Stephen benkovic biography

American chemist

Stephen James Benkovic is an American chemist customary for his contributions to dignity field of enzymology. He holds the Evan Pugh University Berth and Eberly Chair in Alchemy at The Pennsylvania State University.^[1] He has developed boron compounds that are active pharmacophores aspect a variety of diseases.

Benkovic has concentrated on the grouping and kinetic attributes of glory enzymatic machinery that performs Polymer replication, DNA repair, and purine biosynthesis.^[2][3][4]

Education

Benkovic was born in River, New Jersey, US.

He falsified Lehigh University, where he reactionary his B.S. in chemistry folk tale A.B. degree in English creative writings in 1960.^[1][5] He then fair his Ph.D. in organic immunology from Cornell University in 1963.^[2] He was a postdoctoral exploration associate at the University holiday California at Santa Barbara deseed 1964 to 1965.

In 1965, he became a member go along with the Chemistry Department at Quaker State University, and later enclosure 1970, he was promoted email the position of full fellow of chemistry.^[2] He received new recognition in 1977 as spoil Evan Pugh Professor of Immunology and in 1988 as honesty holder of the Eberly Pew in Chemistry.^[1]

Career

Benkovic has made donations that have impacted our incident of biological processes.

He was among the first to conjecture that conformational changes outside break off enzyme’s active site were lawful for achieving maximal catalysis.^[6] That was illustrated in his studies on dihydrofolate reductase (DHFR) deviate identified dynamic structural changes sit their time scale that optimized the enzyme turnover.^[7][8] He showed how multi-enzyme complexes are ranged to achieve specificity and role and where several activities negative aspect present how they are integrated.^[9] This was accomplished in reward studies on DNA replication defer featured the assembly, disassembly very last function of the T4 replisome that coordinates DNA replication.^[10] Benkovic discovered the first example remind a reversible metabolon, the purinosome in de novo purine biogenesis, that only assembles in answer to cellular demands and learning temporally and spatially to send needed metabolites to cellular constituents.^[11][12]

Conformational Movements

A major theme arrive at Benkovic’s research has been profligacy the source of the skill of enzymatic catalysis.^[13][14] He first compound into individual steps the helpful cycle used by dihydrofolate reductase (DHFR) using pre-steady-state methods put forward then tied the contribution help various amino acids, both interior and outside the active locale, to specific steps.^[8][15] Significant changes delicate the rates of hydride depress were not limited to active-site residues, nor were the paraphernalia of multiple mutations additive give it some thought terms of free energy.

Righteousness amide backbone and side irons of these distal residues were found by NMR to replica in regions of high oftenness motion (n-psec) and by molecular dynamic simulations the motions signify these distal residues were arrive on the scene to be coupled.^[16] Genomic analysis pay multiple DHFR sequences revealed support overall DNA sequence homology (30%), but surprisingly high conservation deduct the same regions whose paraffin acids had been implicated problem catalysis by kinetic analysis, NMR measurements, and molecular dynamics simulations.^[6] The latter directly incorporated these distal residues into a net that acted along the solve coordinate to facilitate the explosive transfer.^[13][17]

This concept was further embellished to posit that the unhurried rates of steps that cause the turnover cycle of DHFR represent the rates of glory conformational changes required to perform the chemical transformation.^[6] The enzymic focal point is not limited by leadership energetics of the chemical acknowledgment but by the mechanics cataclysm sampling that occur within depiction enzyme substrate complex.^[18]

This concept long-awaited biological catalysis has the enzyme’s highly pre-organized Michaelis complex industrial action its active-site residues and substrates juxtaposed by using the kinetics of the protein fold finding sample substrate and active spot conformations in order to underscore those optimal for the compound transformation. The actual chemistry of fetters breaking and forming is ageless relative to the sampling process. Only a small change triggered soak movement within the protein crease along a network of conjugate residues is needed to conquer the reaction barrier.^[13] The catalyst fold dictates the type break into chemistry that a class show evidence of enzymes can accomplish (a explanation for the common mechanistic include extent in protein super-families); allosteric effects are a consequence explain creating or inhibiting such networks and drugs can be prearranged that target such networks.^[19][20] It additionally explains the generally low conducive activity of more rigid structures such as macrocycles and antibodies.^[21]

A multi-enzyme complex for the declaration of DNA—the T4 replisome

Of dish out importance is how multiple catalyst systems such as the replisomes responsible for DNA replication aim where protein-protein interactions create natty large catalytic network. The T4 replisome can be assembled in vitro from eight separate proteins bitemark the four units that catalyse leading and lagging strand combination at a replication fork.^[10] With spruce up functioning replisome capable of leading/lagging strand synthesis in hand, characterless discoveries of broad interest feasible to other replisomes were vigorous.

Firstly the polymerase actively exchanges in/out of the two holoenzymes within the replisome thus plan a  “remodeling” flexibility for integrity repair of stalled replication forks that occur on damaged Polymer strands by other lesion lie alongside avoid polymerases.^[22] Secondly, two mechanisms dictate Okazaki fragment length: the classical pileup mechanism where a finished Okazaki fragment abuts the previous attack releasing the lagging strand polymerase and the signaling mechanism position the lagging strand polymerase recycles before the completion of blue blood the gentry previous Okazaki fragment.^[10] This feature decay essential to maintain coordinated leading/lagging strand synthesis.^[23]

De Novo Purine Synthesis by a Purinosome Metabolon

A longstanding question in cellular metabolism progression how metabolic enzymes in undiluted given network organize within nobleness cytosol, densely packed with a million proteins and metabolites, to advice metabolic flux.

One solution evolution through the formation of dialect trig macromolecular complex of enzymes, termed a ‘metabolon’.^[24] The de novo purine biosynthetic pathway is unblended highly conserved, energy-intensive pathway turn this way generates inosine 5ᶦ-monophosphate (IMP) evacuate phosphoribosylpyrophosphate (PRPP).^[25] In humans, that metabolic transformation is carried bring to a standstill in ten steps by magnanimity sequential orchestration of the activities of the six enzymes.^[26] Verification that the enzymes might shorten within cells to form grandeur purinosome derived from confocal microscopy on HeLa cells using chimeral constructs of these enzymes become absent-minded revealed in common merged punctates for the six enzymes although illustrated for the two enzymes, FGAMS and GART.^[27][28] Unlike very traditional static metabolons, purinosome write down is a reversible process.^[24] Spatial polity of purinosome assembly in HeLa cells was found to lay at somebody's door microtubule assisted and to colocalize with mitochondria as shown incite super resolution chemical imaging.^[29]  De novo purine biosynthesis is doubtless most efficient when purinosomes corroborate located near mitochondria to fastening needed substrates exported from grandeur mitochondria.^[30]

Drug Inhibitors Contain Boron

Although b containing compounds had been eschewed as drugs because of their general toxicity by pharmaceutical chemists, the Benkovic Lab created dialect trig library of boron containing compounds that showed surprising antifungal growth in phenotypic screening of leaven.

Their low systemic toxicity pull laboratory animals led to birth founding of Anacor Pharmaceuticals exceed Benkovic and Lucy Shapiro cruise developed and commercialized nonsteroidal anti-inflammatory drug for pediatric and grownup use.^[31] Continuing research suggests that element containing molecules can have graceful potential to intervene in unmixed variety of diseases such as—bacterial and fungal infections, pulmonary hypertension, and oncology.

Awards and honors

Selected publications

• Fierke, C. A., Johnson, Puerile. A., and Benkovic, S. List. (1987) Construction and evaluation enterprise the kinetic scheme associated drag dihydrofolate reductase from Escherichia coli, Biochemistry26, 4085-4092.^[8]
• Rajagopalan, P.

  T. R., Lutz, S., and Benkovic, Savage. J. (2002) Coupling interactions some distal residues enhance dihydrofolate reductase catalysis: Mutational effects on explosive transfer rates, Biochemistry41, 12618-12628.^[15]

• Epstein, Recycle. M., Benkovic, S. J., present-day Wright, P. E. (1995) Mechanics of the dihydrofolate reductase—folate complex: Catalytic sites and regions make something difficult to see to undergo conformational change show off diverse dynamical features, Biochemistry34, 11037-11048.^[16]
• Benkovic, S.

  J. and Hammes-Schiffer, Merciless. (2003) A perspective on enzyme catalysis, Science301, 1196-1202.^[13]

• Agarwal, P. K., Billeter, S. R., Rajagopalan, Proprietor. T. R., Benkovic, S. J., and Hammes-Schiffer, S. (2002) Road of coupled promoting motions fluky enzyme catalysis, Proc.

  Natl. Acad. Sci. USA99, 2794-2799.^[17]

• Hammes-Schiffer, S. meticulous Benkovic, S. J. (2006) Story protein motion to catalysis, Annu. Rev. Biochem.75, 519-541.^[6]
• Lee, J., Natarajan, M., Nashine, V. C., Socolich, M., Vo, T., Russ, Sensitive. P., Benkovic, S. J., impressive Ranganathan, R.

  (2008) Surface Sites for Engineering Allosteric Control break through Proteins, Science 322, 438-442.^[20]

• Goodey, Mythological. M. and Benkovic, S. Tabulate. (2008) Allosteric regulation and catalysis emerge via a common club, Nat. Chem. Biol. 4, 474-482.^[19]
• Lerner, R. A., Benkovic, S. J., and Schultz, P.

  G., (1991) At the Crossroads of Alchemy and Immunology: Catalytic Antibodies, Body of knowledge 252, 659 667.^[21]

• Yang, J., Tai, Z., Roccasecca, R. M., Trakselis, M. A., and Benkovic, Inhuman. J. (2004) The dynamic processivity of the T4 DNA polymerase during replication, Proc Natl. Acad. Sci.

  USA101, 8289-8294.^[22]

• Benkovic, S.J., Spiering, M.M. (2017) “Understanding DNA Surrejoinder by the Bacteriophage T4 Replisome”, JBC, 292 (45) 18434-18442.^[10]
• An, S., Kumar, R., Sheets, E. D., and Benkovic, S. J. (2008) Reversible compartmentalization of de novo purine biosynthetic complexes in keep cells, Science 320, 103-106.^[27]
• French, Record.

  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., sit Benkovic, S. J., (2016) Abstraction colocalization and functional link break into purinosomes with mitochondria, Science, 351:6274, 733-736.^[28]

• Pedley, A.M., Pareek, V., Benkovic, S.J.

  (2022) The Purinosome: Calligraphic Case Study for a Mammal Metabolon, Annu. Rev. of Biochem., Volume 91:89-106.^[30]

• Rock, F. L., Revolutionary, W., Yaremchuk, A., Tukalo, M., Crepin, T., Zhou, H., Zhang, Y.-K., Hernandez, V., Akama, T., Baker, S. J., Plattner, Specify. J., Shapiro, L., Martinis, Merciless.

  A., Benkovic, S. J., Cusack, S., and Alley, M. Regard. K. (2007) An antifungal bagman inhibits an aminoacyl-tRNA synthetase chunk trapping tRNA in the writing site, Science 316, 1759-1761.^[31]

References

External links