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Selective Inhibitors of Helicobacter pylori Methylthioadenosine Nucleosidase and Human Methylthioadenosine Phosphorylase.

Selective Inhibitors of Helicobacter pylori Methylthioadenosine Nucleosidase and Human Methylthioadenosine Phosphorylase.

Authors :
Harijan RK
Hoff O
Ducati RG
Firestone RS
Hirsch BM
Evans GB
Schramm VL
Tyler PC
Source :
Journal of medicinal chemistry [J Med Chem] 2019 Apr 11; Vol. 62 (7), pp. 3286-3296. Date of Electronic Publication: 2019 Mar 28.
Publication Year :
2019

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.

Details

Language :
English
ISSN :
1520-4804
Volume :
62
Issue :
7
Database :
MEDLINE
Journal :
Journal of medicinal chemistry
Publication Type :
Academic Journal
Accession number :
30860833
Full Text :
https://doi.org/10.1021/acs.jmedchem.8b01642