Wang, Yu;
(2021)
Design and use of de novo cascades for new benzylisoquinoline alkaloid biosynthesis.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The benzylisoquinoline alkaloids (BIAs) are one of the most structurally diverse group of compounds among higher plant secondary metabolites. To date, they have been reported to show significant pharmaceutical activities and have been wildly applied in pharmaceutical industries, such as the anti-tumour agent noscapine, the anti-HIV agent norcoclaurine and anti-microbial agent berberine. Natural benzylisoquinoline alkaloids share a common BIA skeleton and are generated from (S)-norcoclaurine, which is produced from the condensation of 4-hydroxyphenylacetaldehyde (4-HPAA) and dopamine. Currently, BIAs are mainly obtained by plant extraction. However, the yield is normally not high due to the low accumulation level of those BIAs in native plant cells, along with other complex metabolites with similar chemical properties. The isolation procedures are also time consuming. Recent advances in chemical total synthesis have contributed to the synthesis of some BIAs with increased yields. However, the complex reactions and lack of regio- and stereochemistry limit their application on an industrial scale. The production of BIAs via synthetic biology approaches can provide a higher yielding strategy compared to the traditional synthetic methods and plant isolation methods. Meanwhile, the reconstruction of BIAs pathways in microorganisms combining heterologous enzymes can also give access to BIAs via cascade reactions in vitro. Importantly, non-natural BIAs can be generated through such artificial pathways. This study describes the synthesis of BIAs by enzyme cascades in vitro using a ‘mix and match’ strategy. Several non-natural BIAs were generated utilizing tyrosinases, decarboxylases, transaminases and norcoclaurine synthases in cascades from amino acids. Additionally, enzyme mutagenesis was applied to a tyrosinase to extend the substrate scope of the enzyme cascades. Interestingly, several hydroxystyryl pyridines were also observed as by-products in some of the cascades, and the synthesis of the styryl pyridines has been further explored.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Design and use of de novo cascades for new benzylisoquinoline alkaloid biosynthesis |
| Event: | University College London |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10121404 |
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| 2. |  United States | 8 |
| 3. |  China | 3 |
| 4. |  Finland | 1 |
| 5. |  Israel | 1 |
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