Selection Patterns on HMGR

Abstract

In humans, many infections caused by fungi such as athlete's foot and yeast infections are relatively benign. However, in individuals with compromised immune systems caused by HIV or the use of immunosuppressant drugs, fungal infections are critically life-threatening. Hospital-acquired infections caused by Candida albicans and C. glabrata have a 47 percent mortality rate and an average treatment cost of $40,000 per infection. The incidence of these pathogens has increased in recent years. Targeting fungal pathogens via antifungal drugs is often complicated by the high degree of similarity between molecular machines of fungi and those of their human hosts. Here we propose a potential new target, the enzyme HMG-CoA Reductase (HMGR), by phylogenetic analysis. HMGR catalyzes the rate-limiting step in the production of cholesterol, and the human HMGR has been a fruitful target for drug design, yielding compounds such as Lipitor. Current inhibitors of human HMGR stop fungal growth, but no fungal-specific HMGR inhibitors currently exist. We examined patterns of evolution on 50 HMGR gene sequences to find differences in human and fungal HMGR that could be exploited to make new antifungal compounds. We found one promising target near the enzyme's active site. We plan to design molecular models of the fungal protein based on the known human structure. This model will be used to design drugs likely to specifically inhibit fungal HMGR.