CHEMICAL & ENGINEERING
NEWS OF THE WEEK OCTOBER 11, 2004 - EDITED BY WILLIAM G. SCHULZ & STEPHEN TRZASKA
CHEMISTRY
NOBEL
PRIZE
PROTEIN BREAKDANCE Prize honors elucidation of ubiquitinmediated protein degradation Ubiquitin-mediated protein degradation plays a key role in cell division, DNArepair, protein synthesis, and the immune system; malfunctions can lead to diseases LAUREATES like cancer. A detailed underHershko (left) and standing of the process is thus imCiechanover portant to drug discovery The first drug that inhibits this proteindegradation pathway—Millennium Pharmaceuticals' Velcade, a treatment for multiple myeloma—was recently approved, and other drugs are being tested. "I was sitting and editing a review article," said Ciechanover by phone from Haifa to a Swedish press conference, 10 minutes after having been informed about the prize. "I was on my way out, and all of a sudden the phone call," he said. "I am not myself" "It's the first Nobel Prize in sciences going Protein Peptide fragments to Israel," Ciechanover Ub = ubiquitin noted. "It shows you ATP = adenosine triphosphate that a tiny ... country ADP = adenosine diphosphate with little resources can COURTESY OF ALFRED GOLDBERG; HARVARD MEDICAL SCHOOL nevertheless have imaginative scientists that are S'H RE D D ER. In the ubiquitin-proteaspme pathway, energy extremely successful." from ATP is used to tag an unwanted protein ubiquitins, marking the protein for slicing and dicing by the In the digestive sysproteasome into peptide fragments. tem, proteolytic enzymes break down the protein in food. But inside living for Research in Medical Sciences cells, a completely different mechatlechnion, Haifa, Israel; and Iranism—the ubiquitin-proteasome win Rose, 78, a physiology and biopathway—regulates the degradaphysics researcher at the Univertion of most proteins that are sity of California, Irvine. They will problematic or no longer needed. share equally an award of nearly The polypeptide ubiquitin marks $1.4 million.
T
HE ROYAL SWEDISH ACAD-
emy of Sciences last week awarded the 2 0 0 4 Nobel Prize in Chemistry to three researchers "for the discovery of ubiquitin-mediated protein degradation," a regulated process by which proteins are cleaved into peptides inside cells. The laureates are Aaron Ciechanover, 57, and Avram Hershko, 67, professors at the Rappaport Family Institute
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each such protein for destruction, and the tagged proteins are then directed to the proteasome, a large protein complex where the tagged proteins are broken down and ubiquitins are released for reuse. Unlike protein digestion, this process is energy dependent, requiring adenosine triphosphate. In the 1970s, cell biology professor Alfred L. Goldberg and coworkers at Harvard Medical School produced a cell-free extract in which this energy-dependent process occurred. Using such extracts, Ciechanover, Hershko, and Rose discovered the molecular mechanism of ubiquitination in the late 1970s and early 1980s. The multistep process involves the ubiquitin-activating and -transferring enzymes El, E2, and E3. Much of the work was done while Ciechanover and Hershko were on sabbatical in Rose's lab. "The selection committee did a very impressive job," Goldberg tells C & E N . "They surprised many people by deciding not to award the prize in medicine for the complete ubiquitin-proteasome pathway, but to do so in chemistry and focus on the tagging of proteins for degradation, which involved a new type ofpostsynthetic protein modification. For cell regulation and medicine, this is a critical step. In my view, there is no question that each laureate merits the honor. And the committee deserves credit for recognizing the major contributions of Rose." The discovery shows "the power of a chemical insight" that intracellular protein degradation was energy dependent, saysJeremy M. Berg, director of the National Institute of General Medical Sciences, which has supported work in the field. "Over the last decade or so, the wide-ranging importance of this system in biology has become clear."—STU BORMAN HTTP://WWW.CEN-ONLINE.ORG
