Selective Inhibitors of Helicobacter pylori Methylthioadenosine Nucleosidase and Human Methylthioadenosine Phosphorylase

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

doi:10.1021/acs.jmedchem.8b01642

Title: Selective Inhibitors of Helicobacter pylori Methylthioadenosine Nucleosidase and Human Methylthioadenosine Phosphorylase

Journal Article · Tue Mar 12 00:00:00 EDT 2019 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.8b01642· OSTI ID:1515305

Harijan, Rajesh K. ^[1]; Hoff, Oskar ^[2];

^[1]; Firestone, Ross S. ^[1]; Hirsch, Brett M. ^[1]; Evans, Gary B. ^[2];

^[1];

^[2]

Albert Einstein College of Medicine, New York, NY (United States)
Victoria Univ. of Wellington (New Zealand). Ferrier Research Inst.

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. We report 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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); New Zealand Foundation for Research Science and Technology; USDOE Office of Science (SC); Eli Lilly Company

Grant/Contract Number:: GM041916; C08X0701; S10 OD020068; AC02-06CH11357

OSTI ID:: 1515305

Journal Information:: Journal of Medicinal Chemistry, Vol. 62, Issue 7; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 8 works

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59 BASIC BIOLOGICAL SCIENCES
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Title: Selective Inhibitors of Helicobacter pylori Methylthioadenosine Nucleosidase and Human Methylthioadenosine Phosphorylase

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