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A plant malonyl-CoA synthetase enhances lipid content and polyketide yield in yeast cells

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Abstract

Malonyl-CoA is the essential building block of natural products such as fatty acids, polyketides, and flavonoids. Engineering the biosynthesis of fatty acids is important for biofuel production while that of polyketides provides precursors of medicines and nutritional supplements. However, microorganisms maintain a small amount of cellular malonyl-CoA, which could limit production of lipid and polyketides under certain conditions. Malonyl-CoA concentration is regulated by multiple pathways and signals, and changes in intracellular malonyl-CoA often lead to complex alterations in metabolism. In the present work, overexpression of a plant malonyl-CoA synthetase gene (AAE13) in Saccharomyces cerevisiae resulted in 1.6- and 2.4-fold increases in lipid and resveratrol accumulation simultaneously. We also demonstrated that AAE13 partially complemented the temperature-sensitive acc1 mutant, replacing this key enzyme in central metabolism. Mechanistic analysis by CoA quantification and transcriptomic measurement suggested that increases in malonyl-CoA concentration were coupled with drastic reductions in other major CoA compounds and clear suppression of tricarboxylic acid cycle-related genes. These results suggest that malonyl-CoA is a critical target for fatty acid and polyketide engineering and that overexpression of malonyl-CoA synthetic enzymes needs to be combined with upregulation of CoA synthesis to maintain metastasis of central metabolism.

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Acknowledgements

We thank Dr. John Browse of Washington State University for the gift of AAE13 gene in pENTR/D-TOPO prior to its publication. This work is support in part by three federal grants: one is from US Department of Energy (DESC0001295), one from National Science Foundation (MCB-0923779), and one from US Department of Agriculture (2010-65116-20514), and National 863 projects (2013AA102801-03).

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  1. Yechun Wang, Hui Chen & Oliver Yu

    Present address: Conagen Inc, 1005 North Warson Rd, Saint Louis, MO, 63132, USA

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  1. Donald Danforth Plant Science Center, 975 North Warson Road, Saint Louis, MO, 63132, USA

    Yechun Wang, Hui Chen & Oliver Yu

  2. Wuxi NewWay Biotech Co., Ltd, 401 Xingyuan North Road, Wuxi, Jiangsu Province, China, 214043

    Oliver Yu

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  1. Yechun Wang
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Wang, Y., Chen, H. & Yu, O. A plant malonyl-CoA synthetase enhances lipid content and polyketide yield in yeast cells. Appl Microbiol Biotechnol 98, 5435–5447 (2014). https://doi.org/10.1007/s00253-014-5612-z

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