Biosynthesis of tasikamides via pathway coupling and diazonium-mediated hydrazone formation
Naturally occurring hydrazones are rare despite the ubiquitous usage of synthetic hydrazones in the preparation of organic compounds and functional materials. In this study, we discovered a family of novel microbial metabolites (tasikamides) that share a unique cyclic pentapeptide scaffold. Surpri...
| Main Authors: | , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2022
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/155779 |
| _version_ | 1811695684366106624 |
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| author | Ma, Guang-Lei Candra, Hartono Pang, Li Mei Xiong, Juan Ding, Yichen Tran, Hoa Thi Low, Zhen Jie Ye, Hong Liu, Min Zheng, Jie Fang, Mingliang Cao, Bin Liang, Zhao-Xun |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Ma, Guang-Lei Candra, Hartono Pang, Li Mei Xiong, Juan Ding, Yichen Tran, Hoa Thi Low, Zhen Jie Ye, Hong Liu, Min Zheng, Jie Fang, Mingliang Cao, Bin Liang, Zhao-Xun |
| author_sort | Ma, Guang-Lei |
| collection | NTU |
| description | Naturally occurring hydrazones are rare despite the ubiquitous usage of synthetic hydrazones in the preparation of
organic compounds and functional materials. In this study, we discovered a family of novel microbial metabolites (tasikamides) that
share a unique cyclic pentapeptide scaffold. Surprisingly, tasikamides A−C (1−3) contain a hydrazone group (CNN) that joins
the cyclic peptide scaffold to an alkyl 5-hydroxylanthranilate (AHA) moiety. We discovered that the biosynthesis of 1−3 requires
two discrete gene clusters, with one encoding a nonribosomal peptide synthetase (NRPS) pathway for assembling the cyclic peptide
scaffold and another encoding the AHA-synthesizing pathway. The AHA gene cluster encodes three ancillary enzymes that catalyze
the diazotization of AHA to yield an aryl diazonium species (diazo-AHA). The electrophilic diazo-AHA undergoes nonenzymatic
Japp−Klingemann coupling with a β-keto aldehyde-containing cyclic peptide precursor to furnish the hydrazone group and yield 1−
3. The studies together unraveled a novel mechanism whereby specialized metabolites are formed by the coupling of two
biosynthetic pathways via an unprecedented in vivo Japp−Klingemann reaction. The findings raise the prospect of exploiting the
arylamine-diazotizing enzymes (AAD) for the in vivo synthesis of aryl compounds and modification of biological macromolecules. |
| first_indexed | 2024-10-01T07:27:23Z |
| format | Journal Article |
| id | ntu-10356/155779 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T07:27:23Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | ntu-10356/1557792024-07-09T06:39:47Z Biosynthesis of tasikamides via pathway coupling and diazonium-mediated hydrazone formation Ma, Guang-Lei Candra, Hartono Pang, Li Mei Xiong, Juan Ding, Yichen Tran, Hoa Thi Low, Zhen Jie Ye, Hong Liu, Min Zheng, Jie Fang, Mingliang Cao, Bin Liang, Zhao-Xun School of Biological Sciences School of Civil and Environmental Engineering Singapore Centre for Environmental Life Sciences and Engineering (SCELSE) Medicine, Health and Life Sciences Biosynthesis Natural Product Enzyme Peptide Naturally occurring hydrazones are rare despite the ubiquitous usage of synthetic hydrazones in the preparation of organic compounds and functional materials. In this study, we discovered a family of novel microbial metabolites (tasikamides) that share a unique cyclic pentapeptide scaffold. Surprisingly, tasikamides A−C (1−3) contain a hydrazone group (CNN) that joins the cyclic peptide scaffold to an alkyl 5-hydroxylanthranilate (AHA) moiety. We discovered that the biosynthesis of 1−3 requires two discrete gene clusters, with one encoding a nonribosomal peptide synthetase (NRPS) pathway for assembling the cyclic peptide scaffold and another encoding the AHA-synthesizing pathway. The AHA gene cluster encodes three ancillary enzymes that catalyze the diazotization of AHA to yield an aryl diazonium species (diazo-AHA). The electrophilic diazo-AHA undergoes nonenzymatic Japp−Klingemann coupling with a β-keto aldehyde-containing cyclic peptide precursor to furnish the hydrazone group and yield 1− 3. The studies together unraveled a novel mechanism whereby specialized metabolites are formed by the coupling of two biosynthetic pathways via an unprecedented in vivo Japp−Klingemann reaction. The findings raise the prospect of exploiting the arylamine-diazotizing enzymes (AAD) for the in vivo synthesis of aryl compounds and modification of biological macromolecules. Nanyang Technological University National Research Foundation (NRF) Submitted/Accepted version This research was supported by an NIMBEL grant (NIM/03/ 2017, Z.-X.L.) from Nanyang Technological Universty and an NRF-SBP grant (SBP-01 Z.-X.L.) from the National Research Foundation of Singapore. 2022-03-21T01:44:20Z 2022-03-21T01:44:20Z 2022 Journal Article Ma, G., Candra, H., Pang, L. M., Xiong, J., Ding, Y., Tran, H. T., Low, Z. J., Ye, H., Liu, M., Zheng, J., Fang, M., Cao, B. & Liang, Z. (2022). Biosynthesis of tasikamides via pathway coupling and diazonium-mediated hydrazone formation. Journal of the American Chemical Society, 144(4), 1622-1633. https://dx.doi.org/10.1021/jacs.1c10369 0002-7863 https://hdl.handle.net/10356/155779 10.1021/jacs.1c10369 4 144 1622 1633 en NIM/03/2017 NRF-SBP-01 Journal of the American Chemical Society doi:10.21979/N9/I4TNKA This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of the American Chemical Society, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/jacs.1c10369. application/pdf |
| spellingShingle | Medicine, Health and Life Sciences Biosynthesis Natural Product Enzyme Peptide Ma, Guang-Lei Candra, Hartono Pang, Li Mei Xiong, Juan Ding, Yichen Tran, Hoa Thi Low, Zhen Jie Ye, Hong Liu, Min Zheng, Jie Fang, Mingliang Cao, Bin Liang, Zhao-Xun Biosynthesis of tasikamides via pathway coupling and diazonium-mediated hydrazone formation |
| title | Biosynthesis of tasikamides via pathway coupling and diazonium-mediated hydrazone formation |
| title_full | Biosynthesis of tasikamides via pathway coupling and diazonium-mediated hydrazone formation |
| title_fullStr | Biosynthesis of tasikamides via pathway coupling and diazonium-mediated hydrazone formation |
| title_full_unstemmed | Biosynthesis of tasikamides via pathway coupling and diazonium-mediated hydrazone formation |
| title_short | Biosynthesis of tasikamides via pathway coupling and diazonium-mediated hydrazone formation |
| title_sort | biosynthesis of tasikamides via pathway coupling and diazonium mediated hydrazone formation |
| topic | Medicine, Health and Life Sciences Biosynthesis Natural Product Enzyme Peptide |
| url | https://hdl.handle.net/10356/155779 |
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