Metabolic Engineering for Efficient Production of Z,Z-Farnesol in

Overview

Journal Microorganisms

Specialty Microbiology

Date 2023 Jun 28

PMID 37375090

Authors

Mengyang Lei

Zetian Qiu

Leilei Guan

Zheng Xiang

Guang-Rong Zhao

Affiliations

Soon will be listed here.

Abstract

Z,Z-farnesol (Z,Z-FOH), the all- isomer of farnesol, holds enormous potential for application in cosmetics, daily chemicals, and pharmaceuticals. In this study, we aimed to metabolically engineer to produce Z,Z-FOH. First, we tested five Z,Z-farnesyl diphosphate (Z,Z-FPP) synthases that catalyze neryl diphosphate to form Z,Z-FPP in . Furthermore, we screened thirteen phosphatases that could facilitate the dephosphorylation of Z,Z-FPP to produce Z,Z-FOH. Finally, through site-directed mutagenesis of -prenyltransferase, the optimal mutant strain was able to produce 572.13 mg/L Z,Z-FOH by batch fermentation in a shake flask. This achievement represents the highest reported titer of Z,Z-FOH in microbes to date. Notably, this is the first report on the de novo biosynthesis of Z,Z-FOH in . This work represents a promising step toward developing synthetic cell factories for the de novo biosynthesis of Z,Z-FOH and other -configuration terpenoids.

References

Dudareva N, Klempien A, Muhlemann J, Kaplan I . Biosynthesis, function and metabolic engineering of plant volatile organic compounds. New Phytol. 2013; 198(1):16-32. DOI: 10.1111/nph.12145. View

Jiang G, Yao M, Wang Y, Zhou L, Song T, Liu H . Manipulation of GES and ERG20 for geraniol overproduction in Saccharomyces cerevisiae. Metab Eng. 2017; 41:57-66. DOI: 10.1016/j.ymben.2017.03.005. View

Sato T, Takizawa K, Orito Y, Kudo H, Hoshino T . Insight into C35 terpene biosyntheses by nonpathogenic Mycobacterium Species: functional analyses of three Z-prenyltransferases and identification of dehydroheptaprenylcyclines. Chembiochem. 2010; 11(13):1874-81. DOI: 10.1002/cbic.201000328. View

de Araujo Delmondes G, Bezerra D, Dias D, de Souza Borges A, Araujo I, da Cunha G . Toxicological and pharmacologic effects of farnesol (CHO): A descriptive systematic review. Food Chem Toxicol. 2019; 129:169-200. DOI: 10.1016/j.fct.2019.04.037. View

Beran F, Rahfeld P, Luck K, Nagel R, Vogel H, Wielsch N . Novel family of terpene synthases evolved from trans-isoprenyl diphosphate synthases in a flea beetle. Proc Natl Acad Sci U S A. 2016; 113(11):2922-7. PMC: 4801258. DOI: 10.1073/pnas.1523468113. View

George K, Thompson M, Kang A, Baidoo E, Wang G, Chan L . Metabolic engineering for the high-yield production of isoprenoid-based C₅ alcohols in E. coli. Sci Rep. 2015; 5:11128. PMC: 4459108. DOI: 10.1038/srep11128. View

Schulbach M, Brennan P, Crick D . Identification of a short (C15) chain Z-isoprenyl diphosphate synthase and a homologous long (C50) chain isoprenyl diphosphate synthase in Mycobacterium tuberculosis. J Biol Chem. 2000; 275(30):22876-81. DOI: 10.1074/jbc.M003194200. View

Hemmerlin A, Harwood J, Bach T . A raison d'être for two distinct pathways in the early steps of plant isoprenoid biosynthesis?. Prog Lipid Res. 2011; 51(2):95-148. DOI: 10.1016/j.plipres.2011.12.001. View

Wu J, Cheng S, Cao J, Qiao J, Zhao G . Systematic Optimization of Limonene Production in Engineered Escherichia coli. J Agric Food Chem. 2019; 67(25):7087-7097. DOI: 10.1021/acs.jafc.9b01427. View

10.

Men X, Wang F, Chen G, Zhang H, Xian M . Biosynthesis of Natural Rubber: Current State and Perspectives. Int J Mol Sci. 2018; 20(1). PMC: 6337083. DOI: 10.3390/ijms20010050. View

11.

Yu J, Kleckley T, Wiemer D . Synthesis of farnesol isomers via a modified Wittig procedure. Org Lett. 2005; 7(22):4803-6. DOI: 10.1021/ol0513239. View

12.

Li M, Hou F, Wu T, Jiang X, Li F, Liu H . Recent advances of metabolic engineering strategies in natural isoprenoid production using cell factories. Nat Prod Rep. 2019; 37(1):80-99. DOI: 10.1039/c9np00016j. View

13.

Chang H, Cheng T, Wang A . Structure, catalysis, and inhibition mechanism of prenyltransferase. IUBMB Life. 2020; 73(1):40-63. PMC: 7839719. DOI: 10.1002/iub.2418. View

14.

Cheng S, Liu X, Jiang G, Wu J, Zhang J, Lei D . Orthogonal Engineering of Biosynthetic Pathway for Efficient Production of Limonene in Saccharomyces cerevisiae. ACS Synth Biol. 2019; 8(5):968-975. DOI: 10.1021/acssynbio.9b00135. View

15.

You S, Chang H, Zhang C, Gao L, Qi W, Tao Z . Recycling Strategy and Repression Elimination for Lignocellulosic-Based Farnesene Production with an Engineered . J Agric Food Chem. 2019; 67(35):9858-9867. DOI: 10.1021/acs.jafc.9b03907. View

16.

Lei D, Qiu Z, Wu J, Qiao B, Qiao J, Zhao G . Combining Metabolic and Monoterpene Synthase Engineering for Production of Monoterpene Alcohols in . ACS Synth Biol. 2021; 10(6):1531-1544. DOI: 10.1021/acssynbio.1c00081. View

17.

Schilmiller A, Schauvinhold I, Larson M, Xu R, Charbonneau A, Schmidt A . Monoterpenes in the glandular trichomes of tomato are synthesized from a neryl diphosphate precursor rather than geranyl diphosphate. Proc Natl Acad Sci U S A. 2009; 106(26):10865-70. PMC: 2705607. DOI: 10.1073/pnas.0904113106. View

18.

Gutensohn M, Nguyen T, McMahon 3rd R, Kaplan I, Pichersky E, Dudareva N . Metabolic engineering of monoterpene biosynthesis in tomato fruits via introduction of the non-canonical substrate neryl diphosphate. Metab Eng. 2014; 24:107-16. DOI: 10.1016/j.ymben.2014.05.008. View

19.

Akhtar T, Matsuba Y, Schauvinhold I, Yu G, Lees H, Klein S . The tomato cis-prenyltransferase gene family. Plant J. 2012; 73(4):640-52. DOI: 10.1111/tpj.12063. View

20.

Shukal S, Chen X, Zhang C . Systematic engineering for high-yield production of viridiflorol and amorphadiene in auxotrophic Escherichia coli. Metab Eng. 2019; 55:170-178. DOI: 10.1016/j.ymben.2019.07.007. View