Tryptophan-75 Is a Low-Energy Channel-Gating Residue that Facilitates Substrate Egress/Access in Cytochrome P450 2D6

Cytochrome P450 Monooxygenases Catalyse Steroid Nucleus Hydroxylation with Regio‐ and Stereo‐Selectivity

“…[94] W75 is a low-energy channel-gating residue facilitating substrate egress/access. [95] The CYP2D6 mutant F483I can convert 3 to 15α-OH-TST. [92b] A double site SM, focused on residues 216 and 483 of CYP2D6, successfully altered the catalytic sites successfully to afford 2β hydroxylation derivatives.…”

“…Residues E216 and D301 are key determinants of substrate specificity and product regioselectivity [94] . W75 is a low‐energy channel‐gating residue facilitating substrate egress/access [95] . The CYP2D6 mutant F483I can convert 3 to 15α‐OH‐TST [92b] .…”

How does multiple substrate binding lead to substrate inhibition of CYP2D6 metabolizing dextromethorphan? A theoretical study

“…Previous studies focused on exploring the interactions between CYP2D6 and drugs and aimed to reveal how the structural changes of CYP2D6 affect its interactions with substrates. For instance, several groups compared the drug metabolism differences between wild type and the allelic variants of CYP2D6, [3][4][5] explored the role of the channel gating residue (Trp75) in CYP2D6's reactivity 6 and proposed the access pathway to the buried catalytic site of CYP2D6 for the ligand. [7][8][9][10] Additional studies aimed to explore the mechanism of CYP2D6 metabolizing drugs, which turns out to be a stepwise process (taking the CYP2D6-dependent O-demethylation reaction as an example): the hydrogen atom transfers from the substrate -OCH 3 species to compound I (Cpd I, a high-valent iron-oxo derivative of the active site heme group 11 ), forming a hydroxy group that coordinates with the iron atom.…”