Faculty

The research efforts in our lab involve three distinct areas of study, although they are somewhat related.

RNA Base Modification:  Approximately 100 chemically distinct modified nucleosides have been found in nucleic acids, ca. 75% of them in tRNAs.  It has been estimated that 5% of the E. coli genome codes for RNA modifying enzymes, yet relatively little is known of their physiological roles.  It remains totally unclear why tRNAs have so many and such diverse modifications when relatively few are found in other RNA species.  We have done much to explore mechanism, substrate recognition and inhibitor design for the eubacterial tRNA-guanine transglycosylase (TGT), the key enzyme responsible for the queuine modification in the anticodon loop of certain tRNAs.  Present efforts in the lab are focused upon exploring the roles and prevalence of base modifications in RNA.

TB Drug Discovery:  Tuberculosis (TB, caused by Mycobacterium tuberculosis) is a human health problem of staggering proportions, causing nearly 2 million deaths in 2005.  TB is now the leading cause of death in HIV/AIDS patients.  Current drugs require up to 9 months of treatment, making compliance very difficult.  Poor compliance allows for the emergence of drug-resistant strains of TB.  Thus, it seems logical that new therapeutics must be developed that are more effective against all strains and act in much shorter treatment regimens if TB is to be eliminated.  We are part of a new, larger cooperative effort to discover new treatments for TB.  Our goal is to develop novel drugs targeting RNA polymerase that avoid currently known resistance mechanisms.

Acute Diarrheal Disease Drug Discovery:  Shigella flexneri is a human enteropathogen that claims more than one million lives per year worldwide.  Shigella infects the cells of the gastrointestinal tract causing severe dysentery.  Absent appropriate antibiotic and electrolyte replacement treatment, shigellosis rapidly leads to dehydration and death.  While Shigella is susceptible to a number of antibiotics, resistant clinical isolates including multi-drug resistance have been observed.  We have recently initiated a new drug discovery effort against Shigella where we are targeting a transcription factor responsible for activating key virulence genes.

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.