Question

Cytochrome P450 (CYP) enzymes catalyze stereoselective C-H hydroxylation of hydrocarbons in the presence of O\( _2 \). The correct statement(s) about the structure and activity of CYP is/are

• A. A thiolate group is coordinated to the Fe center at one of the axial positions around Fe.
• B. While one of the oxygen atoms of O\( _2 \) is inserted into a C-H bond of a hydrocarbon, the other oxygen atom gets reduced to water.
• C. An imidazole group is coordinated to the Fe center at one of the axial positions around Fe.
• D. An iron-oxo species acts as a key oxidant in the catalytic cycle of CYP.

Hint:

Cytochrome P450 enzymes are unique due to their thiolate axial ligand to the heme iron. They function as monooxygenases, inserting one oxygen atom into the substrate and reducing the other to water, with a high-valent iron-oxo species being the active oxidant.

Answer 1

The Correct Option is A, B, D

Cytochrome P450 (CYP) enzymes are a superfamily of heme-containing monooxygenases that play a crucial role in the metabolism of various endogenous and xenobiotic compounds. Let's analyze each statement:

(A) A thiolate group is coordinated to the Fe center at one of the axial positions around Fe.
The heme cofactor in CYP enzymes has an iron center. A unique characteristic of CYPs is that the iron center is coordinated to a thiolate ligand from a cysteine residue of the protein at one of the axial positions. This Fe–S bond is crucial for the enzyme's electronic and catalytic properties.
✅ Correct

(B) While one of the oxygen atoms of O₂ is inserted into a C–H bond of a hydrocarbon, the other oxygen atom gets reduced to water.
CYP enzymes are monooxygenases, meaning they incorporate only one atom of molecular oxygen into the substrate. The overall reaction catalyzed by CYP enzymes is:

RH + O₂ + NADPH + H⁺ → ROH + H₂O + NADP⁺

Here, one oxygen atom is inserted into the hydrocarbon to form an alcohol (ROH), while the other is reduced to water using electrons from NADPH and protons.
✅ Correct

(C) An imidazole group is coordinated to the Fe center at one of the axial positions around Fe.
While imidazole (from histidine) is the axial ligand in proteins like hemoglobin and myoglobin, CYP enzymes use a cysteine thiolate instead. Hence, CYPs do not feature an axial imidazole ligand.
❌ Incorrect

(D) An iron-oxo species acts as a key oxidant in the catalytic cycle of CYP.
Yes, the reactive intermediate in the CYP catalytic cycle is a high-valent iron-oxo species, specifically Fe(IV)=O (ferryl-oxo), which is responsible for C–H bond activation and substrate hydroxylation.
✅ Correct

Conclusion:
Statements (A), (B), and (D) are correct.