Dr. David Berkowitz is active at the interface of synthetic organic chemistry and enzymatic chemistry. Projects in the group include the synthesis and study of unnatural analogues of biological molecules that have been designed to display interesting properties. This includes (a) fluorinated phosphonates designed to act as stable phosphate surrogates or ‘teflon phosphates,’ (b) unnatural, alpha-branched amino acids designed to function as ‘Trojan horse inactivators’ for vitamin B-6 dependent enzymes, and (c) unnatural analogues of the lignan natural product (-)-podophyllotoxin, designed to probe its binding to tubulin. Synthetic methodology development becomes part and parcel of these endeavors.
The newest area of activity in the group is in catalyst development. In particular, we are attempting to address the need for efficient and information-rich screening methods to support combinatorial approaches to catalyst discovery and optimization. This has led to the development of a method that we term In Situ Enzymatic Screening (ISES) that exploits enzyme-based reporters enabling the experimentalist to rapidly rank catalysts, ideally, in terms of relative rate and stereoselectivity. The scope, limitations and application of this technology are currently under investigation.
Recent Awards/Honors (since 2005):
2009 Plenary Speaker, Visions in Chemistry Symposium, Sanofi-Aventis (Bridgewater, NJ)
(one of five speakers chosen nationally – along with Jeff Bode, Bruce Lipshutz, John Wood and Robert Grubbs)
(2005 Nobel Laureat in Chem) See the web site for more details
2009 Invited Speaker, 19th ACS Division of Fluorine Chemistry
Winter Fluorine Conference (St. Petersburg, FL)
2008-09 Japan Society for the Promotion of Science (JSPS) Fellowship
2008 Organizer, ACS Division of Organic Chemistry Symposium on Advances in Combinatorial Catalysis and Screening,
236th National ACS Meeting, Aug. 17-21, 2008 (Philadelphia, PA)
2008 Award for Outstanding Contributions to Undergraduate Research – University of Nebraska-Lincoln
2006 Visiting Professor, Max Planck Institut für molekulare Physiologie, Dortmund, Germany.
Kaushik Panigrahi, David L. Nelson and David B. Berkowitz. “Unleashing a ‘True’ pSer-Mimic in the Cell.” Chemistry and Biology, 2012, 19, 666-667. .pdf
Sandeep K. Ginotra, Jacob A. Friest and David B. Berkowitz. “Halocarbocyclization Entry into the Oxabicyclo[4.3.1]decyl Exomethylene--Lactone Cores of Linearifolin and Zaluzanin A: Exploiting Combinatorial Catalysis.” Organic Letters, 2012, 4, 968-971 .pdf
Jacob A. Friest, Sylvain Broussy, Woo Jin Chung, and David B. Berkowitz. “Combinatorial Catalysis Employing a Visible Enzymatic Beacon in Real Time: Synthetically Versatile (Pseudo)Halometalation/Carbocyclizations.” Angewandte Chemie, Int. Ed. 2011, 50, 8895-8899. pdf
Gregory A. Applegate, Ross W. Cheloha, David L. Nelson, and David B. Berkowitz. "A New Dehydrogenase from Clostridium acetobutylicum for Asymmetric Synthesis: Dynamic Reductive Kinetic Resolution entry into the Taxotère side chain." Chem Comm 2011, 47, 2420-2422. pdf
Featured in: SYNFACTS 2011, 3, 333.
David B. Berkowitz, Sangeeta Dey, Kannan R. Karukurichi and Weijun Shen. "A Method for Measuring the Stereoselectivity and Relative Rate for Organic Chemical Reactions." U.S. Patent No. 7,767,388, issued August 3, 2010.
Jacob A. Friest, Yukari Maezato, Sylvain Broussy, Paul Blum, and David B. Berkowitz. "Use of a Robust Dehydrogenase from an Archael Hyperthermophile in Asymmetric Catalysis - Dynamic Reductive Kinetic Resolution Entry into (S)-Profens." JACS 2010, 132, 5930-5931. pdf
Featured in Chemical and Engineering News, 2010, 88 (16), 34- 35. Featured in SYNFACTS, 2010, 8, 861.
Nicola J. Baxter, Matthew W. Bowler, Tooba Alizadeh, Matthew J. Cliff, Andrea M. Hounslow, Bin Wu, David B. Berkowitz, Nicholas H. Williams, G. Michael Blackburn, and Jonathan P. Waltho. "Atomic details of near-transition state conformers for enzyme phosphoryl transfer revealed by MgF3? rather than by phosphoranes." PNAS 2010, 107 (10) 4555-4560. pdf
Featured in Chemical and Engineering News, 2010, 88 (9), 35.
David B. Berkowitz ; Sylvain Broussy; Argiris Efstratiadis; Apostolos Klinakis; Matthias Szabolcs.Columbia University in the City of New York, USA; University of Nebraska). “Analogues of (-)-Picropodophyllin, Synthesis and Uses Thereof.” PCT Int. Appl. 2009, 114pp. CODEN: PIXXD2 WO 2009100349 A1 20090813
Kaushik Panigrahi, MariJean Eggen, Jun-Ho Maeng, Quanrong Shen, David B. Berkowitz* “The a,a-Difluorinated Phosphonate L-pSer-Analogue: An Accessible Chemical Tool for Studying Kinase-Dependent Signal Transduction, in Vitro and In Living Cells.” Chemistry and Biology 2009, 16(9), 928-936.
David B. Berkowitz,* Kannan R. Karukurichi, Roberto de la Salud-Bea, Gourhari Maiti, Jill M. McFadden and Michelle L. Morris “Stereoselective Synthesis of Quaternary, alpha-Vinyl Amino Acids and their alpha-(2’Z-Fluoro)vinyl Congeners – Promising Candidates for PLP Enzyme Inactivation.” ACS Symposium-In-Print 2009, 1009, 288-303.
Broussy, Sylvain, Cheloha, Ross W., and Berkowitz, David B.. "Enantioselective, Ketoreductase-Based Entry into Pharmaceutical Building Blocks: Ethanol as Tunable Nicotinamide Reductant." Organic Letters 2009, 11(2), 305-308.
David B. Berkowitz*, Kannan R. Karukurichi, Roberto de la Salud-Bea, David L. Nelson, and Christopher D. McCune, “Use of fluorinated functionality in enzyme inhibitor development: Mechanistic and analytical advantages,”
J. Fluorine Chem. 2008, 129, 731–742.
Xiang Fei, Christopher M. Connelly, Richard G. MacDonald,* David B. Berkowitz * “A Set of Phosphatase-Inert “Molecular Rulers” to Probe for Bivalent Mannose 6- Phosphate Ligand-Receptor Interactions” Bioorg. Med. Chem. Lett. 2008, 18, 3085-3089 (Wilfred van der Donk Tetrahedron Young Investigator Award Issue).
Sangeeta Dey, Douglas R. Powell, Chunhua Hu, David B. Berkowitz* “ ‘Cassette’-ISES (In Situ Enzymatic Screening) Identifies Complementary Chiral Scaffolds for Hydrolytic Kinetic Resolution Across a Range of Epoxides,” Angew. Chem. Int. Ed. 2007, 46, 7010-7014.
Amy M. Wilstermann; Ryan P. Bender; Murrell Godfrey; Sungjo Choi; Clemens Anklin; David B. Berkowitz; Neil Osheroff; David E. Graves “Topoisomerase II-Drug Interaction Domains: Identification of Substituents on Etoposide that Interact with the Enzyme.” Biochemistry 2007, 46,8217-8225.
Kannan R. Karukurichi, Roberto de la Salud-Bea, Wan Jin Jahng, David B. Berkowitz* “Examination of the New a-(2’Z-Fluoro)vinyl Trigger with Lysine Decarboxylase: The Absolute Stereochemistry Determines the Reaction Course,”J. Am. Chem. Soc. 2007, 129, 258-259.
Bradley D. Charette, Richard G. MacDonald, Stefan Wetzel, David B. Berkowitz* and Herbert Waldmann* (co-corresponding authors) “PSSC (Protein Structure Similarity Clustering): Dynamic Treatment of PDB Structures Facilitates Clustering, Angew. Chem. Int. Ed. 2006, 45, 7766-7770.
David B. Berkowitz,* Bradley D. Charette, Kannan R. Karukurichi and Jill M. McFadden “a-Vinylic Amino Acids: Natural Occurrence, Asymmetric Synthesis and Biochemical Mechanisms.” Tetrahedron: Asymmetry 2006, 17, 869-882.
David B. Berkowitz, Sangeeta Dey, Kannan R. Karukurichi and Weijun Shen “A Method for Measuring the Stereoselectivity and Relative Rate for Organic Chemical Reactions.” U.S. Patent Application Serial No. 11/434,247, filed May 16, 2006.
David B. Berkowitz,* Bin Wu and Huijie Li “A Formal [3,3]-Sigmatropic Rearrangement Route to Quaternary a-Vinyl Amino Acids: Use of Allylic N-PMP Trifluoroacetimidates.” Org. Lett. 2006, 8, 971-974.
Sangeeta Dey, Kannan R. Karukurichi, Weijun Shen, and David B. Berkowitz,* “Double-Cuvette ISES: In Situ Estimation of Enantioselectivity and Relative Rate for Catalyst Screening.” J. Am. Chem. Soc. 2005, 127, 8610-8611.
David B. Berkowitz,* Mohua Bose and Sungjo Choi “In Situ Screening to Optimize Variables in Organic Reactions. U.S. Patent No. 6,974,665 Date of Issue: December 13, 2005.
Weijun Shen, Molly K. McGath, Ruby Evande and David B. Berkowitz,* “A Continuous Spectrophotometric Assay for Human Cystathionine Beta-Synthase.” Analytical Biochemistry 2005, 342, 103-110.
Recent Postdoctoral and Researchers, Graduates
- Sangeeta Dey, Ph.D. 2007 – Postdoctoral Fellow – Princeton University
- Weijun Shen, Ph.D. 2007 – Postdoctoral Fellow – Scripps Research Institute
- Kannan Karukurichi, Ph.D. 2006 – Postdoctoral Fellow – Johns Hopkins University
- Roberto de la Salud-Bea, Ph.D. 2006 – Postdoctoral Fellow –University of Michigan
- Mohua Bose, (Ph.D. 2002-postdoctoral at Scripps Res. Inst.);
- Sungjo Choi, (Ph.D. 2001- postdoctoral at Texas A&M);
- Huijie Li, (M.S. 2001-GlaxoSmithKline);
- Esmort Chisowa, (M.S. 2001-Pfizer);
- Wan-Jin Jahng, (Ph.D. 2000-postdoctoral at Harvard);
- Jill McFadden, (Ph.D. 2000-NIH postdoctoral fellowship, Johns Hopkins)