Stephen Benkovic

Professional Appointments and Affiliations

Evan Pugh Professor and Eberly Chair in Chemistry

Office 

414 Wartik Laboratory

University Park, PA 16802

Education

B.S., Lehigh University; 1960

Ph.D., Cornell University, 1963

Postdoctoral Research Assoc., University of California at Santa Barbara, 1964-65

Honors and Awards

National Academy of Inventors (NAI) Fellow

National Academy of Science Award in Chemical Sciences

Ralph F. Hirschmann Award in Peptide Chemistry

National Medal of Science

Benjamin Franklin Medal in Life Science

Royal Society Centenary Medal

Nakanishi Prize (ACS)

ASBMB-Merck Award

American Philosophical Society

Christian B. Anfinsen Award

Chemical Pioneer, The American Institute of Chemists

Honorary Doctorate of Science, Lehigh University

Alfred Bader Award

Institute of Medicine, National Academy of Sciences

Bicentennial Scientific Achievement Award, City College of New York

Repligen Award

NIH Merit Award

Arthur C. Cope Scholar Award

The Eberly Chair in Chemistry

Gowland Hopkins Award

National Academy of Sciences

American Academy of Arts and Sciences

Pfizer Enzyme Award

Guggenheim Fellowship

NIH Career Development Award, The Pennsylvania State University

Alfred P. Sloan Fellow, The Pennsylvania State University

Research

Dr. Stephen Benkovic is known for his major contributions that have initiated or shaped our understanding of biological processes. Benkovic was the first to hypothesize that conformational changes outside the enzyme’s active site were necessary for achieving maximal catalysis. This is beautifully illustrated by his studies on dihydrofolate reductase (DHFR).  Benkovic showed how multi-enzyme complexes are assembled to achieve specificity and function and where several activities are present how they are mediated. This was accomplished in his studies on DNA replication that featured assembly, disassembly and function of the T4 replisome that coordinated DNA replication. Benkovic discovered the first example of a reversible metabolon, the purinosome, that only assembles in response to cellular demands and has demonstrated that the purinosome acts temporarily and spatially to form and deliver needed metabolites to cellular constituents.

Selected Publications

Fierke, C. A., Johnson, K. A., and Benkovic, S. J. (1987) Construction and evaluation of the kinetic scheme associated with dihydrofolate reductase from Escherichia coli, Biochemistry 26, 4085-4092.

Kuchta, R. D., Benkovic, P. A., and Benkovic, S. J. (1988) Kinetic Mechanism Whereby DNA Polymerase I (Klenow) Replicates DNA with High Fidelity, Biochemistry 27, 6716-6725.

Lerner, R. A., Benkovic, S. J., and Schultz, P. G., (1991) At the Crossroads of Chemistry and Immunology: Catalytic Antibodies, Science 252, 659 667.

Dahlberg, M. and Benkovic, S. J., (1991) Kinetic Mechanism of DNA Polymerase I (Klenow Fragment): Identification of a Second Conformational Change and Evaluation of the Internal Equilibrium Constant, Biochemistry 30, 4835 4843.

Capson, T. L., Peliska, J. A., Kaboord, B. F., Frey, M. W., Lively, C., Dahlberg, M., and Benkovic, S. J. (1992) Kinetic Characterization of the Polymerase and Exonuclease Activities of the Gene 43 Protein of Bacteriophage T4, Biochemistry 31, 10984-10994.

Peliska, J. A., and Benkovic, S. J., (1992) Mechanism of DNA Strand Transfer Reactions Catalyzed by HIV-1 Reverse Transcriptase, Science 258, 1112-1118.

Hirschmann, R., Smith, A. B. III, Taylor, C. M., Benkovic, P. A., Taylor, S. D., Yager, K. M., Sprengeler, P. A., and Benkovic, S. J., (1994) Peptide Synthesis Catalyzed by an Antibody Containing a Binding Site for Variable Amino Acids, Science 265, 234-237.

Epstein, D. M., Benkovic, S. J., and Wright, P. E. (1995) Dynamics of the dihydrofolate reductase--folate complex: Catalytic sites and regions known to undergo conformational change exhibit diverse dynamical features, Biochemistry 34, 11037-11048.

Rajagopalan, P. T. R., Lutz, S., and Benkovic, S. J. (2002) Coupling interactions of distal residues enhance dihydrofolate reductase catalysis: Mutational effects on hydride transfer rates, Biochemistry 41, 12618-12628.

Agarwal, P. K., Billeter, S. R., Rajagopalan, P. T. R., Benkovic, S. J., and Hammes-Schiffer, S. (2002) Network of coupled promoting motions in enzyme catalysis, Proc. Natl. Acad. Sci. USA 99, 2794-2799.

Benkovic, S. J. and Hammes-Schiffer, S. (2003) A perspective on enzyme catalysis, Science 301, 1196-1202.

Hammes-Schiffer, S. and Benkovic, S. J. (2006) Relating protein motion to catalysis, Annu. Rev. Biochem. 75, 519-541.

Rock, F. L., Mao, W., Yaremchuk, A., Tukalo, M., Crepin, T., Zhou, H., Zhang, Y.-K., Hernandez, V., Akama, T., Baker, S. J., Plattner, J. J., Shapiro, L., Martinis, S. A., Benkovic, S. J., Cusack, S., and Alley, M. R. K. (2007) An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site, Science 316, 1759-1761.

Goodey, N. M. and Benkovic, S. J. (2008) Allosteric regulation and catalysis emerge via a common route, Nat. Chem. Biol. 4, 474-482.

An, S., Kumar, R., Sheets, E. D., and Benkovic, S. J. (2008) Reversible compartmentalization of de novo purine biosynthetic complexes in living cells, Science 320, 103-106.

Lee, J., Natarajan, M., Nashine, V. C., Socolich, M., Vo, T., Russ, W. P., Benkovic, S. J., and Ranganathan, R. (2008) Surface Sites for Engineering Allosteric Control in Proteins, Science 322, 438-442.

Bhabha, G., Lee, J., Ekiert, D. C., Gam, J., Wilson, I. A., Dyson, H. J., Benkovic, S. J., and Wright, P. E.  (2011) A dynamic knockout reveals that conformational fluctuations influence the chemical step of enzyme catalysis, Science 332 (6026) 234-238.

French, J. B., Jones, S.A., Deng, H., Hu, H., Pugh, R. J., Chan C. Y., Kim, D., Pedley, A. M., Zhao, H., Zhang, Y., Huang, T. J., Fang, Y., Zhuang, X., and Benkovic, S. J., (2016) Spatial colocalization and functional link of purinosomes with mitochondria, Science, 351:6274, 733-736.

Pedley, A. M. and Benkovic, S.J. (2017) A new view into the regulation of purine metabolism – the purinosome”, Trends Biochem Sci, 42(2):141-154.

Benkovic, S.J., Spiering, M.M. (2017) “Understanding DNA Replication by the Bacteriophage T4 Replisome”, JBC, 292 (45) 18434-18442.