Generation of Alkaloid Diversity Using Biocatalysts
Lead Research Organisation:
John Innes Centre
Department Name: UNLISTED
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
The enzymes responsible for the biosynthesis of natural products represent a phenomenal starting point for mechanistic and engineering studies. In this proposal we use enzyme engineering as both a tool to understand mechanism and as a means to generate enzymes with new catalytic activities.
General Objectives - Collectively, the experiments described in this proposal will enable the generation of a broad base of biocatalysts that will catalyse the stereoselective production of a variety of beta-carbolines, a chemical scaffold widely used in pharmaceuticals. The work will also provide a mechanistic framework to understand the mode of stereoselectivity in other enzymes. We focus on the Pictet-Spenglerase from indole alkaloid biosynthesis, strictosidine synthase, as well as several halogenases that catalyse chlorination of indoles.
General Objectives - Collectively, the experiments described in this proposal will enable the generation of a broad base of biocatalysts that will catalyse the stereoselective production of a variety of beta-carbolines, a chemical scaffold widely used in pharmaceuticals. The work will also provide a mechanistic framework to understand the mode of stereoselectivity in other enzymes. We focus on the Pictet-Spenglerase from indole alkaloid biosynthesis, strictosidine synthase, as well as several halogenases that catalyse chlorination of indoles.
Planned Impact
unavailable
People |
ORCID iD |
| Sarah O'Connor (Principal Investigator) |
Publications
Glenn WS
(2013)
Recent progress in the metabolic engineering of alkaloids in plant systems.
in Current opinion in biotechnology
Ruff BM
(2012)
Biocatalytic production of tetrahydroisoquinolines.
in Tetrahedron letters
Runguphan W
(2012)
Redesign of a dioxygenase in morphine biosynthesis.
in Chemistry & biology
Runguphan W
(2013)
Diversification of monoterpene indole alkaloid analogs through cross-coupling.
in Organic letters
| Description | We have developed new ways to halogenate high value alkaloids and derivatize them further. THIS GRANT IS LISTED THREE TIMES IN RESEARCHFISH, ONCE IN THE BBSRC SECTION AND TWICE IN THE EPSRC SECTION. We have developed new ways to halogenate high value alkaloids and derivatize them further. This has substantial impact in terms of being able to produce new to nature compounds with potential use to industry. We have taken this research forward by continuing to use heterologous production platforms to generate novel halogenated plant natural products. We have also taken the Pictet SPengler work and are currently using it to discover a new class of Pictet Spenglerase in medicianl plants; this work is funded by the ERC. |
| Exploitation Route | This work can expand the usefulness and applications of plant derived natural products. |
| Sectors | Chemicals Manufacturing including Industrial Biotechology |
| Description | Buell Group Bioinformatics |
| Organisation | Michigan State University |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | The Buell group has provided sequencing and bioinformatics support for our plants. We do the functional characterisation and biochemistry. |
| Collaborator Contribution | The Buell group has seqeunced plants for us, assembled genomes/transcriptomes/annotated them, provided extensive bioinformatics support. |
| Impact | Numerous papers (see publications); an NSF grant from the USA; an extensive database of plant sequence data; more papers underway |
| Start Year | 2009 |
| Description | Transporter Collaboration |
| Organisation | University of Copenhagen |
| Department | Department of Plant and Environmental Sciences |
| Country | Denmark |
| Sector | Academic/University |
| PI Contribution | Collaboration with University of Copenhagen PIs Barbara Halkier and Hassam Nour Eldin. They perform biochemical assays with plant transporters that we have identified. |
| Collaborator Contribution | They performed assay of transporters in oocytes. |
| Impact | Publication in Nature Plants in 2017 |
| Start Year | 2016 |
| Description | Talk at Kew Gardens |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Public/other audiences |
| Results and Impact | A Kew organized event called "State of the World's Plants" |
| Year(s) Of Engagement Activity | 2017 |