Selective Inhibitors of Helicobacter pylori Methylthioadenosine Nucleosidase and Human Methylthioadenosine Phosphorylase

Rajesh K. Harijan, Oskar Hoff, Rodrigo G. Ducati, Ross S. Firestone, Brett M. Hirsch, Gary B. Evans, Vern L. Schramm, Peter C. Tyler

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Bacterial 5′-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) hydrolyzes adenine from its substrates to form S-methyl-5-thioribose and S-ribosyl-l-homocysteine. MTANs are involved in quorum sensing, menaquinone synthesis, and 5′-methylthioadenosine recycling to S-adenosylmethionine. Helicobacter pylori uses MTAN in its unusual menaquinone pathway, making H. pylori MTAN a target for antibiotic development. Human 5′-methylthioadenosine phosphorylase (MTAP), a reported anticancer target, catalyzes phosphorolysis of 5′-methylthioadenosine to salvage S-adenosylmethionine. Transition-state analogues designed for HpMTAN and MTAP show significant overlap in specificity. Fifteen unique transition-state analogues are described here and are used to explore inhibitor specificity. Several analogues of HpMTAN bind in the picomolar range while inhibiting human MTAP with orders of magnitude weaker affinity. Structural analysis of HpMTAN shows inhibitors extending through a hydrophobic channel to the protein surface. The more enclosed catalytic sites of human MTAP require the inhibitors to adopt a folded structure, displacing the phosphate nucleophile from the catalytic site.

Original languageEnglish (US)
Pages (from-to)3286-3296
Number of pages11
JournalJournal of Medicinal Chemistry
Volume62
Issue number7
DOIs
StatePublished - Apr 11 2019

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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