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Biological Chemistry

Mutant enzyme provides a route to novel triterpenes

A single amino acid change leads to synthesis of new structures for important class of natural products

by Stu Borman
July 14, 2016 | APPEARED IN VOLUME 94, ISSUE 29

CORRECTION: This story was updated on Aug. 11, 2016, to correct the structure of the pentacyclic triterpene.

Triterpenes are multiringed natural products useful as drugs, agrochemicals, and even cosmetics.

[+]Enlarge
Native and mutated triterpene synthases catalyze the synthesis of five- and four-ring triterpene structures, respectively.
Native and mutated triterpene synthases catalyze the synthesis of five- and four-ring triterpene structures, respectively.

Researchers report that a single amino acid mutation in the enzymes that synthesize these compounds can produce novel products with four-ring triterpene core structures instead of the usual five-ring ones (Proc. Natl. Acad. Sci. USA 2016, DOI: 10.1073/pnas.1605509113). The modified enzymes could be engineered into microorganisms or plants to generate a variety of novel triterpenes that would be difficult or impossible to synthesize any other way.

The researchers, led by Anne Osbourn of the John Innes Centre, notes that their findings reveal “hidden functional diversity within triterpene synthases.” They hope to use the mutant enzymes in a “triterpene machine” that yields custom-built triterpenes.

Plants make triterpenes by using triterpene synthase enzymes to cyclize a linear substrate, 2,3-oxidosqualene, into pentacyclic natural products, such as the analgesic and anti-inflammatory agent β-amyrin. Other enzymes then further modify these triterpenes to produce a variety of derivatives, such as saponins, which are sugar-containing compounds that have been used as surfactants and vaccine adjuvants.

The key mutation for producing new triterpenes involved swapping a serine residue for a phenylalanine. When the team expressed the modified enzyme in yeast, they found that it could still cyclize the usual substrate, 2,3-oxidosqualene, but more readily catalyzed the cyclization of a more oxygenated substrate, dioxidosqualene. This yielded an unusual oxygen-enriched compound with a tetracyclic triterpene core structure.

Osbourn envisions developing a triterpene machine by inserting genes for the mutated enzymes into yeast or tobacco plants to enable the organisms to produce customized cyclic triterpenes cost-effectively and on a large scale.

“The novelty of the work is that the group is getting unique or unusual products that would not be readily available by conventional chemical synthesis, or any other means at the moment,” says Joseph Chappell of the University of Kentucky, an expert on the biosynthesis of terpene-based compounds. “No organism I know of would make these unique molecules.”


This article has been translated into Spanish by Divulgame.org and can be found here.


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Comments
RB Williams (July 18, 2016 1:38 PM)
The structure of beta-amyrin is wrong. The C-28 methyl should be at the C-17 position.
Stu Borman (July 25, 2016 4:02 PM)
Dear RB Williams -- Thanks for alerting us that the structure is incorrect. We are issuing a correction, It should be posted online soon, and it will also appear in print. I'm sorry about the error.

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