Sustainable Enzymatic pathways to novel and non-natural alkaloids

Project ID: 2531ad1510

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Research Theme: Manufacturing The Future

UCL Lead department: Chemistry

Project Summary:

Tetrahydroisoquinoline alkaloids (THIAs) are a diverse group of metabolites with significant therapeutic activities, such as the anti-bacterial berberine, analgesic morphine and anti-psychotic aporphine. New stereoselective routes to THIAs are highly sought after as they are privileged pharmacophores. We have recently pioneered the use of enzyme cascades to make known and novel THIAs.

We have recently developed an NCS mutant that can synthesise THIAs with inverted stereochemistry compared to the wild-type enzyme. This is a key discovery as it enables access to (R)-norcoclaurine, the key first intermediate in the biosynthetic route to morphine and other alkaloids, but they are normally generated via (S)-norcoclaurine and a subsequent inversion of the stereochemistry. Access to the (R)-product means that a shorter pathway can be constructed to many THIAs. Our overall aim is use these enzymes, together with other enzymes, in cascades to produce alkaloids via scalable processes.

Initial studies will focus on using the (R)-selective NCS with a range of phenethylamines and aldehydes to probe the substrates accepted. Enzyme mutagenesis will be carried out to increase activities, and substrate scope. In subsequent years, other enzymes will be used to tailor products of the NCS reaction to produce more complex alkaloids, and construct sustainable enzyme cascades.

This is a collaborative project between Helen Hailes (primary supervisor), and Jack Jeffries (subsidiary supervisor - Biochemical Engineering). For this project we are seeking a talented organic/biological chemist who wishes to develop sustainable biocatalytic cascades. They will need to work in an interdisciplinary environment, and be keen to learn new skills.