Engineering de novo formatotrophy in the non-model yeast Y.lipolytica
File(s)
Published version
Author(s)
Newell, William
Hapeta, Piotr
Bell, David
Ledesma-Amaro, Rodrigo
Type
Journal Article
Abstract
Formate is an exciting potential microbial feedstock as it can be derived from CO2 and electricity. Despite this, limited progress has been made in engineering formatotrophy in yeasts, and no yeasts grow using formate naturally. Here we use metabolic modelling to find two potential formatotrophy pathways in Yarrowia lipolytica. We then use C13 tracer analysis and computationally guided growth experiments to show that wild-type Y. lipolytica possesses strong formate dissimilation and a cyclical C1 pathway with similar architecture to the synthetic serine–threonine cycle, which it uses to co-assimilate formate and glycerol. Messenger RNA sequencing shows that formate exposure results in increased oxidative stress and changes in the tricarboxylic acid cycle, redox and C1 metabolism. Following this, we use model-guided adaptive laboratory evolution to produce a formatotrophic strain of Y. lipolytica using the eukaryotic serine–threonine cycle. We then use further messenger RNA sequencing to show that formatotrophy is supported by changes in adenosine triphosphate and reactive oxygen species metabolism. Subsequently, we engineer nicotinamide adenine dinucleotide phosphate (NADPH) and reactive oxygen species metabolism to create a strain with substantially improved growth. This strain reaches about 10% of the theoretical maximum biomass yield, highlighting its potential for additional engineering approaches. Finally, we show that beta-carotene production from formate is possible in our engineered strain, opening the door to formatotrophic eukaryote bioprocesses.
Date Issued
2026-09-01
Date Acceptance
2026-04-14
Citation
Nature Synthesis, 2026, 5 (9), pp.1360-1373
ISSN
2731-0582
Publisher
Nature Research
Start Page
1360
End Page
1373
Journal / Book Title
Nature Synthesis
Volume
5
Issue
9
Copyright Statement
© The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/42718654
PII: 1076
Subjects
Industrial microbiology
Synthetic biology
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2026-06-12