DOI QR코드

DOI QR Code

Effect of Different Biosynthetic Precursors on the Production of Nargenicin $A_1$ from Metabolically Engineered Nocardia sp. CS682

  • Koju, Dinesh (Institute of Biomolecule Reconstruction, Sun Moon University) ;
  • Maharjan, Sushila (Institute of Biomolecule Reconstruction, Sun Moon University) ;
  • Dhakal, Dipesh (Institute of Biomolecule Reconstruction, Sun Moon University) ;
  • Yoo, Jin Cheol (Department of Pharmacy, College of Pharmacy, Chosun University) ;
  • Sohng, Jae Kyung (Institute of Biomolecule Reconstruction, Sun Moon University)
  • Received : 2012.02.14
  • Accepted : 2012.04.13
  • Published : 2012.08.28

Abstract

Nargenicin $A_1$ is a 28-membered polyketide macrolide, with antibacterial activity against methicillin-resistant Staphylococcus aureus, produced by Nocardia sp. CS682. In this study, the production of nargenicin $A_1$ was improved by enhancing the supply of different biosynthetic precursors. In Nocardia sp. CS682 (KCTC11297BP), this improvement was ~4.62-fold with the supplementation of 30 mM methyl oleate, 4.25-fold with supplementation of 15mM sodium propionate, and 2.81-fold with supplementation of 15 mM sodium acetate. In Nocardia sp. metK18 and Nocardia sp. CS682 expressing S-adenosylmethionine synthetase (MetK), the production of nargenicin $A_1$ was improved by ~5.57-fold by supplementation with 30 mM methyl oleate, 5.01-fold by supplementation with 15 mM sodium propionate, and 3.64-fold by supplementation with 15 mM sodium acetate. Furthermore, supplementing the culture broth of Nocardia sp. ACC18 and Nocardia sp. CS682 expressing the acetyl-CoA carboxylase complex (AccA2 and AccBE) with 30 mM methyl oleate, 15 mM sodium propionate, or 15 mM sodium acetate resulted in ~6.99-, 6.46-, and 5.58-fold increases, respectively, in nargenicin $A_1$ production. Our overall results showed that among the supplements, methyl oleate was the most effective precursor supporting the highest titers of nargenicin $A_1$ in Nocardia sp. CS682, Nocardia sp. metK18, and Nocardia sp. ACC18.

Keywords

References

  1. Cane, D. E. and C. C. Yang. 1984. Biosynthetic origin of the carbon skeleton and oxygen atoms of nargenicin A1. J. Am. Chem. Soc. 106: 784-787. https://doi.org/10.1021/ja00315a052
  2. Celmer, W. D., G. N. Chmurny, C. E. Moppett, R. S. Ware, P. C. Watts, and E. B. Whipple. 1980. Structure of natural antibiotic CP-47,444. J. Am. Chem. Soc. 102: 4203-4209. https://doi.org/10.1021/ja00532a036
  3. Chan, Y. A., A. M. Podevels, B. M. Kevany, and M. G. Thomas. 2009. Biosynthesis of polyketide synthase extender units. Nat. Prod. Rep. 26: 90-114. https://doi.org/10.1039/b801658p
  4. Cho, S. S., J. K. Sohng, H. J. Lee, S. J. Park, J. R. Simkhada, and J. C. Yoo. 2009. Quantitative analysis of nargenicin in Nocardia sp. CS682 culture by high performance liquid chromatography. Arch. Pharm. Res. 32: 335-340. https://doi.org/10.1007/s12272-009-1304-0
  5. Gunnarsson, N., A. Eliasson, and J. Nielsen. 2004. Control of fluxes towards antibiotics and the role of primary metabolism in production of antibiotics. Adv. Biochem. Eng. Biotechnol. 88: 137-178.
  6. Hopwood, D. A. 1997. Genetic contributions to understanding polyketide synthases. Chem. Rev. 97: 2465-2497. https://doi.org/10.1021/cr960034i
  7. Iannitelli, R. C. and M. Ikawa. 1980. Effect of fatty acids on action of polyene antibiotics. Antimicrob. Agents Chemother. 17: 861-864. https://doi.org/10.1128/AAC.17.5.861
  8. Jing, K., X. Hao, and Y. Lu. 2011. Effect of propionate on the production of natamycin with Streptomyces gilvosporeus XM-172. Afr. J. Biotechnol. 10: 10030-10033.
  9. Katz, L. 1997. Manipulation of modular polyketide synthases. Chem. Rev. 97: 2557-2575. https://doi.org/10.1021/cr960025+
  10. Kim, D. J., J. H. Huh, Y. Y. Yang, C. M. Kang, I. H. Lee, C. G. Hyun, et al. 2003. Accumulation of S-adenosyl-L-methionine enhances production of actinorhodin but inhibits sporulation in Streptomyces lividans TK23. J. Bacteriol. 185: 592-600. https://doi.org/10.1128/JB.185.2.592-600.2003
  11. Kim, S. H., J. C. Yoo, and T. S. Kim. 2009. Nargenicin enhances 1,25-dihydroxyvitamin D3- and all-trans retinoic acidinduced leukemia cell differentiation via $PKC{\beta}I/MAPK$ pathways. Biochem. Pharmacol. 77: 1694-1701. https://doi.org/10.1016/j.bcp.2009.03.004
  12. Lee, P. C., T. Umeyama, and S. Horinouchi. 2002. AfsS is a target of AfsR, a transcriptional factor with ATPase activity that globally controls secondary metabolism in Streptomyces coelicolor A3(2). Mol. Microbiol. 43: 1413-1430. https://doi.org/10.1046/j.1365-2958.2002.02840.x
  13. Li, C., G. Florova, A. Konstatin, and K. A. Reynolds. 2004. Crotonylcoenzyme A reductase provides methylmalonyl-CoA precursors for monensin biosynthesis by Streptomyces cinnamonensis in an oil-based extended fermentation. Microbiology 150: 3463-3472. https://doi.org/10.1099/mic.0.27251-0
  14. Li, L. Z., H. Zheng, and Y. Yuan. 2007. Effects of propionate on streptolydigin production and carbon flux distribution in Streptomyces lydicus AS 4.2501. Chin. J. Chem. Eng. 15: 143-149. https://doi.org/10.1016/S1004-9541(07)60049-4
  15. Maharjan, S., D. Koju, H. C. Lee, J. C. Yoo, and J. K. Sohng. 2012. Metabolic engineering of Nocardia sp. CS682 for enhanced production of nargenicin A1. Appl. Biochem. Biotechnol. 166: 805-817. https://doi.org/10.1007/s12010-011-9470-1
  16. Maharjan, S., J. W. Park, Y. J. Yoon, H. C. Lee, and J. K. Sohng. 2010. Metabolic engineering of Streptomyces venezuelae for malonyl-CoA biosynthesis to enhance heterologous production of polyketides. Biotechnol. Lett. 32: 277-282. https://doi.org/10.1007/s10529-009-0152-9
  17. Maharjan, S., T. J. Oh, H. C. Lee, and J. K. Sohng. 2008. Heterologous expression of metK1-sp and afsR-sp in Streptomyces venezuelae for the production of pikromycin. Biotechnol. Lett. 30: 1621-1626. https://doi.org/10.1007/s10529-008-9735-0
  18. Mo, S., Y. H. Ban, J. W. Park, Y. J. Yoo, and Y. J. Yoon. 2009. Enhanced FK506 production in Streptomyces clavuligerus CKD1119 by engineering the supply of methylmalonyl-CoA precursor. J. Ind. Microbiol. Biotechnol. 36: 1473-1482. https://doi.org/10.1007/s10295-009-0635-7
  19. Mouslim, J., L. David, G. Petel, and M. Gendraud. 1993. Effect of exogeneous methyl oleate on the time course of some parameters of Streptomyces hygroscopicus NRRL B-1865 culture. Appl. Microbiol. Biotechnol. 39: 585-588. https://doi.org/10.1007/BF00205056
  20. Murli, S., J. Kennedy, L. C. Dayem, J. R. Carney, and J. T. Kealey. 2003. Metabolic engineering of Escherichia coli for improved 6-deoxyerythronolide B production. J. Ind. Microbiol. Biotechnol. 30: 500-509. https://doi.org/10.1007/s10295-003-0073-x
  21. Okamoto, S., A. Lezhava, T. Hosaka, Y. Okamoto-Hosoya, and K. Ochi. 2003. Enhanced expression of S-adenosylmethionine synthetase causes overproduction of actinorhodin in Streptomyces coelicolor A3(2). J. Bacteriol. 185: 601-609. https://doi.org/10.1128/JB.185.2.601-609.2003
  22. Olano, C., F. Lombo, C. Mendez, and J. A. Salas. 2008. Improving production of bioactive secondary metabolites in actinomycetes by metabolic engineering. Metab. Eng. 10: 281-292. https://doi.org/10.1016/j.ymben.2008.07.001
  23. Paudel, S., H. C. Lee, B. S. Kim, and J. K. Sohng. 2011. Enhancement of pradimicin production in Actinomadura hibisca P157-2 by metabolic engineering. Microbiol. Res. 167: 32-39. https://doi.org/10.1016/j.micres.2011.02.007
  24. Reeves, A. R., I. A. Brikun, W. H. Cernota, B. I. Leach, M. C. Gonzalez, and J. M. Weber. 2006. Effects of methylmalonyl-CoA mutase gene knockouts on erythromycin production in carbohydrate-based and oil-based fermentations of Saccharopolyspora erythraea. J. Ind. Microbiol. Biotechnol. 33: 600-609. https://doi.org/10.1007/s10295-006-0094-3
  25. Reeves, A. R., I. A. Brikun, W. H. Cernota, B. I. Leach, M. C. Gonzalez, and J. M. Weber. 2007. Engineering of the methylmalonyl-CoA metabolite node of Saccharopolyspora erythraea for increased erythromycin production. Metab. Eng. 9: 293-303. https://doi.org/10.1016/j.ymben.2007.02.001
  26. Ryu, Y. G., M. J. Butler, K. F. Chater, and K. J. Lee. 2006. Engineering of primary carbohydrate metabolism for increased production of actinorhodin in Streptomyces coelicolor. Appl. Environ. Microbiol. 72: 7132-7139. https://doi.org/10.1128/AEM.01308-06
  27. Sohng, J., T. Yamaguchi, C. Seong, K. Baik, S. Park, H. Lee, S. Jang, J. Simkhada, and J. Yoo. 2008. Production, isolation and biological activity of nargenicin from Nocardia sp. CS682. Arch. Pharm. Res. 31: 1339-1345. https://doi.org/10.1007/s12272-001-2115-0
  28. Wang, Y., B. A. Boghigian, and B. A. Pfeifer. 2007. Improving heterologous polyketide production in Escherichia coli by overexpression of an S-adenosylmethionine synthetase gene. Appl. Microbiol. Biotechnol. 77: 367-373. https://doi.org/10.1007/s00253-007-1172-9
  29. Yoon, G. S., K. H. Ko, H. W. Kang, J. W. Suh, Y. S. Kim, and Y. W. Ryu. 2006. Characterization of S-adenosylmethionine synthetase from Streptomyces avermitilis NRRL8165 and its effect on antibiotic production. Enzyme Microb. Technol. 39: 466-473. https://doi.org/10.1016/j.enzmictec.2005.11.049
  30. Zhao, X. Q., Y. Y. Jin, and H. J. Kwon. 2006. S-Adenosylmethionine (SAM) regulates antibiotic biosynthesis in Streptomyces spp. in a mode independent of its role as a methyl donor. J. Microbiol. Biotechnol. 16: 927-932.

Cited by

  1. Comparative metabolic profiling-based improvement of rapamycin production by Streptomyces hygroscopicus vol.97, pp.12, 2012, https://doi.org/10.1007/s00253-013-4852-7
  2. Enhancement of FK506 production by engineering secondary pathways of Streptomyces tsukubaensis and exogenous feeding strategies vol.40, pp.9, 2012, https://doi.org/10.1007/s10295-013-1301-7
  3. 토양 균주 발효 추출물 Nargenicin 및 그 유도체의 항생제 대체 효과능 평가 vol.22, pp.3, 2014, https://doi.org/10.11625/kjoa.2014.22.3.469
  4. Herboxidiene biosynthesis, production, and structural modifications: prospect for hybrids with related polyketide vol.99, pp.20, 2015, https://doi.org/10.1007/s00253-015-6860-2
  5. Enhanced production of nargenicin A1 and creation of a novel derivative using a synthetic biology platform vol.100, pp.23, 2016, https://doi.org/10.1007/s00253-016-7705-3
  6. Genetic Manipulation of Nocardia Species vol.40, pp.1, 2012, https://doi.org/10.1002/9780471729259.mc10f02s40
  7. Bioactive molecules from Nocardia: diversity, bioactivities and biosynthesis vol.46, pp.3, 2012, https://doi.org/10.1007/s10295-018-02120-y
  8. Natural Products from Nocardia and Their Role in Pathogenicity vol.31, pp.3, 2012, https://doi.org/10.1159/000516864