Dataset Information

Targeting the IspD Enzyme in the MEP Pathway: Identification of a Novel Fragment Class.

ABSTRACT: The enzymes of the 2-C-methylerythritol-d-erythritol 4-phosphate (MEP) pathway (MEP pathway or non-mevalonate pathway) are responsible for the synthesis of universal precursors of the large and structurally diverse family of isoprenoids. This pathway is absent in humans, but present in many pathogenic organisms and plants, making it an attractive source of drug targets. Here, we present a high-throughput screening approach that led to the discovery of a novel fragment hit active against the third enzyme of the MEP pathway, PfIspD. A systematic SAR investigation afforded a novel chemical structure with a balanced activity-stability profile (16). Using a homology model of PfIspD, we proposed a putative binding mode for our newly identified inhibitors that sets the stage for structure-guided optimization.

SUBMITTER: Diamanti E

PROVIDER: S-EPMC9305118 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Targeting the IspD Enzyme in the MEP Pathway: Identification of a Novel Fragment Class.

Diamanti Eleonora E Hamed Mostafa M MM Lacour Antoine A Bravo Patricia P Illarionov Boris B Fischer Markus M Rottmann Matthias M Witschel Matthias M Hirsch Anna K H AKH

ChemMedChem 20220111 5

The enzymes of the 2-C-methylerythritol-d-erythritol 4-phosphate (MEP) pathway (MEP pathway or non-mevalonate pathway) are responsible for the synthesis of universal precursors of the large and structurally diverse family of isoprenoids. This pathway is absent in humans, but present in many pathogenic organisms and plants, making it an attractive source of drug targets. Here, we present a high-throughput screening approach that led to the discovery of a novel fragment hit active against the thir ...[more]

PMID: 34918860

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Project description:Dimethylallyl diphosphate (DMADP) and isopentenyl diphosphate (IDP) serves as the universal C5 precursors of isoprenoid biosynthesis in plants. These compounds are formed by the last step of the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway, catalyzed by (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate reductase (HDR). In this study, we investigated the major HDR isoforms of two woody plant species, Norway spruce (Picea abies) and gray poplar (Populus × canescens), to determine how they regulate isoprenoid formation. Since each of these species has a distinct profile of isoprenoid compounds, they may require different proportions of DMADP and IDP with proportionally more IDP being needed to make larger isoprenoids. Norway spruce contained two major HDR isoforms differing in their occurrence and biochemical characteristics. PaHDR1 produced relatively more IDP than PaHDR2 and it encoding gene was expressed constitutively in leaves, likely serving to form substrate for production of carotenoids, chlorophylls, and other primary isoprenoids derived from a C20 precursor. On the other hand, Norway spruce PaHDR2 produced relatively more DMADP than PaHDR1 and its encoding gene was expressed in leaves, stems, and roots, both constitutively and after induction with the defense hormone methyl jasmonate. This second HDR enzyme likely forms a substrate for the specialized monoterpene (C10), sesquiterpene (C15), and diterpene (C20) metabolites of spruce oleoresin. Gray poplar contained only one dominant isoform (named PcHDR2) that produced relatively more DMADP and the gene of which was expressed in all organs. In leaves, where the requirement for IDP is high to make the major carotenoid and chlorophyll isoprenoids derived from C20 precursors, excess DMADP may accumulate, which could explain the high rate of isoprene (C5) emission. Our results provide new insights into the biosynthesis of isoprenoids in woody plants under conditions of differentially regulated biosynthesis of the precursors IDP and DMADP.

Dataset Information

Targeting the IspD Enzyme in the MEP Pathway: Identification of a Novel Fragment Class.

Publications

Targeting the IspD Enzyme in the MEP Pathway: Identification of a Novel Fragment Class.

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