Cornell Chemical Biology Brings Physical Science to Life
Fabricated “nano keys” to new therapeutic approaches; a novel radical SAM enzyme involved in protein posttranslational modification; a newly discovered molecule for breaking cancer cells' “addiction” to glutamine; a surprising ability of nitric oxide; and solutions to the puzzle of enzyme evolution — all achievements by researchers in Cornell Chemical Biology that bring physical science to life.
A New Set of Keys to Cell Signaling. Advanced techniques in nanobiotechnology are enabling a Cornell Chemical Biology group, led by Barbara A. Baird to probe the basic molecular mechanisms of cell surface receptors that mediate transmembrane signals. Their interdisciplinary studies focus on the receptor (FcεRI) for immunoglobulin E (IgE) that plays a central role in the allergic immune response and serves as a model for other types of immune receptors. One result is a fabricated set of “nano-keys” on the same scale as molecules to interact with receptors on cell membranes and trigger larger-scale responses within cells, such as the release of histamines in an allergic response. At first, the nano keys can help explain spatial regulation in cell signaling, says Baird, “Then, medical scientists might use the insights gained from this approach to develop new drug therapies to treat allergies, high cholesterol, and perhaps even viral infections.”
Chemical Biology for the discovery of new chemistry in biological systems. To understand how protein posttranslational modifications contribute to regulation of various biological pathways and human diseases, a Cornell Chemical Biology group led by Hening Lin examines several interesting enzyme-catalyzed protein posttranslational modifications. A novel radical SAM enzyme that uses a [4Fe-4S] cluster to cleave S-adenosylmethionine and generates a 3-amino-3-carboxypropyl radical was discovered in the process of studying one of the modifications, diphthamide. One focus of the Lin laboratory is nicotinamide adenine dinucleotide (NAD)-consuming reactions and biological pathways that are regulated by known or new NAD-consuming reactions. Their combination of organic synthesis, biochemistry, biophysics, molecular biology, and cell biology to study the enzymology of the biosynthetic enzymes, Lin says, is starting to identify the modified proteins, and show how the modification affects protein structure/function. “Ultimately, we hope to use the molecular understanding of these biological processes to benefit human well-being.”
Breaking Cancer Cell’s “Addiction” to Glutamine. For years a multidisciplinary research program, led by Richard Cerione in Cornell Chemical Biology (and Pharmacology of Veterinary Medicine) endeavored broadly to understand the molecular mechanisms as signals are transmitted from cell surface receptors to biological effectors. Their efforts to identifying new signaling molecules (capable of influencing the growth and differentiation of mammalian cells) began to pay off with the discovery of a small molecule that can block cancer cells from using glutamine, thereby inhibiting their growth. Calling the molecule that breaks cancer cells’ “addiction” to glutamine Molecule 968, the Cerione group reports experiments that effectively stopped the growth of breast cancer cells without affecting normal mammary cells. “This new information,” Cerione says, “now offers exciting possibilities for designing strategies to stop tumor growth, to effectively reverse cellular transformation.”
Nitric Oxide’s Role in Recovering from UV Exposure. A Chemical Biology group led by Brian Crane studies biological systems that link molecular reactivity and signaling events to biological behavior. Their interdisciplinary approach has contributed to understanding how transmembrane receptor systems assemble and signal, how and why bacteria produce nitric oxide, and how light signals are propagated by circadian clock light sensors. When they examined Deinococcus radiodurans (the bacterium that can withstand extreme temperatures, drought conditions, lack of nutrients, and a thousand times more radiation than a human being) they demonstrated nitric oxide’s key role in D. radiodurans' recovery from ultraviolet radiation. (UV). “Bacteria are much more sensitive to radiation damage when nitric oxide is not there,” says Crane. “If you block the nitric oxide signal, the cell will repair but will not divide.” While the D. radiodurans organism could have a role in bioremediation of sites contaminated with radiation and toxic chemicals, Crane sees wider implications from the nitric-oxide discovery: For example, a better understanding of how nitric oxides act as signals in mammals for cell-to-cell communication, as well as the dilation of the vascular system and activating the immune system.
A Puzzle Worth Solving. A Cornell Chemical Biology group led by Steven Ealick uses X-ray crystallography to study the three-dimensional structures of proteins — making structural information available for drug design, protein engineering, as well as a more detailed understanding of catalytic mechanisms underlying protein evolution. When the Ealick group turned their attention to a key enzyme in the biosynthesis of vitamin B1 (HMP-P synthase) they were puzzled: How has HMP-P synthase evolved the ability to perform a complex series of some 15 to 20 steps? Understanding the enzyme’s function—the most complex unresolved chemical reaction in primary metabolism—is like solving a classic Rubik’s cube, according to Ealick. But it’s a problem worth solving because of the potential implications for antibiotic development, and for more efficient and cost effective ways of producing thiamine for food fortification, he emphasizes.
X-ray Crystallography Across Campus. One X-ray crystallography facility used by researchers in Cornell Chemical Biology (and by visiting scientists worldwide) is right on campus at— at MacCHESS, an NIH-supported program at CHESS, the Cornell High Energy Synchrotron Source. Already state-of-the-art, the X-ray diffraction capabilities of CHESS and MacCHESS could improve significantly with construction of the Proposed Energy Recovery Linac at Cornell’s Wilson Synchrotron Laboratory.