Stephen J. Benkovic

Stephen James Benkovic is an American chemist known for his contributions to the field of enzymology. He holds the Evan Pugh University Professorship and Eberly Chair in Chemistry at The Pennsylvania State University. He has developed boron compounds that are active pharmacophores against a variety of diseases. Benkovic has concentrated on the assembly and kinetic attributes of the enzymatic machinery that performs DNA replication, DNA repair, and purine biosynthesis.

Education Benkovic was born in Orange, New Jersey, US. He attended Lehigh University, where he received his B.S. in chemistry and A.B. degree in English literature in 1960. He then earned his Ph.D. in organic chemistry from Cornell University in 1963. He showed how multi-enzyme complexes are assembled to achieve specificity and function and where several activities are present how they are integrated. This was accomplished in his studies on DNA replication that featured the assembly, disassembly and function of the T4 replisome that coordinates DNA replication. Benkovic discovered the first example of a reversible metabolon, the purinosome in de novo purine biosynthesis, that only assembles in response to cellular demands and acts temporally and spatially to deliver needed metabolites to cellular constituents.

Conformational Movements

A major theme of Benkovic's research has been understanding the source of the efficiency of enzymatic catalysis. He first dissected into individual steps the catalytic cycle used by dihydrofolate reductase (DHFR) using pre-steady-state methods and then tied the contribution of various amino acids, both within and outside the active site, to specific steps. The enzymic reaction is not limited by the energetics of the chemical reaction but by the mechanics of sampling that occur within the enzyme substrate complex.

This concept of biological catalysis has the enzyme's highly pre-organized Michaelis complex with its active-site residues and substrates juxtaposed by using the dynamics of the protein fold to sample substrate and active site conformations in order to find those optimal for the chemical transformation. The actual chemistry of bond breaking and forming is fast relative to the sampling process. Only a small change triggered by movement within the protein fold along a network of coupled residues is needed to surmount the reaction barrier.

De Novo Purine Biosynthesis by a Purinosome Metabolon

A longstanding question in cellular metabolism is how metabolic enzymes in a given network organize within the cytosol, densely packed with myriad proteins and metabolites, to facilitate metabolic flux. One solution is through the formation of a macromolecular complex of enzymes, termed a 'metabolon'. In humans, this metabolic transformation is carried out in ten steps by the sequential orchestration of the activities of the six enzymes. Evidence that the enzymes might condense within cells to form the purinosome derived from confocal microscopy on HeLa cells using chimeric constructs of these enzymes that revealed in common merged punctates for the six enzymes as illustrated for the two enzymes, FGAMS and GART. Spatial control of purinosome assembly in HeLa cells was found to be microtubule assisted and to colocalize with mitochondria as shown by super resolution chemical imaging. De novo purine biosynthesis is likely most efficient when purinosomes are located near mitochondria to capture needed substrates exported from the mitochondria. Continuing research suggests that boron containing molecules can have a potential to intervene in a variety of diseases such as—bacterial and fungal infections, pulmonary hypertension, and oncology.

Awards and honors

1977 - Pfizer Award in Enzyme Chemistry from the American Chemical Society 1984 - Fellow of the American Academy of Arts and Sciences 1985 - Elected to the National Academy of Sciences 1986 – Gowland Hopkins Award 1989 - Repligen Award in Chemistry of Biological Processes 1994 – Institute of Medicine, National Academy of Sciences 1995 – Honorary Doctorate of Science, Lehigh University 1998 - Chemical Pioneer Award, The American Institute of Chemists 2000 - Christian B. Anfinsen Award 2002 - Elected to membership in the American Philosophical Society 2003 - ASBMB–Merck Award 2005 - Nakanishi Prize 2006 – Royal Society Centenary Medal 2009 - Benjamin Franklin Medal in Life Science 2010 - Ralph F. Hirschmann Award in Peptide Chemistry 2011 – National Academy of Science Award in Chemical Sciences 2015 – National Academy of Inventors (NAI) Fellow 2018 – College of Physicians of Philadelphia Fellow 2021 – Foreign Member of the Royal Society (ForMemRS)

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. 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. 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. Goodey, N. M. and Benkovic, S. J. (2008) Allosteric regulation and catalysis emerge via a common route, Nat. Chem. Biol. 4, 474-482. Yang, J., Zhuang, Z., Roccasecca, R. M., Trakselis, M. A., and Benkovic, S. J. (2004) The dynamic processivity of the T4 DNA polymerase during replication, Proc Natl. Acad. Sci. USA 101, 8289-8294. Benkovic, S.J., Spiering, M.M. (2017) "Understanding DNA Replication by the Bacteriophage T4 Replisome", JBC, 292 (45) 18434-18442. 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., Pareek, V., Benkovic, S.J. (2022) The Purinosome: A Case Study for a Mammalian Metabolon, Annu. Rev. of Biochem., Volume 91:89-106. 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.