Generation of Alkaloid Diversity Using Biocatalysts

Lead Research Organisation: John Innes Centre
Department Name: Contracts Office

Abstract

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.

Publications

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Glenn WS (2013) Recent progress in the metabolic engineering of alkaloids in plant systems. in Current opinion in biotechnology

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Ruff BM (2012) Biocatalytic production of tetrahydroisoquinolines. in Tetrahedron letters

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Runguphan W (2012) Redesign of a dioxygenase in morphine biosynthesis. in Chemistry & biology

 
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