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ATP drives efficient terpene biosynthesis in marine thraustochytrids

Aiqing Zhang, Kaya Mernitz, Chao Wu, Wei Xiong, Yaodong He, Guangyi Wang, View ORCID ProfileXin Wang
doi: https://doi.org/10.1101/2020.11.20.391870
Aiqing Zhang
1Department of Microbiology, Miami University, Oxford, OH 45056, USA
2School of Environmental Science and Engineering, Tianjin University, Tianjin 300354, China
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Kaya Mernitz
1Department of Microbiology, Miami University, Oxford, OH 45056, USA
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Chao Wu
3Biosciences Center, National Renewable Energy Laboratory, Golden, CO 80401, USA
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Wei Xiong
3Biosciences Center, National Renewable Energy Laboratory, Golden, CO 80401, USA
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Yaodong He
2School of Environmental Science and Engineering, Tianjin University, Tianjin 300354, China
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Guangyi Wang
2School of Environmental Science and Engineering, Tianjin University, Tianjin 300354, China
4Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China
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  • For correspondence: xwang@miamioh.edu gywang@tju.edu.cn
Xin Wang
1Department of Microbiology, Miami University, Oxford, OH 45056, USA
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  • ORCID record for Xin Wang
  • For correspondence: xwang@miamioh.edu gywang@tju.edu.cn
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ABSTRACT

Understanding carbon flux-controlling mechanisms in a tangled metabolic network is an essential question of cell metabolism. Secondary metabolism, such as terpene biosynthesis, has evolved with low carbon flux due to inherent pathway constraints. Thraustochytrids are a group of heterotrophic marine unicellular protists, and can accumulate terpenoids under the high salt condition in their natural environment. However, the mechanism behind the terpene accumulation is not well understood. Here we show that terpene biosynthesis in Thraustochytrium sp. ATCC 26185 is constrained by local thermodynamics in the mevalonate pathway. Thermodynamic analysis reveals the metabolite limitation in the nondecarboxylative Claisen condensation of acetyl-CoA to acetoacetyl-CoA step catalyzed by the acetyl-CoA acetyltransferase (ACAT). Through a sodium elicited mechanism, higher respiration leads to increased ATP investment into the mevalonate pathway, providing a strong thermodynamic driving force for enhanced terpene biosynthesis. The proteomic analysis further indicates that the increased ATP demands are fulfilled by shifting energy generation from carbohydrate to lipid metabolism. This study demonstrates a unique strategy in nature using ATP to drive a low-flux metabolic pathway, providing an alternative solution for efficient terpene metabolic engineering.

IMPORTANCE Terpenoids are a large class of lipid molecules with important biological functions, and diverse industrial and medicinal applications. Metabolic engineering for terpene production has been hindered by the low flux distribution to its biosynthesis pathway. In practice, a high substrate load is generally required to reach high product titers. Here we show that the mevalonate-derived terpene biosynthesis is constrained by local pathway thermodynamics, which can only be partially relieved by increasing substrate levels. Through comparative proteomic and biochemical analyses, we discovered a unique mechanism for high terpene accumulation in marine protists thraustochytrids. Through a sodium induced mechanism, thraustochytrids shift their energy metabolism from carbohydrate to lipid metabolism for enhanced ATP production, providing a strong thermodynamic driving force for efficient terpene biosynthesis. This study reveals an important mechanism in eukaryotes to overcome the thermodynamic constraint in low-flux pathways by increased ATP consumption. Engineering energy metabolism thus provides an important alternative to relieve flux constraints in low-flux and energy-consuming pathways.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 26, 2020.
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ATP drives efficient terpene biosynthesis in marine thraustochytrids
Aiqing Zhang, Kaya Mernitz, Chao Wu, Wei Xiong, Yaodong He, Guangyi Wang, Xin Wang
bioRxiv 2020.11.20.391870; doi: https://doi.org/10.1101/2020.11.20.391870
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ATP drives efficient terpene biosynthesis in marine thraustochytrids
Aiqing Zhang, Kaya Mernitz, Chao Wu, Wei Xiong, Yaodong He, Guangyi Wang, Xin Wang
bioRxiv 2020.11.20.391870; doi: https://doi.org/10.1101/2020.11.20.391870

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