5β-Reduced steroids and human Δ4-3-ketosteroid 5β-reductase (AKR1D1)
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5β-Reduced steroids are non-planar steroids that have a 90° bend in their structure to create an A/B cis-ring junction. This novel property is required for bile-acids to act as emulsifiers, but in addition 5β-reduced steroids have remarkable physiology and may act as potent tocolytic agents, endogenous cardiac glycosides, neurosteroids, and can act as ligands for orphan and membrane bound receptors. In humans there is only a single 5β-reductase gene AKR1D1, which encodes Δ(4)-3-ketosteroid-5β-reductase (AKR1D1). This enzyme is a member of the aldo-keto reductase superfamily, but possesses an altered catalytic tetrad, in which Glu120 replaces the conserved His residue. This predominant liver enzyme generates all 5β-dihydrosteroids in the C19-C27 steroid series. Mutations exist in the AKR1D1 gene, which result in loss of protein stability and are causative in bile-acid deficiency.
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5α/β-reduction is irreversible, with stereochemistry playing important role in regulating biological activity of androgens.
“Importantly, 5α/β-reduction is irreversible, with the stereochemistry of this reduction playing an important role in regulating the biological activity of androgens (Section 4.3.2) [93].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [93]
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“The liver has high levels of the 5b-reductase AKR1D1 and primarily produces 5b-reduced androgens (e.g. etiochonanolone, 5bandrostan-3a-ol-17-one, ETIO) in contrast to peripheral tissue which produce 5a-reduced species (Charbonneau and The, 2001; Chen and Penning, 2014; Penning, 2010).”
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Hayama, N., Shiojiri, K., Okamoto, R., Higashida, R., & Usami, Y. (2026) · Results in Chemistry · doi:10.1016/j.rechem.2026.103666
Garwolinska, A., Łaniewski, P., & Herbst‐Kralovetz, M. M. (2026) · BMC Medicine · doi:10.1186/s12916-026-05070-w
- Authors
- Chen, M., & Penning, T. M.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Penning, Trevor M.
- Venue
- Steroids
- Publisher
- Elsevier BV
- Published
- 2014-05
- Volume
- 83
- Pages
- 17-26
- ISSN
- 0039-128X (ISSN-L)
- PMC
- PMC3971473
- OpenAlex
- W2052427467
- Cited by
- 55
- References
- 138
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 8 · 2023: 4 · 2022: 2 · 2021: 6 · 2020: 3 · 2019: 6 · 2018: 2 · 2017: 5 · 2016: 3 · 2015: 1 · 2014: 3
- FWCI
- 0.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Steroids (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK47015, F32DK089827, R01DK047015)
- National Institute of Environmental Health Sciences (P30ES13508, P30ES013508)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- AKR1D1, bile acids, aldo-keto reductase superfamily, tocolytic agents, endogenous cardiac glycosides, neurosteroids, orphan receptors, bile acid deficiency
- MeSH terms
- Humans, Oxidation-Reduction, Oxidoreductases, Steroids, Gene Expression Profiling
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