Research Interests

We are studying chemical catalysis with biological systems (enzymes), using tools of organic and physical chemistry. Chemical catalysis in biological systems is highly stereo- and regio-specific and selective. Most enzymes catalyze reactions at ambient temperature and pressure. These qualities are of great interest when developing new catalysts for organic reactions. Studying enzyme mechanism on the molecular level leads to an in-depth understanding of how evolution uses the principles of chemistry and physics to direct, enhance and control biological processes. Additionally, understanding how enzymes work can lead to development of new drugs of medical importance, new paths in organic synthesis, and new methodologies in biotechnology. Two main directions will be pursued:

The role of protein dynamics and quantum mechanical effects in enzyme catalyzed hydrogen transfer.

Enzymes involved in DNA biosynthesis are being studied (TS, DHFR and SHMT). These are small proteins that catalyze hydrogen transfer by many orders of magnitude and are of great medical interest. Many anti-cancer and antibiotic drugs target these enzymes (Figure 1).

Studies of an alternative TS.

Several human pathogens and a few other microorganisms do not have the genes encoding for the above cycle. Instead, dTMP (T in the DNA sequence) is synthesized by a newly discovered flavin dependent enzyme (FDTS). Our studies revealed that its mechanism is completely different than that of the classical TS and made this enzyme a prime target for antibiotic and anti biological-warfare agent drugs.

The mechanism of dinitrogen reduction by nitrogenases.

These enzymes are metalo-enzymes that catalyze the following reaction:

The N₂ bond is one of the most stable bond in nature. Nitrogenases cleave that bond under ambient condition which is of great interest in industry, agriculture, and basic science studies.

In both projects, an interdisciplinary approach is proposed where the techniques of synthetic organic chemistry and molecular biology will be used to manipulate substrates and enzymes, respectively. Students in the group will gain knowledge and hands-on experience in organic synthesis, molecular biology and protein purification, structural biology and drug design, enzyme assays and kinetics, isotope effect measurements, and various theoretical aspects of catalysis.