Research Abstracts Online
January 2010 - March 2011
University of Minnesota Twin Cities
College of Biological Sciences
PI: Brett C. Couch
Selection on the Catalytic Domain of HMGR
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 Human Immunodeficiency Virus (HIV) due to the use of immunosuppressant drugs, fungal infections are life-threatening. Infections caused by Candida albicans and C. 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 have 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 are being used to identify drugs likely to specifically inhibit fungal HMGR using intelligent drug design.
Mitch Biermann, Undergraduate Student