NEWS OF THE WEEK
NEW CANCER VACCINE STRATEGY CANCER TREATMENT: Twoheaded molecule summons immune-system attack The left end of this small molecule can bind to a prostate cancer cell antigen while the right end recruits human antibodies.
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TWO-HEADED small molecule could marshal
a cancer patient’s immune system to seek out and destroy prostate tumor cells. In current immunotherapy strategies, researchers target cancer cells by linking chemotherapy drugs or raO
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dionuclides to antibodies for proteins on the cells’ surface. Although the antibodies shuttle most of O these toxic agents to cancer cells, the drugs can still hit healthy cells, leading to unwanted side effects. “We wanted to develop a strategy in which a patient’s own immune system, rather than a toxic compound, kills prostate cancer cells,” says David A. Spiegel, a chemist at Yale University. To do so, Spiegel and his collaborators designed a molecule that consists of two chemical groups linked OH
MAKING DINITROGEN Kartal and coworkers studied K. stuttgartiensis grown in a bioreactor.
ENVIRONMENT: Pathway involves
COURTESY OF BORAN KARTAL
microbial oxidation of ammonia via nitric oxide and hydrazine
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HE MECHANICS of a key biogeochemical reac-
tion that affects atmospheric chemistry have been identified by an international research group. The research shows how one of two major routes for putting dinitrogen into the atmosphere happens via a microbiological process known as anammox, for anaerobic ammonium oxidation. In the new work, Boran Kartal of the Netherlands’ Radboud University Nijmegen and colleagues demonstrate that microbes turn ammonium into dinitrogen anaerobically through a pathway that involves the intermediates nitric oxide and hydrazine (Nature, DOI: 10.1038/nature10453). To pin down the reaction sequence, Kartal and colleagues worked with the bacterium Kuenenia stuttgartiensis. They grew the microbe in a bioreactor and studied which genes the microbe transcribed, which enzymes it made, and the activity of those enzymes. Kartal and colleagues found that K. stuttgartiensis WWW.CEN-ONLINE.ORG
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together: 2-[3-(1,3-dicarboxypropyl)-ureido]pentanedioic acid (DUPA) and 2,4-dinitrophenyl (DNP). Other researchers have shown that DUPA selectively binds to a unique prostate cancer cell protein (Mol. Pharm., DOI: 10.1021/mp900069d). DNP is a well-known environmental contaminant that, for unknown reasons, most people already have antibodies against. The team envisioned that the DUPA end of the molecule would grab on to prostate cancer cells and the DNP end would attract these circulating antibodies to trigger an immune response to destroy the cells. The researchers tested their hypothesis in mice that had human prostate tumors grafted under the skin of their right flanks. After two weeks of three treatments per week of the two-headed molecule, tumors in the mice were about 80% smaller than NO2 those in mice treated with DUPA alone (ACS Chem. Biol., DOI: 10.1021/ N cb200222s). When the researchers anaH NO2 lyzed tumor tissue samples from mice treated with the two-headed molecule, they discovered that lymphocytes called natural killer cells had infiltrated the tumor. Laura L. Kiessling, a biochemist at the University of Wisconsin, Madison, says that, because the small molecule is modular, the new approach “lays the groundwork” for targeting not only prostate cancer, but also other cancer types. “In principle, any cell-targeting agent can be combined with an antibody recruitment agent,” she says.—LAURA CASSIDAY, special to C&EN
first uses a reductase enzyme to convert NO2– to NO. Then a three-protein hydrazine synthase complex combines NO and NH4+ to form N2H4. Finally, a hydrazine dehydrogenase enzyme converts N2H4 to N2. The electrons for the first two steps of the process come from the final oxidation of N2H4 to N2. Scientists used to think that N2 in the atmosphere came only from denitrification, or reduction of NO3– to N2. But about 15 years ago, anammox came to light, and now researchers believe that as much as half of atmospheric N2 comes from that process, says Daniel J. Arp, a professor of botany and plant pathology at Oregon State University. Anammox is also of interest as a way to remove nitrogen from wastewater streams. Although there was some evidence that allowed researchers to guess at the mechanics of the anammox process,“there was not a fully integrated pathway with supporting evidence for each step,” Arp says. The new work provides that complete pathway. Arp was not involved in the research. Arp is particularly excited to learn more about the hydrazine synthase complex that Kartal and coworkers discovered. “It will be fascinating to learn about the mechanism” of hydrazine formation and what intermediates are formed, how electrons are transferred, and which metals may be involved, he says.—JYLLIAN KEMSLEY
OCTOBER 10, 2011
