Total mycosynthesis

Total mycosynthesis[1] is the combination of the use of a filamentous fungal host organism with a genetic expression system that allows the assembly and controlled expression of one or more biosynthetic genes. Total mycosynthesis involves the reconstruction and/or engineering of biosynthetic pathways for the production of secondary metabolites. It is competitive with chemical total synthesis. It can be used both for the production of known natural products, and for the engineering of pathways to produce new compounds or pathway intermediates.

Total MycoSynthesis and Engineering of the Fungal Metabolite Tenellin

Examples include the total mycosynthesis of tenellin[2] where the tenS, tenC, tenA and tenB genes were transferred from Beauveria bassiana to the expression host Aspergillus oryzae. The expression system allows the engineering of TenS to control chain-length and methylation pattern.[3][4]

Examples
Metabolite Year Group Host Step Count Titre mg/L Reference
Citridone B 2020 Watanabe

Tang

 A. nidulans 6 0.6 https://doi.org/10.1002/anie.202008321
Monacolin J 2022 Wang A. niger 3 143 https://doi.org/10.3390/jof8040407
Tenellin 2010 Cox

Lazarus

 A. oryzae 3 200 https://doi.org/10.1002/cbic.201000259
Aurovertin B 2016 CCC Wang A. nidulans 7 nd https://doi.org/10.1021/acs.orglett.6b00299
Anditomin 2014 Abe A. oryzae 13 5 https://doi.org/10.1021/ja508127q
Xenovulene A 2018 Cox A. oryzae 9 0.5 https://doi.org/10.1038/s41467-018-04364-9

References
  1. Kahlert, Lukas; Schotte, Carsten; Cox, Russell J. (July 2021). "Total Mycosynthesis: Rational Bioconstruction and Bioengineering of Fungal Natural Products". Synthesis. 53 (14): 2381–2394. doi:10.1055/a-1401-2716. ISSN 0039-7881. S2CID 233967389.
  2. Heneghan, Mary N.; Yakasai, Ahmed A.; Halo, Laura M.; Song, Zhongshu; Bailey, Andrew M.; Simpson, Thomas J.; Cox, Russell J.; Lazarus, Colin M. (2010-06-23). "First Heterologous Reconstruction of a Complete Functional Fungal Biosynthetic Multigene Cluster". ChemBioChem. 11 (11): 1508–1512. doi:10.1002/cbic.201000259. PMID 20575135. S2CID 45670640.
  3. Fisch, Katja M.; Bakeer, Walid; Yakasai, Ahmed A.; Song, Zhongshu; Pedrick, Jennifer; Wasil, Zahida; Bailey, Andrew M.; Lazarus, Colin M.; Simpson, Thomas J. (2011-09-26). "Rational Domain Swaps Decipher Programming in Fungal Highly Reducing Polyketide Synthases and Resurrect an Extinct Metabolite". Journal of the American Chemical Society. 133 (41): 16635–16641. doi:10.1021/ja206914q. PMID 21899331. Retrieved 2021-07-09.
  4. Yang, Xiao-Long; Friedrich, Steffen; Yin, Sen; Piech, Oliver; Williams, Katherine; Simpson, Thomas J.; Cox, Russell J. (2019). "Molecular basis of methylation and chain-length programming in a fungal iterative highly reducing polyketide synthase". Chemical Science. 10 (36): 8478–8489. doi:10.1039/C9SC03173A. ISSN 2041-6520. PMC 6839510. PMID 31803427.


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