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Journal of Lipid Research, Vol. 44, 1515-1522, August 2003
Copyright © 2003 by American Society for Biochemistry and Molecular Biology
* Department of Pharmaceutical Biosciences, Division of Biochemistry, University of Uppsala, Box 578, S-751 23 Uppsala, Sweden
Division of Clinical Chemistry, Karolinska Institute, Huddinge University Hospital, S-141 86 Huddinge, Sweden
1 To whom correspondence should be addressed. e-mail: kjell.wikvall{at}farmbio.uu.se
The mitochondrial sterol 27-hydroxylase (CYP27A1) is required for degradation of the C27-sterol side chain in 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 (CTX)]. These subjects have symptoms ranging from accumulation of bile alcohols and cholestanol to accelerated atherosclerosis and progressive neurologic impairment. The present work describes a detailed investigation on the substrate specificity of recombinant human CYP27A1. 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 oxysterols 24S-hydroxycholesterol and 25-hydroxycholesterol were 27-hydroxylated less efficiently than cholesterol, possibly due to steric hindrance. Surprisingly, sterols with a 3-oxo-
4 structure were found to be hydroxylated at a much higher rate than the corresponding sterols with a 3ß-hydroxy-5 structure. The rates of hydroxylation of the sterols were: 7
-hydroxy-4-cholesten-3-one>4-cholesten-3-one>7-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 CTX.
Supplementary key words sterol 27-hydroxylase • cerebrotendinous xanthomatosis • cholesterol sulfate
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