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January 28, 2010

Fluorinase Success

Biosynthesis: In a chemical first, an engineered microbe yields a bioactive fluorinated compound

Stephen K. Ritter

FERMENTED FLUORINE By replacing a gene in the bacterium <em>S. tropica</em> with one for the fluorinase enzyme, researchers have biosynthesized a fluorinated version of salinosporamide. View Enlarged Image
FERMENTED FLUORINE By replacing a gene in the bacterium S. tropica with one for the fluorinase enzyme, researchers have biosynthesized a fluorinated version of salinosporamide.
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By reprogramming a deep-sea microbe to make a fluorinated version of the anticancer drug candidate salinosporamide A, scientists have for the first time achieved gene cloning of the fluorinase enzyme into a host organism to generate a fluorinated metabolite (J. Nat. Prod., DOI: 10.1021/np900719u). Although the efficiency of the biosynthesis is low, the achievement is a major step toward practical fermentation production of fluorinated drugs.

Organofluorine compounds play an important role in medicinal chemistry—about 15% of all pharmaceuticals include at least one fluorine atom to improve bioavailability and efficacy. Although halogenated natural products are common in nature, natural organofluorine compounds are rare, with only five examples reliably known. In 2002, the fluorinase enzyme that gives rise to these fluorinated compounds was first isolated from the soil bacterium Streptomyces cattleya, in which fluorinase uses fluoride ion to generate C–F bonds.

David O'Hagan of Scotland's University of St. Andrews and colleagues accomplished the original work to isolate and decipher the function of fluorinase. Now, O'Hagan, in collaboration with Alessandra S. Eustáquio and Bradley S. Moore of Scripps Institution of Oceanography at the University of California, San Diego, has coaxed the bacterium Salinospora tropica to accept the fluorinase gene and put it to work.

In 2007, Moore and coworkers sequenced the genome of S. tropica, one of many Salinospora species found in ocean sediments that are producers of anticancer and antibiotic compounds. Salinosporamide A, a key chlorinated natural product made by S. tropica, is in clinical trials as an anticancer drug. To make fluorosalinosporamide, O'Hagan, Eustáquio, and Moore replaced the chlorinase gene in S. tropica with the corresponding sequence from fluorinase. This switch enables the engineered microbe to convert S-adenosyl-L-methionine to 5'-fluorodeoxyadenosine, the lead step in the fluorosalinosporamide biosynthesis.

"For salinosporamides, fluorine substitution has the potential to alter the cytotoxic potency of the compound because the halogen is involved in the drug's mechanism of action," notes Guy T. Carter, assistant vice president of chemical technologies at Pfizer. "One can now envision creating other fluorine-containing precursors through mechanisms linked to the metabolism of intermediate fluorosugars and hence broaden the array of fluorinated products."

The efficiency of fluorosalinosporamide production is currently hampered because the engineered microbe is sensitive to fluoride ions, O'Hagan notes. "We still need to work out how to engineer fluoride-ion resistance into the host organism," O'Hagan says. "We have some clues how this can be done from the relevant gene cluster in S. cattleya, which is where we are going in the next phase of our research."

"Introducing the halide is just the first step in a remarkable sequence of some 15 transformations initiated by the halogenase enzyme," Moore notes. "Some of the intermediates, including fluorosugars, have the potential to be shunted off in different directions to make other types of fluorochemicals and expand the utility of the engineered bacterium."

Many obstacles hamper the use of combinatorial biosynthesis in drug manufacturing, says Iwao Ojima, director of the Institute of Chemical Biology & Drug Discovery at the State University of New York, Stony Brook. "The fluorosalinosporamide synthesis is a beginning to possible production of fluorinated natural products by genetic engineering, but it has a long way to go to reach a practical level," Ojima says. "We can be cautiously optimistic for this approach to eventually become synthetically useful."

Chemical & Engineering News
ISSN 0009-2347
Copyright © 2011 American Chemical Society
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