Abstract
Oxysterol 7α-hydroxylase has broad substrate specificity for sterol metabolites and may be involved in many metabolic processes including bile acid synthesis and neurosteroid metabolism. The cloned human oxysterol 7α-hydroxylase (CYP7B1) cDNA encodes a polypeptide of 506 amino acid residues that shares 40% sequence identity to human cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme in the conversion of cholesterol to bile acids in the liver. In contrast to the liver-specific expression of CYP7A1, CYP7B1 mRNA transcripts were detected in human tissues involved in steroid genesis (brain, testes, ovary, and prostate) and in bile acid synthesis (liver) and reabsorption (colon, kidney, and small intestine). The human oxysterol 7α-hydroxylase transiently expressed in 293/T cells was able to catalyze 7α-hydroxylation of 27-hydroxycholesterol and dehydroepiandrosterone (DHEA). The human CYP7A1 and CYP7B1 both contain six exons and five introns. However, CYP7B1 spans at least 65 kb of the genome and is about 6-fold longer than CYP7A1. The transcription start site (+1) was localized 204 bp upstream of the initiation codon. No TATA box-like sequence was found near the transcription start site. Transient transfection assays of CYP7B1 promoter/luciferase reporter constructs in HepG2 cells revealed that the promoter was highly active. The 5′ upstream region from nt –83 to +189 is the core promoter of the gene.—Wu, Z., K. O. Martin, N. B. Javitt, and J. Y. L. Chiang. Structure and functions of human oxysterol 7α-hydroxylase cDNAs and gene CYP7B1.
Highlights
Oxysterol 7␣-hydroxylase has broad substrate specificity for sterol metabolites and may be involved in many metabolic processes including bile acid synthesis and neurosteroid metabolism
Sequence analysis revealed that human oxysterol 7␣-hydroxylase gene (CYP7B1) shared 64.6% amino acid sequence identity with mouse cyp7b1 [10] and 40.4% identity with human cholesterol 7␣-hydroxylase gene (CYP7A1) [18]
Activities of the truncated and full-length enzymes were similar toward both the above substrates, indicating that the N-terminal membrane-binding domain may not be required for catalytic activity, similar to the finding for cholesterol 7␣-hydroxylase [29]. These data provided further evidence that the human CYP7B1 clone we isolated does encode oxysterol 7␣-hydroxylase. It is rather surprising from our study that the CYP7B1 mRNA and its gene are much larger than CYP7A1 the intron/exon structures of the two are very similar
Summary
Oxysterol 7␣-hydroxylase has broad substrate specificity for sterol metabolites and may be involved in many metabolic processes including bile acid synthesis and neurosteroid metabolism. Oxysterol 7␣-hydroxylase activity expressed after 18 days of life might be responsible for the synthesis of 7␣hydroxylated bile acids in cyp7a (Ϫ/Ϫ) mice [14]. A full-length human CYP7B1 cDNA was isolated from a phage clone H107 and was subcloned into pBluescript KS (IIϩ).
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