Decarboxylation and Protonation Enigma in the H85Q Mutant of Cytochrome P450.

Cytochrome P450 (CYP450), a member of CYP450 peroxygenases, catalyzes unusual decarboxylation activity. Unlike other members of the peroxygenases family, CYP450 possesses a histidine at the 85th position, which was supposed to be the root cause of the decarboxylation activity in CYP450. This work addresses the His85 → Gln mutant paradox, where mutation of His → Gln still shows efficient decarboxylation activity in CYP450. The MD simulation of the H85Q mutant of CYP450 shows that in the absence of the histidine at the 85th position, an Asp239 plays a similar role via a well-organized water channel. Our simulation shows that such a water channel is vital for the optimal substrate positioning needed for the decarboxylation activity and is gated by the Q85-N242 residue pair. Interestingly, the MD simulation of the WT CYP450BSβ shows a closed channel that blocks access to the Glu236 (analogous residue to Asp239 in CYP450), and therefore, CYP450BSβ shows low decarboxylation activity.