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Better Living through Chemistry: New Tools in Chemical Biology

Better Living through Chemistry
Reported by
Megan Stephan

Posted October 16, 2006


Chemical biology encompasses a highly diverse array of experimental approaches, and this diversity was quite well represented at a meeting on May 31, 2006, at the Academy. Keynote speaker James Rothman of Columbia University described his work on vesicle fusion in eukaryotic cells, a process that is critical for functions as diverse as insulin release and synaptic transmission.

Qunzhao Wang (Albert Einstein College of Medicine) spoke about the engineered peptides he has developed that can act as fluorescent reporters of protein kinase activity for intracellular signaling studies. Ross Chapman (NYU) described the synthesis of conformationally stabilized peptides that can retain their biological activity even when removed from the context of a full protein. Justin Potuzak (Memorial Sloan-Kettering Cancer Center) presented his work on the synthesis of spiroketals. And Edmund Schwartz (The Rockefeller University) showed how conditional splicing may be used to gain the precise temporal control of protein activity that is needed for some types of studies.

Web Sites

2002 Albert Lasker Award for Basic Medical Research: Membrane Trafficking
A graphic depiction of the vesicle fusion process. Click here to see an animation.

Circadian Rhythms
Tutorial by Andrew Millar of the University of Warwick's Interdisciplinary Programme for Cellular Regulation

The Genome Center at Columbia University

The Handbook: A Guide to Fluorescent Probes and Labeling Technologies
An online guide published by Invitrogen giving omprehensive resource on fluorophores and their uses.

Howard Hughes Medical Institute — What is chemical genetics?
Brief description of chemical genetics on the Howard Hughes Medical Institute Web site.
A useful compendium of protein kinase information.

Molecular libraries and imaging, from the NIH Roadmap for Medical Research
NIH roadmap section pertaining to molecular libraries and high throughput cell biology.

Protein kinase resource
A browseable database of kinase structures, with links to additional resources.

National Library of Medicine resource that will store data generated by the MLSCN.

Lab Web Sites

The Rothman Lab
Affiliated with The Columbia University Department of Physiology and Cellular Biochemistry, The Genome Center at Columbia University, and The Molecular Libraries Screening Center Network.

The Arora Lab, New York University

David Scott Lawrence, Albert Einstein College of Medicine

Derek S. Tan, Memorial Sloan-Kettering Cancer Center

Tom W. Muir Lab, The Rockefeller University

Michael W. Young Lab, The Rockefeller University

Journal Articles

Two Kinds of Chemical Biology

Antinozzi, P. A., A. Garcia-Diaz, C. Hu & J. E. Rothman. 2006. Functional mapping of disease susceptibility loci using cell biology. Proc Natl. Acad. Sci. USA 103: 3698-3703.

Cosson, P., M. Ravazzola, O. Varlamov et al. 2005. Dynamic transport of SNARE proteins in the Golgi apparatus. Proc. Natl. Acad. Sci. USA 102: 14647-14652.

Fix, M., T. J. Melia, J. K. Jaiswal et al. 2004. Imaging single-membrane fusion events mediated by SNARE proteins. Proc. Natl. Acad. Sci. USA 101: 7311-7316. Full Text

Giraudo, C. G., W.S. Eng, T.J. Melia et al. 2006. A clamping mechanism involved in SNARE-dependent exocytosis. Science Jun 22, 2006. [Epub ahead of print]

Hu, C., M. Ahmed, T. J. Melia et al. 2003. Fusion of cells by 'flipped' SNAREs. Science 300: 1745-1749.

Parlati, F., O. Varlamov, K. Paz et al. 2002. Distinct SNARE complexes mediating membrane fusion in Golgi transport based on combinatorial specificity. Proc. Natl. Acad. Sci. USA 99: 5424-5429. Full Text

Rothman, J. E. 2002. Lasker Basic Medical Research Award. The machinery and principles of vesicle transport in the cell. Nat. Med. 8: 1059-1062.

Ungermann, C. & D. Langosch. 2005. Functions of SNAREs in intracellular membrane fusion and lipid bilayer mixing. J. Cell Sci. 118: 3819-3828. Full Text

Waggoner, A. 2006. Fluorescent labels for proteomics and genomics. Curr. Opin. Chem. Biol. 10: 62-66.

Fluorescent Reporters of Protein Tyrosine Kinase Activity

Chen, C. A., R. H. Yeh, X. Yan & D. S. Lawrence. 2004. Biosensors of protein kinase action: from in vitro assays to living cells. Biochim. Biophys. Acta. 1697: 39-51.

Lawrence, D. S. 2005. The preparation and in vivo applications of caged peptides and proteins. Curr. Opin. Chem. Biol. 9: 570-575.

Veldhuyzen, W. F., Q. Nguyen, G. McMaster & D. S. Lawrence. 2003. A light-activated probe of intracellular protein kinase activity. J. Am. Chem. Soc. 125: 13358-13359.

Wang, Q. & D. S. Lawrence. 2005. Phosphorylation-driven protein-protein interactions: a protein kinase sensing system. J. Am. Chem. Soc. 127: 7684-7685.

Wang, Q., S. M. Cahill, M. Blumenstein & D. S. Lawrence. 2006. Self-reporting fluorescent substrates of protein tyrosine kinases. J. Am. Chem. Soc. 128: 1808-1809.

Synthesis and Biological Potential of the Hydrogen Bond Surrogate-Based Helices

Chapman, R. N., G. Dimartino & P. S. Arora. 2004. A highly stable short alpha-helix constrained by a main-chain hydrogen-bond surrogate. J. Am. Chem. Soc. 126: 12252-12253.

Dimartino, G., D. Wang, R. N. Chapman & P. S. Arora. 2005. Solid-phase synthesis of hydrogen-bond surrogate-derived alpha-helices. Org. Lett. 7: 2389-2392.

Kappe, C. O. 2004. Controlled microwave heating in modern organic synthesis. Angew Chem. Int. Ed. Engl. 43: 6250-6284.

Martin, W. H. & S. Blechert S. 2005. Ring closing metathesis in the synthesis of biologically interesting peptidomimetics, sugars and alkaloids. Curr. Top. Med. Chem. 5: 1521-1540.

Sia, S. K., P. A. Carr, A. G. Cochran, et al. 2002. Short constrained peptides that inhibit HIV-1 entry. Proc. Natl. Acad. Sci. USA 99: 14664-14669. Full Text

Wang, D., W. Liao & P. S. Arora. 2005. Enhanced metabolic stability and protein-binding properties of artificial alpha-helices derived from a hydrogen-bond surrogate: application to Bcl-xL. Angew. Chem. Int. Ed. Engl. 44: 6525-6529. Full Text

Stereocontrolled Synthesis of Spiroketals Using Novel Kinetic Cyclization Reactions

Diblasi, C. M., D. E. Macks & D. S. Tan. 2005. An acid-stable tert-butyldiarylsilyl (TBDAS) linker for solid-phase organic synthesis. Org. Lett. 7: 1777-1780.

Moilanen, S. B. & D. S. Tan. 2005. Enantioselective synthesis of erythro-4-deoxyglycals as scaffolds for target- and diversity-oriented synthesis: new insights into glycal reactivity. Org. Biomol. Chem. 3: 798-803.

Moilanen, S. B., J. S. Potuzak & D. S. Tan. 2006. Stereocontrolled synthesis of spiroketals via Ti(Oi-Pr)4-mediated kinetic spirocyclization of glycal epoxides with retention of configuration. J. Am. Chem. Soc. 128: 1792-1793.

Potuzak, J. S., S. B. Moilanen & D. S. Tan. Discovery and applications of small molecule probes for studying biological processes. Biotechnol. Genet. Eng. Rev. 21: 11-78.

Potuzak, J. S., S. B. Moilanen & D. S. Tan. 2005. Stereocontrolled synthesis of spiroketals via a remarkable methanol-induced kinetic spirocyclization reaction. J. Am. Chem. Soc. 127: 13796-13797.

Potuzak, J. S. & D. S. Tan. 2004. Synthesis of C1-alkyl and C1-acylglycals from glycals using a B-alkyl Suzuki–Miyaura cross coupling approach. Tetrahedron Lett. 45: 1797-1801.

Tan, D. S. 2005. Diversity-oriented synthesis: exploring the intersections between chemistry and biology. Nat. Chem. Biol. 1: 74-84.

Rapid in vivo Activation of an Enzyme through Conditional Protein Splicing

Cyran, S. A., G. Yiannoulos, A. M. Buchsbaum et al. 2005. The double-time protein kinase regulates the subcellular localization of the Drosophila clock protein period. J. Neurosci. 25:5430-5437. Full Text

Giriat, I., T. W. Muir & F. B. Perler. 2001. Protein splicing and its applications. Genet. Eng. (NY). 23: 171-199.

Harms, E., S. Kivimae, M. W. Young & L. Saez. 2004. Posttranscriptional and posttranslational regulation of clock genes. J. Biol. Rhythms. 19: 361-373.

Mootz, H. D., E. S. Blum, A. B. Tyszkiewicz & T. W. Muir. 2003. Conditional protein splicing: a new tool to control protein structure and function in vitro and in vivo. J. Am. Chem. Soc. 125: 10561-10569.

Mootz, H. D., E. S. Blum & T. W. Muir. 2004. Activation of an autoregulated protein kinase by conditional protein splicing. Angew Chem. Int. Ed. Engl. 43: 5189-5192.

Mootz, H. D. & T. W. Muir. 2002. Protein splicing triggered by a small molecule. J. Am. Chem. Soc. 124: 9044-9045.

Romanelli, A., A. Shekhtman, D. Cowburn, & T. W. Muir. 2004. Semisynthesis of a segmental isotopically labeled protein splicing precursor: NMR evidence for an unusual peptide bond at the N-extein-intein junction. Proc. Natl. Acad. Sci. USA 101: 6397-6402. Full Text

Schwartz, E. C., T. W. Muir & A. B. Tyszkiewicz. 2003. "The splice is right": how protein splicing is opening new doors in protein science. Chem. Commun. (Camb). 17: 2087-2090.

Shi, J. & T. W. Muir. 2005. Development of a tandem protein trans-splicing system based on native and engineered split inteins. J. Am. Chem. Soc. 127: 6198-6206.

Wijnen, H., F. Naef, C. Boothroyd et al. 2006. Control of daily transcript oscillations in Drosophila by light and the circadian clock. PLoS Genet. 2: e39. Full Text

Young, M. W. 2000. Life's 24-hour clock: molecular control of circadian rhythms in animal cells. Trends Biochem. Sci. 25: 601-606.


James E. Rothman, MD, PhD

Columbia University
email | web site | publications

James Rothman is the director of the Chemical Biology Center at Columbia University, Clyde and Helen Wu Professor of Chemical Biology, and a professor in the Department of Physiology and Cellular Biophysics at Columbia University College of Physicians and Surgeons. He previously held professorships at Stanford and Princeton Universities, and until 2003 was the chairman of the Cellular Biochemistry and Biophysics Program at the Memorial Sloan Kettering Institute. He has received many awards and honors over the course of his distinguished career, including a Lasker Basic Research Award with Randy Schekman in 2002. He has also served on the editorial boards of numerous journals, including Science, Cell, and the Annual Review of Biochemistry, where he is currently an associate editor. Rothman graduated with a BA from Yale in 1971 and attended Harvard Medical School where he received an MD and PhD in 1976.

Qunzhao Wang, PhD

Albert Einstein College of Medicine

Qunzhao Wang is a research associate in the laboratory of David S. Lawrence at the Albert Einstein College of Medicine. Lawrence's group is active in the development of inhibitors, activators, and substrates for specific enzymes in signaling pathways, particularly protein kinases. Wang holds a PhD in organic synthesis from Duquesne University, and a Master's degree in polymer chemistry from Zhongshan University, Guangzhou, China. He did postdoctoral work in Bruce Ganem's laboratory at Columbia University, and has also worked as a chemical engineer at Gaoming Second Plastics Holding Shares Ltd., China.

Ross Chapman

New York University
email | web site | publications

Ross Chapman is a fourth-year graduate student in Paramjit Arora's laboratory in the Department of Chemistry at New York University (NYU). Chapman was born and raised in Southhampton, England and received a BSc in Chemistry from Birmingham University, England in 2000. He also received a Master's degree in bio-organic chemistry from NYU in 2004. His research project on the stabilization of helical peptides is part of Arora's research program on designing and synthesizing structured mimetics of biomolecules (peptides, nucleic acids, and carbohydrates) for use as drugs and biochemical probes. Chapman received a Dean's Dissertation Award from the Graduate School of Arts and Science at NYU in 2006.

Justin Potuzak

Memorial Sloan-Kettering Cancer Center and Cornell University
email | web site | publications

Justin Potuzak is a graduate student in the Weill Cornell Pharmacology Program at Cornell University. He is performing his doctoral research in Derek Tan's laboratory at Memorial Sloan Kettering Cancer Center, where his project forms part of Tan's overall work on the design and synthesis of small-molecule probes for use in biology and medicine. Potuzak recently received the 2006 Vincent du Vigneaud Award for his presentation on diversity-oriented synthesis of spiroketals. He received his BA from Drew University in 2000.

Edmund Schwartz

The Rockefeller University

Edmund Schwartz is a graduate fellow in Tom Muir's laboratory at The Rockefeller University. He received a BS with highest distinction from the University of Virginia in 2002, with majors in chemistry and biology. At UVA he was an Echols scholar and was also named a Howard Hughes Medical Institute pre-doctoral fellow in 2003. Schwartz's work on conditional splicing is a part of Muir's effort to design chemistry-driven technologies for studying biological processes, including prokaryotic and eukaryotic signal transduction. Schwartz and Muir are collaborating with Michael Young of Rockefeller to apply these technologies to the proteins involved in circadian rhythms in the fruit fly Drosophila.

Megan Stephan

Megan Stephan studied transporters and ion channels at Yale University for nearly two decades before giving up the pipettor for the pen. She specializes in covering research at the interface between biology, chemistry, and physics. Her work has appeared in The Scientist and Yale Medicine. Stephan holds a PhD in biology from Boston University.