NEWS OF THE WEEK SCIENCE
PATHTOENEDIYNES Engineering of biosynthetic route could lead to better anticancer drugs
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tic schemes have been devised for a number of members of the enediyne class of potent anticancer agents. But relatively little has been known about how these bacterial natural products are synthesized in nature. Not anymore. Two teams of researchers from the University of Wisconsin, Madison, have shown that the enediyne cores of both C-1027 and calicheamicin are synthesized via a common polyketide pathway, suggesting that all enediynes are biosynthesized in the same manner [Science, 297, WO and 1173(2002)}.
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Enediynes are characterized by a nine- or 10-membered ring containing two triple bonds separated by a double bond. T h e enediyne group readily cyclizes via a diradical intermediate that cleaves D N A , giving rise to enediynes' powerful antitumor activity But just how bacteria create the enediyne core—and whether they all use the same method— has long been controversial. Hypotheses have included a polyke-
NeWp Independent Monsanto Emerges onsanto once again became an independent company when Pharmacia shed its 84% interest in the firm last week. At the close of trading on Aug. 13, Pharmacia issued its shareholders 0.170593 shares of Monsanto stock for each Pharmacia share. Hendrik A. Verfaillie, Monsanto's president and CEO, said the spin-off "marks an important milestone, affirming Monsanto's place as a company solely dedicated to agriculture" through an integrated strategy that combines seeds, biotechnology, and agrochemicals. Monsanto was established in 1901 and grew to become a leading diversified chemical company, it launched Roundup, its flagship herbicide product that still garners billions in annual sales, in 1974. In 1985, Monsanto purchased the drug firm G. D. Searle. Soon after, it began divesting
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tide pathway in which the enediyne core is built up sequentially from two-carbon units and a pathway in which the enediyne core is created by degrading an unsaturated fatty acid precursor. Ben Shen, associate professor of pharmaceutical sciences and
chemical businesses and then embarked on a biotech and seed company acquisition spree. Its life sciences focus was cemented with the spin-off of its chemical operations as Solutia in 1997. Pharmacia bought Monsanto in March 2000 to get the Searle business. Just seven months later, it sold 16% of Monsanto through a stock offering. Although the full spin-off was always planned, Pharmacia completed it sooner than expected as a condition of being acquired by Pfizer (C&EN, July 22, page 9). Analysts anticipated that Pharmacia shareholders, more interested in owning the drug company's stock, would quickly sell their new Monsanto shares. Although trading volumes were high, Monsanto's stock did much better than expected, rising 7.6% to $17.01 per share on Aug. U.—ANN THAYER
chemistry and coworkers cloned and characterized the stretch of the Streptomyces globisporus genome necessary for biosynthesis of the nine-membered enediyne C-1027. Disruption of the single polyketide synthase (PKS) gene in this region stops C-1027 production, they find. Working in Micromonospora echinospora ssp. calichensis, pharmaceutical sciences associate professor Jon S. Thorson, Chris M. Farnet of EcopiaBiosciences, and coworkers found that a homologous PKS gene in the calicheamicin gene cluster is required for production of this 10-membered enediyne. In both sequence and organization, the C-1027 and calicheamicin PKSs are remarkably similar. "Taken together, our findings suggest that all enediynes share a common polyketide biosynthetic pathway," Thorson says. Despite their potency, the enediynes' reactivity and toxicity have limited their usefulness as drugs. But by disrupting a hydroxylase gene in the C-1027 cluster, Shen's team created a novel C-1027 analog with improved chemical stability "The work opens the door to genetic manipulation of these biosynthetic pathways to develop new drug candidates," Shen says.—AMANDA YARNELL
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C & E N / A U G U S T 19, 2002
H T T P : / / P U B S . ACS.ORG/CEN
