Recent advances in production of 5-aminolevulinic acid using biological strategies

  • Zhen Kang
  • Wenwen Ding
  • Xu Gong
  • Qingtao Liu
  • Guocheng Du
  • Jian Chen
Review
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Accepted:
  • 417 Downloads

Abstract

5-Aminolevulinic acid (5-ALA) is the precursor for the biosynthesis of tetrapyrrole compounds and has broad applications in the medical and agricultural fields. Because of the disadvantages of chemical synthesis methods, microbial production of 5-ALA has drawn intensive attention and has been regarded as an alternative in the last years, especially with the rapid development of metabolic engineering and synthetic biology. In this mini-review, recent advances on the application and microbial production of 5-ALA using novel biological approaches (such as whole-cell enzymatic-transformation, metabolic pathway engineering and cell-free process) are described and discussed in detail. In addition, the challenges and prospects of synthetic biology are discussed.

Keywords

5-Aminolevulinic acid Enzymatic transformation Metabolic engineering Microbial cell factory Photodynamic therapy 
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Notes

Acknowledgements

This work was financially supported by the Fundamental Research Funds for the Central Universities (JUSRP51707A), the National Natural Science Foundation of China (31670092) and the Program for Changjiang Scholars and Innovative Research Team in University (No. IRT_15R26).

References

  1. Ali AH et al (2011) 5-Aminolevulinic acid-induced fluorescence diagnosis of pleural malignant tumor. Lung Cancer 74:48–54. doi: 10.1016/j.lungcan.2011.01.031 CrossRefGoogle Scholar
  2. Ang JM, Riaz IB, Kamal MU, Paragh G, Zeitouni NC (2017) Photodynamic therapy and pain: a systematic review. Photodiagn Photodyn Ther. doi: 10.1016/j.pdpdt.2017.07.002 Google Scholar
  3. Cornelius JF, Slotty PJ, El Khatib M, Giannakis A, Senger B, Steiger HJ (2014) Enhancing the effect of 5-aminolevulinic acid based photodynamic therapy in human meningioma cells. Photodiagn Photodyn 11:1–6. doi: 10.1016/j.pdpdt.2014.01.001 CrossRefGoogle Scholar
  4. De Souza AL et al (2016) Comparing desferrioxamine and light fractionation enhancement of ALA-PpIX photodynamic therapy in skin cancer. Br J Cancer 115:805–813. doi: 10.1038/bjc.2016.267 CrossRefGoogle Scholar
  5. Ding WW, Weng HJ, Du GC, Chen J, Kang Z (2017) 5-Aminolevulinic acid production from inexpensive glucose by engineering the C4 pathway in Escherichia coli. J Ind Microbiol Biotechnol 44:1127–1135. doi: 10.1007/s10295-017-1940-1 CrossRefGoogle Scholar
  6. Etminan N et al (2011) Modulation of migratory activity and invasiveness of human glioma spheroids following 5-aminolevulinic acid based photodynamic treatment laboratory investigation. J Neurosurg 115:281–288. doi: 10.3171/2011.3.JNS10434 CrossRefGoogle Scholar
  7. Feng LL, Zhang Y, Fu J, Mao YF, Chen T, Zhao XM, Wang ZW (2016) Metabolic engineering of Corynebacterium glutamicum for efficient production of 5-aminolevulinic acid. Biotechnol Bioeng 113:1284–1293. doi: 10.1002/bit.25886 CrossRefGoogle Scholar
  8. Filonenko EV, Kaprin AD, Alekseev BYA, Apolikhin OI, Slovokhodov EK, Ivanova-Radkevich VI, Urlova AN (2016) 5-Aminolevulinic acid in intraoperative photodynamic therapy of bladder cancer (results of multicenter trial). Photodiagn Photodyn 16:106–109. doi: 10.1016/j.pdpdt.2016.09.009 CrossRefGoogle Scholar
  9. Friesen SA, Hjortland GO, Madsen SJ, Hirschberg H, Engebraten O, Nesland JM, Peng Q (2002) 5-aminolevulinic acid-based photodynamic detection and therapy of brain tumors (review). Int J Oncol 21:577–582Google Scholar
  10. Fu XZ, Tan D, Aibaidula G, Wu Q, Chen JC, Chen GQ (2014) Development of Halomonas TD01 as a host for open production of chemicals. Metab Eng 23:78–91. doi: 10.1016/j.ymben.2014.02.006 CrossRefGoogle Scholar
  11. Fukuda H, Casas A, Batlle A (2005) Aminolevulinic acid: from its unique biological function to its star role in photodynamic therapy. Int J Biochem Cell Biol 37:272–276. doi: 10.1016/j.biocel.2004.04.018 CrossRefGoogle Scholar
  12. Grigalavicius M, Juraleviciute M, Kwitniewski M, Juzeniene A (2017) The influence of photodynamic therapy with 5-aminolevulinic acid on senescent skin cancer cells. Photodiagn Photodyn Ther 17:29–34. doi: 10.1016/j.pdpdt.2016.10.008 CrossRefGoogle Scholar
  13. Herceg V, Lange N, Allemann E, Babic A (2017) Activity of phosphatase-sensitive 5-aminolevulinic acid prodrugs in cancer cell lines. J Photochem Photobiol B 171:34–42. doi: 10.1016/j.jphotobiol.2017.04.029 CrossRefGoogle Scholar
  14. Hodgman CE, Jewett MC (2012) Cell-free synthetic biology: thinking outside the cell. Metab Eng 14:261–269. doi: 10.1016/j.ymben.2011.09.002 CrossRefGoogle Scholar
  15. Inoue K (2017) 5-Aminolevulinic acid-mediated photodynamic therapy for bladder cancer. Int J Urol 24:97–101. doi: 10.1111/iju.13291 CrossRefGoogle Scholar
  16. Inoue K et al (2009) Regulation of 5-aminolevulinic acid-mediated protoporphyrin IX accumulation in human urothelial carcinomas pathobiology. Pathobiology 76:303–314. doi: 10.1159/000245896 CrossRefGoogle Scholar
  17. Inoue K et al (2013) Photodynamic therapy involves an antiangiogenic mechanism and is enhanced by ferrochelatase inhibitor in urothelial carcinoma. Cancer Sci 104:765–772. doi: 10.1111/cas.12147 CrossRefGoogle Scholar
  18. Ishizuka M et al (2011) Novel development of 5-aminolevurinic acid (ALA) in cancer diagnoses and therapy. Int Immunopharmacol 11:358–365. doi: 10.1016/j.intimp.2010.11.029 CrossRefGoogle Scholar
  19. Jin P, Kang Z, Zhang JL, Zhang LP, Du GC, Chen J (2016a) Combinatorial evolution of enzymes and synthetic pathways using one-step PCR. ACS Synth Biol 5:259–268. doi: 10.1021/acssynbio.5b00240 CrossRefGoogle Scholar
  20. Jin P, Zhang L, Yuan P, Kang Z, Du G, Chen J (2016b) Efficient biosynthesis of polysaccharides chondroitin and heparosan by metabolically engineered Bacillus subtilis. Carbohydr Polym 140:424–432. doi: 10.1016/j.carbpol.2015.12.065 CrossRefGoogle Scholar
  21. Kang Z, Gao C, Wang Q, Liu H, Qi Q (2010a) A novel strategy for succinate and polyhydroxybutyrate co-production in Escherichia coli. Bioresour Technol 101:7675–7678. doi: 10.1016/j.biortech.2010.04.084 CrossRefGoogle Scholar
  22. Kang Z, Gao CJ, Wang QA, Liu HM, Qi Q (2010b) A novel strategy for succinate and polyhydroxybutyrate co-production in Escherichia coli. Bioresour Technol 101:7675–7678. doi: 10.1016/j.biortech.2010.04.084 CrossRefGoogle Scholar
  23. Kang Z, Du L, Kang J, Wang Y, Wang Q, Liang Q, Qi Q (2011a) Production of succinate and polyhydroxyalkanoate from substrate mixture by metabolically engineered Escherichia coli. Bioresour Technol 102:6600–6604. doi: 10.1016/j.biortech.2011.03.070 CrossRefGoogle Scholar
  24. Kang Z, Wang Y, Gu PF, Wang Q, Qi Q (2011b) Engineering Escherichia coli for efficient production of 5-aminolevulinic acid from glucose. Metab Eng 13:492–498. doi: 10.1016/j.ymben.2011.05.003 CrossRefGoogle Scholar
  25. Kang Z, Wang Y, Wang Q, Qi Q (2011c) Metabolic engineering to improve 5-aminolevulinic acid production. Bioeng Bugs 2:342–345. doi: 10.4161/bbug.2.6.17237 CrossRefGoogle Scholar
  26. Kang Z, Zhang J, Zhou J, Qi Q, Du G, Chen J (2012) Recent advances in microbial production of delta-aminolevulinic acid and vitamin B12. Biotechnol Adv 30:1533–1542. doi: 10.1016/j.biotechadv.2012.04.003 CrossRefGoogle Scholar
  27. Kang Z, Huang H, Zhang Y, Du G, Chen J (2017) Recent advances of molecular toolbox construction expand Pichia pastoris in synthetic biology applications. World J Microbiol Biotechnol 33:19. doi: 10.1007/s11274-016-2185-2 CrossRefGoogle Scholar
  28. Kishi K et al (2016) Usefulness of diagnostic laparoscopy with 5-aminolevulinic acid (ALA)-mediated photodynamic diagnosis for the detection of peritoneal micrometastasis in advanced gastric cancer after chemotherapy. Surg Today 46:1427–1434. doi: 10.1007/s00595-016-1328-2 CrossRefGoogle Scholar
  29. Kitada M, Ohsaki Y, Matsuda Y, Hayashi S, Ishibashi K (2015) Photodynamic diagnosis of pleural malignant lesions with a combination of 5-aminolevulinic acid and intrinsic fluorescence observation systems. BMC Cancer 15:174. doi: 10.1186/s12885-015-1194-0 CrossRefGoogle Scholar
  30. Koh RH, Song HG (2007) Effects of application of Rhodopseudomonas sp on seed germination and growth of tomato under axenic conditions. J Microbiol Biotechnol 17:1805–1810Google Scholar
  31. Koizumi N, Harada Y, Minamikawa T, Tanaka H, Otsuji E, Takamatsu T (2016) Recent advances in photodynamic diagnosis of gastric cancer using 5-aminolevulinic acid. World J Gastroenterol 22:1289–1296. doi: 10.3748/wjg.v22.i3.1289 CrossRefGoogle Scholar
  32. Lee JH, Wendisch VF (2017) Production of amino acids—genetic and metabolic engineering approaches. Bioresour Technol. doi: 10.1016/j.biortech.2017.05.065 Google Scholar
  33. Lee KH, Koh RH, Song HG (2008) Enhancement of growth and yield of tomato by Rhodopseudomonas sp under greenhouse conditions. J Microbiol 46:641–646. doi: 10.1007/s12275-008-0159-2 CrossRefGoogle Scholar
  34. Li F, Wang Y, Gong K, Wang Q, Liang Q, Qi Q (2014) Constitutive expression of RyhB regulates the heme biosynthesis pathway and increases the 5-aminolevulinic acid accumulation in Escherichia coli. FEMS Microbiol Lett 350:209–215. doi: 10.1111/1574-6968.12322 CrossRefGoogle Scholar
  35. Li T, Guo YY, Qiao GQ, Chen GQ (2016) Microbial synthesis of 5-aminolevulinic acid and its coproduction with polyhydroxybutyrate. ACS Synth Biol 5(11):1264–1274. doi: 10.1021/acssynbio.6b00105 Google Scholar
  36. Liang Q, Qi Q (2014) From a co-production design to an integrated single-cell biorefinery. Biotechnol Adv 32:1328–1335. doi: 10.1016/j.biotechadv.2014.08.004 CrossRefGoogle Scholar
  37. Lin J, Fu W, Cen P (2009) Characterization of 5-aminolevulinate synthase from Agrobacterium radiobacter, screening new inhibitors for 5-aminolevulinate dehydratase from Escherichia coli and their potential use for high 5-aminolevulinate production. Bioresour Technol 100:2293–2297. doi: 10.1016/j.biortech.2008.11.008 CrossRefGoogle Scholar
  38. Liu S, Zhang G, Li X, Zhang J (2014) Microbial production and applications of 5-aminolevulinic acid. Appl Microbiol Biotechnol 98:7349–7357. doi: 10.1007/s00253-014-5925-y CrossRefGoogle Scholar
  39. Liu S, Zhang G, Li J, Li X, Zhang J (2016) Optimization of biomass and 5-aminolevulinic acid production by Rhodobacter sphaeroides ATCC17023 via response surface methodology. Appl Biochem Biotechnol 179:444–458. doi: 10.1007/s12010-016-2005-z CrossRefGoogle Scholar
  40. Lou JW, Zhu L, Wu MB, Yang LR, Lin JP, Cen PL (2014) High-level soluble expression of the hemA gene from Rhodobacter capsulatus and comparative study of its enzymatic properties. J Zhejiang Univ Sci B 15:491–499. doi: 10.1631/jzus.B1300283 CrossRefGoogle Scholar
  41. Meng QL, Zhang YF, Ma CL, Ma HW, Zhao XM, Chen T (2015) Purification and functional characterization of thermostable 5-aminolevulinic acid synthases. Biotechnol Lett 37:2247–2253. doi: 10.1007/s10529-015-1903-4 CrossRefGoogle Scholar
  42. Meng QL et al (2016) Production of 5-aminolevulinic acid by cell free multi-enzyme catalysis. J Biotechnol 226:8–13. doi: 10.1016/j.jbiotec.2016.03.024 CrossRefGoogle Scholar
  43. Mohammadpour H, Fekrazad R (2016) Antitumor effect of combined Dkk-3 and 5-ALA mediated photodynamic therapy in breast cancer cell’s colony. Photodiagn Photodyn Ther 14:200–203. doi: 10.1016/j.pdpdt.2016.04.001 CrossRefGoogle Scholar
  44. Namikawa T et al (2014) Photodynamic diagnosis using 5-aminolevulinic acid during gastrectomy for gastric cancer. J Surg Oncol 109:213–217. doi: 10.1002/jso.23487 CrossRefGoogle Scholar
  45. Noh MH, Lim HG, Park S, Seo SW, Jung GY (2017) Precise flux redistribution to glyoxylate cycle for 5-aminolevulinic acid production in Escherichia coli. Metab Eng 43:1–8. doi: 10.1016/j.ymben.2017.07.006 CrossRefGoogle Scholar
  46. Nunkaew T, Kantachote D, Kanzaki H, Nitoda T, Ritchie RJ (2014) Effects of 5-aminolevulinic acid (ALA)-containing supernatants from selected Rhodopseudomonas palustris strains on rice growth under NaCl stress, with mediating effects on chlorophyll, photosynthetic electron transport and antioxidative enzymes. Electron J Biotechnol. doi: 10.1016/j.ejbt.2013.12.004 Google Scholar
  47. Ramzi AB, Hyeon JE, Kim SW, Park C, Han SO (2015) 5-Aminolevulinic acid production in engineered Corynebacterium glutamicum via C5 biosynthesis pathway. Enzyme Microb Technol 81:1–7. doi: 10.1016/j.enzmictec.2015.07.004 CrossRefGoogle Scholar
  48. Sakpirom J, Kantachote D, Nunkaew T, Khan E (2017) Characterizations of purple non-sulfur bacteria isolated from paddy fields, and identification of strains with potential for plant growth-promotion, greenhouse gas mitigation and heavy metal bioremediation. Res Microbiol 168:266–275. doi: 10.1016/j.resmic.2016.12.001 CrossRefGoogle Scholar
  49. Sasaki K, Watanabe M, Tanaka T, Tanaka T (2002) Biosynthesis, biotechnological production and applications of 5-aminolevulinic acid. Appl Microbiol Biotechnol 58:23–29CrossRefGoogle Scholar
  50. Shimamura Y et al (2016) 5-aminolevulinic acid enhances ultrasound-mediated antitumor activity via mitochondrial oxidative damage in breast cancer. Anticancer Res 36:3607–3612Google Scholar
  51. Tan D, Xue YS, Aibaidula G, Chen GQ (2011) Unsterile and continuous production of polyhydroxybutyrate by Halomonas TD01. Bioresour Technol 102:8130–8136. doi: 10.1016/j.biortech.2011.05.068 CrossRefGoogle Scholar
  52. Tan D, Wu Q, Chen JC, Chen GQ (2014) Engineering Halomonas TD01 for the low-cost production of polyhydroxyalkanoates. Metab Eng 26:34–47. doi: 10.1016/j.ymben.2014.09.001 CrossRefGoogle Scholar
  53. Tian T, Ali B, Qin YB, Malik Z, Gill RA, Ali S, Zhou WJ (2014) Alleviation of lead toxicity by 5-aminolevulinic acid Is related to elevated growth, photosynthesis, and suppressed ultrastructural damages in oilseed rape. Biomed Res Int. doi: 10.1155/2014/530642 Google Scholar
  54. Wachowska M et al (2011) Aminolevulinic Acid (ALA) as a prodrug in photodynamic therapy of cancer. Molecules 16:4140–4164. doi: 10.3390/molecules16054140 CrossRefGoogle Scholar
  55. Wang Q, Yu H, Xia Y, Kang Z, Qi Q (2009) Complete PHB mobilization in Escherichia coli enhances the stress tolerance: a potential biotechnological application. Microb Cell Fact 8:47. doi: 10.1186/1475-2859-8-47 CrossRefGoogle Scholar
  56. Wendisch VF, Jorge JMP, Perez-Garcia F, Sgobba E (2016) Updates on industrial production of amino acids using Corynebacterium glutamicum. World J Microbiol Biotechnol 32:105. doi: 10.1007/s11274-016-2060-1 CrossRefGoogle Scholar
  57. Wu JN, Han HJ, Jin Q, Li ZH, Li H, Ji J (2017) Design and proof of programmed 5-aminolevulinic acid prodrug nanocarriers for targeted photodynamic cancer therapy. ACS Appl Mater Interfaces 9:14596–14605. doi: 10.1021/acsami.6b15853 CrossRefGoogle Scholar
  58. Yang P, Liu WJ, Cheng XL, Wang J, Wang Q, Qi Q (2016) A new strategy for production of 5-aminolevulinic acid in recombinant Corynebacterium glutamicum with high yield. Appl Environ Microbiol 82:2709–2717. doi: 10.1128/Aem.00224-16 CrossRefGoogle Scholar
  59. Yu X, Jin H, Liu W, Wang Q, Qi Q (2015) Engineering Corynebacterium glutamicum to produce 5-aminolevulinic acid from glucose. Microb Cell Fact 14:183. doi: 10.1186/s12934-015-0364-8 CrossRefGoogle Scholar
  60. Zhang L, Chen J, Chen N, Sun J, Zheng P, Ma Y (2013) Cloning of two 5-aminolevulinic acid synthase isozymes HemA and HemO from Rhodopseudomonas palustris with favorable characteristics for 5-aminolevulinic acid production. Biotechnol Lett 35:763–768. doi: 10.1007/s10529-013-1143-4 CrossRefGoogle Scholar
  61. Zhang J, Kang Z, Chen J, Du G (2015a) Optimization of the heme biosynthesis pathway for the production of 5-aminolevulinic acid in Escherichia coli. Sci Rep 5:8584. doi: 10.1038/srep08584 CrossRefGoogle Scholar
  62. Zhang ZP, Miao MM, Wang CL (2015b) Effects of ALA on photosynthesis, antioxidant enzyme activity, and gene expression, and regulation of proline sccumulation in tomato seedlings under NaCl stress. J Plant Growth Regul 34:637–650. doi: 10.1007/s00344-015-9499-4 CrossRefGoogle Scholar
  63. Zhang J, Kang Z, Ding W, Chen J, Du G (2016) Integrated optimization of the in vivo heme biosynthesis pathway and the in vitro iron concentration for 5-aminolevulinate production. Appl Biochem Biotechnol 178:1252–1262. doi: 10.1007/s12010-015-1942-2 CrossRefGoogle Scholar
  64. Zhang J, Weng H, Ding W, Kang Z (2017) N-terminal engineering of glutamyl-tRNA reductase with positive charge arginine to increase 5-aminolevulinic acid biosynthesis. Bioengineered 8:424–427. doi: 10.1080/21655979.2016.1230572 CrossRefGoogle Scholar
  65. Zou Y, Chen T, Feng L, Zhang S, Xing D, Wang Z (2017) Enhancement of 5-aminolevulinic acid production by metabolic engineering of the glycine biosynthesis pathway in Corynebacterium glutamicum. Biotechnol Lett 39:1369–1374. doi: 10.1007/s10529-017-2362-x CrossRefGoogle Scholar

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© Springer Science+Business Media B.V. 2017

Authors and Affiliations

  1. 1.Key Laboratory of Industrial Biotechnology, Ministry of Education, School of BiotechnologyJiangnan UniversityWuxiChina
  2. 2.The Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of BiotechnologyJiangnan UniversityWuxiChina
  3. 3.Synergetic Innovation Center of Food Safety and NutritionWuxiChina

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