was obtained almost as a single regioisomer (Figure ), all four isomers of the racemic epoxide 5 were converted, affording a complex and inseparable mixture of isomers (Figure ). A similar situation existed with the combination of thiocyanate and 5, where NMR analysis of the product mixture confirmed the formation of all possible regioisomers (Figure ), albeit with synthetically useful TTNs (Figure ). In contrast, HHDH-catalyzed ring-opening with cyanate generally proved much more selective and provided moderate to high enantiocontrol for the oxazolidinones arising from 1 and 4, as HheG and HheG2 afforded 4c with >80% ee (Figure ). This result is in good agreement with previous reports from the Chen group who showed that HheG confers moderate enantiocontrol in the ring opening of styrene oxides with cyanate. With formate as the nucleophile, only 5 gave any ringopened product, while ring-opening with nitrite proceeded only with epoxides 1 and 2. While the transdiols arising from non-enzymatic hydrolysis of the epoxides in the aqueous reaction mixture constituted minor byproducts in all cases, ring-opening with nitrite yielded the cis-diol 1f* as the main product via hydrolysis of 1f (Figure ). The nitroalcohols 1f and 2f could be obtained with HheG3 with low to moderate TTNs, but the nitroalcohols arising from 3-5 were either not formed or proved too instable under our reaction conditions. Collectively, this analysis revealed that the G-type HHDHs harbor significant promiscuity regarding the accepted epoxides and nucleophiles. In addition to slight activity differences of the three HHDHs (Figure ), the catalytic performance of these enzymes appeared to be largely determined by their stability under operational conditions. As a general trend, the labile HheG2 gave the lowest TTNs and converted the fewest epoxides, while the much more stable HheG3 proved the most productive of the three enzymes. However, our dataset presents several exceptions to this trend (Figure , e.g. 2b, 5b and 5c) and studies to elucidate the reasons for this atypical behavior are ongoing. In conclusion, we have identified and characterized a new member of the G subtype of HHDHs and explored the substrate promiscuity of this enzyme and its relatives regarding their ring-opening activity with cyclic epoxides and a range of anionic nucleophiles. In contrast to other known HHDHs, G-type HHDHs convert 5-and 6-membered cyclic epoxides with a range of small anionic C-, N-, O-and Snucleophiles. Although the selectivity and activity of these enzymes toward several of the investigated epoxide-nucleophile combinations would need to be improved to deliver high yields of enantioenriched product, we anticipate that this can be achieved through protein engineering supported by computational design . As such, the catalytic promiscuity displayed by the G-type HHDHs outlined herein presents an ideal starting point for such campaigns. Lastly, we believe that the additional stability and cosolvent resistance of the newly identified HheG3 will prove useful in this regard, as the introduction of thermal and solvent stability in G-type HHDHs by means of protein engineering has historically been challenging. Financial support of AS and FK by the German Research Foundation (DFG) within the Priority Programme 1934 (DiSPBiotech) and through project 492196858, respectively, is gratefully acknowledged.