Phage Display on the Anti‐infective Target 1‐Deoxy‐d‐xylulose‐5‐phosphate Synthase Leads to an Acceptor–Substrate Competitive Peptidic Inhibitor. (11th December 2017)

• Record Type: Journal Article
• Authors: Marcozzi, Alessio; Masini, Tiziana; Zhu, Di; Pesce, Diego; Illarionov, Boris; Fischer, Markus; Herrmann, Andreas; Hirsch, Anna K. H.
• Is Part Of: Chembiochem. Volume 19:Number 1(2018)
• Page Start: 58
• Page End: 65
• Publication Date: 2017-12-11
• Subjects: enzymes -- inhibitors -- methylerythritol phosphate pathway -- peptides -- phage display; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201700402
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: 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. Abstract : In a bind : Phage panning against DXS, an anti‐infective target, leads to the isolation of the first known peptidic inhibitor of DXS, a dodecamer linear peptide (MAIPTRGKMPQY) that acts as a substrate‐competitive inhibitor. This study shines light on the mode of interaction between the peptide and the enzyme and suggests possible overlap in the cofactor‐ and acceptor‐substrate‐binding pockets.