Cholesterol 24-hydroxylase

In enzymology, a cholesterol 24-hydroxylase (EC 1.14.13.98) is an enzyme that catalyzes the chemical reaction In enzymology, a cholesterol 24-hydroxylase (EC 1.14.13.98) is an enzyme that catalyzes the chemical reaction The 4 substrates of this enzyme are cholesterol, NADPH, H+, and O2, whereas its 3 products are (24S)-24-hydroxycholesterol, NADP+, and H2O. The systematic name of this enzyme class is cholesterol,NADPH:oxygen oxidoreductase (24-hydroxylating). Other common names include cholesterol 24-monooxygenase, CYP46, CYP46A1, cholesterol 24S-hydroxylase, and cytochrome P450 46A1. This enzyme belongs to the highly conserved family of enzymes known as cytochrome P450s (CYP). Like many other cholesterol-targeting cytochrome P450s, Cholesterol-24 hydroxylase is a monooxygenase that hydroxylates the side-chain of cholesterol. Present mainly in the brain, this enzyme works to convert cholesterol from degraded neurons into 24S-hydroxycholesterol to allow for the elimination of cholesterol from the brain. Because the highly aliphatic cholesterol is normally unable to pass the blood-brain barrier, Cholesterol-24 hydroxylase is required to convert cholesterol into the more polar 24S-hydroxycholesterol to allow for passage into the bloodstream, where it is then carried to the liver for degradation. This enzyme has also been found in insignificant quantities in the retina, where it serves a similar (but limited) function of catalyzing the hydroxylation of cholesterol for cholesterol-elimination from the eye. Genetic cloning of encoding gene (CYP46A1) was first accomplished in 1999 and an extensive Escherichia coli expression and purification system was later developed in 2003. 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 residues) monomeric heme-containing protein bound to the endoplasmic reticulum in neurons. Cholesterol-24 hydroxylase is similar in structure to many other cytochrome P450s, possessing, for example, the conserved stretch of 23 hydrophobic residues in the N-terminus that make up a transmembrane-anchoring domain (residues 3-27). 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.