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FOR RELEASE ON Thursday, November 8, 2007 11:00 AM PST
Thursday, November 8, 2007
Scripps, U-M Biochemists Add New Molecular Weapon to their Arsenal
Scripps Institution of Oceanography / University of California, San DiegoUniversity of Michigan (U-M) and Scripps Institution of Oceanography at UC San Diego
researchers have acquired a new molecular tool that could help them transform a toxin from coral-reef bacteria into a next-generation cancer drug.
U-M Life Sciences Institute (LSI) researchers David Sherman and Janet Smith led a cross-disciplinary team that uncovered new functions for an ancient, well-known family of proteins found in many organisms, from microbes to humans.
The discovery of new roles for the GNAT family of proteins adds weapons to the arsenal of "synthetic biologists" who rearrange the building blocks of natural substances in an effort to make better pharmaceuticals, said Sherman, director of LSI's Center for Chemical Genomics and the Hans W. Valteich professor of medicinal chemistry at the U-M College of Pharmacy.
A clump of L. majuscula bacteria collected from a reef is shown underwater off Panama. These bacteria create a potent toxin that has proven effective against several human cancers in laboratory tests.
"Nature usually gives us sub-optimal drug candidates," Sherman said. "But we can chop them apart and reassemble them at will to engineer compounds that may have better properties as drugs."
The LSI-led team will report its findings in Friday's issue of the journal Science.
The Sherman team, along with William Gerwick of Scripps' Center for Marine Biotechnology and Biomedicine and the Skaggs School of Pharmacy and Pharmaceutical Sciences at UC San Diego, analyze chemical compounds pulled from marine organisms living in coral reef sediments, blue-green algae, sponges and soft corals. They look for substances, such as bacterial toxins, that can kill or disable cancer cells in the laboratory. Currently, more than a dozen such compounds from marine sources are in pre-clinical or clinical trials as cancer therapeutics.
One such substance is curacin A, a leading anti-cancer drug candidate first derived from a Caribbean coral reef cyanobacterium, L. majuscula, in 1994 by Gerwick's group. In the lab, curacin A is effective against colon, kidney and breast cancer cell lines.
Sherman and his colleagues have been trying to understand how the biochemical machines inside L. majuscula assemble the curacin A molecule. In 2004, the group published a blueprint showing all the proteins that are responsible for making the curacin A molecular chain.
L. majuscula filaments magnified 400 times.
Since then, they've focused on determining the functions of the roughly 60 biological catalysts used in the assembly line-like curacin A synthesis process. The team's latest finding is that the first links in the curacin-A chain include a member of the GNAT family of proteins, a group of enzymes that has long been known to play roles in gene regulation, hormone synthesis and antibiotic resistance.
The big surprise was finding that a GNAT enzyme helps initiate the chain-building process that forms curacin A. "It's a totally new function for these GNAT enzymes," Sherman said.
"Decoding these biosynthetic pathways is like trying to understand a series of hieroglyphics," he said. "And this GNAT discovery is like finding the Rosetta stone. It helps us decipher previously unknown or misunderstood symbols."
While Sherman's group carried out the enzymology for the study, Smith's team captured X-ray crystallography images of the GNAT enzyme's structure. Smith is director of LSI's Center for Structural Biology. Gerwick's team made the original discovery of curacin A and provided the cyanobacterial DNA for this study.
L. majuscula is a cyanobacterium, which are among the oldest organisms on Earth. Roughly 3 billion years ago, cyanobacteria began producing atmospheric oxygen that, much later, allowed more complex life forms to emerge. In the L. majuscula bacterium, the curacin A toxin likely performs a defense function, possibly protecting the microbe from predators.
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Scripps Institution of Oceanography, at University of California, San Diego, is one of the oldest, largest and most important centers for global science research and education in the world. The National Research Council has ranked Scripps first in faculty quality among oceanography programs nationwide Now in its second century of discovery, the scientific scope of the institution has grown to include biological, physical, chemical, geological, geophysical and atmospheric studies of the earth as a system. Hundreds of research programs covering a wide range of scientific areas are under way today in 65 countries. The institution has a staff of about 1,300, and annual expenditures of approximately $155 million from federal, state and private sources. Scripps operates one of the largest U.S. academic fleets with four oceanographic research ships and one research platform for worldwide exploration.
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