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Natural products development under epigenetic modulation in fungi

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Abstract

Natural products derived from microorganisms play a key role in the discovery and development of drug candidates. Several drugs have originated from secondary metabolites or their derivatives from microorganisms in clinical therapy, such as penicillin, cyclosporine, and lovastatin. Application of epigenetic methodology on modulation and stimulation of secondary metabolites from fungi provides a practical way to investigate fungal natural products. Addition of enzyme inhibitors such as histone deacetylase (HDAC) or DNA methyltransferase (DNMT) inhibitors to activate silent biosynthetic gene clusters result in the potential for generating a variety of secondary metabolites with novel skeletons and diversity of stereochemistry, as well as unprecedented heterocyclic rings. After triggering the epigenetic modifiers, some species were affected and produced several uncovered secondary metabolites. Although this strategy has been successfully carried out for few reports, the results of this research field have demonstrated high potential for engineering the secondary metabolites from fungi. By utilizing the above strategy, modulation and characterization of the secondary metabolites from fungi make them able to generate several novel or bioactive natural products that will provide sources for discovering new candidates. Furthermore, the epigenetic modulation technique integrated with pharmacological assays for further investigation becomes a promising avenue for improvement of natural products research and development. This review summarizes the progression and development of epigenetic manipulation in fungal natural product research.

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Abbreviations

4mC:

N4-methylcytosine

5mC:

C5-methylcytosine

6mA:

N6-methyladenine

5-AZ:

5-Azacytidine

BGC:

Biosynthetic gene cluster

CTCL:

Cutaneous T-cell lymphoma

DNMT:

DNA methyltransferase

EGCG:

(–)-Epigallocatechin-3-gallate

EMA:

European Medicines Agency

FDA:

Food and Drug Administration

HATs:

Histone acetyltransferases

HDAC:

Histone deacetylase

HKMT:

Histone lysine methyltransferase

NAD:

Nicotinamide adenine dinucleotide

PARP:

Poly-ADP-ribose polymerase

PRMT:

Protein arginine methyltransferase

RG108:

N-phthaloyl-l-tryptophan

RPD3:

Reduced potassium dependency-3

SAM:

S-adenyl methionine

SAHA:

Suberylanilide hydroxamic acid

SBHA:

Suberyl bis-hydroxamic acid

VPA:

Valproic acid

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Acknowledgements

This work was supported by Grants from the Ministry of Science and Technology, Taiwan (Grant Number: MOST 105-2628-B-037-001-MY3, MOST 106-2320-B-037-008-MY2 and MOST 108-2320-B-037-022-MY3 award to F.-R. Chang). In addition, this research was funded by the Drug Development and Value Creation Research Center, Kaohsiung Medical University & Department of Medical Research, Kaohsiung Medical University Hospital (Grant Number: KMU-TC108A03-11 awarded to F.-R. Chang).

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Authors and Affiliations

  1. Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, 807, Taiwan

    Chi-Ying Li, Yu-Ming Chung & Fang-Rong Chang

  2. Graduate Institute of Integrated Medicine, China Medical University, Taichung, 404, Taiwan

    Yang-Chang Wu

  3. Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, 404, Taiwan

    Yang-Chang Wu

  4. Institute of Pharmacognosy, Interdisciplinary Excellence Center, University of Szeged, Szeged, 6720, Hungary

    Attila Hunyadi

  5. Interdisciplinary Centre for Natural Products, University of Szeged, Szeged, 6720, Hungary

    Attila Hunyadi

  6. Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA, 90089, USA

    Clay C. C. Wang

  7. Department of Chemistry, Dornsife College of Letters, Arts, and Sciences, University of Southern California, 3551 Trousdale Pkwy, Los Angeles, CA, 90089, USA

    Clay C. C. Wang

  8. Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, 807, Taiwan

    Fang-Rong Chang

  9. Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 807, Taiwan

    Fang-Rong Chang

  10. Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, 804, Taiwan

    Fang-Rong Chang

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  1. Chi-Ying Li
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  2. Yu-Ming Chung
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  3. Yang-Chang Wu
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  4. Attila Hunyadi
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  5. Clay C. C. Wang
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  6. Fang-Rong Chang
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Correspondence to Clay C. C. Wang or Fang-Rong Chang.

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Li, CY., Chung, YM., Wu, YC. et al. Natural products development under epigenetic modulation in fungi. Phytochem Rev 19, 1323–1340 (2020). https://doi.org/10.1007/s11101-020-09684-7

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