Cholesterol-metabolizing cytochromes P450.
By catalyzing the first steps in different pathways of cholesterol degradation, cytochromes P450 (P450s) 7A1, 27A1, 11A1, and 46A1 play key roles in cholesterol homeostasis. CYP7A1 is a microsomal liver-specific enzyme that converts cholesterol to 7alpha-hydroxycholesterol. CYP27A1 is a ubiquitously expressed mitochondrial P450 that metabolizes cholesterol to 27-hydroxycholesterol. CYP11A1 also resides in mitochondria but is expressed mainly in steroidogenic tissues, where it catalyzes the conversion of cholesterol to pregnenolone. Finally, CYP46A1 is a brain-selective microsomal monooxygenase producing 24S-hydroxycholesterol from cholesterol. Catalytic efficiencies of cholesterol-metabolizing P450s vary significantly and probably reflect physiological requirements of different organs for the rate of cholesterol turnover. P450s 7A1, 27A1, 11A1, and 46A1 represent a unique system for elucidation of how different enzymes have adapted to fit their specific roles in cholesterol elimination. Studies of cholesterol-metabolizing P450s suggest that their activities could be modulated post-translationally and that they should also be considered as targets for regulation of cholesterol homeostasis.
Pikuleva
Irina A
IA
Department of Pharmacology and Toxicology, University of Texas, Medical Branch, 301 University Blvd., Galveston, TX 77555-1031, USA. irpikule@utmb.edu
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D020134:Catalytic Domain; D053493:Cholestanetriol 26-Monooxygenase; D002784:Cholesterol / Q000378:metabolism*; D000072556:Cholesterol 24-Hydroxylase; D002790:Cholesterol 7-alpha-Hydroxylase / Q000737:chemistry / Q000378:metabolism*; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000737:chemistry / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D011487:Protein Conformation; D013250:Steroid Hydroxylases / Q000737:chemistry / Q000378:metabolism*
D000924:Anticholesteremic Agents; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D013250:Steroid Hydroxylases; D051544:Cytochrome P-450 CYP3A; D002790:Cholesterol 7-alpha-Hydroxylase; D000072556:Cholesterol 24-Hydroxylase; C510163:CYP3A4 protein, human; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; D002786:Cholesterol Side-Chain Cleavage Enzyme