Stephen J. Benkovic

Last updated
Stephen James Benkovic
Stephen James Benkovic.jpg
Born (1938-04-20) April 20, 1938 (age 85)
Orange, New Jersey, U.S.
Alma mater Lehigh University, Cornell University, University of California, Santa Barbara
Awards Pfizer Award in Enzyme Chemistry (1977)
National Medal of Science (2009)
NAS Award in Chemical Sciences (2011)
Scientific career
Fields mechanistic enzymology, biochemistry
Institutions Penn State University
Academic advisors Thomas C. Bruice

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. [1] 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. [2] [3] [4]

Contents

Education

Benkovic was born in Orange, New Jersey, USA. He attended Lehigh University, where he received his B.S. in Chemistry and A.B. degree in English literature in 1960. [1] [5] He then earned his Ph.D. in Organic Chemistry from Cornell University in 1963. [2] He was a Postdoctoral Research Associate at the University of California at Santa Barbara from 1964-65.

In 1965, he became a member of the Chemistry Department at Penn State University, and later in 1970, he was promoted to the position of Full Professor of Chemistry. [2] He received further recognition in 1977 as an Evan Pugh Professor of Chemistry and in 1988 as the holder of the Eberly Chair in Chemistry. [1]

Career

Benkovic has made contributions that have impacted our understanding of biological processes. He was among the first to hypothesize that conformational changes outside an enzyme’s active site were necessary for achieving maximal catalysis. [6] This was illustrated in his studies on dihydrofolate reductase (DHFR) that identified dynamic structural changes and their time scale that optimized the enzyme turnover. [7] [8] He showed how multi-enzyme complexes are assembled to achieve specificity and function and where several activities are present how they are integrated. [9] This was accomplished in his studies on DNA replication that featured the assembly, disassembly and function of the T4 replisome that coordinates DNA replication. [10] 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. [11] [12]

Conformational Movements

A major theme of Benkovic’s research has been understanding the source of the efficiency of enzymatic catalysis. [13] [14]  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. [8] [15]  Significant changes in the rates of hydride transfer were not limited to active-site residues, nor were the effects of multiple mutations additive in terms of free energy. The amide backbone and side chains of these distal residues were found by NMR to be in regions of high frequency motion (n-psec) and by molecular dynamic simulations the motions of these distal residues were found to be coupled. [16]  Genomic analysis of multiple DHFR sequences revealed low overall DNA sequence homology (30%), but surprisingly high conservation in the same regions whose amino acids had been implicated in catalysis by kinetic analysis, NMR measurements, and molecular dynamics simulations. [6] The latter directly incorporated these distal residues into a network that acted along the reaction coordinate to facilitate the hydride transfer. [13] [17]

Illustration NADPH image.png
Illustration

This concept was further elaborated to posit that the measured rates of steps that constitute the turnover cycle of DHFR represent the rates of the conformational changes required to execute the chemical transformation. [6]  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. [18]

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. [13] The protein fold dictates the type of chemistry that a class of enzymes can accomplish (a rationale for the common mechanistic element extent in protein super-families); allosteric effects are a consequence of creating or inhibiting such networks and drugs can be designed that target such networks. [19] [20]  It also explains the generally low catalytic activity of more rigid structures such as macrocycles and antibodies. [21]

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

Of particular importance is how multiple protein systems such as the replisomes responsible for DNA replication function where protein-protein interactions create a large catalytic network. The T4 replisome can be assembled in vitro from eight separate proteins into the four units that catalyze leading and lagging strand synthesis at a replication fork. [10]  With a functioning replisome capable of leading/lagging strand synthesis in hand, key discoveries of broad interest applicable to other replisomes were made. Firstly the polymerase actively exchanges in/out of the two holoenzymes within the replisome thus providing a  “remodeling” flexibility for the repair of stalled replication forks that occur on damaged DNA strands by other lesion bypass polymerases. [22]  Secondly, two mechanisms dictate Okazaki fragment length: the classical collision mechanism where a finished Okazaki fragment abuts the previous one releasing the lagging strand polymerase and the signaling mechanism where the lagging strand polymerase recycles before the completion of the previous Okazaki fragment. [10]  This feature is essential to maintain coordinated leading/lagging strand synthesis. [23]

FGMAS GART FGMAS GART and MERGE.png
FGMAS GART

De Novo Purine Biosynthesis by a Purinosome Metabolon

De Novo Purine Biosynthesis De Novo Purine Biosynthesis.png
De Novo Purine Biosynthesis

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’. [24] The de novo purine biosynthetic pathway is a highly conserved, energy-intensive pathway that generates inosine 5ᶦ-monophosphate (IMP) from phosphoribosylpyrophosphate (PRPP). [25] In humans, this metabolic transformation is carried out in ten steps by the sequential orchestration of the activities of the six enzymes. [26] 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. [27] [28] Unlike more traditional static metabolons, purinosome formation is a reversible process. [24]  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. [29]   De novo purine biosynthesis is likely most efficient when purinosomes are located near mitochondria to capture needed substrates exported from the mitochondria. [30]

Drug Inhibitors Contain Boron

Although boron containing compounds had been eschewed as drugs because of their general toxicity by pharmaceutical chemists, the Benkovic Lab created a library of boron containing compounds that showed surprising antifungal activity in phenotypic screening of yeast. Their low systemic toxicity in laboratory animals led to the founding of Anacor Pharmaceuticals by Benkovic and Lucy Shapiro that developed and commercialized nonsteroidal anti-inflammatory drug for pediatric and adult use. [31]  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

Selected publications

Related Research Articles

<span class="mw-page-title-main">Enzyme</span> Large biological molecule that acts as a catalyst

Enzymes are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. Almost all metabolic processes in the cell need enzyme catalysis in order to occur at rates fast enough to sustain life. Metabolic pathways depend upon enzymes to catalyze individual steps. The study of enzymes is called enzymology and the field of pseudoenzyme analysis recognizes that during evolution, some enzymes have lost the ability to carry out biological catalysis, which is often reflected in their amino acid sequences and unusual 'pseudocatalytic' properties.

<span class="mw-page-title-main">Dihydrofolate reductase</span> Mammalian protein found in Homo sapiens

Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as an electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in 1-carbon transfer chemistry. In humans, the DHFR enzyme is encoded by the DHFR gene. It is found in the q14.1 region of chromosome 5.

<span class="mw-page-title-main">DNA polymerase</span> Form of DNA replication

A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create two identical DNA duplexes from a single original DNA duplex. During this process, DNA polymerase "reads" the existing DNA strands to create two new strands that match the existing ones. These enzymes catalyze the chemical reaction

<span class="mw-page-title-main">Ribonucleotide</span> Nucleotide containing ribose as its pentose component

In biochemistry, a ribonucleotide is a nucleotide containing ribose as its pentose component. It is considered a molecular precursor of nucleic acids. Nucleotides are the basic building blocks of DNA and RNA. Ribonucleotides themselves are basic monomeric building blocks for RNA. Deoxyribonucleotides, formed by reducing ribonucleotides with the enzyme ribonucleotide reductase (RNR), are essential building blocks for DNA. There are several differences between DNA deoxyribonucleotides and RNA ribonucleotides. Successive nucleotides are linked together via phosphodiester bonds.

<span class="mw-page-title-main">Binding site</span> Molecule-specific coordinate bonding area in biological systems

In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may include other proteins, enzyme substrates, second messengers, hormones, or allosteric modulators. The binding event is often, but not always, accompanied by a conformational change that alters the protein's function. Binding to protein binding sites is most often reversible, but can also be covalent reversible or irreversible.

A nucleoside triphosphate is a nucleoside containing a nitrogenous base bound to a 5-carbon sugar, with three phosphate groups bound to the sugar. They are the molecular precursors of both DNA and RNA, which are chains of nucleotides made through the processes of DNA replication and transcription. Nucleoside triphosphates also serve as a source of energy for cellular reactions and are involved in signalling pathways.

In molecular biology, biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. This process often consists of metabolic pathways. Some of these biosynthetic pathways are located within a single cellular organelle, while others involve enzymes that are located within multiple cellular organelles. Examples of these biosynthetic pathways include the production of lipid membrane components and nucleotides. Biosynthesis is usually synonymous with anabolism.

An antimetabolite is a chemical that inhibits the use of a metabolite, which is another chemical that is part of normal metabolism. Such substances are often similar in structure to the metabolite that they interfere with, such as the antifolates that interfere with the use of folic acid; thus, competitive inhibition can occur, and the presence of antimetabolites can have toxic effects on cells, such as halting cell growth and cell division, so these compounds are used as chemotherapy for cancer.

<span class="mw-page-title-main">Replisome</span> Molecular complex

The replisome is a complex molecular machine that carries out replication of DNA. The replisome first unwinds double stranded DNA into two single strands. For each of the resulting single strands, a new complementary sequence of DNA is synthesized. The total result is formation of two new double stranded DNA sequences that are exact copies of the original double stranded DNA sequence.

<span class="mw-page-title-main">Formylation</span>

Formylation refers to any chemical processes in which a compound is functionalized with a formyl group (-CH=O). In organic chemistry, the term is most commonly used with regards to aromatic compounds. In biochemistry the reaction is catalysed by enzymes such as formyltransferases.

<span class="mw-page-title-main">Enzyme inhibitor</span> Molecule that blocks enzyme activity

An enzyme inhibitor is a molecule that binds to an enzyme and blocks its activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which substrate molecules are converted into products. An enzyme facilitates a specific chemical reaction by binding the substrate to its active site, a specialized area on the enzyme that accelerates the most difficult step of the reaction.

<span class="mw-page-title-main">DNA clamp</span>

A DNA clamp, also known as a sliding clamp, is a protein complex that serves as a processivity-promoting factor in DNA replication. As a critical component of the DNA polymerase III holoenzyme, the clamp protein binds DNA polymerase and prevents this enzyme from dissociating from the template DNA strand. The clamp-polymerase protein–protein interactions are stronger and more specific than the direct interactions between the polymerase and the template DNA strand; because one of the rate-limiting steps in the DNA synthesis reaction is the association of the polymerase with the DNA template, the presence of the sliding clamp dramatically increases the number of nucleotides that the polymerase can add to the growing strand per association event. The presence of the DNA clamp can increase the rate of DNA synthesis up to 1,000-fold compared with a nonprocessive polymerase.

<span class="mw-page-title-main">Tetrahydrofolic acid</span> Chemical compound

Tetrahydrofolic acid (THFA), or tetrahydrofolate, is a folic acid derivative.

Metabolite channeling is the passing of the intermediary metabolic product of one enzyme directly to another enzyme or active site without its release into solution. When several consecutive enzymes of a metabolic pathway channel substrates between themselves, this is called a metabolon. Channeling can make a metabolic pathway more rapid and efficient than it would be if the enzymes were randomly distributed in the cytosol, or prevent the release of unstable intermediates. It can also protect an intermediate from being consumed by competing reactions catalyzed by other enzymes.

<span class="mw-page-title-main">Phosphoribosylglycinamide formyltransferase</span>

Phosphoribosylglycinamide formyltransferase (EC 2.1.2.2, 2-amino-N-ribosylacetamide 5'-phosphate transformylase, GAR formyltransferase, GAR transformylase, glycinamide ribonucleotide transformylase, GAR TFase, 5,10-methenyltetrahydrofolate:2-amino-N-ribosylacetamide ribonucleotide transformylase) is an enzyme with systematic name 10-formyltetrahydrofolate:5'-phosphoribosylglycinamide N-formyltransferase. This enzyme catalyses the following chemical reaction

Thomas C. Bruice was a professor of chemistry and biochemistry at University of California, Santa Barbara. He was elected to the National Academy of Sciences in 1974. He was a pioneering researcher in the area of chemical biology, and is one of the 50 most cited chemists.

Gordon G. Hammes is a distinguished service professor of biochemistry, emeritus, at Duke University, professor emeritus at Cornell University, and member of United States National Academy of Sciences. Hammes' research involves the study of enzyme mechanisms and enzyme regulation.

<span class="mw-page-title-main">Purinosome</span>

The purinosome is a putative multi-enzyme complex that carries out de novo purine biosynthesis within the cell. It is postulated to include all six of the human enzymes identified as direct participants in this ten-step biosynthetic pathway converting phosphoribosyl pyrophosphate to inosine monophosphate:

Ann M. Valentine is an American bioinorganic chemist whose research focuses on biomineralization, the uptake and transport of metals and their medical applications in areas such as cancer research. She has received awards including the 2014 AICChemical Pioneer Award "for her outstanding contributions towards advancing the science of chemistry and impacting the chemical profession" and the 2009 Paul D. Saltman Award for Metals in Biology for "outstanding contributions to the field of metals in biology" and "groundbreaking work on the structures and reactions of complexes containing titanium."

Charles Clifton Richardson is an American biochemist and professor at Harvard University. Richardson received his undergraduate education at Duke University, where he majored in medicine. He received his M.D. at Duke Medical School in 1960. Richardson works as a professor at Harvard Medical School, and he served as editor/associate editor of the Annual Review of Biochemistry from 1972 to 2003. Richardson received the American Chemical Society Award in Biological Chemistry in 1968, as well as numerous other accolades.

References

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