Analysis of the human gene encoding the kidney isozyme of 11β-hydroxysteroid dehydrogenase

Anil K. Agarwal, Fraser M. Rogerson, Tomoatsu Mune, Perrin C. White

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

11β-Hydroxysteroid dehydrogenase (11β-HSD) catalyzes the conversion of cortisol to cortisone. This activity may be deficient in the syndrome of apparent mineralocorticoid excess (AME). 11β-HSD L (Type I), isolated from liver, is widely expressed and utilizes NADP+ as a cofactor. The gene for 11β-HSD L was found to be normal in patients of AME. A second isoform, 11β-HSD K (Type II), isolated from kidney, is more tissue specific in expression and utilizes NAD+ as a cofactor. The cDNA clone encoding 11β-HSD K was isolated from sheep kidney. The cDNA is 1.8 kb in length and encodes a protein of 404 amino acid residues with a predicted Mr 43,953. The recombinant enzyme functions as an NAD+-dependent 11β-dehydrogenase with very high affinity for steroids, but it has no detectable reductase activity. It is 37% identical in amino acid sequence to an NAD+-dependent isozyme of 17β-hydroxysteroid dehydrogenase. It is expressed at high levels in the kidney, placenta, adrenal and at lower levels in colon, stomach, heart and skin. The human 11β-HSD K gene consists of five exons spread over 6 kb. The nucleotide binding domain lies in the first and the second exon, and the catalytic domain in the fourth exon. The promoter for 11β-HSD K gene lacks a TATA box and has a high GC base content, suggesting that the gene may be transcriptionally regulated by factors that recognize GC-rich sequences. Fluorescent in situ hybridization of metaphase chromosomes with a positive bacteriophage P1 genomic 11β-HSD K clone localized the gene to chromosome 16q22. In contrast, the 11β-HSD L gene is located on chromosome 1 and contains 6 exons; the coding sequences of these genes are only 21% identical. Different transcriptional start sites are utilized in kidney and placenta.

Original languageEnglish (US)
Pages (from-to)473-479
Number of pages7
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume55
Issue number5-6
DOIs
StatePublished - Dec 1995

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

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