*2.1. P450 Characterization of CYP2C8\*1*/*\*2*/*\*3*/*R139*/*K399-ND*

In order to assess if these variants of CYP2C8 lead to unfolding of the protein and improper ligation of the heme group, we performed anaerobic CO-binding assays. All the variants showed a 90%–100% shift in the heme absorbance to 450 nm and resemble CYP2C8\*1 characteristics (Figure 2 and Table S2). Therefore, these variants are well-folded.

**Figure 2.** *CO-binding di*ff*erence spectra.* (**A**) CYP2C8\*1, (**B**) CYP2C8\*2, (**C**) CYP2C8\*3, (**D**) CYP2C8-R139K, and (**E**) CYP2C8-K399R.
