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Title: Trifluoroselenomethionine: A new unnatural amino acid

Author
item BLOCK, ERIC - State University Of New York (SUNY)
item BOOKER, SQUIRE - Pennsylvania State University
item FLORES-PENALBA, SONIA - State University Of New York (SUNY)
item GEORGE, GRAHAM - University Of Saskatchewan
item LANDGRAF, BRADLEY - Pennsylvania State University
item LI, FEI - University Of Delaware
item LODGE, STEPHENE - State University Of New York (SUNY)
item PUSHIE, JAKE - University Of Saskatchewan
item ROZOVSKY, SHARON - University Of Delaware
item VATTEKKATTE, ABITH - State University Of New York (SUNY)
item YAGHI, RAMA - State University Of New York (SUNY)
item Zeng, Huawei

Submitted to: ChemBioChem
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/7/2016
Publication Date: 9/15/2016
Publication URL: http://handle.nal.usda.gov/10113/5852156
Citation: Block, E., Booker, S., Flores-Penalba, S., George, G., Landgraf, B., Li, F., Lodge, S.N., Pushie, J., Rozovsky, S., Vattekkatte, A., Yaghi, R., Zeng, H. 2016. Trifluoroselenomethionine: A new unnatural amino acid. ChemBioChem. 17(18):1738-1751.

Interpretive Summary: Epidemiological evidence indicates that selenium (Se) status is inversely associated with cancer/bacterial infection risk, and results from several intervention studies show that high Se intakes effectively reduce colon cancer risk. It has been documented that methylseleninic acid (MSeA), a methylselenol precursor, is a superior choice of Se for cancer chemoprevention over other Se compounds. Trifluoromethionine and selenomethionine are of interest as prodrugs (again cancer and bacterial infection), affording cytotoxic trifluoromethanethiol and methylselenol, respectively. In the present study, we demonstrated trifluoroselenomethionine, a new non-natural amino acid with enhanced methioninase-induced cytotoxicity toward human colon cancer cells. These research data open new avenues to studying anticancer/infection. The immediate application of our findings is to determine trifluoroselenomethionine’s anti-(colon cancer) property with animal models and human intervention studies, which may lead to yield the next generation Se compound against human diseases. Collectively, the information will be useful for scientists and health-care professionals who are interested in using Se as a nutrient/drug in the prevention/treatment of human cancer/bacterial infection.

Technical Abstract: Trifluoroselenomethionine (TFSeM), a novel non-natural amino acid, was synthesized in seven steps from N-(tert-butoxycarbonyl)-L-aspartic acid tert-butyl ester. TFSeM shows enhanced methioninase-induced cytotoxicity toward human colon cancer derived HCT- 116 cells compared to selenomethionine (SeM). Mechanistic explanations for this enhanced activity are computationally and experimentally examined. Comparison of TFSeM and SeM by selenium EXAFS and DFT calculations showed them to be spectroscopically and structurally very similar. None-the-less, when two different mutants of the protein GB1 were expressed in the E. Coli methionine auxotroph cell line B834(DE3) using TFSeM and methionine in a 9:1 ratio, it was found that, surprisingly, 90% of the proteins were composed of SeM, even though no SeM had been added, implying loss of the trifluoromethyl group from TFSeM.