Novel sterols synthesized via the CYP27A1 metabolic pathway.
A major biologic role of the ubiquitous mitochondrial P450 enzyme CYP27A1 is the generation of ligands such as 27-hydroxycholesterol and 3 beta-hydroxy-5-cholestenoic acid, which regulate the expression of nuclear receptors that govern many aspects of cholesterol homeostasis. We now report that sterol intermediates in cholesterol synthesis, beginning with the initial post-cyclization sterol, lanosterol, continuing with zymosterol, and ending with desmosterol are also substrates for the enzyme. Using the human enzyme expressed in Escherichia coli, we characterized the retention times and major mass fragments of these novel metabolites. Although sequestration of the enzyme in the inner mitochondrial membrane and normal subcellular organization probably greatly restrict the proportion of these and other intermediates in cholesterol synthesis that undergo side chain oxidation, disruption of compartmentalization can bypass cholesterol as the end product and give rise to potent ligands that further modify gene expression.
Pikuleva
Irina
I
Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555-103, USA. irpikule@utmb.edu
Javitt
Norman B
NB
D002384:Catalysis; D053493:Cholestanetriol 26-Monooxygenase; D002784:Cholesterol / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D003684:Dehydrocholesterols / Q000737:chemistry / Q000378:metabolism; D003897:Desmosterol / Q000737:chemistry / Q000378:metabolism; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D007810:Lanosterol / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000737:chemistry* / Q000378:metabolism; D013261:Sterols / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D013379:Substrate Specificity
D003684:Dehydrocholesterols; D011994:Recombinant Proteins; D013261:Sterols; D007810:Lanosterol; D003897:Desmosterol; D002784:Cholesterol; C016705:7-dehydrocholesterol; D013250:Steroid Hydroxylases; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; C015582:zymosterol