Sterol 27-hydroxylases

Figure 26-7. Biosynthesis and degradation of bile acids. A second pathway in mitochondria involves hy-droxylation of cholesterol by sterol 27-hydroxylase. Asterisk Catalyzed by microbial enzymes.

Cali JJ, Hsieh CL, Francke U, Russell DW. 1991. Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis. J Biol Chem 266 7779-7783. 

Sugama S, Kimura A, Chen W, Kubota S, Sepma Y, et al. 2001. Frontal lobe dementia with abnormal cholesterol metabolism and heterozygous mutation in sterol 27-hydroxylase gene CYP27). J Inherit Metab Dis 24 379-392. 

Wakamatsu N, Hayashi M, Kawai H, Kondo H, Gotoda Y, et al. 1999. Mutations producing premature termination of translation and an amino acid substitution in the sterol 27-hydroxylase gene cause cerebrotendinous xanthomatosis associated with parkinsonism. J Neurol Neurosurg Psychiatry 67 195-198. 

Babiker A, Andersson O, Lund E, et al. Elimination of cholesterol in macrophages and endothelial cells by the sterol 27-hydroxylase mechanism. Comparison with high-density lipoprotein-mediated reverse cholesterol transport. J Biol Chem 1997 272 26253-26261. 

Bjorkhem, I., Andersson, O., Diczfalusy, U., Sevastik, B., Xiu, R.-J., Duan, C., Lund, E.G. 1994. Atherosclerosis and sterol 27-hydroxylase evidence for a role of this enzyme in elimination of cholesterol from human macrophages. Proc. Natl. Acad Sci. USA 91, 8592-8596. 

While these studies were in progress, Reshef etal. reported the analysis of die sterol 27-hydroxylase gene mutant allele in a Jewish family of Algerian origin (64). They further stated that the CTX disorder which is characterized by extensive nervous system involvement, juvenile cataracts, tendon xanthomatosis and premature atheroselerosis was caused by the sterol 27-... 

Leitersdorf, E., Reshef, A., Meiner, V., Levitzki, R., Schwartz, S. P., Dann, E. J., Berkman, N., Cali, J. J., Klapholz, L. and Berginer, V. M. (1993). Frameshift and splice-j-junction mutations in the sterol 27-hydroxylase gene cause cerebrotendinous xanthomathosis in Jews of Moroccan origin., /. Clin. Invest. 91 2488-2496. 

Cali, J. J., Russell, D. W. (1991). Characterization of the human sterol 27-hydroxylase a mitochondrial P-4S0 that catalyzes mutiple oxidation reactions in bile acid biosyntheis. J. Biol. Chem. 266 lllA-111%. 

A 17-year-old female, whose parents were first cousins, presents to a neurologist because of recurring seizures despite being on anticonvul-sive therapy. Nodules that appeared to be fatty deposits were present on her Achilles tendon and several of her joints. Plasma cholesterol concentrations were elevated, and an assay of plasma sterols indicated elevated cholestanol. Cultured skin fibroblasts did not contain any sterol 27-hydroxylase activity. A diagnosis of cerebrotendinous xanthomatosis, a genetic disease inherited in an autosomal fashion, was made. A deficiency in sterol 27-hydroxylase would lead to a decrease in the synthesis of which of the following compounds ... 

A. The enzyme sterol 27-hydroxylase catalyzes the hydroxylation of carbon 27 of the steroid side chain in the conversion of cholesterol to the primary bile acids. It is a mitochondrial, cytochrome P450 enzyme that has a broad specificity and can act on cholesterol as well as its reduced and hydroxylated metabolites. A deficiency in this enzyme leads to decreased bile acid synthesis and increased conversion of cholesterol to cholestanol. 

Meir, K., Kitsberg, D., Alkalay, I., Szafer, F., Rosen, H., Shpitzen, S., Avi, L. B., Staels, B., Fievet, C., Meiner, V., et al. (2002) Human sterol 27-hydroxylase (CYP27) overexpressor transgenic mouse model. Evidence against 27-hydroxycholesterol as a critical regulator of cholesterol homeostasis. J. Biol. Chem. 277, 34036-34041. 

Fig. 4. The bile acid biosynthetic pathways. The classical pathway operates entirely in the liver and cholesterol 7a-hydroxylase (CYP7A1) initiates the pathway. In other tissues, the entry of cholesterol into the alternate pathways is facilitated by sterol 27-hydroxylase (CYP27A1), cholesterol 24-hydroxylase (CYP46A1), and cholesterol 25-hydroxylase (CH25H). The oxysterols generated by these enzynies are 7a-hydroxylated by oxysterol 7a-hydroxylases CYP7B1 and CYP39A1, and the products enter the latter steps of the classical pathway.

The existence of an alternate pathway for the synthesis of bile acids was suspected because it was possible for oxysterols to be converted into bile acids (N. Wachtel, 1968). It is now recognized that a variety of oxysterols produced by an assortment of cell types can be converted into bile acids. The production of these oxysterols is catalyzed by several sterol hydroxylases sterol 27-hydroxylase (CYP27A1) (J.J. Cali, 1991), cholesterol 25-hydroxylase (CH25H) (E.G. Lund, 1998), and cholesterol 24-hydroxylase (CYP46A1) (E.G. Lund, 1999). Cholesterol 25-hydroxylase is not a cytochrome P-450 monooxygenase, unlike the two other enzymes. Almost all of the 24-hydroxycholesterol that ends up in the liver originates from the brain, and it has been suggested that the production of... 

Rosen, H., Reshef, A., Maeda, N., Lippoldt, A., Shpizen, S., Triger, L., Eggertsen, G., Bjorkhem, I., Leitersdorf, E. 1998. Markedly reduced bile acid synthesis but maintained levels of cholesterol and vitamin D metabolites in mice with disrupted sterol 27-hydroxylase gene. J. Biol. Chem. 273 14805-14812. 

Oxysterols have diverse roles in cholesterol efflux, a critical topic in foam cell biology. On the one hand, cells incubated with 7-ketocholesterol and 25-hydroxycholesterol have decreased cholesterol efflux. Possible mechanisms include inhibition of membrane desorption of cholesterol or phospholipids or, as mentioned above, inhibition of lysosomal sphingomyelinase leading to lysosomal sequestration of cholesterol (M. Aviram, 1995). On the other hand, the conversion of cholesterol by macrophage sterol 27-hydroxylase to 27-hydroxycholesterol and 3[l-hydroxy-5-cholestenoic acid, which are efficiently effluxed from cells, has been proposed to promote sterol efflux from foam cells (1. Bjorkhem,... 

Post, S.M., E.C. de Wit, and H.M. Princen (1997). Cafestol, the cholesterol-raising factor in boiled coffee, suppresses bile acid synthesis by downregulation of cholesterol 7a-hydroxy-lase and sterol 27-hydroxylase in rat hepato-cytes. Arterioscler. Thromb. Vase. Biol. 17, 3064-3070. 

Shiga, K., R. Fukuyama, S. Kiraura, K. Nakajima, and S. Fushiki (1999). Mutation of the sterol 27-hydroxylase gene (CYP27) results in truncation of mRNA expressed in leucocytes in a Japanese family with cerebrotendinous xanthomatosis. J. Neurol. Neurosurg. Psychiatr. 67, 675-677. 

Garuti, R., M.A. Croce, R. Tiozzo, M.T. Dotti, A. Federico, S. Bertolini et al. (1997). Four novel mutations of sterol 27-hydroxylase gene in Italian patients with cerebrotendinous xanthomatosis. J. Lipid Res. 38, 2322-2334. 

Chen, W., S. Kubota, H. Ujike, T. Ishihara, and Y. Seyama (1998). A novel Arg362Ser mutation in the sterol 27-hydroxylase gene (CYP27) Its effects on pre-mRNA splicing and enzyme activity. Biochemistry 37, 15050-15056. 

S. Shpizen, L. Triger et al. (1998). Markedly reduced bile acid synthesis but maintained levels of cholesterol and vitamin D metabolites in mice with disrupted sterol 27-hydroxylase gene. 

D. Sviridov (2003). Expression of sterol 27-hydroxylase (CYP27A1) enhances cholesterol efflux. J. Biol. Chem. 278, 11015-11019. 

Memon RA, Moser AH, Shigenaga JK, Grunfeld C, Feingold KR (2001) In vivo and in vitro regulation of sterol 27-hydroxylase in the liver during the acute phase response. Potential role of hepatocyte nuclear factor-1. J Biol Chem 276 30118-30126... 

Hansson M, Wikvall K, Babiker A(2005) Regulation of sterol 27-hydroxylase in human monocyte-derived macrophages up-regulation by transforming growth factor betal. Biochim Biophys Acta 1687 44-51... 

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