Structural analysis of dioxygenases from opium poppy: towards the production of new biocatalytic tools for morphinan production

This is a White Rose BBSRC DTP funded project.

Background
Opium poppy (Papaver somniferum) remains the sole source of morphinan alkaloids. Together with their semi-synthetic derivatives these compounds represent the largest class of painkiller drugs in use today and are of major value to the pharmaceutical industry. Two dioxygenase genes, CODM and T6ODM encoding enzymes that play a central role in the production of morphine and codeine have recently been described (Hagel and Facchini, 2010 Nat Chem Biol. 6, 273-5; see figure opposite) and a first report on site-directed mutagenesis of CODM highlights the need to determine the structure of these and related enzymes from opium poppy (Runguphan et al., 2012 Chemistry & Biology 19, 674–678).

Objectives
The determination of the crystal structures of CODM and T6ODM, in the presence and absence of each of their substrates, will be completed through parallel site-directed mutagenesis at conserved sites based on alignment of the entire suite of dioxygenases expressed in poppy capsules. This studentship will provide a sound training in molecular and structural biology in the context of metabolic pathway engineering, enzyme design and biocatalysis.

Novelty and Timeliness
This project builds on recent publications from other groups and the work published in Science earlier this year by the Graham lab (Winzer et al., 2012 Science 336, 1704-1708). This area is a hot topic and there is significant industrial biotechnology potential in being able design enzymes with altered specificities and activities in this valuable branch of alkaloid metabolism.