Skip to main content
SpringerLink
Log in

Tetramic acid-motif natural products from a marine fungus Tolypocladium cylindrosporum FB06 and their anti-Parkinson activities

  • Research Paper
  • Published:
Marine Life Science & Technology Aims and scope Submit manuscript

Abstract

Tetramic acid-containing natural products are attracting significantly increasing attention from biologists and chemists due to their intriguing structures and biological activities. In the present study, two new tetramic acid alkaloids tolypyridone I (1) and tolypyridone J (2), together with five known ones (3–7), were isolated from cultures of a marine fungus Tolypocladium cylindrosporum FB06 isolate obtained from a marine sediment in Beaufort sea of North Alaska. Their structures were elucidated using 1D, 2D NMR, and HRESIMS. Their configurations were established on the basis of 1H coupling constants, ROESY correlations and DP4 calculations. Compound 2 was isolated as mixtures of rotational isomers with C-3 to C-7 axis between 4-hydroxy-2-pyridone and 1-ethyl-3,5-dimethylcyclohexane, hindering rotation. In our unbiased screening to discover neuroprotective compounds in an in vitro Parkinson’s disease (PD) model, SH-SY5Y dopaminergic cells were treated with isolated compounds followed by treatment with 1-methyl-4-phenylpyridinium (MPP+), a parkinsonian neurotoxin. Among tested compounds, F-14329 (7) significantly protected cells from MPP+-induced cytotoxicity. MPP+-mediated cell death is known to be related to the regulation of Bcl-2 family proteins, specifically the down-regulation of anti-apoptotic Bcl-2 and the up-regulation of pro-apoptotic Bax levels. Treatment with 2 mmol/L of MPP+ for 24 h significantly reduced Bcl-2 levels compared to control treated with vehicle. However, treatment with F-14329 (7) attenuated such reduction. This study demonstrates that tetramic acid-motif compounds could be potential lead compounds for treating PD.

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

Access this article

Log in via an institution

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

Similar content being viewed by others

Data availability

The data that support the findings of this study are included in the supplementary information file.

References

  • Abraham EP (1979) A glimpse of the early history of the cephalosporins. Rev Infect Dis 1:99–105

    Article  CAS  PubMed  Google Scholar 

  • Ahn KH, Kim YS, Kim SY, Huh Y, Park C, Jeong JW (2009) Okadaic acid protects human neuroblastoma SH-SY5Y cells from 1-methyl-4-phenylpyridinium ion-induced apoptosis. Neurosci Lett 449:93–97

    Article  CAS  PubMed  Google Scholar 

  • Aoki S, Higuchi K, Ye Y, Satari R, Kobayashi M (2000) Melophlins A and B, novel tetramic acids reversing the phenotype of ras-transformed cells, from the marine sponge Melophlus sarassinorum. Tetrahedron 56:1833–1836

    Article  CAS  Google Scholar 

  • Bissett J (1983) Notes on Tolypocladium and related genera. Can J Bot 61:1311–1329

    Article  Google Scholar 

  • Bugni TS, Ireland CM (2004) Marine-derived fungi: a chemically and biologically diverse group of microorganisms. Nat Prod Rep 21:143–163

    Article  CAS  PubMed  Google Scholar 

  • Chun HS, Gibson GE, DeGiorgio LA, Zhang H, Kidd VJ, Son JH (2001) Dopaminergic cell death induced by MPP(+), oxidant and specific neurotoxicants shares the common molecular mechanism. J Neurochem 76:1010–1021

    Article  CAS  PubMed  Google Scholar 

  • Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39:889–909

    Article  CAS  PubMed  Google Scholar 

  • Du L, Robles AJ, King JB, Powell DR, Miller AN, Mooberry SL, Cichewicz RH (2014) Crowdsourcing natural products discovery to access uncharted dimensions of fungal metabolite diversity. Angew Chem Int Ed Engl 53:804–809

    Article  CAS  PubMed  Google Scholar 

  • Friedman A, Sienkiewicz J (1991) Psychotic complications of long-term levodopa treatment of Parkinson’s disease. Acta Neurol Scand 84:111–113

    Article  CAS  PubMed  Google Scholar 

  • Fukuda T, Sudoh Y, Tsuchiya Y, Okuda T, Matsuura N, Motojima A, Oikawa T, Igarashi Y (2015) Tolypoalbin, a new tetramic acid from Tolypocladium album TAMA 479. J Antibiot 68:399–402

    Article  CAS  Google Scholar 

  • Hai Y, Wei MY, Wang CY, Gu YC, Shao CL (2021) The intriguing chemistry and biology of sulfur-containing natural products from marine microorganisms (1987–2020). Mar Life Sci Technol 3:488–518

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Hirsch L, Jette N, Frolkis A, Steeves T, Pringsheim T (2016) The Incidence of Parkinson’s disease: a systematic review and meta-analysis. Neuroepidemiology 46:292–300

    Article  PubMed  Google Scholar 

  • Humber RA (2012) Entomophthoromycota: a new phylum and reclassification for entomophthoroid fungi. Mycotaxon 120:477–492

    Article  Google Scholar 

  • Jeong JS, Piao Y, Kang S, Son M, Kang YC, Du XF, Ryu J, Cho YW, Jiang HH, Oh MS, Hong SP, Oh YJ, Pak YK (2018) Triple herbal extract DA-9805 exerts a neuroprotective effect via amelioration of mitochondrial damage in experimental models of Parkinson’s disease. Sci Rep 8:15953

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  • Jiang M, Chen S, Li J, Liu L (2020) The biological and chemical diversity of tetramic acid compounds from marine derived microorganisms. Mar Drugs 18:114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kalivendi SV, Kotamraju S, Cunningham S, Shang T, Hillard CJ, Kalyanaraman B (2003) 1-Methyl-4-phenylpyridinium (MPP+)-induced apoptosis and mitochondrial oxidant generation: role of transferrin-receptor-dependent iron and hydrogen peroxide. Biochem J 371:151–164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kassam R, Yadav J, Chawla G, Kundu A, Hada A, Jaiswal N, Bollinedi H, Kamil D, Devi P, Rao U (2021) Identification, characterization, and evaluation of nematophagous fungal species of Arthrobotrys and Tolypocladium for the management of Meloidogyne incognita. Front Microbiol 12:790223

    Article  PubMed  PubMed Central  Google Scholar 

  • Khan I, Peng J, Fang Z, Liu W, Zhang W, Zhang Q, Ma L, Zhang G, Zhang C, Zhang H (2021) Cylindromicin from arctic-derived fungus Tolypocladium sp. SCSIO 40433. Molecules 26:1080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kish LP, Allen GE, Kimbrough JW, Kuitert LC (1974) A survey of fungi associated with the lovebug, Plecia nearctica, in Florida. Fla Entomol 57:281–284

    Article  Google Scholar 

  • Li XB, Li L, Zhu RX, Li W, Chang WQ, Zhang LL, Wang XN, Zhao ZT, Lou HX (2015) Tetramic acids and pyridone alkaloids from the endolichenic fungus Tolypocladium cylindrosporum. J Nat Prod 78:2155–2160

    Article  CAS  PubMed  Google Scholar 

  • Li H, Kim J, Tran HNK, Lee CH, Hur J, Kim MC, Yang HO (2021) Extract of Polygala tenuifolia, Angelica tenuissima, and Dimocarpus longan reduces behavioral defect and enhances autophagy in experimental models of Parkinson’s disease. Neuromolecular Med 23:428–443

    Article  CAS  PubMed  Google Scholar 

  • Lundgren B, Baath E, Soderstrom BE (1978) Antagonistic effects of tolypocladium species. TBMS 70:305–307

    Article  Google Scholar 

  • Nugroho AE, Morita H (2014) Circular dichroism calculation for natural products. J Nat Med 68:1–10

    Article  CAS  PubMed  Google Scholar 

  • O’Malley KL, Liu J, Lotharius J, Holtz W (2003) Targeted expression of BCL-2 attenuates MPP+ but not 6-OHDA induced cell death in dopaminergic neurons. Neurobiol Dis 14:43–51

    Article  PubMed  Google Scholar 

  • Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, Schrag AE, Lang AE (2017) Parkinson disease. Nat Rev Dis Primers 3:17013

    Article  PubMed  Google Scholar 

  • Rateb ME, Ebel R (2011) Secondary metabolites of fungi from marine habitats. Nat Prod Rep 28:290–344

    Article  CAS  PubMed  Google Scholar 

  • Saleem M, Shaiq Ali M, Hussain S, Jabbar A, Ashraf M, Lee YS (2007) Marine natural products of fungal origin. Nat Prod Rep 24:1142–1152

    Article  CAS  PubMed  Google Scholar 

  • Scorsetti AC, Elíades LA, Stenglein SA, Cabello MN, Pelizza SA, Saparrat MC (2012) Pathogenic and enzyme activities of the entomopathogenic fungus Tolypocladium cylindrosporum (Ascomycota: Hypocreales) from Tierra del Fuego, Argentina. Rev Biol Trop 60:833–841

    Article  PubMed  Google Scholar 

  • Shang Z, Li L, Espósito BP, Salim AA, Khalil ZG, Quezada M, Bernhardt PV, Capon RJ (2015) New PKS-NRPS tetramic acids and pyridinone from an Australian marine-derived fungus, Chaunopycnis sp. Org Biomol Chem 13:7795–7802

    Article  CAS  PubMed  Google Scholar 

  • Shin MK, Choi MS, Chae HJ, Kim JW, Kim HG, Kim KL (2019) Ganglioside GQ1b ameliorates cognitive impairments in an Alzheimer’s disease mouse model, and causes reduction of amyloid precursor protein. Sci Rep 9:8512

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  • Teshima Y, Shin-ya K, Shimazu A, Furihata K, Chul HS, Furihata K, Hayakawa Y, Nagai K, Seto H (1991) Isolation and structural elucidation of pyridoxatin, a free radical scavenger of microbial origin. J Antibiot 44:685–687

    Article  CAS  Google Scholar 

  • Wang CY, Wang BG, Wiryowidagdo S, Wray V, van Soest R, Steube KG, Guan HS, Proksch P, Ebel R (2003) Melophlins C–O, thirteen novel tetramic acid derivatives from the marine sponge Melophlus sarassinorum. J Nat Prod 66:51–56

    Article  CAS  PubMed  Google Scholar 

  • Wiese J, Imhoff JF (2019) Marine bacteria and fungi as promising source for new antibiotics. Drug Dev Res 80:24–27

    Article  CAS  PubMed  Google Scholar 

  • Xu WF, Wu NN, Wu YW, Qi YX, Wei MY, Pineda LM, Ng MG, Spadafora C, Zheng JY, Lu L (2022) Structure modification, antialgal, antiplasmodial, and toxic evaluations of a series of new marine-derived 14-membered resorcylic acid lactone derivatives. Mar Life Sci Technol 4:88–97

    Article  ADS  CAS  PubMed  Google Scholar 

  • Zhang WY, Zhong Y, Yu Y, Shi DF, Huang HY, Tang XL, Wang YH, Chen GD, Zhang HP, Liu CL, Hu D, Gao H, Yao XS (2020) 4-Hydroxy pyridones from heterologous expression and cultivation of the native host. J Nat Prod 83:3338–3346

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by the New Faculty Startup Fund from Seoul National University and the National Research Foundation of Korea (NRF-2021R1A2C1004958, 2022R1A4A3022401, and RS-2023-00209597).

Author information

Author notes

  1. Yuna Jung and Chaesun Kwon have contributed equally to this work.

Authors and Affiliations

  1. Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea

    Yuna Jung, Taeyeon Kim, Min-Kyoo Shin & Sang Hee Shim

  2. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea

    Chaesun Kwon & Min-Kyoo Shin

  3. College of Pharmacy, Duksung Women’s University, Seoul, 01369, Republic of Korea

    Jin Woo Lee

Authors
  1. Yuna Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chaesun Kwon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Taeyeon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jin Woo Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Min-Kyoo Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sang Hee Shim
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YJ and CK conducted experiment implementation and prepared the original draft manuscript. JK conducted the computational work. JWL, M-KS, and SHS provided the experimental ideas, helped data analysis, and revised the manuscript. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Min-Kyoo Shin or Sang Hee Shim.

Ethics declarations

Conflict of interest

The authors they have no conflicts of interest relevant to this study to disclose.

Animal and human rights statement

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

Additional information

Edited by Chengchao Chen.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 1928 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jung, Y., Kwon, C., Kim, T. et al. Tetramic acid-motif natural products from a marine fungus Tolypocladium cylindrosporum FB06 and their anti-Parkinson activities. Mar Life Sci Technol 6, 84–92 (2024). https://doi.org/10.1007/s42995-023-00198-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s42995-023-00198-7

Keywords

Search

Navigation