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October 2000
Vol. 3, No. 8, p. 12.

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Expanding biosynthetic pathways

Luckily for geneticists, E. coli is a tireless worker. With a relatively simple and well-understood genetic code, scientists have turned the bacterium into a biochemical workhorse, often hijacking its genetic machinery to express DNA cloned from foreign organisms. But now biochemists have added another layer to the exploitation of E. coli. By expressing foreign DNA in E. coli to... produce enzymes that extend certain metabolic pathways, researchers have enabled the organism to “breed” entirely new and sometimes unpredicted compounds—some of which may have great potential as nutrients and pharmaceuticals.

Scientists from the California Institute of Technology (Pasadena) and the University of Minnesota (St. Paul) demonstrated the concept of molecular breeding with genes that allow E. coli to produce a class of compounds called carotenoids, which have antioxidant properties. The ability of carotenoids to influence cellular communication in tumors has led people to speculate about their use as anticancer therapeutics, but their structural complexity makes it difficult to chemically synthesize them. Although previous groups have shown that E. coli can be manipulated to produce this class of compounds, recently published experiments show that expressing a library of carotenoid-producing enzymes in E. coli can result in novel, synthetically inaccessible compounds (Nature Biotechnol. 2000, 18, 750–753).

To accomplish this, the team targeted two enzymes that lie at the branch points of the carotenoid biosynthetic pathway, phytoene desaturase and lycopene cyclase. In one experiment, the researchers chose three carotenoid-producing genes from different microorganisms and assembled them in E. coli, but they replaced one of the genes with a library of gene hybrids corresponding to variations of phytoene desaturase. The researchers then determined which types of carotenoids each culture contained. They then repeated the breeding with the newly derived strains, expanding their carotenoid repertoire.

What makes the molecular breeding technique interesting, says Claudia Schmidt-Dannert, a biochemist at the University of Minnesota, is that the researchers could not predict exactly which carotenoids the manipulated E. coli would produce. “You have a great factory for making new compounds,” she says. “Not only do you create new types of compounds, but you also have the machinery for creating others.”

JOHN MACNEIL

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