David B. Berkowitz
Professor
Hamilton Hall 824A
402.472.2738
dbb@unlserve.unl.edu
Berkowitz Research Group
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Current Research
Our group uses the power of stereocontrolled organic synthesis to address questions in biological chemistry, particularly those related to protein-ligand interactions. For example, Fig. 1 illustrates the first catalytic, asymmetric synthesis of (-)-podophyllotoxin, which serves as a tool for us to examine how the structure of the E-ring affects drug binding to tubulin. Total synthesis has yielded compounds more potent than the natural product itself, both in the tubulin assay and against human cancer cell lines.
We are also engaged in the synthesis and evaluation of unnatural analogues of amino acids (e.g. Fig. 2), designed to inactivate target enzymes. Coworkers on this project learn protein purification skills (Fig. 3), as well as enzyme kinetics, to characterize the nature of the inactivation. In a complementary endeavor, we construct mimics of natural phosphate esters that are inert to ubiquitous, digestive phosphatase enzymes. We use these phosphate mimics as bioorganic tools to build unnatural ligands for important natural phosphate binding pockets in enzymes (e.g. glucose 6-phosphate dehydrogenase) or receptors (e.g. M6P-IGF2R). Our phosphoserine mimic has served as an important bioorganic tool for biomedical scientists, at the NIH and Johns Hopkins, respectively, to study signal transduction in human tumor suppression (p53 pathway), and in production of the time-keeping hormone, melatonin.
In an exciting new development, we have turned the tables, and use enzymes to assist organic chemists in inventing new reactions through combinatorial catalysis. Arrays of potential catalysts are screened with "reporting" enzymes to provide the chemist with on the fly information about catalyst rate and enantioselectivity. We term this approach ISES (In Situ Enzymatic Screening).
- bioorganic chemistry
- asymmetric synthesis
- modular natural product synthesis
- enzyme-assisted synthesis
- combinatorial catalysis
- catalyst screening
- mechanism-based enzyme inhibition
- enzyme purification and kinetics
- medicinal chemistry
- phosphate mimics
- unnatural amino acids
A graduate or postdoctoral student in my group can expect to receive training in synthetic and bioorganic chemistry and significant exposure to one or more of the following specialties: asymmetric synthesis – including methods that employ chiral organic catalysts, enzymes, organic chiral auxiliaries or self-reproduction of chirality; enzyme inhibition/binding – especially the design, synthesis and enzyme kinetic evaluation of pseudo-substrates or mechanism-based inhibitors, combinatorial catalysis – particularly the parallel In Situ Enzymatic Screening (ISES) of catalyst arrays; and medicinal chemistry.
