Molecular breeding of a fungus producing a precursor diterpene suitable for semi-synthesis by dissection of the biosynthetic machinery.
Many clinically useful pharmaceuticals are semi-synthesized from natural products produced by actinobacteria and fungi. The synthetic protocols usually contain many complicated reaction steps and thereby result in low yields and high costs. It is therefore important to breed microorganisms that prod...
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2012
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oai:doaj.org-article:df1cc149159240dfa4e787f5d52cfc832021-11-18T07:10:05ZMolecular breeding of a fungus producing a precursor diterpene suitable for semi-synthesis by dissection of the biosynthetic machinery.1932-620310.1371/journal.pone.0042090https://doaj.org/article/df1cc149159240dfa4e787f5d52cfc832012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22870285/?tool=EBIhttps://doaj.org/toc/1932-6203Many clinically useful pharmaceuticals are semi-synthesized from natural products produced by actinobacteria and fungi. The synthetic protocols usually contain many complicated reaction steps and thereby result in low yields and high costs. It is therefore important to breed microorganisms that produce a compound most suitable for chemical synthesis. For a long time, desirable mutants have been obtained by random mutagenesis and mass screening. However, these mutants sometimes show unfavorable phenotypes such as low viability and low productivity of the desired compound. Fusicoccin (FC) A is a diterpene glucoside produced by the fungus Phomopsis amygdali. Both FC and the structurally-related cotylenin A (CN) have phytohormone-like activity. However, only CN exhibits anti-cancer activity. Since the CN producer lost its ability to proliferate during preservation, a study on the relationship between structure and activity was carried out, and elimination of the hydroxyl group at position 12 of FC was essential to mimic the CN-like activity. Based on detailed dissection of the biosynthetic machinery, we constructed a mutant producing a compound without a hydroxyl group at position 12 by gene-disruption. The mutant produced this compound as a sole metabolite, which can be easily and efficiently converted into an anti-cancer drug, and its productivity was equivalent to the sum of FC-related compounds produced by the parental strain. Our strategy would be applicable to development of pharmaceuticals that are semi-synthesized from fungal metabolites.Motoyoshi NoikeYusuke OnoYuji ArakiRyo TanioYusuke HiguchiHajime NittaYoshimitsu HamanoTomonobu ToyomasuTakeshi SassaNobuo KatoTohru DairiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 8, p e42090 (2012) |
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Medicine R Science Q |
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Medicine R Science Q Motoyoshi Noike Yusuke Ono Yuji Araki Ryo Tanio Yusuke Higuchi Hajime Nitta Yoshimitsu Hamano Tomonobu Toyomasu Takeshi Sassa Nobuo Kato Tohru Dairi Molecular breeding of a fungus producing a precursor diterpene suitable for semi-synthesis by dissection of the biosynthetic machinery. |
| description |
Many clinically useful pharmaceuticals are semi-synthesized from natural products produced by actinobacteria and fungi. The synthetic protocols usually contain many complicated reaction steps and thereby result in low yields and high costs. It is therefore important to breed microorganisms that produce a compound most suitable for chemical synthesis. For a long time, desirable mutants have been obtained by random mutagenesis and mass screening. However, these mutants sometimes show unfavorable phenotypes such as low viability and low productivity of the desired compound. Fusicoccin (FC) A is a diterpene glucoside produced by the fungus Phomopsis amygdali. Both FC and the structurally-related cotylenin A (CN) have phytohormone-like activity. However, only CN exhibits anti-cancer activity. Since the CN producer lost its ability to proliferate during preservation, a study on the relationship between structure and activity was carried out, and elimination of the hydroxyl group at position 12 of FC was essential to mimic the CN-like activity. Based on detailed dissection of the biosynthetic machinery, we constructed a mutant producing a compound without a hydroxyl group at position 12 by gene-disruption. The mutant produced this compound as a sole metabolite, which can be easily and efficiently converted into an anti-cancer drug, and its productivity was equivalent to the sum of FC-related compounds produced by the parental strain. Our strategy would be applicable to development of pharmaceuticals that are semi-synthesized from fungal metabolites. |
| format |
article |
| author |
Motoyoshi Noike Yusuke Ono Yuji Araki Ryo Tanio Yusuke Higuchi Hajime Nitta Yoshimitsu Hamano Tomonobu Toyomasu Takeshi Sassa Nobuo Kato Tohru Dairi |
| author_facet |
Motoyoshi Noike Yusuke Ono Yuji Araki Ryo Tanio Yusuke Higuchi Hajime Nitta Yoshimitsu Hamano Tomonobu Toyomasu Takeshi Sassa Nobuo Kato Tohru Dairi |
| author_sort |
Motoyoshi Noike |
| title |
Molecular breeding of a fungus producing a precursor diterpene suitable for semi-synthesis by dissection of the biosynthetic machinery. |
| title_short |
Molecular breeding of a fungus producing a precursor diterpene suitable for semi-synthesis by dissection of the biosynthetic machinery. |
| title_full |
Molecular breeding of a fungus producing a precursor diterpene suitable for semi-synthesis by dissection of the biosynthetic machinery. |
| title_fullStr |
Molecular breeding of a fungus producing a precursor diterpene suitable for semi-synthesis by dissection of the biosynthetic machinery. |
| title_full_unstemmed |
Molecular breeding of a fungus producing a precursor diterpene suitable for semi-synthesis by dissection of the biosynthetic machinery. |
| title_sort |
molecular breeding of a fungus producing a precursor diterpene suitable for semi-synthesis by dissection of the biosynthetic machinery. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/df1cc149159240dfa4e787f5d52cfc83 |
| work_keys_str_mv |
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