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Cloning and expression of cDNA of human Δ4‐3‐oxosteroid 5β‐reductase and substrate specificity of the expressed enzyme
Open accessAbstract
The enzyme delta 4-3-oxosteroid 5 beta-reductase (3-oxo-5 beta-steroid: NADP+ oxidoreductase and 4,5 beta-dihydrocortisone: NADP+ delta 4-oxidoreductase) catalyzes the reduction of the delta 4 double bond of bile acid intermediates and steroid hormones carrying the delta 4-3-one structure in the A/B cis configuration. Human delta 4-3-oxosteroid 5 beta-reductase cDNA was isolated from a liver cDNA library by cross hybridization with a previously cloned rat cDNA, which was used as a probe [Onishi, Y. Noshiro, M., Shimosato, T. & Okuda, K.-I. (1991) FEBS Lett. 283, 215-218]. DNA sequence analysis of a hybridization-positive clone predicted the human delta 4-3-oxosteroid 5 beta-reductase to contain 326 amino acids. The amino acid sequence of the human delta 4-3-oxosteroid 5 beta-reductase had 79% overall identity to the rat enzyme sequence. It also showed 54% and 50% overall identity with rat 3 alpha-hydroxysteroid dehydrogenase and human aldose reductase, respectively. RNA blotting analysis demonstrated the existence of a single delta 4-3-oxosteroid 5 beta-reductase mRNA of approximately 2.7 kb in human liver. Transfection of the cDNA into COS cells resulted in the expression of an active enzyme with a high activity toward the bile acid intermediates 7 alpha,12 alpha-dihydroxy-4-cholesten-3-one and 7 alpha-hydroxy-4-cholesten-3-one. In addition, the expressed enzyme showed a small but significant 5 beta-reduction activity toward 11 beta,17 alpha,21-trihydroxy-delta 4-pregnene-3,20-dione (cortisol) and 17 beta-hydroxy-delta 4-androsten-3-one (testosterone) whereas no activity was observed toward delta 4-pregnene-3,20-dione (progesterone) or delta 4-androstene-3-17-dione (androstenedione). The substrate specificity of the human enzyme is considerably narrower than that of the rat enzyme, and the enzyme seems to be more important for bile acid biosynthesis than for metabolism of steroid hormones.
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“AKR1D1 is expressed mainly in liver as might be expected by its role in bile acid biosynthesis”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [26]
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Metadata
- Authors
- KONDO, K., KAI, M., SETOGUCHI, Y., EGGERTSEN, G., SJÖBLOM, P., SETOGUCHI, T., OKUDA, K., & BJÖRKHEM, I.
- Affiliations
- Karolinska Institutet (SE)
- University of Miyazaki (JP)
- Corresponding author
- KONDO, Kazu‐Hiro
- Venue
- European Journal of Biochemistry
- Publisher
- Wiley
- Published
- 1994-01
- Volume
- 219
- Issue
- 1-2
- Pages
- 357-363
- ISSN
- 0014-2956 (ISSN-L)
- 1432-1033
- OpenAlex
- W1985481419
- Cited by
- 139
- References
- 36
- Citations by year
- 2025: 3 · 2024: 2 · 2023: 3 · 2022: 1 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 4 · 2017: 7 · 2016: 3 · 2015: 3 · 2014: 7 · 2013: 5 · 2012: 7
- FWCI
- 1.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Steroid Chemistry and Biochemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Keywords
- human cDNA cloning, substrate specificity, bile acid intermediates, 3α-hydroxysteroid dehydrogenase, aldose reductase, liver mRNA, recombinant enzyme expression, cortisol reduction, testosterone suppression
- MeSH terms
- Amino Acid Sequence, Animals, Base Sequence, Cell Line, Cloning, Molecular, Escherichia coli, Humans, Liver, Molecular Sequence Data, Oxidoreductases, Recombinant Proteins, RNA, Substrate Specificity, Transfection, Immunoblotting, Restriction Mapping, Gene Expression, Sequence Homology, Amino Acid, DNA, Complementary, Rats
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