Program

The sodium-dependent NADH dehydrogenase (Na+-NQR) is an essential part of the respiratory chain of a number of pathogens. This enzyme is not found in the human cell and has evolved separately from the main families of ion transporters and respiratory enzymes, which makes it an ideal target for drug design.

Epilepsy is a family of chronic neurological disorders that affect about 65 million people worldwide. They result from abnormal and excessive neuronal activity in the central nervous system. Our lab has developed many potent γ-aminobutyric acid aminotransferase inactivators for the treatment of epilepsy, one of which has finished a Phase 1 clinical trial.

Predicting the function of a "hypothetical protein" is a difficult endeavor, because activities have been experimentally confirmed for only a small percentage of proteins. Our work on the acetoacetate decarboxylase-like superfamily shows that even in this relatively small group of ~2000 sequences, there is variation in both substrate and reaction specificity.

Phospholipase C enzymes regulate intracellular calcium levels, and thus are essential for normal cardiovascular function. However, the regulation of these enzymes under basal and disease states is poorly understood. Using X-ray crystallography, electron microscopy, and biochemical assays, we seek to determine the molecular mechanisms underlying the regulation of these enzymes.

Dihydrofolate reductase as long served as a model system to elucidate roles of dynamics in enzyme catalysis. Two modern techniques for such studies will be described: isotopic enrichment of native enzymes and determination of the temperature dependence of kinetic isotope effects. An understanding of enzyme dynamics could lead to new drug targets and biomimetic catalysts.

The C-C bond cleavage of oxalate is difficult without a catalyst. The observation of the formation of Mn(III) during turnover of oxalate decarboxylase (OxDc) by EPR spectroscopy demonstrates how nature facilitates a chemically difficult reaction by an enzyme. It also suggests that OxDc can be classified as a redox manganese enzyme.

Methicillin-resistant Staphylococcus aureus (MRSA) causes ~1,000 deaths a year in the U.S. and has been classified as a serious threat to public health by the CDC. The newly discovered quinazolinone antibiotics have shown efficacy in treating MRSA infections in mice and work by inhibiting the penicillin-binding proteins.

Peptides are important in drug discovery and have high potential to thwart bacterial resistance, an emerging global health threat. This talk discloses the biosynthetic pathway to a novel class of RiPPs, synthesized by class II lanthionine synthases and tailoring enzymes including an intriguing flavin reductase that incorporates a D-amino acid.

This study defines a novel mechanism for recognition and excision of DNA damage. Specifically, it provides the first example of catalytic CH-π interactions and illustrates the roles these interactions play in the unprecedented repair of a bulky DNA adduct by a DNA glycosylase.

Ancient flavoenzymes able to trade quantity of electrons for potency as reductants make possible such energy-intensive reactions as N2 fixation and H2 production, even based on low-grade fuels. This is significant because N2 fixation accounts for 10% of our industrial energy consumption. Capacity to 'upgrade' their fuels enables bacteria to exploit highly diverse metabolic strategies.