Research Abstracts Online
January 2009 - March 2010
University of Minnesota Twin Cities
College of Biological Sciences
PI: Brett C. Couch
Assembly of Sequence Data for Tomato Genomic Clones
Modeling of HMGR and Drug Design
These researchers used MSI resources for two projects. The first investigated plant disease resistance genes, which occur in multiple copies throughout plant genomes. As part of a project in the laboratory of Georgiana May (Department of Ecology, Evolution, and Behavior) to study the evolution of disease resistance genes in the Solanaceae, DNA sequences were generated for four ~100 KB tomato genomic DNA clones. These clones contain gene sequences related to the tomato disease resistance gene, I2, which confers resistance to race 2 of the fungus Fusarium oxysporum. Previous work has mapped these clones to different locations along chromosome 11 in tomato. Assembly of the sequence data generated by the new 454 GS FLX System requires access to the sequence assembly and analysis programs available through MSI.
The second project investigated pathogenic fungi. In humans, many infections caused by fungi such as athletes foot and yeast infections are uncomfortable but relatively benign. However, in individuals whose immune systems have been compromised due to infection with HIV due to the use of immunosuppressant drugs, fungal infections are life-threatening. Infections caused by Candida albicans and Candida glabrata have a 47% mortality rate and an average treatment cost of $40,000 per infection. Identification and development of antifungal compounds for treatment of fungal infections or for prophylaxis requires identification of fungal-specific drug targets to avoid toxicity in humans. Many antifungal drugs target parts of the sterol biosynthesis pathway that are unique to fungi. These researchers are examining a potential new drug target in the sterol biolsynthetic pathway, the enzyme 3-hydroxy-3-methylglutaryl-Coenzyme A Reductase (HMGR). HMGR is a highly conserved protein in eukaryotes that catalyzes the rate-limiting step in the production of sterols in both humans and fungi. At first glance, the presence of this protein in both humans and fungi makes this protein an unlikely drug target. Known inhibitors of HMGR affect both the human and fungal enzymes but are not used as treatments for systemic fungal infections. The researchers examined patterns of selection on 50 HMGR gene sequences to find differences in human and fungal HMGR that could be exploited to make new antifungal compounds. They found one promising target near the enzyme’s active site. Molecular models incorporating differences between human and fungal of HMGR proteins will be used to identify drugs likely to specifically inhibit fungal HMGR using intelligent drug design.
Mitch Biermann, Undergraduate Student