Education

Merck Postdoctoral Fellowship, Yale University
Ph.D., Harvard University
B.S., University of Chicago

National/International Leadership

Assistant Director (Lead), NSF MPS Directorate (2024-present; ~200 staff; ~$1.7 B budget)
Division Director, NSF Division of Chemistry (2020-2024; ~40 staff; ~$250 M budget)
Co-Chair, Gordon Research Conference on Biocatalysis (2018)                                                                                            

Awards/Honors

2025 - Plenary Speaker, ACS Global Editors Conference
2024 - Fellow, American Chemical Society
2020-2024 - Chemical Sciences Roundtable (NAS)
2019-2020 - Board on Chemical Sciences & Technology (NAS)
2018 - Chair, Gordon Research Conference on Biocatalysis
2016 - Board of Editors - Organic Reactions
2015 - Fellow, American Association for the Advancement of Science (AAAS)
2008 - Japan Society for the Promotion of Science (JSPS) Fellow
2006 - Visiting Professor, Max Planck Institute for Molecular Physiology, Dortmund, Germany
2005 - Visiting Professor, U. de Rouen, Rouen, France
1997-2001 - CAlfred P. Sloan Fellow
                                                                                   

Research Interests

Catalyst screening and reaction development, asymmetric synthesis, biocatalysis, fluorinated phosphonates, mechanism-based enzyme inhibitors, PLP enzymes and neuronal signaling, lignan natural products

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.

• Figure 1 Stereocontrolled and Ring-E Modular Synthesis of Bioactive Lignan Natural Products
• Figure 2a
• Figure 2b

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.

• Figure 3 Purification of Lysine Decarboxylase and Inactivation with a Designed, Mechanism-Based Inhibitor

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).

For more information, please visit the Berkowitz Research Group Website.

Selected Publications

(1) Gaurav P. Kudalkar, Virendra K. Tiwari, David B. Berkowitz* “Exploiting Archaeal/Thermostable Enzymes in Synthetic Chemistry: Back to the Future?” ChemCatChem 2024, e202400835; 1-17 DOI: 10.1002/cctc.202400835     

(2) Stephany Ramos de Dios, Danielle L. Graham, Jared L. Hass, Nivesh Kumar, Aina E. Antony; Martha D. Morton, David B. Berkowitz* “Information-Rich, Dual Function ¹³C/²H-Isotopic Crosstalk Assay for Human Serine Racemase (hSR) Provides a PLP Enzyme ‘Partitioning Fingerprint’ and Reveals Disparate Chemotypes for hSR Inhibition,”. JACS., 2023, 145, 3158-3174; DOI: 10.1021/jacs.2c12774      

(3) Stephany Ramos de Dios, Virendra K. Tiwari, Christopher D. McCune, Ranjeet A. Dhokale, David B. Berkowitz*  “Biomacromolecule-Assisted Screening for Reaction Discovery and Catalyst Optimization,” Chem. Rev. 2022,121, 13800-13880; DOI: 10.1021/acs.chemrev.2c00213  (Chemical Reviews journal cover: https://pubs.acs.org/cms/10.1021/chreay.2022.122.issue-16/asset/chreay.2022.122.issue-16.xlargecover-2.jpg)

(4) Virendra K. Tiwari, Douglas R. Powell, Sylvain Broussy, David B. Berkowitz*  “Rapid Enantioselective and Diastereoconvergent Hybrid Organic/Biocatalytic Entry into the Oseltamivir Core,” J. Org. Chem. 2021, 86, 6494-6503;  DOI: 10.1021/acs.joc.1c00326 – Selected for the journal cover! See: https://pubs.acs.org/cms/10.1021/joceah.2021.86.issue-9/asset/joceah.2021.86.issue-9.xlargecover-4.jpg

(5) Gaurav P. Kudalkar, Virendra K. Tiwari, Joshua D. Lee, David B. Berkowitz,* “Hammett Study of Clostridium acetobutylicum Alcohol Dehydrogenase (CaADH): An Enzyme with Remarkable Substrate Promiscuity and Utility for Organic Synthesis,” Synlett, 2020, 31, 237-247; DOI: 10.1055/s-0039-1691576

– included in a special Synlett Cluster on Biocatalysis                                                                               

(6) Kaushik Panigrahi, Xiang Fei, Masato Kitamura,* David B. Berkowitz,* “Rapid Entry into Biologically Relevant a,a-Difluorophosphonates Bearing Allyl Protection - Deblocking Under Ru (II)/(IV) Catalysis,” Organic Letters, 2019, 21, 9846-9851; DOI: 10.1021/acs.orglett.9b03707

(7) Danielle L. Graham, Matthew L. Beio, David L. Nelson, David B. Berkowitz* “Human Serine Racemase: Key Active Site Residues/Motifs and Their Relation to Enzyme Function,” Frontiers in Molecular Biosciences 2019,  DOI: 10.3389/fmolb.2019.00008 (13 March 2019)

(8) Yuping Tu; Cheryl A. Kreinbring, Megan Hill, Cynthia Liu, Gregory A. Petsko, Christopher D. McCune, David B. Berkowitz, Dali Liu, Dagmar Ringe,* “Crystal Structures of Cystathionine g-Synthase from Saccharomyces cerivisiae: One Enzymatic Step at a Time,”Biochemistry 2018, 57, 3134-3145;DOI: 10.1021/acs.biochem.8b00092

(9) Robert A. Swyka & David B. Berkowitz “The In Situ Enzymatic Screening (ISES) Approach to Reaction Discovery and Catalyst Identification” Current Protocols in Chemical Biology, 2017, 9(4), 285-305; DOI: 10.1002/cpch.30

(10) Guillaume Malik, Rob Swyka, Virendra Tiwari, Xiang Fei, Greg Applegate, and David B. Berkowitz* “A thiocyanopalladation/carbocyclization transformation identified through enzymatic screening: stereocontrolled tandem C–SCN and C–C bond formation” Chem. Sci., 2017, 8, 8050-8060; DOI: 10.1039/C7SC04083K

(11) Christopher D. McCune, Matthew L. Beio, Jill M Sturdivant, Roberto de la Salud-Bea, Brendan M. Darnell, and David B. Berkowitz “Synthesis and Deployment of an Elusive Fluorovinyl Cation Equivalent: Access to Quaternary α-(1’-Fluoro)vinyl Amino Acids as Potential PLP Enzyme Inactivators” JACS, 2017, 139, 14077-14089; DOI: 10.1021/jacs.7b04690

(12) Christopher D. McCune; Su Jing Chan; Matthew; Beio; Weijun Shen; Woo Jin Chung,; Laura Szczesniak; Chou Chai;  Shu Qing Koh , Peter T.-H. Wong;* David Berkowitz*  “Zipped Synthesis” by Cross-Metathesis Provides a CBS (Cystathionine β-Synthase) Inhibitor that Attenuates Cellular H₂S Levels and Reduces Neuronal Infarction in a Rat Ischemic Stroke Model," ACS Central Science 2016,  ASAP; DOI: 10.1021/acscentsci.6b00019; featured in Science Daily: https://www.sciencedaily.com/releases/2016/03/160309082748.htm; featured in Medical News Today: https://www.medicalnewstoday.com/releases/307731.php

Complete list of publications