SpringerLink
Log in

Identification of biosynthetic genes for the β-carboline alkaloid kitasetaline and production of the fluorinated derivatives by heterologous expression

  • Genetics and Molecular Biology of Industrial Organisms - Original Paper
  • Published:
Journal of Industrial Microbiology & Biotechnology

Abstract

β-Carboline alkaloids exhibit a broad spectrum of pharmacological and biological activities and are widely distributed in nature. Genetic information on the biosynthetic mechanism of β-carboline alkaloids has not been accumulated in bacteria, because there are only a few reports on the microbial β-carboline compounds. We previously isolated kitasetaline, a mercapturic acid derivative of a β-carboline compound, from the genetically modified Kitasatospora setae strain and found a plausible biosynthetic gene cluster for kitasetaline. Here, we identified and characterized three kitasetaline (ksl) biosynthetic genes for the formation of the β-carboline core structure and a gene encoding mycothiol-S-conjugate amidase for the modification of the N-acetylcysteine moiety by using heterologous expression. The proposed model of kitasetaline biosynthesis shows unique enzymatic systems for β-carboline alkaloids. In addition, feeding fluorotryptophan to the heterologous Streptomyces hosts expressing the ksl genes led to the generation of unnatural β-carboline alkaloids exerting novel/potentiated bioactivities.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Aroonsri A, Kitani S, Hashimoto J et al (2012) Pleiotropic control of secondary metabolism and morphological development by KsbC, a butyrolactone autoregulator receptor homologue in Kitasatospora setae. Appl Environ Microbiol 78:8015–8024. https://doi.org/10.1128/AEM.02355-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Aroonsri A, Kitani S, Ikeda H, Nihira T (2012) Kitasetaline, a novel β-carboline alkaloid from Kitasatospora setae NBRC 14216T. J Biosci Bioeng 114:56–58. https://doi.org/10.1016/j.jbiosc.2012.02.027

    Article  CAS  PubMed  Google Scholar 

  3. Arshad N, Zitterl-Eglseer K, Hasnain S, Hess M (2008) Effect of Peganum harmala or its β-carboline alkaloids on certain antibiotic resistant strains of bacteria and protozoa from poultry. Phyther Res 22:1533–1538. https://doi.org/10.1002/ptr.2528

    Article  CAS  Google Scholar 

  4. Bégué JP, Bonnet-Delpon D (2006) Recent advances (1995–2005) in fluorinated pharmaceuticals based on natural products. J Fluor Chem 127:992–1012. https://doi.org/10.1016/j.jfluchem.2006.05.006

    Article  CAS  Google Scholar 

  5. Berridge MV, Tan AS (1993) Characterization of the cellular reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT): subcellular localization, substrate dependence, and involvement of mitochondrial electron transport in MTT reduction. Arch Biochem Biophys 303:474–482. https://doi.org/10.1006/abbi.1993.1311

    Article  CAS  Google Scholar 

  6. Cane DE, He X, Kobayashi S et al (2006) Geosmin biosynthesis in Streptomyces avermitilis. Molecular cloning, expression, and mechanistic study of the germacradienol/geosmin synthase. J Antibiot (Tokyo) 59:471–479. https://doi.org/10.1038/ja.2006.66

    Article  CAS  Google Scholar 

  7. Cao R, Peng W, Wang Z, Xu A (2007) β-Carboline alkaloids: biochemical and pharmacological functions. Curr Med Chem 14:479–500. https://doi.org/10.2174/092986707779940998

    Article  CAS  PubMed  Google Scholar 

  8. Chen Q, Ji C, Song Y et al (2013) Discovery of McbB, an enzyme catalyzing the β-carboline skeleton construction in the marinacarboline biosynthetic pathway. Angew Chem Int Ed 52:9980–9984. https://doi.org/10.1002/anie.201303449

    Article  CAS  Google Scholar 

  9. Chen Q, Zhang S, **e Y (2018) Characterization of a new microbial Pictet–Spenglerase NscbB affording the β-carboline skeletons from Nocardiopsis synnemataformans DSM 44143. J Biotechnol 281:137–143. https://doi.org/10.1016/j.jbiotec.2018.07.007

    Article  CAS  PubMed  Google Scholar 

  10. Djamshidian A, Bernschneider-Reif S, Poewe W, Lees AJ (2016) Banisteriopsis caapi, a forgotten potential therapy for parkinson’s disease? Mov Disord Clin Pract 3:19–26. https://doi.org/10.1002/mdc3.12242

    Article  PubMed  Google Scholar 

  11. Förster H, Tyler B, Coffey M (1994) Phytophthora sojae races have arisen by clonal evolution and by rare outcrosses. Mol Plant Microbe Interact 7:780–791. https://doi.org/10.1094/MPMI-7-0780

    Article  Google Scholar 

  12. Herraiz T, González D, Ancín-Azpilicueta C et al (2010) β-Carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO). Food Chem Toxicol 48:839–845. https://doi.org/10.1016/j.fct.2009.12.019

    Article  CAS  PubMed  Google Scholar 

  13. Ikeda H, Shin-ya K, Nagamitsu T, Tomoda H (2016) Biosynthesis of mercapturic acid derivative of the labdane-type diterpene, cyslabdan that potentiates imipenem activity against methicillin-resistant Staphylococcus aureus: cyslabdan is generated by mycothiol-mediated xenobiotic detoxification. J Ind Microbiol Biotechnol 34:325–342. https://doi.org/10.1007/s10295-015-1694-6

    Article  CAS  Google Scholar 

  14. Isanbor C, O’Hagan D (2006) Fluorine in medicinal chemistry: a review of anti-cancer agents. J Fluor Chem 127:303–319. https://doi.org/10.1016/j.jfluchem.2006.01.011

    Article  CAS  Google Scholar 

  15. Jeschke P (2004) The unique role of fluorine in the design of active ingredients for modern crop protection. ChemBioChem 5:571–589. https://doi.org/10.1002/cbic.200300833

    Article  CAS  PubMed  Google Scholar 

  16. Jothivasan VK, Hamilton CJ (2008) Mycothiol: synthesis, biosynthesis and biological functions of the major low molecular weight thiol in actinomycetes. Nat Prod Rep 25:1091–1117. https://doi.org/10.1039/b616489g

    Article  CAS  PubMed  Google Scholar 

  17. Kamal A, Sathish M, Nayak VL et al (2015) Design and synthesis of dithiocarbamate linked β-carboline derivatives: DNA topoisomerase II inhibition with DNA binding and apoptosis inducing ability. Bioorg Med Chem 23:5511–5526. https://doi.org/10.1016/j.bmc.2015.07.037

    Article  CAS  PubMed  Google Scholar 

  18. Kodani S, Imoto A, Mitsutani A, Murakami M (2002) Isolation and identification of the antialgal compound, harmane (1-methyl-β-carboline), produced by the algicidal bacterium, Pseudomonas sp. K44-1. J Appl Phycol 14:109–114. https://doi.org/10.1023/A:1019533414018

    Article  CAS  Google Scholar 

  19. Komatsu M, Tsuda M, Omura S et al (2008) Identification and functional analysis of genes controlling biosynthesis of 2-methylisoborneol. Proc Natl Acad Sci 105:7422–7427. https://doi.org/10.1073/pnas.0802312105

    Article  PubMed  Google Scholar 

  20. Komatsu M, Uchiyama T, Omura S et al (2010) Genome-minimized Streptomyces host for the heterologous expression of secondary metabolism. Proc Natl Acad Sci 107:2646–2651. https://doi.org/10.1073/pnas.0914833107

    Article  PubMed  Google Scholar 

  21. Lee AS (2007) GRP78 induction in cancer: therapeutic and prognostic implications endoplasmic reticulum stress and cancer. Cancer Res 67:3496–3505. https://doi.org/10.1158/0008-5472.CAN-07-0325

    Article  CAS  PubMed  Google Scholar 

  22. Lee DS, Eom SH, Jeong SY et al (2013) Anti-methicillin-resistant Staphylococcus aureus (MRSA) substance from the marine bacterium Pseudomonas sp. UJ-6. Environ Toxicol Pharmacol 35:171–177. https://doi.org/10.1016/j.etap.2012.11.011

    Article  CAS  PubMed  Google Scholar 

  23. Li Y, Liang F, Jiang W et al (2007) DH334, a β-carboline anti-cancer drug, inhibits the CDK activity of budding yeast. Cancer Biol Ther 6:1193–1199. https://doi.org/10.4161/cbt.6.8.4382

    Article  CAS  PubMed  Google Scholar 

  24. Luo B, Lee AS (2013) The critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies. Oncogene 32:805–818. https://doi.org/10.1038/onc.2012.130

    Article  CAS  PubMed  Google Scholar 

  25. Maresh JJ, Giddings LA, Friedrich A et al (2008) Strictosidine synthase: mechanism of a Pictet–Spengler catalyzing enzyme. J Am Chem Soc 130:710–723. https://doi.org/10.1021/ja077190z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mori T, Hoshino S, Sahashi S et al (2015) Structural basis for β-carboline alkaloid production by the microbial homodimeric enzyme McbB. Chem Biol 22:898–906. https://doi.org/10.1016/j.chembiol.2015.06.006

    Article  CAS  PubMed  Google Scholar 

  27. Mukaihara T, Tamura N, Murata Y, Iwabuchi M (2004) Genetic screening of Hrp type III-related pathogenicity genes controlled by the HrpB transcriptional activator in Ralstonia solanacearum. Mol Microbiol 54:863–875. https://doi.org/10.1111/j.1365-2958.2004.04328.x

    Article  CAS  PubMed  Google Scholar 

  28. Murphy CD, Clark BR, Amadio J (2009) Metabolism of fluoroorganic compounds in microorganisms: impacts for the environment and the production of fine chemicals. Appl Microbiol Biotechnol 84:617–629. https://doi.org/10.1007/s00253-009-2127-0

    Article  CAS  PubMed  Google Scholar 

  29. Namba T, Tian F, Chu K et al (2013) CDIP1-BAP31 complex transduces apoptotic signals from endoplasmic reticulum to mitochondria under endoplasmic reticulum stress. Cell Rep 5:331–339. https://doi.org/10.1016/j.celrep.2013.09.020

    Article  CAS  PubMed  Google Scholar 

  30. Newton GL, Arnold K, Price MS et al (1996) Distribution of thiols in microorganisms: mycothiol is a major thiol in most actinomycetes. J Bacteriol 178:1990–1995. https://doi.org/10.1128/jb.178.7.1990-1995.1996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pulsawat N, Kitani S, Fukushima E, Nihira T (2009) Hierarchical control of virginiamycin production in Streptomyces virginiae by three pathway-specific regulators: VmsS, VmsT and VmsR. Microbiology 155:1250–1259. https://doi.org/10.1099/mic.0.022467-0

    Article  CAS  PubMed  Google Scholar 

  32. Rawat M, Av-Gay Y (2007) Mycothiol-dependent proteins in actinomycetes. FEMS Microbiol Rev 31:278–292. https://doi.org/10.1111/j.1574-6976.2006.00062.x

    Article  CAS  PubMed  Google Scholar 

  33. Rawat M, Uppal M, Newton G et al (2004) Targeted mutagenesis of the Mycobacterium smegmatis mca gene, encoding a mycothiol-dependent detoxification protein. J Bacteriol 186:6050–6058. https://doi.org/10.1128/JB.186.18.6050-6058.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Shankaraiah N, Sharma P, Pedapati S et al (2016) Synthesis of novel C3-linked β-carboline-pyridine derivatives employing khronke reaction: DNA-binding ability and molecular modeling studies. Lett Drug Des Discov 13:335–342. https://doi.org/10.2174/1570180812666150924000250

    Article  CAS  Google Scholar 

  35. Song Y, Kesuma D, Wang J et al (2004) Specific inhibition of cyclin-dependent kinases and cell proliferation by harmine. Biochem Biophys Res Commun 317:128–132. https://doi.org/10.1016/j.bbrc.2004.03.019

    Article  CAS  PubMed  Google Scholar 

  36. Stöckigt J, Antonchick AP, Wu F, Waldmann H (2011) The Pictet–Spengler reaction in nature and in organic chemistry. Angew Chem Int Ed 50:8538–8564. https://doi.org/10.1002/anie.201008071

    Article  CAS  Google Scholar 

  37. Szabó LF (2008) Rigorous biogenetic network for a group of indole alkaloids derived from strictosidine. Molecules 13:1875–1896. https://doi.org/10.3390/molecules13081875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ueda S, Kitani S, Namba T et al (2018) Engineered production of kitasetalic acid, a new tetrahydro-β-carboline with the ability to suppress glucose-regulated protein synthesis. J Antibiot (Tokyo) 71:854–861. https://doi.org/10.1038/s41429-018-0074-7

    Article  CAS  Google Scholar 

  39. Zhu XM, Hackl S, Thaker MN et al (2015) Biosynthesis of the fluorinated natural product nucleocidin in Streptomyces calvus is dependent on the bldA-specified Leu-tRNAUUA molecule. ChemBioChem 16:2498–2506. https://doi.org/10.1002/cbic.201500402

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a Grant-in-Aid for Scientific Research (C) (Grant number 18K05390) from the Japan Society for the Promotion of Science (JSPS) to S.K., by a Grant-in-Aid for Scientific Research on Innovative Areas (Grant number 18H04618) from JSPS to S.K., and by a New Chemical Technology Research Encouragement Award from the Japan Association for Chemical Innovation to S.K.

Author information

Authors and Affiliations

  1. International Center for Biotechnology, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Shohei Ueda, Yukinori Ikejiri, Yuri Nishimoto, Takuya Nihira & Shigeru Kitani

  2. Kitasato Institute for Life Sciences, Kitasato University, 1-15-1 Kitasato, Sagamihara, Kanagawa, 252-0373, Japan

    Haruo Ikeda

  3. Science Research Center, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan

    Takushi Namba

  4. Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Masayoshi Arai

  5. MU-OU Collaborative Research Center for Bioscience and Biotechnology, Faculty of Science, Mahidol University, Rama VI Rd, Bangkok, 10400, Thailand

    Takuya Nihira

Authors
  1. Shohei Ueda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haruo Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takushi Namba
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yukinori Ikejiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuri Nishimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masayoshi Arai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Takuya Nihira
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shigeru Kitani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shigeru Kitani.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This research was conducted by Shohei Ueda in partial fulfillment of the requirements for a Ph.D.

Takuya Nihira: Deceased 17 September 2018.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 1161 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ueda, S., Ikeda, H., Namba, T. et al. Identification of biosynthetic genes for the β-carboline alkaloid kitasetaline and production of the fluorinated derivatives by heterologous expression. J Ind Microbiol Biotechnol 46, 739–750 (2019). https://doi.org/10.1007/s10295-019-02151-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10295-019-02151-z

Keywords

Search

Navigation