Cholesterol 24-hydroxylase

[2][6] The enzymatic structure of the human cholesterol-24 hydroxylase was determined via crystallography at the Stanford Synchrotron Radiation Lightsource, and was shown to be a 57kDa (500 residue) monomeric heme-containing protein bound to the endoplasmic reticulum in neurons.

[7] Even so, the cholesterol-24 hydroxylase C-terminus has a unique proline-rich region of 5 repeated proline residues, a structural motif absent in all other related cytochrome p450 enzymes.

While the exact function of these proline residues remain highly speculative, it has been shown that the deletion of this region results in a two-fold decrease in the enzyme’s catalytic efficiency.

[11] Only around 6–7 mg of cholesterol, however, are hydroxylated by this enzyme on a daily basis, suggesting the existence of alternative functions – presently unknown.

[16] As a result, there is a marked increase of cholesterol in the brain tissue,[17] consistent with the trend observed in AD patients.

While some studies have shown that polymorphisms in the encoding gene for cholesterol-24 hydroxylase have an established positive correlation with AD onset, other publications did not find such an association.

[20][21] Increased expression of cholesterol-24 hydroxylase has also been observed in patients of traumatic brain injury, leading to decreased levels of cholesterol in the plasma membrane.

[13] The ability for inhibition by various xenobiotics makes this enzyme a prime candidate for drug therapy for AD or other brain injuries.

Cholesterol-24 hydroxylase active site and heme molecule with bound cholesterol 3-sulfate. Hydrophobic residues interacting with the aliphatic tail of the cholesterol are labelled in white. Created in pyMOL from PDB 2Q9F
Cholester-24 hydroxylase (CYP46A1) with placement of active site shown in red. created in pyMOL from PDB 2Q9F.
Cholesterol-24 hydroxylase mechanism. The heme molecule forms an oxyferryl intermediate that abstracts a hydrogen from cholesterol. The subsequent alkyl intermediate then reacts with the activated oxygen to form the final product. [ 9 ] [ 10 ]
Substrates metabolized by cholesterol-24 hydroxylase. The red box contains a list of xenobiotics the enzyme can metabolize. The reactions in blue are commonly observed in the brain as part of maintaining cholesterol homeostasis.