Rewiring yarrowia lipolytica toward triacetic acid lactone for materials generation

Kelly A. Markham, Claire M. Palmer, Malgorzata Chwatko, James M. Wagner, Clare Murray, Sofia Vazquez, Arvind Swaminathan, Ishani Chakravarty, Nathaniel A. Lynd, Hal S. Alper

Research output: Contribution to journalArticlepeer-review

140 Scopus citations


Polyketides represent an extremely diverse class of secondary metabolites often explored for their bioactive traits. These molecules are also attractive building blocks for chemical catalysis and polymerization. However, the use of polyketides in larger scale chemistry applications is stymied by limited titers and yields from both microbial and chemical production. Here, we demonstrate that an oleaginous organism (specifically, Yarrowia lipolytica) can overcome such production limitations owing to a natural propensity for high flux through acetyl–CoA. By exploring three distinct metabolic engineering strategies for acetyl–CoA precursor formation, we demonstrate that a previously uncharacterized pyruvate bypass pathway supports increased production of the polyketide triacetic acid lactone (TAL). Ultimately, we establish a strain capable of producing over 35% of the theoretical conversion yield to TAL in an unoptimized tube culture. This strain also obtained an averaged maximum titer of 35.9 ± 3.9 g/L with an achieved maximum specific productivity of 0.21 ± 0.03 g/L/h in bioreactor fermentation. Additionally, we illustrate that a β-oxidation-related overexpression (PEX10) can support high TAL production and is capable of achieving over 43% of the theoretical conversion yield under nitrogen starvation in a test tube. Next, through use of this bioproduct, we demonstrate the utility of polyketides like TAL to modify commodity materials such as poly(epichlorohydrin), resulting in an increased molecular weight and shift in glass transition temperature. Collectively, these findings establish an engineering strategy enabling unprecedented production from a type III polyketide synthase as well as establish a route through O-functionalization for converting polyketides into new materials.

Original languageEnglish
Pages (from-to)2096-2101
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number9
StatePublished - Feb 27 2018

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We thank Yuki Naito for updating CRISPRdirect to include a specificity check to Y. lipolytica. We would also like to thank Cory Schwartz and Ian Wheeldon for providing the pCRISPRyl plasmid. This work was funded through the Camille and Henry Dreyfus Foundation. N.A.L. acknowledges support through Welch Foundation Grant F-1904.


  • Biorenewable chemicals
  • O-functionalization
  • Polyketide synthase
  • Triacetic acid lactone
  • Yarrowia lipolytica

ASJC Scopus subject areas

  • General


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