In brief

Fungal sesquiterpene synthases (STSs) identified in Lactarius deliciosus produce a novel sesquiterpene compound with a unique spiro-tricyclic scaffold for diverse biotechnology applications.

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Mushroom blueprint scores biotech breakthroughs

29 Mar 2024

An innovative genomic approach speeds up the search for new fungal enzymes to sustainably create industrial products ranging from perfumes to jet fuel.

They’re a fungal fraternity known for their ‘milk’; Lactarius mushrooms exude colourful latex fluids when their flesh is damaged. In particular, the vibrant, orange-hued latex of Lactarius deliciosus—also known as the saffron milkcap mushroom—forms part of its defences. Intriguingly, this latex holds a variety of compounds called sesquiterpenes, which may not only help develop medicines and cosmetics, but may even be used as jet fuel.

To enable more industrial applications for sesquiterpenes, it’s critical to get a clearer picture of the molecular machines that help produce them in nature: enzymes called sesquiterpene synthases (STSs), said Yee Hwee Lim, Director of the Chemical Biotechnology and Biocatalysis division at A*STAR’s Institute of Sustainability for Chemicals, Energy and Environment (ISCE2).

“Currently, scientists still can’t accurately predict the products of STSs,” Lim explained, adding that attempts to unravel the enzymes’ functions with conventional methods have been slow and costly.

However, innovative genomic and bioinformatic approaches could shed more light on the mechanics of how STSs form sesquiterpenes. This would enable researchers to both predict thousands of naturally-occurring, yet undiscovered STS products; and to engineer STSs that efficiently and sustainably produce sesquiterpenoids of practical use, said Lim.

In partnership with Congqiang Zhang, a Principal Investigator at A*STAR’s Singapore Institute of Food and Biotechnology Innovation (SIFBI), and other collaborators from ISCE2, SIFBI and the University of Illinois, US, Lim’s team embarked on comprehensive analyses to characterise STSs made by L. deliciosus.

First, the researchers hunted for clues in the mushroom’s genome, using bioinformatics to predict the likeliest genes behind STS production. To validate their predictions, these genes were then expressed in a specially-engineered strain of Escherichia coli bacteria.

“With our proprietary E. coli platform, which is efficient and easily scalable, we can essentially produce any terpene from fungi and plants,” said Zhang.

The STSs they made were then analysed using gas chromatography-mass spectrometry to determine their chemical compositions. Excitingly, this led to the discovery of the first member of a previously-unknown STS clade which creates unique terpene ‘scaffolds’: spiralling loops held together by three interlocked rings.

A phylogenetic analysis—akin to a family tree—also offered clues on the evolutionary relationships between the new clade and other known STSs. “Although we’ve been working on fungal terpenoids for about a decade, this study revealed that there are still many unknowns in their biosynthesis,” Lim said.

The research group continues to explore uncharted territory in novel STSs and their potential applications. At present, they have filed two patents for the use of their newly discovered STS in cosmetic fragrances and biofuels, leveraging the compound’s energy-rich hydrocarbon properties.

The A*STAR-affiliated researchers contributing to this research are from the Institute of Sustainability for Chemicals, Energy and Environment (ISCE2) and the Singapore Institute of Food and Biotechnology Innovation (SIFBI).

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Cheong, C.B., Peh, G., Wei, Y., T, R. and Ang, E.L. A spirobicyclo[3.1.0]terpene from the investigation of sesquiterpene synthases from Lactarius deliciosus. ACS Chemical Biology 18 , 134-140 (2023). | article

About the Researchers

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Yee Hwee Lim

Director, Chemical Biotechnology and Biocatalysis

Institute of Sustainability for Chemicals, Energy and Environment (ISCE2)
Yee Hwee Lim leads the Chemical Biotechnology and Biocatalysis division at the Institute of Sustainability for Chemicals, Energy and Environment (ISCE2), A*STAR. Her team focuses on developing integrative technologies at the interface between chemistry, biology, informatics and engineering for sustainable chemical manufacturing. As a chemist trained in the UK and US, she is passionate about advancing chemistry’s frontiers and harnessing nature's catalytic powers to solve molecular challenges. She also serves as the programme director for SIBER 2.0, an A*STAR programme in sustainable chemicals biomanufacturing from alternative feedstocks, hosted at ISCE2.
Congqiang Zhang (Simon) received his undergraduate and master training in chemical engineering at Tianjin University, China. He then continued with his PhD training in Chemical and Pharmaceutical Engineering in a joint programme between National University of Singapore and Massachusetts Institute of Technology. He is now a Principal Investigator at the Singapore Institute of Food and Biotechnology Innovation (SIFBI) leading a team working on multiple academic and industrial projects. His expertise is in metabolic engineering, synthetic biology, enzyme engineering, discovery and biosynthesis of natural products and industrial biotechnology. He has co-authored over 30 papers and has 10 international patents. He served as an associate editor for two peer-reviewed journals, Advanced Biotechnology and Frontiers in Bioengineering and Biotechnology; and is the secretary for the BioEnergy Society of Singapore.

This article was made for A*STAR Research by Wildtype Media Group