Faculty

Our primary research interests involve the biosynthesis and physiological roles of modified nucleosides in nucleic acids. Specifically, we use chemical biology approaches (enzyme kinetics, bioorganic chemistry, protein chemistry, cloning, expression, site-directed mutagenesis and X-ray crystallography-in collaboration) to study the process of post-transcriptional modification of RNA from a chemical/molecular point of view. Using these approaches, it is our goal to elucidate the processes by which proteins recognize RNA and modified heterocyclic bases, the chemical and kinetic mechanisms of the enzymes involved and, ultimately the physiological roles of these modified bases.

The process of base modification in RNA has many implications in human disease including autoimmune disease, cancer, and viral disease. For example, all tRNAs are post-transcriptionally modified such that anywhere from 5% to 20% (depending upon the species) of the bases contain some covalent modification. These modifications vary from the very simple, such as methylation, to the very elaborate. The exact roles of the vast majority of these post-transcriptional modifications are not yet known, however, it has been shown some modifications alter the amino acid identity of the tRNA and others are linked to differentiation and proliferation.

Our research on base modification involves three related programs of study. The first is to elucidate the pathway for the biosynthesis of the modified base queuine in eubacteria. Our second program is to compare and contrast tRNA-guanine transglycosylases from archaebacteria, eubacteria, and eukaryotes. The third program is to use the knowledge that we have gained in these studies to probe the physiological role(s) of queuine (in eubacteria and eukaryotes) and archaeosine (in archaebacteria).

Awards

Student Appreciation Award, University of Michigan College of Pharmacy, 2005
National Institutes of Health Postdoctoral Research Fellowship, 1988-1990
American Foundation for Pharmaceutical Education, 1987
"Johnson & Johnson Pharmaceutical Chemistry Fellow," 1987
American Foundation for Pharmaceutical Education "H. A. B. Dunning Memorial Fellow," 1985-87
University of California Regent's Fellowship, 1983-86
University of California, San Francisco Graduate Division, Minority Mentorship, 1984-85

Representative Publications

1. Meyer, M.M., Roth, A., Chervin, S.M., Garcia, G.A., Braeker, R.R., "Donfirmation of a Second Natural PreQ₁ Aptamer in Streptococcaceae Bacteria" RNA, 2008, 14, 685.

2. Tidten, N., Stengl, B., Heine, A., Garcia, G.A., Klebe, G., Reuter, K., "Glutamate versus Glutamin Exchange Swaps Substrate Selectivity in tRNA-Guamine Transglycosylase" J. Mol. Biol., 2007, 374(30), 764.

3. Hurt, J.K., Olgen, S., Garcia, G.A., "Site-specific Modificatin of Shigella flexneri virF nRNA by tRNA-Guanine Transglycocosylase In vitro" Nucleic Acids Reserch, 2007, 35, 4905.

4. Chervin, S.M., Kittendorf, J.D., Garcia, G.A., "Probing the Intermediacy of Covalent RNA Enzyme Complexes in RNA Modification Enzymes" Methods in Enzymology, 2007, 425, 121.

5. Todorov, K.W., Garcia, G.A., "The Role of Aspartate 143 in E. coli tRNA-Guanine Transglycosylase: Alteration of Heterocyclic Substrate Specificity", Biochemistry, 2006, 45(2), 617.

6. Garcia, G. A. and Kittendorf, J. D., "Transglycosylation, a Mechanism for RNA Modification (and Editing?)", Bioorganic Chem., 2005, 33(3), 229-251.

7. Todorov, K.W., Tan, Z.J., Nonekowski, S.T., Garcia, G.A., Carlson, H.A., "The Role of Aspartic Acid 143 in E. coli tRNA-Guanine Transglycosylase: Insights from Mutagenesis Studies and Computational Modeling", Biophysical J, 2005, 89(3), 1965.