Our research is directed toward elucidation of the active site structures and catalytic mechanisms of enzymes involved in nucleoside metabolism. Enzymes presently under study include S-adenosylmethionine synthetase (ATP: L-methionine S-adenosyltransferase) which catalyzes formation of the primary biological alkylating agent, and inosine monophosphate dehydrogenase which catalyzes the rate limiting step in guanine nucleoside biosynthesis. These enzymes are recognized targets for chemotheraputic agents, and the availability of structural and mechanistic information promises the ability to develop new inhibitors through rational drug design methods. The research utilizes a multi-faceted approach that encompasses kinetic and spectroscopic studies of natural and designed mutant enzymes, and computational studies of the structures and energies of molecular interactions.
Description of research projectsFox Chase Programs
- Pimkin M, Pimkina J, Markham GD. A regulatory role of the Bateman domain of IMP dehydrogenase in adenylate nucleotide biosynthesis. J Biol Chem. 2009 Mar 20;284(12):7960-9. Epub 2009 Jan 18. PubMed
- Taylor JC, Bock CW, Takusagawa F, Markham GD. Discovery of novel types of inhibitors of S-adenosylmethionine synthesis by virtual screening. J Med Chem. 2009 Oct 8;52(19):5967-73. PubMed
- Larkin JD, Markham GD, Milkevitch M, Brooks BR, Bock CW. Computational investigation of the oxidative deboronation of boroglycine, H2N-CH2-B(OH)2, Using H2O and H2O2. J Phys Chem A. 2009 Oct 15;113(41):11028-34. PubMed
- Markham GD, Pajares MA. Structure-function relationships in methionine adenosyltransferases. Cell Mol Life Sci. 2009 Feb;66(4):636-48. Review. PubMed
- Lawrence SH, Ramirez UD, Tang L, Fazliyez F, Kundrat L, Markham GD, Jaffe EK. Shape shifting leads to small-molecule allosteric drug discovery. Chem.Biol. 2008;15:586-96. PubMed