Selective Inhibitors of Helicobacter pylori Methylthioadenosine Nucleosidase and Human Methylthioadenosine Phosphorylase
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. 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.
- Authors:
-
[1];
[1];
[2]
- Albert Einstein College of Medicine, New York, NY (United States)
- Victoria Univ. of Wellington (New Zealand). Ferrier Research Inst.
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- National Institutes of Health (NIH); New Zealand Foundation for Research Science and Technology; USDOE Office of Science (SC); Eli Lilly Company
- OSTI Identifier:
- 1515305
- Grant/Contract Number:
- GM041916; C08X0701; S10 OD020068; AC02-06CH11357
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Medicinal Chemistry
- Additional Journal Information:
- Journal Volume: 62; Journal Issue: 7; Journal ID: ISSN 0022-2623
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Peptides and proteins; Inhibitors; Phosphates; Noncovalent interactions; Screening assays
Citation Formats
Harijan, Rajesh K., Hoff, Oskar, Ducati, Rodrigo G., Firestone, Ross S., Hirsch, Brett M., Evans, Gary B., Schramm, Vern L., and Tyler, Peter C. Selective Inhibitors of Helicobacter pylori Methylthioadenosine Nucleosidase and Human Methylthioadenosine Phosphorylase. United States: N. p., 2019.
Web. doi:10.1021/acs.jmedchem.8b01642.
Harijan, Rajesh K., Hoff, Oskar, Ducati, Rodrigo G., Firestone, Ross S., Hirsch, Brett M., Evans, Gary B., Schramm, Vern L., & Tyler, Peter C. Selective Inhibitors of Helicobacter pylori Methylthioadenosine Nucleosidase and Human Methylthioadenosine Phosphorylase. United States. https://doi.org/10.1021/acs.jmedchem.8b01642
Harijan, Rajesh K., Hoff, Oskar, Ducati, Rodrigo G., Firestone, Ross S., Hirsch, Brett M., Evans, Gary B., Schramm, Vern L., and Tyler, Peter C. Tue .
"Selective Inhibitors of Helicobacter pylori Methylthioadenosine Nucleosidase and Human Methylthioadenosine Phosphorylase". United States. https://doi.org/10.1021/acs.jmedchem.8b01642. https://www.osti.gov/servlets/purl/1515305.
@article{osti_1515305,
title = {Selective Inhibitors of Helicobacter pylori Methylthioadenosine Nucleosidase and Human Methylthioadenosine Phosphorylase},
author = {Harijan, Rajesh K. and Hoff, Oskar and Ducati, Rodrigo G. and Firestone, Ross S. and Hirsch, Brett M. and Evans, Gary B. and Schramm, Vern L. and Tyler, Peter C.},
abstractNote = {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.},
doi = {10.1021/acs.jmedchem.8b01642},
journal = {Journal of Medicinal Chemistry},
number = 7,
volume = 62,
place = {United States},
year = {Tue Mar 12 00:00:00 EDT 2019},
month = {Tue Mar 12 00:00:00 EDT 2019}
}
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