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LUKASZ LEBIODA , PhD
Professor, USC, Dept. Chemistry and Biochemistry
DEGREES
B.S., 1965, Jagiellonian University (Poland)
Ph.D., 1972, Jagiellonian University
D.Sc, 1979, Jagiellonian University
RESEARCH INTERESTS
Structural biochemistry. Rational drug design based on enzyme structures and mechanisms. Protein engineering and thermostability. Molecular evolution.
My laboratory is involved in studies of the structure-function relationship of enzymes either related to cancer chemotherapy or having potential environmental applications.
The crystal structure of the complex of human thymidylate synthase (TS) with a substrate, dUMP and a drug, Tomudex, determined at USC, is shown here. Inhibitors of TS are used in cancer chemotherapy. However, cancer cells develop resistance to the existing drugs typically by increasing the TS levels by a factor between 4 and 10. One of the mechanisms proposed to explain this phenomenon is increased stability to intracellular degradation upon formation of complexes with presently used drugs. We are developing a new class of TS inhibitors that should not generate this problem. In our approach we stabilize an unusual conformational transition specific to human TS that leads to an inactive conformation rather than following the old approach of developing inhibitors targeting the active site.
My group, in collaboration with Dr. John Dawson is studying the structure-function relationship in enzymes catalyzing dehalogenation and halogenation of halocarbons. The most advanced are investigations of the structure and activity of dehalogenase from the marine polychaete organism amphitrite ornata (DHP). This enzyme utilizes the oxidative potential of hydrogen peroxide to dehalogenate chlorophenols (and also fluorophenols, bromophenols, and iodophenols) and is an order of magnitude faster than any other known dehalogenase despite its miniscule size, 16 kD per subunit. Contamination of waste water from paper mills and other industrial operations with chlorophenols is a serious environmental problem. In order to develop industrial biocatalysts with dehalogenase activity, DHP has been immobilized with retention of its catalytic activity. The enzyme, however, is not stable enough for large-scale applications. We are studying its structure and activity to engineer changes in the molecule that will lead to an increase in the enzyme's stability. Such changes could include the introduction of cysteine bridges, elimination of solvent cavities, and reduction of the peptides chain flexibility by increasing the contents of proline residues and reducing the contents of glycine residues. The DHP ability to defluorinate halophenols is unique; we are not aware of any other enzyme that can catalyze the breakage of the carbon-fluorine bond. We would like to utilize the enzymatic capability and work on engineering such modifications to the active site of DHP that will switch the affinity from the natural substrates, halophenols, to haloaromatics and even freons. The modified enzyme should find applications in the destruction of these pollutants responsible for the creation of the ozone holes.
RECOGNITION
Foreign Member of the Polish Academy of Arts and Sciences
Educational Foundation Research Award for Science, Mathematics, and Engineering, University of South Carolina, 1998.
CONTACT INFORMATION
University of South Carolina
Department of Chemistry and Biochemistry
631 Sumter St.
Columbia, SC 29208 | E-mail
Office: 803 . 777 . 2140 | Lab1: 803 . 777 . 6494 | Lab2: 803 . 777 . 6108 | Lab3: 803 . 777 . 4751
Fax: 803 . 777 . 9521
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