Barry S. Cooperman

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Contact information
358N Chemistry
231 South 34th Street
Philadephia, PA 19104-6323
Office: (215) 898-6330
Education:
BA
Columbia College, 1962.
Ph.D.
Harvard, 1968.
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Description of Research Expertise

Our overall thrust is to study the linkage between biological structure and function, using the broad array of chemical, physical, and biological tools that are now available. Our major efforts fall in four principal areas.

Yeast and E. coli inorganic pyrophosphatases (PPases)

Our previous work on native enzyme has involved determination of an overall kinetic scheme, evaluation of microscopic rate constants, identification of active site residues through chemical modification, and determination of metal-ion:phosphoryl ligand and metal-ion:metal ion distances at the enzyme active site through NMR and EPR measurements. Now, in conjunction with ongoing X-ray crystallographic studies, we are determining the effects of mutation amino acid residues at the active sites of both enzymes on specific aspects of enzyme function and structure.

E. coli ribosomes

We make extensive use of photoaffinity labeling to localize functional sites on this highly complex enzyme. With this approach we have determined the identities of ribosomal proteins and RNA bases within ribosomal RNA (rRNA) at binding sites for several ribosomal antibiotics (e.g., puromycin, tetracycline, chloramphenicol), for tRNA for initiation factor IF-3, and for oligoDNAs complementary to single-stranded regions of rRNA. We also use reconstitution methods to prepare ribosomal subunits that have reporter functions specifically incorporated at given sites within the ribosome. A particular example of such reporter groups are haptens. Electron microscopic examinations of the complex between the hapten and its corresponding antibody molecule allows three- dimensional localization of the site of hapten incorporation into the ribosome.

Serine proteinase inhibitors ("serpins")

Serpins are known to be of great importance for inflammation process in mammals. We seek to understand the structural basis for the specificity of interaction of these serpins with a variety of serine proteases, using a combination of chemical modification and genetic engineering approaches to both alter and enhance such specificity. This work involves a very active collaboration with faculty in Penn's School of Medicine who are testing clinical applications of serpins and point-specific serpin mutants.

Ribonucleotide reductase (RR)

RR catalyzes the reduction of nucleoside diphosphates to deoxynucleoside diphosphates and is the key enzyme controlling the rate of DNA synthesis. As such it is highly regulated and is a target enzyme for inhibitors of viral and parasitic diseases. Our studies focus on the RRs derived from mammalian cells and from plasmodium, the malarial parasite. We are investigating subunit:subunit interaction within this enzyme, genetic engineering and chemical modification approaches to the study of structure and function, and the development of novel and specific enzyme inhibitors.

Description of Itmat Expertise

Dr. Cooperman's projects involve the development of inhibitors for ribonucleotide reductase, a key target for cancer chemotherapy, and depolymerizing human serpin aggregates and on ribosomal antibiotics for therapeutic purposes.

Selected Publications

Kashlan, O. B., Cooperman, B. S.: Comprehensive model for allosteric regulation of mammalian ribonucleotide reductase: refinements and consequences. Biochemistry 42(6): 1696-1706, 2003.

Cooperman, B. S., Kashlan, O. B.: A comprehensive model for the allosteric regulation of Class Ia ribonucleotide reductases. Adv Enzyme Regul 43: 167-82, 2003.

Cooperman, B. S.: Oligopeptide inhibition of class I ribonucleotide reductases. Biopolymers 71(2): 117-131, 2003.

Seo, H. S., Cooperman, B. S.: Large-scale motions within ribosomal 50S subunits as demonstrated using photolabile oligonucleotides. Bioorg Chem 30(3): 163-187, 2002.

Kashlan, O. B., Scott, C. P., Lear, J. D., Cooperman, B. S.: A comprehensive model for the allosteric regulation of mammalian ribonucleotide reductase. Functional consequences of ATP- and dATP-induced oligomerization of the large subunit. Biochemistry 41(2): 462-474, 2002.

Hsieh, M. C., Cooperman, B. S.: Inhibition of prostate-specific antigen (PSA) by alpha(1)-antichymotrypsin: salt-dependent activation mediated by a conformational change. Biochemistry 41(9): 2990-2997, 2002.

Halonen, P., Baykov, A. A., Goldman, A., Lahti, R., Cooperman, B. S.: Single-turnover kinetics of Saccharomyces cerevisiae inorganic pyrophosphatase. Biochemistry 41(40): 12025-31, 2002.

Gao, Y., Liehr, S., Cooperman, B. S.: Affinity-driven selection of tripeptide inhibitors of ribonucleotide reductase. Bioorg Med Chem Lett 12(4): 513-15, 2002.

Scott, C. P., Kashlan, O. B., Lear, J. D., Cooperman, B. S.: A quantitative model for allosteric control of purine reduction by murine ribonucleotide reductase. Biochemistry 40(6): 1651-61, 2001.

Pohjanjoki, P., Fabrichniy, I. P., Kasho, V. N., Cooperman, B. S., Goldman, A., Baykov, A. A., Lahti, R.: Probing essential water in yeast pyrophosphatase by directed mutagenesis and fluoride inhibition measurements. J Biol Chem 276(1): 434-441, 2001.

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Last updated: 08/25/2004
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