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

Marcozzi, A., Masini, T., Zhu, D., Pesce, D., Illarionov, B., Fischer, M., Herrmann, A. & Hirsch, A. K. H., 4-Jan-2018, In : ChemBioChem. 19, 1, p. 58-65 8 p.

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DOI

Enzymes of the 2-C-methyl-d-erythritol-4-phosphate pathway for the biosynthesis of isoprenoid precursors are validated drug targets. By performing phage display on 1-deoxy-d-xylulose-5-phosphate synthase (DXS), which catalyzes the first step of this pathway, we discovered several peptide hits and recognized false-positive hits. The enriched peptide binder P12 emerged as a substrate (d-glyceraldehyde-3-phosphate)-competitive inhibitor of Deinococcus radiodurans DXS. The results indicate possible overlap of the cofactor- and acceptor-substrate-binding pockets and provide inspiration for the design of inhibitors of DXS with a unique and novel mechanism of inhibition.

Original languageEnglish
Pages (from-to)58-65
Number of pages8
JournalChemBioChem
Volume19
Issue number1
Early online date8-Nov-2017
Publication statusPublished - 4-Jan-2018

    Keywords

  • enzymes, inhibitors, methylerythritol phosphate pathway, peptides, phage display, NON-MEVALONATE PATHWAY, 5-PHOSPHATE SYNTHASE, MYCOBACTERIUM-TUBERCULOSIS, ISOPRENOID BIOSYNTHESIS, CRYSTAL-STRUCTURE, ESCHERICHIA-COLI, HIGHER-PLANTS, DXP SYNTHASE, ENZYME, TRANSKETOLASE

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