1. Trifluoroselenomethionine: A New Unnatural Amino Acid.
- Author
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Block E, Booker SJ, Flores-Penalba S, George GN, Gundala S, Landgraf BJ, Liu J, Lodge SN, Pushie MJ, Rozovsky S, Vattekkatte A, Yaghi R, and Zeng H
- Subjects
- Amino Acids chemical synthesis, Amino Acids pharmacology, Carbon-Sulfur Lyases metabolism, Cell Proliferation drug effects, Dose-Response Relationship, Drug, HCT116 Cells, Humans, Models, Molecular, Molecular Conformation, Quantum Theory, Selenomethionine chemical synthesis, Selenomethionine chemistry, Selenomethionine pharmacology, Structure-Activity Relationship, Amino Acids chemistry, Selenomethionine analogs & derivatives
- Abstract
Trifluoroselenomethionine (TFSeM), a new unnatural amino acid, was synthesized in seven steps from N-(tert-butoxycarbonyl)-l-aspartic acid tert-butyl ester. TFSeM shows enhanced methioninase-induced cytotoxicity, relative to selenomethionine (SeM), toward HCT-116 cells derived from human colon cancer. 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. Nonetheless, when two different variants of the protein GB1 were expressed in an Escherichia coli methionine auxotroph cell line in the presence of TFSeM and methionine (Met) in a 9:1 molar ratio, it was found that, surprisingly, 85 % of the proteins contained SeM residues, even though no SeM had been added, thus implying loss of the trifluoromethyl group from TFSeM. The transformation of TFSeM into SeM is enzymatically catalyzed by E. coli extracts, but TFSeM is not a substrate of E. coli methionine adenosyltransferase., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2016
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