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BOOSTING TAXOL PRODUCTION NATURAL PRODUCTS:
OPP
Engineered bacteria churn out cancer drug precursors
IPP OPP DMAPP
A H
H
Taxa-4(5),11(12)-diene
Taxol PP = diphosphate
Taxadiene is a key intermediate in the biosynthesis of Taxol.
NEWLY OPTIMIZED biosynthetic route in bac-
teria yields taxadiene, a precursor to the cancer drug paclitaxel (Taxol), at an amount that is 1,000-fold higher than previous efforts (Science 2010, 330, 70). Researchers have also for the first time engineered the oxidation of taxadiene to taxadien-5α-ol, the next step in the paclitaxel pathway. Several subsequent genes in the paclitaxel biosynthesis pathway are unknown, so a full biosynthesis is not yet possible. Nevertheless, the increase in yield for taxadiene and its precursor chemicals is “quite impressive,” says Susan C. Roberts, a chemical engineering professor at the University of Massachussetts, Amherst, who was not involved in the new work. Roberts notes that the precursors are also intermediates in the biosynthesis of a variety of other natural products. Paclitaxel was originally isolated from the bark of the
EARTH GETS A DOPPELGANGER EXOPLANETS: Astronomers discover habitable planet orbiting nearby star
F
ered a planet outside our solar system that has the potential to support life. The planet, which orbits a star only 20 light-years away from Earth, is similar in size and temperature to Earth, making it possible for liquid water and an atmosphere to exist—two essential criteria for habitability. Team members Steven S. Vogt, professor of astronomy and astrophysics at the University of California, Santa Cruz, and astronomer R. Paul Butler of Carnegie Institution of Washington announced their findings at a press conference on Sept. 28. Using the HIRES spectrometer designed by Vogt, at the Keck I Telescope on top of Mauna Kea in Hawaii, the team observed a dim star 240 times over a period of 11 years and indirectly detected the planet, known as Gliese 581g, from a small but telltale gravitational wobble it generates in the star. The discovery will be reported in an upcoming issue of Astrophysical Journal. LYNETTE COOK
An artist’s rendition shows the possible Earth-like nature of exoplanet Gliese 581g.
OR THE FIRST TIME, astronomers have discov-
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Pacific yew tree, in amounts that necessitated sacrificing two to four trees per patient. The drug is currently produced by chemically modifying baccatin III, which is isolated from needles of the European yew tree. Developing a biosynthetic pathway in bacteria or yeast should boost yields of the drug, as well as allow chemists to make derivatives for new drug candidates, say study authors Gregory N. Stephanopoulos and Blaine A. Pfeifer, chemical engineering professors at Massachusetts Institute of Technology and Tufts University, respectively. The researchers divided the biosynthesis of taxadiene into two sections. One produces the building blocks isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), and the other turns those chemicals into taxadiene. The group optimized each in Escherichia coli in a combinatorial fashion by varying parameters such as gene promoter sequences and the number of gene copies and eventually produced taxadiene at concentrations of 1 g/L. They then engineered the next step in the biosynthesis, oxidation of taxadiene using a cytochrome P450 oxidase, to produce taxadien-5α-ol at 58 mg/L. “If one could make Taxol at 100 mg/L, then the global demand of Taxol of 1 ton per year would be possible to satisfy by a single 200-m3 fermentor, which is a rather small operation,” Stephanopoulos says.—JYLLIAN KEMSLEY
Although nearly 500 exoplanets have been discovered since the first was found in 1992, none has been small enough, cool enough, or warm enough to be deemed habitable. Many of them are giant planets that are likely similar to our gas giants Jupiter and Saturn. As telescopic technology improves, astronomers have in recent years been finding exoplanets that are more similar to Earth in size and orbit. The researchers said their discovery was made possible by data another team had generated using the HARPS spectrometer at the Geneva Observatory. That team discovered four of the six planets in the same system. The orbits of two of those planets bracket the orbit of Gliese 581g. The planet closest to the sun is too hot to support life, whereas the one farther out is too cold. But Gliese 581g, in the middle, jokingly dubbed “Goldilocks,” is “just right,” Vogt said. One side of Gliese 581g is constantly exposed to the sun, and the other is constantly shaded. In between these areas, Vogt said, are likely patches with constant habitable conditions. Direct spectroscopic examination of an exoplanet’s atmosphere for species such as O2, water, or methane requires that the planet pass directly in front of its star from Earth’s line of sight. Gliese 581g’s orbit isn’t properly oriented for such observations, but discovering another such exoplanet won’t take long, Butler predicted. “It’s likely that in the next couple of years many more [Earth-like exoplanets] will be found,” he said.—ELIZABETH WILSON
OCTOBER 4, 2010
