Analysis of the human gene encoding the kidney isozyme of 11 beta-hydroxysteroid dehydrogenase.
11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) catalyzes the conversion of cortisol to cortisone. This activity may be deficient in the syndrome of apparent mineralocorticoid excess (AME). 11 beta-HSD L (Type I), isolated from liver, is widely expressed and utilizes NADP+ as a cofactor. The gene for 11 beta-HSD L was found to be normal in patients of AME. A second isoform, 11 beta-HSD K (Type II), isolated from kidney, is more tissue specific in expression and utilizes NAD+ as a cofactor. The cDNA clone encoding 11 beta-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 M(r) 43,953. The recombinant enzyme functions as an NAD(+)-dependent 11 beta-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 17 beta-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 11 beta-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 11 beta-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 11 beta-HSD K clone localized the gene to chromosome 16q22. In contrast, the 11 beta-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.
Agarwal
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Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas 75235-9063, USA.
Rogerson
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FM
Mune
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White
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D042842:11-beta-Hydroxysteroid Dehydrogenases; D000595:Amino Acid Sequence; D002885:Chromosomes, Human, Pair 16; D003001:Cloning, Molecular; D015870:Gene Expression; D005796:Genes; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D007527:Isoenzymes / Q000235:genetics*; D007668:Kidney / Q000201:enzymology*; D008901:Mineralocorticoids / Q000378:metabolism*; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D007527:Isoenzymes; D008901:Mineralocorticoids; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases