Improved de novo production of prostaglandin F2α from glucose with engineered Yarrowia lipolytica strains

1. Lv, X. et al. Structures of human prostaglandin F_2α receptor reveal the mechanism of ligand and G protein selectivity. Nat. Commun. 14, 8136 (2023).

   Google Scholar 

2. Wang, Y. J. et al. Prostaglandin F_2α synthase promotes oxaliplatin resistance in colorectal cancer through prostaglandin F_2α-dependent and F_2α-independent mechanism. World J. Gastroenterol. 29, 5452–5470 (2023).

   Google Scholar 

3. Li, C. Y., Lawrence, K., Merlo-Coyne, J. & Juntti, S. A. Prostaglandin F_2α drives female pheromone signaling in cichlids, revealing a basis for evolutionary divergence in olfactory signaling. Proc. Natl. Acad. Sci. USA 120, e2214418120 (2023).

   Google Scholar 

4. Baudouin, C. et al. A phase III study comparing preservative-free latanoprost eye drop emulsion with preserved latanoprost in open-angle glaucoma or ocular hypertension. Eye (Lond). 39, 1599–1607 (2025).

5. Corey, E. J., Weinshenker, N. M., Schaaf, T. K. & Huber, W. Stereo-controlled synthesis of prostaglandins F-2α and E-2 (dl). J. Am. Chem. Soc. 91, 5675–5677 (1969).

   Google Scholar 

6. Coulthard, G., Erb, W. & Aggarwal, V. K. Stereocontrolled organocatalytic synthesis of prostaglandin PGF_2α in seven steps. Nature 489, 278–281 (2012).

   Google Scholar 

7. Zhang, F. H. et al. Concise, scalable and enantioselective total synthesis of prostaglandins. Nat. Chem. 13, 692–697 (2021).

   Google Scholar 

8. Zhu, K. J. et al. A unified strategy to prostaglandins: chemoenzymatic total synthesis of cloprostenol, bimatoprost, PGF_2α, fluprostenol, and travoprost guided by biocatalytic retrosynthesis. Chem. Sci. 12, 10362–10370 (2021).

   Google Scholar 

9. Funk, C. D. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294, 1871–1875 (2001).

   Google Scholar 

10. Mohamed, M. E. & Lazarus, C. M. Prostanoid production in Saccharomyces cerevisiae provides a novel assay for nonsteroidal anti-inflammatory drugs. FEMS Yeast Res. 9, 420–427 (2009).

    Google Scholar 

11. Mohamed, M. E. & Lazarus, C. M. Production of prostaglandins in transgenic Arabidopsis thaliana. Phytochemistry 102, 74–79 (2014).

    Google Scholar 

12. Takemura, M., Kanamoto, H., Nagaya, S. & Ohyama, K. Bioproduction of prostaglandins in a transgenic liverwort, Marchantia polymorpha. Transgenic Res. 22, 905–911 (2013).

    Google Scholar 

13. Kanamoto, H., Takemura, M. & Ohyama, K. Identification of a cyclooxygenase gene from the red alga Gracilaria vermiculophylla and bioconversion of arachidonic acid to PGF(2α) in engineered Escherichia coli. Appl. Microbiol. Biotechnol. 91, 1121–1129 (2011).

    Google Scholar 

14. Maeda, Y. et al. Prostaglandin production by the microalga with heterologous expression of cyclooxygenase. Biotechnol. Bioeng. 118, 2734–2743 (2021).

    Google Scholar 

15. Liu, H. H., Ji, X. J. & Huang, H. Biotechnological applications of Yarrowia lipolytica: Past, present and future. Biotechnol. Adv. 33, 1522–1546 (2015).

    Google Scholar 

16. Cui, Z. et al. Reconfiguration of the reductive TCA cycle enables high-level succinic acid production by Yarrowia lipolytica. Nat. Commun. 14, 8480 (2023).

    Google Scholar 

17. Xiao, Z. et al. Metabolic analyses of Yarrowia lipolytica for biopolymer production reveals roadblocks and strategies for microbial utilizing volatile fatty acids as sustainable feedstocks. Bioresour. Technol. 417, 131855 (2025).

    Google Scholar 

18. Liu, H. H. et al. Improved production of arachidonic acid by combined pathway engineering and synthetic enzyme fusion in Yarrowia lipolytica. J. Agric. Food Chem. 67, 9851–9857 (2019).

    Google Scholar 

19. Seo, M. J. & Oh, D. K. Prostaglandin synthases: Molecular characterization and involvement in prostaglandin biosynthesis. Prog. Lipid Res. 66, 50–68 (2017).

    Google Scholar 

20. Qi, B. et al. Identification of a cDNA encoding a novel C18-Delta (9) polyunsaturated fatty acid-specific elongating activity from the docosahexaenoic acid (DHA)-producing microalga, Isochrysis galbana. FEBS Lett. 510, 159–165 (2002).

    Google Scholar 

21. Xue, Z. et al. Production of omega-3 eicosapentaenoic acid by metabolic engineering of Yarrowia lipolytica. Nat. Biotechnol. 31, 734–740 (2013).

    Google Scholar 

22. Chang, Y. et al. Morphological changes and strong cytotoxicity in Yarrowia lipolytica by overexpressing delta-12-desaturase. J. Fungi (Basel). 10, 126 (2024).

    Google Scholar 

23. Chellamuthu, M., Subramanian, S. & Eswaran, K. Enhancement of sesame omega-3 fatty acid content using Fusarium moniliforme bifunctional desaturase gene. South Afr. J. Bot. 150, 285–295 (2022).

    Google Scholar 

24. Wallis, J. G. & Browse, J. The Δ8-desaturase of Euglena gracilis: an alternate pathway for synthesis of 20-carbon polyunsaturated fatty acids. Arch. Biochem. Biophys. 365, 307–316 (1999).

    Google Scholar 

25. Qiao, K. et al. Lipid production in Yarrowia lipolytica is maximized by engineering cytosolic redox metabolism. Nat. Biotechnol. 35, 173–177 (2017).

    Google Scholar 

26. Xu, P., Qiao, K., Ahn, W. S. & Stephanopoulos, G. Engineering Yarrowia lipolytica as a platform for synthesis of drop-in transportation fuels and oleochemicals. Proc. Natl. Acad. Sci. USA 113, 10848–10853 (2016).

    Google Scholar 

27. Azi, F., Li, Z. & Xu, P. Expanding Yarrowia lipolytica’s metabolic potential for detoxification of cyanogenic glycosides in edible plants. Commun. Biol. 8, 188 (2025).

    Google Scholar 

28. Jeung, K. et al. Cell-free systems: a synthetic biology tool for rapid prototyping in metabolic engineering. Biotechnol. Adv. 79, 108522 (2025).

    Google Scholar 

29. Li, Y. et al. A cell-free biosensor signal amplification circuit with polymerase strand recycling. Nat. Chem. Biol. 21, 949–958 (2025).

30. Yin, Y., Wang, J. & Li, J. A concise and scalable chemoenzymatic synthesis of prostaglandins. Nat. Commun. 15, 2523 (2024).

    Google Scholar 

31. Farida Asras, M. F. et al. Production of prostaglandin F_2α by molecular breeding of an oleaginous fungus Mortierella alpina. Biosci. Biotechnol. Biochem. 83, 774–780 (2019).

    Google Scholar 

32. Gu, Y. et al. Directed evolution of artificial metalloenzymes in whole cells. Angew. Chem. Int. Ed. Engl. 61, e202110519 (2022).

    Google Scholar 

33. Kissman, E. N. et al. Expanding chemistry through in vitro and in vivo biocatalysis. Nature 631, 37–48 (2024).

    Google Scholar 

34. Ells, R., Kock, J. L., Albertyn, J. & Pohl, C. H. Arachidonic acid metabolites in pathogenic yeasts. Lipids Health Dis. 11, 100 (2012).

    Google Scholar 

35. Chakraborty, T., Tóth, R. & Gácser, A. Eicosanoid production by Candida parapsilosis and other pathogenic yeasts. Virulence 10, 970–975 (2019).

    Google Scholar 

36. Zheng, N. et al. Tailoring industrial enzymes for thermostability and activity evolution by the machine learning-based iCASE strategy. Nat. Commun. 16, 604 (2025).

    Google Scholar 

37. Fox, B. W. et al. Evolutionarily related host and microbial pathways regulate fat desaturation in C. elegans. Nat. Commun. 15, 1520 (2024).

    Google Scholar 

38. Wang, J. et al. Reprogramming the fatty acid metabolism of Yarrowia lipolytica to produce the customized omega-6 polyunsaturated fatty acids. Bioresour. Technol. 383, 129231 (2023).

    Google Scholar 

39. Wang, J. et al. Rational multienzyme architecture design with iMARS. Cell 188, 1349–1362.e17 (2025).

    Google Scholar 

40. Hu, L. et al. Regulating cellular metabolism and morphology to achieve high-yield synthesis of hyaluronan with controllable molecular weights. Nat. Commun. 16, 2076 (2025).

    Google Scholar 

41. Donnelly, M. L. L. et al. The ‘cleavage’ activities of foot-and-mouth disease virus 2A site-directed mutants and naturally occurring ‘2A-like’ sequences. J. Gen. Virol. 82, 1027–1041 (2001).

    Google Scholar 

42. Liu, Z. et al. Systematic comparison of 2A peptides for cloning multi-genes in a polycistronic vector. Sci. Rep. 7, 2193 (2017).

    Google Scholar 

43. Baker, J. J. et al. ML-enhanced peroxisome capacity enables compartmentalization of multienzyme pathway. Nat. Chem. Biol. 21, 727–735 (2025).

44. Tang, H. et al. Engineering yeast for the de novo synthesis of jasmonates. Nat. Synth. 3, 224–235 (2024).

    Google Scholar 

45. Liu, Y. et al. Complete biosynthesis of QS-21 in engineered yeast. Nature 629, 937–944 (2024).

    Google Scholar 

46. Chen, R. et al. Engineering cofactor supply and recycling to drive phenolic acid biosynthesis in yeast. Nat. Chem. Biol. 18, 520–529 (2022).

    Google Scholar 

47. Sha, Y. et al. Advances in metabolic engineering for enhanced acetyl-CoA availability in yeast. Crit. Rev. Biotechnol. 45, 904–922 (2025).

48. Yocum, H. C., Bassett, S. & Da Silva, N. A. Enhanced production of acetyl-CoA-based products via peroxisomal surface display in Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. USA 119, e2214941119 (2022).

    Google Scholar 

49. Tang, Y. X. et al. Engineering Yarrowia lipolytica for sustainable Cis-13, 16-docosadienoic acid production. Bioresour. Technol. 406, 130978 (2024).

    Google Scholar 

50. Huffman, M. A. et al. Design of an in vitro biocatalytic cascade for the manufacture of islatravir. Science 366, 1255–1259 (2019).

    Google Scholar 

51. Ravindran, R. et al. Peroxisome biogenesis initiated by protein phase separation. Nature 617, 608–615 (2023).

    Google Scholar 

52. Ujihara, M. et al. Prostaglandin D2 formation and characterization of its synthetases in various tissues of adult rats. Arch. Biochem. Biophys. 260, 521–531 (1988).

Download references