NEWS OF T HE W EEK
A NEW TERPENE SYNTHASE PLANT BIOLOGY: Researchers
discover how plants make unusual cyclic iridoids
M
ANY PLANTS and insects produce a curious
family of bioactive cyclic terpene molecules called iridoids. Now, a team of researchers led by biochemist Sarah E. O’Connor and postdoc Fernando Geu-Flores at the John Innes Centre, in Norwich, England, have discovered the plant enzyme responsible for turning monoterpenes into these cyclic compounds (Nature, DOI: 10.1038/nature11692). Iridoids include nepetalactone, the component of catnip that drives felines blissfully crazy, and the aphid sex pheromone nepetalactol. They are also important building blocks for a potent group of anticancer agents called monoterpene indole alkaloids. The new synthase will permit researchers to make a whole host of iridoids through biotechnology, instead of relying on synthetic chemistry or extraction to acquire useful quantities of the cyclic terpenes, says Jonathan Gershenzon at the Max Planck Institute for Chemical Ecology in Jena, Germany. “Researchers have been chasing [the new enzyme] for a very long time because iridoids are so widespread,” Gershenzon says. “People knew the reaction involved some kind of reduction and obviously cyclization, but how these two processes were coupled was a mystery.” The new iridoid synthase cyclizes monoterpenes in two main steps, Geu-Flores explains. The precursor 10-oxogeranial undergoes a traditional reduction to form an enol intermediate, which then cyclizes through either a Diels-Alder cycloaddition or a Michael addition.
“We haven’t figured out which one it is—both are possible,” Geu-Flores says. He adds that very few enzymes catalyze Diels-Alder cycloadditions, but it is possible that iridoid synthase is an unusual example of one that does. The enzyme’s mechanism of cyclization also extends classic terpene chemistry. Many students learn about the biogenic isoprene rule made famous by Leopold Ruzicka, who won the 1939 Nobel Prize in Chemistry. The rule states that “terpenes are assembled from chains of isoprene units in reactions that include cationic intermediates called carbocations,” notes Joseph Chappell, a plant scientist at the University of Kentucky, in a commentary about the work (Nature, DOI: 10.1038/nature11754). But iridoids defy the Ruzicka rule, Chappell adds,“because their biosynthesis could not be deduced from conventional carbocation chemistry.” Next up, the John Innes team is working to get plants to produce insect iridoids. Namely, they want tobacco plants to produce aphid sex hormone so farmers can grow a row of decoy plants that would entice the agricultural pests away from important crops. The research team is also digging deeper into the mechanism of iridoid cyclization. Because the first step involves reduction and many enzymes catalyze reductions, the team is investigating whether other enzymes can be evolved or engineered to cyclize terpenes.—SARAH EVERTS
TYING THINGS UP Monoterpenes were long known to cyclize through carbocation intermediates (top). But now, researchers have discovered an enzyme that catalyzes such reactions by reduction followed by Diels-Alder or Michael addition chemistry.
INSIDER TRADING Prosecutors crack down on drug company stock schemes Federal authorities last week filed charges against several investors and a fund manager in two insider-trading schemes involving big pharma firm stocks. The Securities & Exchange Commission and the U.S. Department of Justice filed the complaints. One case is against former SAC Capital Advisors fund manager Mathew Martoma. He is accused of making $276 million in illegal profits and avoided losses in July 2008 by trading in securities of Elan and Wyeth, now part of Pfizer. Prosecutors say the case is “the most lucrative insider-trading scheme ever charged.”
Prosecutors allege that Sidney Gilman, a neurologist, tipped off Martoma about poor results from a Phase II clinical trial for the two companies’ Alzheimer’s disease drug candidate, bapineuzumab. News of the results caused double-digit declines in the shares of both firms, but not before Martoma turned the information to his advantage. Gilman, who chaired the safety monitoring committee overseeing the clinical trial, has agreed to pay more than $234,000 in fines. If convicted, Martoma faces up to 45 years in prison and millions of dollars in fines.
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In the second case, federal attorneys allege that Mark S. Cupo and John Lazorchak, who held senior accounting positions at Sanofi and Celgene, respectively, funneled inside information to at least four other people, generating $1.4 million in illegal profits. For five years, beginning in 2007, the six allegedly traded tips on quarterly earnings, drug approvals, and mergers, including Celgene’s 2008 acquisition of Pharmion. If they are found guilty, the defendants face jail time and thousands of dollars in fines.—MARC REISCH
