Selective Inhibitors of Helicobacter pylori Methylthioadenosine Nucleosidase and Human Methylthioadenosine Phosphorylase
| Autor: | Ross S. Firestone, Rajesh K. Harijan, Oskar Hoff, Vern L. Schramm, Peter C. Tyler, Rodrigo G. Ducati, Brett M. Hirsch, Gary B. Evans |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
01 natural sciences
Article Substrate Specificity 03 medical and health sciences Glycogen phosphorylase Structure-Activity Relationship Methylthioadenosine nucleosidase Catalytic Domain Drug Discovery Hydrolase Transferase Structure–activity relationship Humans Enzyme Inhibitors 030304 developmental biology Phosphorolysis 0303 health sciences Helicobacter pylori Chemistry Orders of magnitude (mass) 0104 chemical sciences 010404 medicinal & biomolecular chemistry Quorum sensing Biochemistry Purine-Nucleoside Phosphorylase Molecular Medicine Thiolester Hydrolases |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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