Applied Microbiology and Biotechnology

, Volume 103, Issue 1, pp 191–199 | Cite as

Biosynthesis of ω-hydroxy fatty acids and related chemicals from natural fatty acids by recombinant Escherichia coli

  • Sun-Ki Kim
  • Yong-Cheol ParkEmail author


ω-Hydroxy fatty acids (ω-HFAs) are of great interest because they provide the long carbon chain monomers in the synthesis of polymer materials due to the location of the hydroxyl group close to the end of the first methyl carbon. ω-HFAs are widely used as building blocks and intermediates in the chemical, pharmaceutical, and food industries. Recent achievements in metabolic engineering and synthetic biology enabled Escherichia coli to produce these fatty acids with high yield and productivity. These include (i) design and engineering of the ω-HFA biosynthetic pathways, (ii) enzyme engineering to enhance stability and activity, and (iii) increase of tolerance of E. coli to toxic effects of fatty acids. Strategies for improving product yield and productivity of ω-HFAs and their related chemicals (e.g., α,ω-dicarboxylic acids and ω-amino carboxylic acids) are systematically demonstrated in this review.


ω-Hydroxyl fatty acid α,ω-Dicarboxylic acid ω-Amino carboxylic acid Biotransformation Recombinant Escherichia coli 


Funding information

This work was financially supported by the National Research Foundation of Korea (NRF) Grants (2016R1A2B4010842 and 2018R1C1B5044416) funded by the Korean Ministry of Science, ICT and Future Planning, and also by the R&D Program of MOTIE/KEIT (10048684).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals by any of the authors.


  1. Baek AH, Jeon EY, Lee SM, Park JB (2015) Expression levels of chaperones influence biotransformation activity of recombinant Escherichia coli expressing Micrococcus luteus alcohol dehydrogenase and Pseudomonas putida Baeyer-Villiger monooxygenase. Biotechnol Bioeng 112:889–895. CrossRefPubMedGoogle Scholar
  2. Balke K, Kadow M, Mallin H, Sass S, Bornscheuer UT (2012) Discovery, application and protein engineering of Baeyer-Villiger monooxygenases for organic synthesis. Org Biomol Chem 10:6249–6265. CrossRefPubMedGoogle Scholar
  3. Bergeron LM, Tokatlian T, Gomez L, Clark DS (2009) Redirecting the inactivation pathway of penicillin amidase and increasing amoxicillin production via a thermophilic molecular chaperone. Biotechnol Bioeng 102:417–424. CrossRefPubMedGoogle Scholar
  4. Biermann U, Bornscheuer U, Meier MAR, Metzger JO, Schafer HJ (2011) Oils and fats as renewable raw materials in chemistry. Angew Chem Int Edit 50:3854–3871. CrossRefGoogle Scholar
  5. Cao Y, Zhang X (2013) Production of long-chain hydroxy fatty acids by microbial conversion. Appl Microbiol Biotechnol 97:3323–3331. CrossRefPubMedGoogle Scholar
  6. Cha HJ, Seo EJ, Song JW, Jo HJ, Kumar AR, Park JB (2018) Simultaneous enzyme/whole-cell biotransformation of C18 ricinoleic acid into (R)-3-hydroxynonanoic acid, 9-hydroxynonanoic acid, and 1,9-nonanedioic acid. Adv Synth Catal 360:696–703. CrossRefGoogle Scholar
  7. Chance DL, Gerhardt KO, Mawhinney TP (1998) Gas-liquid chromatography mass spectrometry of hydroxy fatty acids as their methyl esters tert.-butyldimethylsilyl ethers. J Chromatogr A 793:91–98. CrossRefPubMedGoogle Scholar
  8. Cho YH, Kim SJ, Kim HW, Kim JY, Gwak JS, Chung D, Kim KH, Park K, Park YC (2017) Continuous supply of glucose and glycerol enhances biotransformation of ricinoleic acid to (E)-11-(heptanoyloxy) undec-9-enoic acid in recombinant Escherichia coli. J Biotechnol 253:34–39. CrossRefPubMedGoogle Scholar
  9. Cho YH, Kim SJ, Kim JY, Lee DH, Park K, Park YC (2018) Effect of PelB signal sequences on Pfe1 expression and omega-hydroxyundec-9-enoic acid biotransformation in recombinant Escherichia coli. Appl Microbiol Biotechnol 102:7407–7416. CrossRefGoogle Scholar
  10. DiRusso CC, Black PN (1999) Long-chain fatty acid transport in bacteria and yeast. Paradigms for defining the mechanism underlying this protein-mediated process. Mol Cell Biochem 192:41–52. CrossRefPubMedGoogle Scholar
  11. Eschenfeldt WH, Zhang Y, Samaha H, Stols L, Eirich LD, Wilson CR, Donnelly MI (2003) Transformation of fatty acids catalyzed by cytochrome P450 monooxygenase enzymes of Candida tropicalis. Appl Environ Microbiol 69:5992–5999. CrossRefPubMedPubMedCentralGoogle Scholar
  12. Griehl W, Ruestem D (1970) Nylon-12-preparation, properties, and applications. Ind Eng Chem 62:16–22. CrossRefGoogle Scholar
  13. Hou CT, Kuo TM, Lanser AC (1999) Production of hydroxy fatty acids by biocatalysis. In: Knothe J, Derksen JTP (eds) Recent developments in the synthesis of fatty acid derivatives, 1st edn. AOCS Press, Champaign, Illinois, pp 213–226CrossRefGoogle Scholar
  14. Jang HY, Jeon EY, Baek AH, Lee SM, Park JB (2014) Production of omega-hydroxyundec-9-enoic acid and n-heptanoic acid from ricinoleic acid by recombinant Escherichia coli-based biocatalyst. Process Biochem 49:617–622. CrossRefGoogle Scholar
  15. Jang HY, Singha K, Kim HH, Kwon YU, Park JB (2016) Chemo-enzymatic synthesis of 11-hydroxyundecanoic acid and 1,11-undecanedioic acid from ricinoleic acid. Green Chem 18:1089–1095. CrossRefGoogle Scholar
  16. Jarboe LR, Royce LA, Liu P (2013) Understanding biocatalyst inhibition by carboxylic acids. Front Microbiol 4:272. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Jeon EY, Baek AH, Bornscheuer UT, Park JB (2015) Enzyme fusion for whole-cell biotransformation of long-chain sec-alcohols into esters. Appl Microbiol Biotechnol 99:6267–6275. CrossRefPubMedGoogle Scholar
  18. Jeon EY, Seo JH, Kang WR, Kim MJ, Lee JH, Oh DK, Park JB (2016) Simultaneous enzyme/whole-cell biotransformation of plant oils into C9 carboxylic acids. ACS Catal 6:7547–7553. CrossRefGoogle Scholar
  19. Jeon EY, Song JW, Cha HJ, Lee SM, Lee J, Park JB (2018) Intracellular transformation rates of fatty acids are influenced by expression of the fatty acid transporter FadL in Escherichia coli cell membrane. J Biotechnol 281:161–167. CrossRefPubMedGoogle Scholar
  20. Joo YC, Seo ES, Kim YS, Kim KR, Park JB, Oh DK (2012) Production of 10-hydroxystearic acid from oleic acid by whole cells of recombinant Escherichia coli containing oleate hydratase from Stenotrophomonas maltophilia. J Biotechnol 158:17–23. CrossRefPubMedGoogle Scholar
  21. Jung SM, Seo JH, Lee JH, Park JB, Seo JH (2015) Fatty acid hydration activity of a recombinant Escherichia coli-based biocatalyst is improved through targeting the oleate hydratase into the periplasm. Biotechnol J 10:1887–1893. CrossRefPubMedGoogle Scholar
  22. Karmakar G, Ghosh P (2015) Soybean oil as a biocompatible multifunctional additive for lubricating oil. ACS Sustain Chem Eng 3:19–25. CrossRefGoogle Scholar
  23. Kim KR, Oh DK (2013) Production of hydroxy fatty acids by microbial fatty acid-hydroxylation enzymes. Biotechnol Adv 31:1473–1485. CrossRefPubMedGoogle Scholar
  24. Kim SK, Park YC, Lee HH, Jeon ST, Min WK, Seo JH (2015) Simple amino acid tags improve both expression and secretion of Candida antarctica lipase B in recombinant Escherichia coli. Biotechnol Bioeng 112:346–355. CrossRefPubMedGoogle Scholar
  25. Kockritz A, Martin A (2011) Synthesis of azelaic acid from vegetable oil-based feedstocks. Eur J Lipid Sci Tech 113:83–91. CrossRefGoogle Scholar
  26. Koppireddi S, Seo JH, Jeon EY, Chowdhury PS, Jang HY, Park JB, Kwon YU (2016) Combined biocatalytic and chemical transformations of oleic acid to omega-hydroxynonanoic acid and alpha,omega-nonanedioic acid. Adv Synth Catal 358:3084–3092. CrossRefGoogle Scholar
  27. Lease RA, Smith D, McDonough K, Belfort M (2004) The small noncoding DsrA RNA is an acid resistance regulator in Escherichia coli. J Bacteriol 186:6179–6185. CrossRefPubMedPubMedCentralGoogle Scholar
  28. Lee YA, Jeon EY, Lee SM, Bornscheuer UT, Park JB (2014) Engineering the substrate-binding domain of an esterase enhances its hydrolytic activity toward fatty acid esters. Process Biochem 49:2101–2106. CrossRefGoogle Scholar
  29. Liu C, Liu F, Cai J, Xie W, Long TE, Turner SR, Lyons A, Gross RA (2011) Polymers from fatty acids: poly(omega-hydroxyl tetradecanoic acid) synthesis and physico-mechanical studies. Biomacromolecules 12:3291–3298. CrossRefPubMedGoogle Scholar
  30. Liu G, Kong X, Wan H, Narine S (2008) Production of 9-hydroxynonanoic acid from methyl oleate and conversion into lactone monomers for the synthesis of biodegradable polylactones. Biomacromolecules 9:949–953. CrossRefPubMedGoogle Scholar
  31. Luo HB, Robb FT (2011) A modulator domain controlling thermal stability in the group II chaperonins of archaea. Arch Biochem Biophys 512:111–118. CrossRefPubMedGoogle Scholar
  32. Maloy SR, Ginsburgh CL, Simons RW, Nunn WD (1981) Transport of long and medium chain fatty acids by Escherichia coli K12. J Biol Chem 256:3735–3742PubMedGoogle Scholar
  33. Metzger JO, Bornscheuer U (2006) Lipids as renewable resources: current state of chemical and biotechnological conversion and diversification. Appl Microbiol Biotechnol 71:13–22. CrossRefPubMedGoogle Scholar
  34. Mittaine JF (2016) Oilseeds and vegetable oils in Asia: a world of diversity. Ocl Oils Fat Crop Li 23:D602. CrossRefGoogle Scholar
  35. Oh HJ, Kim SU, Song JW, Lee JH, Kang WR, Jo YS, Kim KR, Bornscheuer UT, Oh DK, Park JB (2015) Biotransformation of linoleic acid into hydroxy fatty acids and carboxylic acids using a linoleate double bond hydratase as key enzyme. Adv Synth Catal 357:408–416. CrossRefGoogle Scholar
  36. Orru R, Dudek HM, Martinoli C, Torres Pazmino DE, Royant A, Weik M, Fraaije MW, Mattevi A (2011) Snapshots of enzymatic Baeyer-Villiger catalysis: oxygen activation and intermediate stabilization. J Biol Chem 286:29284–29291. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Pazmino DET, Snajdrova R, Baas BJ, Ghobrial M, Mihovilovic MD, Fraaije MW (2008) Self-sufficient Baeyer-Villiger monooxygenases: effective coenzyme regeneration for biooxygenation by fusion engineering. Angew Chem Int Edit 47:2275–2278. CrossRefGoogle Scholar
  38. Royce LA, Yoon JM, Chen YX, Rickenbach E, Shanks JV, Jarboe LR (2015) Evolution for exogenous octanoic acid tolerance improves carboxylic acid production and membrane integrity. Metab Eng 29:180–188. CrossRefPubMedGoogle Scholar
  39. Schoneich C (2008) Mechanisms of protein damage induced by cysteine thiyl radical formation. Chem Res Toxicol 21:1175–1179. CrossRefPubMedGoogle Scholar
  40. Seo EJ, Yeon YJ, Seo JH, Lee JH, Bongol JP, Oh Y, Park JM, Lim SM, Lee CG, Park JB (2018) Enzyme/whole-cell biotransformation of plant oils, yeast derived oils, and microalgae fatty acid methyl esters into n-nonanoic acid, 9-hydroxynonanoic acid, and 1,9-nonanedioic acid. Bioresour Technol 251:288–294. CrossRefPubMedGoogle Scholar
  41. Seo JH, Baek SW, Lee J, Park JB (2017) Engineering Escherichia coli BL21 genome to improve the heptanoic acid tolerance by using CRISPR-Cas9 system. Biotechnol Bioprocess Eng 22:231–238. CrossRefGoogle Scholar
  42. Seo JH, Kim HH, Jeon EY, Song YH, Shin CS, Park JB (2016) Engineering of Baeyer-Villiger monooxygenase-based Escherichia coli biocatalyst for large scale biotransformation of ricinoleic acid into (Z)-11-(heptanoyloxy) undec-9-enoic acid. Sci Rep 6:28223. CrossRefPubMedPubMedCentralGoogle Scholar
  43. Seo JH, Lee SM, Lee J, Park JB (2015) Adding value to plant oils and fatty acids: biological transformation of fatty acids into omega-hydroxycarboxylic, alpha,omega-dicarboxylic, and omega-aminocarboxylic acids. J Biotechnol 216:158–166. CrossRefPubMedGoogle Scholar
  44. Song JW, Jeon EY, Song DH, Jang HY, Bornscheuer UT, Oh DK, Park JB (2013) Multistep enzymatic synthesis of long-chain α,ω-dicarboxylic and ω-hydroxycarboxylic acids from renewable fatty acids and plant oils. Angew Chem Int Ed Engl 52:2534–2537. CrossRefPubMedGoogle Scholar
  45. Song JW, Lee JH, Bornscheuer UT, Park JB (2014) Microbial synthesis of medium-chain, -dicarboxylic acids and -aminocarboxylic acids from renewable long-chain fatty acids. Adv Synth Catal 356:1782–1788. CrossRefGoogle Scholar
  46. Song JW, Woo JM, Jung GY, Bornscheuer UT, Park JB (2016) 3'-UTR engineering to improve soluble expression and fine-tuning of activity of cascade enzymes in Escherichia coli. Sci Rep 6:29406. CrossRefPubMedPubMedCentralGoogle Scholar
  47. Woo JM, Jeon EY, Seo EJ, Seo JH, Lee DY, Yeon YJ, Park JB (2018) Improving catalytic activity of the Baeyer-Villiger monooxygenase-based Escherichia coli biocatalysts for the overproduction of (Z)-11-(heptanoyloxy)undec-9-enoic acid from ricinoleic acid. Sci Rep 8:10280. CrossRefPubMedPubMedCentralGoogle Scholar
  48. Woo JM, Kim JW, Song JW, Blank LM, Park JB (2016) Activation of the glutamic acid-dependent acid resistance system in Escherichia coli BL21(DE3) leads to increase of the fatty acid biotransformation activity. PLoS One 11:e0163265. CrossRefPubMedPubMedCentralGoogle Scholar
  49. Yachnin BJ, Sprules T, McEvoy MB, Lau PC, Berghuis AM (2012) The substrate-bound crystal structure of a Baeyer-Villiger monooxygenase exhibits a Criegee-like conformation. J Am Chem Soc 134:7788–7795. CrossRefPubMedPubMedCentralGoogle Scholar
  50. Zhang F, Huang CH, Xu TW (2009) Production of sebacic acid using two-phase bipolar membrane electrodialysis. Ind Eng Chem Res 48:7482–7488. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Food Science and TechnologyChung-Ang UniversityAnseongRepublic of Korea
  2. 2.Department of Bio and Fermentation Convergence Technology and BK21 Plus ProgramKookmin UniversitySeoulRepublic of Korea

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