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Genomics-directed activation of cryptic natural product pathways deciphers codes for biosynthesis and molecular function

Natural products, which can be isolated from living organisms worldwide, have played a pivotal role in drug discovery since ancient times. However, it has become more challenging to identify a structurally novel molecule with promising biological activity for pharmaceutical development, mainly due t...

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Autor principal: Tsunematsu, Yuta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Singapore 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902601/
https://www.ncbi.nlm.nih.gov/pubmed/33274411
http://dx.doi.org/10.1007/s11418-020-01466-x
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author Tsunematsu, Yuta
author_facet Tsunematsu, Yuta
author_sort Tsunematsu, Yuta
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description Natural products, which can be isolated from living organisms worldwide, have played a pivotal role in drug discovery since ancient times. However, it has become more challenging to identify a structurally novel molecule with promising biological activity for pharmaceutical development, mainly due to the limited methodologies for their acquisition. In this review, we summarize our recent studies that activate the biosynthetic potential of filamentous fungi by genetic engineering to harness the metabolic flow for the efficient production of unprecedented natural products. The recent revolution in genome sequencing technology enables the accumulation of vast amounts of information on biosynthetic genes, the blueprint of the molecular construction. Utilizing the established heterologous expression system, activation of the pathway-specific transcription factor coupled with a knockout strategy, and manipulating the global regulatory gene, the biosynthetic genes were exploited to activate biosynthetic pathways and decipher the encoded enzyme functions. We show that this methodology was beneficial for acquiring fungal treasures for drug discovery. These studies also enabled the investigation of the molecular function of natural products in fungal development.
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spelling pubmed-79026012021-03-05 Genomics-directed activation of cryptic natural product pathways deciphers codes for biosynthesis and molecular function Tsunematsu, Yuta J Nat Med Review Natural products, which can be isolated from living organisms worldwide, have played a pivotal role in drug discovery since ancient times. However, it has become more challenging to identify a structurally novel molecule with promising biological activity for pharmaceutical development, mainly due to the limited methodologies for their acquisition. In this review, we summarize our recent studies that activate the biosynthetic potential of filamentous fungi by genetic engineering to harness the metabolic flow for the efficient production of unprecedented natural products. The recent revolution in genome sequencing technology enables the accumulation of vast amounts of information on biosynthetic genes, the blueprint of the molecular construction. Utilizing the established heterologous expression system, activation of the pathway-specific transcription factor coupled with a knockout strategy, and manipulating the global regulatory gene, the biosynthetic genes were exploited to activate biosynthetic pathways and decipher the encoded enzyme functions. We show that this methodology was beneficial for acquiring fungal treasures for drug discovery. These studies also enabled the investigation of the molecular function of natural products in fungal development. Springer Singapore 2020-12-03 2021 /pmc/articles/PMC7902601/ /pubmed/33274411 http://dx.doi.org/10.1007/s11418-020-01466-x Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Review
Tsunematsu, Yuta
Genomics-directed activation of cryptic natural product pathways deciphers codes for biosynthesis and molecular function
title Genomics-directed activation of cryptic natural product pathways deciphers codes for biosynthesis and molecular function
title_full Genomics-directed activation of cryptic natural product pathways deciphers codes for biosynthesis and molecular function
title_fullStr Genomics-directed activation of cryptic natural product pathways deciphers codes for biosynthesis and molecular function
title_full_unstemmed Genomics-directed activation of cryptic natural product pathways deciphers codes for biosynthesis and molecular function
title_short Genomics-directed activation of cryptic natural product pathways deciphers codes for biosynthesis and molecular function
title_sort genomics-directed activation of cryptic natural product pathways deciphers codes for biosynthesis and molecular function
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902601/
https://www.ncbi.nlm.nih.gov/pubmed/33274411
http://dx.doi.org/10.1007/s11418-020-01466-x
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