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Papers In Press, published online ahead of print June 1, 2003
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Department of Pharmaceutical Biosciences, University of Uppsala, Uppsala SE-751 23
Corresponding Author: Kjell.Wikvall{at}farmbio.uu.se
The mitochondrial sterol 27-hydroxylase (CYP27A1) is required for the degradation of the C27-sterol side chain in connection with bile acid biosynthesis. CYP27A1 seems, however, to have roles beyond this, as illustrated by patients with a deficient sterol 27-hydroxylase due to mutations of the CYP27A1 gene (cerebrotendinous xanthomatosis). The latter subjects have symptoms ranging from accumulation of bile alcohols and cholestanol to accelerated atherosclerosis and progressive neurologic impairment. In the present work, a detailed investigation was carried out on the substrate specificity of the human recombinant CYP27A1 enzyme. In accordance with some previous work with rat liver mitochondria, the activity in general increased with the polarity of the substrate. An obvious example was the finding that cholesterol was 27-hydroxylated more efficiently than cholesterol oleate but less efficiently than cholesterol sulfate. The side-chain oxidized oxysterols 24S-hydroxycholesterol and 25-hydroxycholesterol were 27-hydroxylated less efficiently than cholesterol, possibly due to steric hindrance. Surprisingly, sterols with a 3-oxo-Delta4 structure were found to be hydroxylated at a much higher rate than the corresponding sterols with a 3beta-hydroxy-Delta5 structure. The rate of CYP27A1-mediated hydroxylation of the various sterols were: 7alpha-hydroxy-4-cholesten-3-one > 4-cholesten-3-one > 7alpha-hydroxycholesterol > 24-hydroxy-4-cholesten-3-one > cholesterol > 25-hydroxy-4-cholesten-3-one > 24-hydroxycholesterol * 25-hydroxycholesterol. The possibility is discussed that the findings may have implications for oxysterol-mediated regulation of gene expression. The very high activity of CYP27A1 towards the cholestanol precursor 4-cholesten-3-one may be of importance in connection with the accumulation of cholestanol in patients with cerebrotendinous xanthomatosis.
Revised on May 16, 2003
Accepted on May 16, 2003
On the substrate specificity of human CYP27A1: Implications for bile acid and cholestanol formation
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