library was constructed from samples of the 2-months-old, in vitro cultured leaves and roots, which generated 1,047 leaf cDNA and 1,034 root cDNA clones representing 48.5% and 61.5% unique sequences. The ESTs from leaf and root grouped into 239 and 230 clusters representing 22.8% and 22.2% of total sequences. Of these, about 70% encoded proteins found similar (E-value > or =10(-14)) to characterized or annotated proteins from the NCBI non-redundant database and diverse molecular functions and biological processes based on gene ontology (GO) classification. We identified genes with potential role in photosynthesis (cytochrome p-450), pathogenesis (arginine decarboxylase, chitinase) and withanolide biosynthesis (squalene epoxidase, CDP-ME kinase). Highly expressed transcripts, with a particularly high abundance of cytochrome p-450 (0.85% in leaf) were noticed. Pfam analysis revealed the presence of functional domains in selected sequences. W. somnifera is a source of multifarious and beneficial alkaloids referred as withanolides. High levels of withanolides accumulate in mature leaves and roots. Since, the knowledge for synthesis and presence of some of these important biochemical constituent is limited, identification of the genes involved in two different pathways of secondary metabolite synthesis (MVA and MEP), in different tissue will be requisite for articulation of withanolide biosynthesis. This investigation aimed at elucidating the differential gene expression in two vital sites where withanolides essentially found and leaf and root transcriptomes were comparatively analyzed. The comparative analysis of the sequences provides a framework for future research in proteomics and evolutionary genomics in the withanolide biosynthesis.
Mol Biol Rep 2010 Feb
PMID:Generation and analysis of expressed sequence tags from leaf and root of Withania somnifera (Ashwgandha). 1966 65