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Asymmetric ene-reduction of α,β-unsaturated compounds by F420-dependent oxidoreductases A (FDOR-A) enzymes from Mycobacterium smegmatis

Jackson, C. J.; Kang, S. W.; Antoney, J.; Scott, C.; Lupton, D.; Speight, R.

2022-11-05 biochemistry
10.1101/2022.11.05.515281 bioRxiv
Show abstract

The stereoselective reduction of alkenes conjugated to electron-withdrawing groups by ene-reductases has been extensively applied to the commercial preparation of fine chemicals. Although several different enzyme families are known to possess ene-reductase activity, the Old Yellow Enzyme (OYE) family has been the most thoroughly investigated. Recently, it was shown that a subset of ene-reductases belonging to the flavin/deazaflavin oxidoreductase (FDOR) superfamily exhibit enantioselectivity that is generally complementary to that seen in the OYE family. These enzymes belong to one of several FDOR subgroups that use the unusual deazaflavin cofactor F420. Here, we explore several enzymes of the FDOR-A subgroup, characterizing their substrate range and enantioselectivity, including the complete conversion of both isomers of citral to (R)-citronellel with 99% ee. Protein crystallography combined with computational docking has allowed the observed stereoselectivity to be mechanistically rationalized for two enzymes. These findings add further support for the FDOR and OYE families of ene-reductases being generally stereocomplementary to each other and highlight their potential value in asymmetric ene-reduction.

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