We are interested in merging chemical biology with more classical biochemical and enzymological approaches in the investigation and manipulation of two enzyme superfamilies of therapeutic interest.

1. The Pentein Superfamily: This group of proteins contains a number of enzymes that catalyze transformations of substrates bearing guanidines. Of current interest are 1) DDAH, an enzyme that catabolizes dimethylarginine and thereby controls nitric oxide production; 2) PAD, an enzyme that catalyzes posttranslational citrullination of protein substrates, and 3) AstB, a microbial enzyme that catalyzes an unusual dihydrolase reaction. Many enzymes in this superfamily are putative drug targets for developing treatments for septic shock, cancer, multiple sclerosis, arthritis and bacterial infections, among others.


2. The Metallo-beta-Lactamase Superfamily: This group of proteins contains a number of metal-dependent enzymes with mono- or dinuclear metal centers. Of current interest are 1) AHL lactonase, an enzyme that blocks quorum-sensing of some Gram-negative bacterial pathogens; and 2) NDM-1, a "superbug" antibiotic resistance determinant that confers resistance to almost all clinically-used beta-lactams.

The Fast Lab uses rational and library-based approaches along with a spectrum of biochemical and biophysical techniques to understand the structure and reactivity of enzymes, both in their purified forms and in their cellular contexts. These studies are then related to the larger questions of enzyme evolution and diagnostic / therapeutic development.