Biocatalytic Cascades toward Iminosugar Scaffolds Reveal Promiscuous Activity of Shikimate Dehydrogenases

Iminosugar scaffolds are highly sought-after pharmaceutical targets, but their chemical synthesis is lengthy and can suffer from poor scalability and purification. Here we report protectinggroup-free chemoenzymatic and biocatalytic cascades to synthesize iminosugars from sugar-derived aminopolyols in two steps. Using galactose oxidase variant F-2 followed by a chemical or enzymatic reduction provided an efficient one-pot route to these targets, with product formation >70%. Key to success of this strategy was the application of genome mining, which identified bacterial shikimate dehydrogenases as promiscuous iminosugar reductases. The cell-free protocols allowed for isolation of highly polar iminosugar products from biotransformations in a single step through development of a gradient-elution cation exchange purification. The two-step pathway provides a short synthetic route that can be used as a cell-free platform for broader iminosugar synthesis.

Automated summary

In this study, a protecting group-free chemoenzymatic and biocatalytic cascade was developed to synthesize iminosugars from sugar-derived aminopolyols in two steps. The use of galactose oxidase variant F-2 followed by a chemical or enzymatic reduction allowed for efficient one-pot synthesis of these targets, with a product formation rate of over 70%. Genome mining was utilized to identify bacterial shikimate dehydrogenases as promiscuous iminosugar reductases, which was crucial for the success of this strategy. The cell-free protocols enabled isolation of highly polar iminosugar products from biotransformations in a single step through the development of a gradient-elution cation exchange purification. This two-step pathway provides a short synthetic route that can serve as a cell-free platform for broader iminosugar synthesis.