Abstract
Photosynthetic terpene production represents one of the most carbon and energy-efficient routes for converting CO2 into hydrocarbon. In photosynthetic organisms, metabolic engineering has led to limited success in enhancing terpene productivity, partially due to the low carbon partitioning. In this study, we employed systems biology analysis to reveal the strong competition for carbon substrates between primary metabolism (e.g., sucrose, glycogen, and protein synthesis) and terpene biosynthesis in Synechococcus elongatus PCC 7942. We then engineered key "source" and "sink" enzymes. The "source" limitation was overcome by knocking out either sucrose or glycogen biosynthesis to significantly enhance limonene production via altered carbon partitioning. Moreover, a fusion enzyme complex with geranyl diphosphate synthase (GPPS) and limonene synthase (LS) was designed to further improve pathway kinetics and substrate channeling. The synergy between "source" and "sink" achieved a limonene titer of 21.0 mg/L. Overall, the study demonstrates that balancing carbon flux between primary and secondary metabolism can be an effective approach to enhance terpene bioproduction in cyanobacteria. The design of "source" and "sink" synergy has significant potential in improving natural product yield in photosynthetic species.
Highlights
IntroductionTerpenoids are a large class of natural products with diverse biological functions, including photon harvesting (e.g., chlorophylls), membrane stability (e.g., sterols), and multitrophic signaling [1, 2]
Terpenoids are a large class of natural products with diverse biological functions, including photon harvesting, membrane stability, and multitrophic signaling [1, 2]
By creating a strong limonene sink through high ls gene expression, the strain L1118 serves as an effective platform to investigate additional metabolic and biochemical limits in terpene biosynthesis
Summary
Terpenoids are a large class of natural products with diverse biological functions, including photon harvesting (e.g., chlorophylls), membrane stability (e.g., sterols), and multitrophic signaling [1, 2]. Many terpenoids are valuable chemicals with broad applications in the pharmaceutical, nutraceutical, cosmetic, and biofuel industries [3]. The past decade has witnessed a rapid increase in atmospheric CO2 levels due to fossil fuel combustion and deforestation. Photosynthetic terpene production represents a promising technology to mitigate global climate change by directly converting CO2 into hydrocarbon for “drop-in” biofuels, which could both reduce fossil fuel utilization and enable sustainable carbon capture and utilization [4, 5]. Photosynthetic organisms produce some of the most valuable terpenoid-derived medicines and vaccine adjuvants including taxol, artemisinin, vinblastine, and squalene [3]. The design of efficient CO2 conversion to terpenes in photosynthetic organisms has a broad industrial implication
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