Recently, we reported on the characterization of thermostabilized mutants of HheG from Ilumatobacter coccineus. Unlike most other HHDHs, wild-type HheG exhibits ring-opening activity with cyclic epoxides such as cyclohexene oxide (1) and limonene oxide (2). However, HheG is comparably thermolabile (𝑇 𝑚 = 38 °C in Tris-EDTA buffer containing 10% (v/v) glycerol) and shows only moderate enantioselectivity, e.g. in the desymmetrization of cyclohexene oxide (ca. 45% ee) . We found that mutations in a distal loop region confer increases in stability and activity, presumably by regulating loop dynamics. Moreover, as HheG is remarkably easy to crystallize, its immobilization as cross-linked enzyme crystals yields considerable increases in stability, too, even under various reaction conditions. In addition, a close relative of HheG, HheG2 from I. nonamiensis (74% sequence identity to HheG), also exhibited significant activity with the studied cyclic epoxides 1 and 2. Based on these findings, we were intrigued by the catalytic potential of the G-type HHDHs and hypothesized that these enzymes could provide synthetically useful activities with other cyclic epoxides. As HheG and HheG2 were previously only examined with azide and cyanide as nucleophiles, but the acceptance of other anionic nucleophilic species such as formate, cyanate, thiocyanate, and nitrite is known for HheC, we envisioned that a diversification of the nucleophile scope in the G-type HHDHs could open new opportunities for biocatalytic reaction engineering. Herein, we report on the exploration of the substrate scope of HheG, HheG2 and a newly identified, more thermostable member of the family, HheG3, with a variety of sterically demanding cyclic epoxides and anionic nucleophiles. This analysis extends the known catalytic repertoire of HHDHs and reveals thermostability under operational conditions as a major determinant for HHDH productivity.