An
enzymatic biosynthesis approach is described for codeine, the
most widely used medicinal opiate, providing a more environmentally
sustainable alternative to current chemical conversion, with yields
and productivity compatible with industrial production. Escherichia coli strains were engineered to express
key enzymes from poppy, including the recently discovered neopinone
isomerase, producing codeine from thebaine. We show that compartmentalization
of these enzymes in different cells is an effective strategy that
allows active spatial and temporal control of reactions, increasing
yield and volumetric productivity and reducing byproduct generation.
Codeine is produced at a yield of 64% and a volumetric productivity
of 0.19 g/(L·h), providing the basis for an industrially applicable
aqueous whole-cell biotransformation process. This approach could
be used to redirect thebaine-rich feedstocks arising from the U.S.
reduction of opioid manufacturing quotas or applied to enable total
biosynthesis and may have broader applicability to other medicinal
plant compounds.
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