When you hear about making fragrance ingredients with microorganisms, you may imagine producing compounds found in plants by another route. But can living cells also make fragrance ingredients that have not been found in nature?
In a study published in 2025, Lina Wang and colleagues developed a method using genetically modified yeast to alter the carbon skeletons of isoprenoids, a large group of compounds that includes terpenes. The aim was not simply to produce one fragrance ingredient, but to make molecules with progressively modified structures and examine differences in their aromas and functions.
Changing the building blocks expands the range of molecules
Many terpenes are built by combining basic units containing five carbon atoms. Linalool and limonene have ten carbons, for example, while caryophyllene has fifteen. These combinations provide the starting point for their molecular skeletons.
The researchers created an alternative entry point at this building-block stage. Two plant-derived enzymes operating in yeast converted alcohols with unusual carbon numbers or branching positions into materials that could enter the biosynthetic pathway. The system processes externally supplied materials inside yeast cells.
Seven alcohols were used in the experiments, producing molecules resembling limonene with eleven or twelve carbons, counterparts of caryophyllene with sixteen or seventeen carbons, and a squalene analog with thirty-one carbons. The products were examined using mass spectrometry and other methods, and NMR was also used to confirm the structures of major compounds that could be isolated.
However, the method did not allow any imaginable skeleton to be made at will. In some cases, precursors for larger classes could not be produced. Whether intermediate enzymes could accept the new building blocks imposed constraints.
Producing the synthetic fragrance ingredient ethyllinalool in yeast
Ethyllinalool was chosen as an example of fragrance application. It resembles linalool, which occurs widely in nature, but the paper treats ethyllinalool as a fragrance ingredient not found in nature and previously supplied through chemical synthesis.
Ethyllinalool has E and Z forms that differ in arrangement around a double bond. When the researchers supplied yeast with a mixture of precursors corresponding to both forms, the product was mainly the E form, with only a small amount of the Z form. The ability to discriminate between different arrangements of molecules with the same constituent atoms is important.
Experiments examining production conditions yielded approximately 22 milligrams of the E form per liter of culture. This is a laboratory proof-of-concept value, not a commercial production volume or an industrial production cost. Moreover, the product was not made entirely from sugar: an alcohol used to modify the skeleton was supplied externally.
The E and Z forms also smelled different
A fragrance professional evaluated the isolated E and Z forms. The E form was described as fruity and floral, with a strong impression. The Z form was described as weaker, with prominent grassy or countryside-like notes.
On this basis, the authors consider predominantly producing the E form with the desired scent characteristics an advantage. However, the evaluation involved one expert, not a large preference survey or a test demonstrating statistically superior performance. It does not establish that everyone prefers the E form.
Three additional linalool analogs with different carbon additions were also produced. The expert’s descriptions included one with prominent citrus-peel freshness and spiciness and another with a strong pineapple-like fruitiness and almost no floral character. This suggests that small changes to the skeleton may expand the palette of aromas.
From fragrance production to a tool for investigating molecular function
In another proof of concept, cannabinoid analogs were produced, and some activated receptors more strongly than the original compounds. These were cellular assays using yeast containing human receptors. They did not establish therapeutic efficacy or safety in people.
What these two examples share is the connection between a method for producing molecules and a method for evaluating their properties. Beyond applying it to existing microbial production systems, the authors suggest incorporating it into plants and bacteria as a tool to study how molecular structure affects cellular properties and interactions between organisms.
Practical application still requires work on sourcing materials, improving enzymes, yields, and purification. Although the authors see economic and scaling potential, this paper did not compare industrial-scale costs or assess the environmental impact of the entire manufacturing process. Microbial production alone also does not determine natural-fragrance labeling, environmental superiority, or safety.
Summary
Yeast served not only to reproduce fragrance ingredients found in nature but also as a platform for using unconventional starting materials to produce molecules with new carbon skeletons. Selective production of the E form of ethyllinalool illustrates how a manufacturing method may also help select particular aroma characteristics.
The study’s broader significance lies in making it possible to produce and investigate insufficiently explored structures related to familiar molecules. Expanding fragrance candidates and understanding the properties created by small structural differences are complementary goals. This method offers possibilities for advancing both.
References
Wang, L., Rosenfeldt, M., Koutsaviti, A., Harizani, M., Zhao, Y., Leelahakorn, N., Frachon, A., Raadam, M. H., Miettinen, K., Pateraki, I., Ioannou, E., & Kampranis, S. C. (2025). Systematic biotechnological production of isoprenoid analogs with bespoke carbon skeletons. Nature Communications, 16, 2098. DOI: 10.1038/s41467-025-57494-2 / Full original article.
The research was supported by the Novo Nordisk Foundation, the Independent Research Fund Denmark, a grant from the University of Athens, and a China Scholarship Council scholarship. Three authors are co-inventors on a related patent application. The author responsible for sensory evaluation is an employee of EvodiaBio ApS, and another author declared financial interests in the company. The remaining authors declared no competing interests. Original article: © 2025 The Author(s), CC BY-NC-ND 4.0.
