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Publication Abstract from PubMed

Bacterial 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) catalyzes the hydrolysis of adenine from S-methyl-5'-thioadenosine (MTA) and S-adenosyl L-homocysteine (SAH) to form S-methyl-5'-thioribose (MTR) and S-ribosyl-L-homocysteine (SRH), respectively. The MTANs are involved in quorum sensing pathways and hydrolyze MTA to metabolites for recycling to S-adenosylmethionine (SAM). A few bacterial species use the futalosine pathway for menaquinone synthesis and in these, MTAN catalyzes an essential step, making it a candidate for species-specific antibiotic development. Helicobacter pylori uses the unusual futalosine pathway for menaquinone biosynthesis and the MTAN from H. pylori (HpMTAN) is a target for antibiotic development. Human 5'-methylthioadenosine phosphorylase (MTAP) catalyzes phosphorylation reactions with substrate specificity similar to the bacterial MTANs. It plays a metabolic role in the salvage of MTA for SAM salvage pathways and has been reported to be an anticancer target. Transition state analogues designed for HpMTAN and for MTAP have been reported and show significant overlap in specificity. It is desirable to design transition state analogues specific for the HpMTAN as an antibiotic in the treatment of H. pylori infections. Fifteen unique transition state analogues are described here and are used to explore the inhibitor specificity and the structural scaffolds for HpMTAN and MTAP. Several inhibitors are transition-state analogues of H. pylori MTAN with dissociation constants in the picomolar range while inhibiting human MTAP with orders of magnitude weaker affinity. X-ray crystal structures of HpMTAN and MTAP show inhibitors of HpMTAN extending through a hydrophobic channel to the protein surface, while the more enclosed catalytic sites of human MTAP require the inhibitors to adopt a folded structure, displacing the catalytic site phosphate nucleophile.

"Selective inhibitors of H. pylori methylthioadenosine nucleosidase and human methylthioadenosine phosphorylase".,Harijan RK, Hoff O, Ducati RG, Firestone RS, Hirsch BM, Evans GB, Schramm VL, Tyler PC J Med Chem. 2019 Mar 12. doi: 10.1021/acs.jmedchem.8b01642. PMID:30860833^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.