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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
Author(s) -
Marcozzi Alessio,
Masini Tiziana,
Zhu Di,
Pesce Diego,
Illarionov Boris,
Fischer Markus,
Herrmann Andreas,
Hirsch Anna K. H.
Publication year - 2018
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201700402
Subject(s) - biochemistry , enzyme , chemistry , substrate (aquarium) , atp synthase , stereochemistry , biosynthesis , peptide , lyase , cofactor , phage display , biology , ecology
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.