Abstract
5'-Deoxy-5'-methylthioadenosine (MTA), an important intermediate in methionine recycling, can be metabolized by one of two mechanisms that appear to be mutually exclusive. In human cells, MTA is degraded in one step to adenine and 5-methylthioribose 1-phosphate (MTR-1-P) via MTA phosphorylase. In contrast, certain microbes metabolize MTA in two steps: first to 5-methylthioribose (MTR) followed by conversion to MTR-1-P. The enzymes involved in this two-step conversion are MTA nucleosidase and MTR kinase. In both cases, MTR-1-P is subsequently recycled to methionine. Because MTR kinase is "unique" to microbes (it is also found in plant tissue) and since it is essential to microbial methionine salvage, we hypothesized that MTR kinase is a promising target for chemotherapeutic exploitation. We demonstrate that 5-trifluoromethylthioribose (TFMTR), a structural analog of MTR, is a potent inhibitor of the MTR kinase-containing organism Klebsiella pneumoniae. TFMTR not only inhibits the growth of K. pneumoniae in a dose-dependent manner (50% inhibition at approximately 40 nM) but also competitively inhibits MTR kinase activity (Ki approximately 7 microM). Furthermore, TFMTR is shown to be a substrate for MTR kinase (Km = 1.7 microM), suggesting that the drug could be converted to toxic products (e.g. trifluoromethionine or carbonothionic difluoride) in enzyme-containing organisms. Structural analogs of MTR represent a new class of compounds with the potential for treating diseases caused by MTR kinase-containing microorganisms.
Highlights
From the $Department of Veterans Affairs Medical Center, Portland, Oregon 97201, the SDepartment of Medicine, Oregon Health Sciences University, Portland, Oregon 97201, and YlEpitope Inc., Beaverton, Oregon 97006
Because MTR kinase is “unique” to microbes and since it is essential to microbial methionine salvage, we hypothesized that
We demonstrate that 5-trifluoromethylthioribose (TFMTR), a structural analog of MTR, is a potent inhibitor of the MTR kinase-containing organism Klebsiellapneumoniae
Summary
Affairs Medical Center, Medical Research Service, 15i-0,371O S. Since MTR kinase is essential for methionine salvage in many procaryotic and lower eucaryotic microbes, it represents a promising site against which to direct agents capable of perturbing methionine metabolism in these organisms To test the hypothesis that MTR kinase-containing microorganisms would be selectively inhibited by structural analogs of MTR, we synthesized 5-trifluoromethylthioribose (TFMTR) and examined its effects on the growth of Klebsiella pneumoniue. This organism was chosen for two reasons: (a). Furfine and Abeles [14] have shown that K. pneumoniae is able to metabolize MTR-1-P to methionine; and (b) MTR kinase activity has been detected recently in cell-free extracts of K. pneumoniue [20,21]. We demonstrate that TFMTR is a potent inhibitor of the growth of this organism
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
