The School of Molecular and Cellular Biology at the University of Illinois at Urbana-Champaign

The research in our laboratory is directed towards the understanding of enzymatic transformations that are of pharmaceutical importance. One area of interest involves the study of enzymes that are involved in inflammation such as prostaglandin synthase, also called cyclooxygenase. The second main focus described in more detail below is on the biosynthesis of clinically promising antibiotics.

We are interested in the mechanism of biosynthesis of the so-called lantibiotics, a class of ribosomally synthesized peptide antibacterial agents. Its best known member, nisin, has ben used commercially for 40 years in more than 80 countries without detection of resistance, which is very uncommon for ubiquitously used antibiotics. In recent years it has become clear that nisin uses multiple modes of action, which explains both its high potency and its longevity. We are interested in the biosynthetic pathway for the production of nisin and other lantibiotics. After ribosomal synthesis these peptides are modified to their bioactive forms by multi-enzyme complexes. These transformations include dehydration of serine and threonine residues to form a,b-unsaturated amino acids in the peptide. Subsequently, a cyclase catalyzes the intramolecular addition of cysteine residues onto these unsaturated centers, and the biosynthesis is usually completed by removal of the N-terminal peptide by a protease. We have recently succeeded in the first in vitro reconstitution of the biosynthesis of a lantibiotic. We are now investigating the mode of action of these fascinating enzymatic transformations. Furthermore, we are exploring the scope of substrates that can be used by the multi-enzyme complex in an effort to reprogram the biosynthetic pathway and engineer lantibiotic variants with improved properties. This work may lead to the design of new, more effective antibiotics, and may provide new insights into the mechanisms by which these compounds exert their cytotoxic activity.

A second focus of our research concentrates on the biosynthesis of the antibiotic fosfomycin. This compound is used clinically for the treatment of various infectious diseases and displays a broad spectrum of antibacterial activity. Our interest in fosfomycin involves an unusual reaction during its biosynthesis, a vitamin B12 dependent methylation. In order to study this transformation, we are in the process of purifying the enzyme that carries out this step. Synthetic substrate analogs have been prepared that will be used to address specific questions regarding the mechanism of fosfomycin's biosynthesis.