Substrate specificity and inhibitor analyses of human steroid 5β-reductase (AKR1D1)
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Human steroid 5β-reductase (aldo-keto reductase 1D1) catalyzes the stereospecific NADPH-dependent reduction of the C4-C5 double bond of Δ(4)-ketosteroids to yield an A/B cis-ring junction. This cis-configuration is crucial for bile acid biosynthesis and plays important roles in steroid metabolism. The biochemical properties of the enzyme have not been thoroughly studied and conflicting data have been reported, partially due to the lack of highly homogeneous protein. In the present study, we systematically determined the substrate specificity of homogeneous human recombinant AKR1D1 using C18, C19, C21, and C27 Δ(4)-ketosteroids and assessed the pH-rate dependence of the enzyme. Our results show that AKR1D1 proficiently reduced all the steroids tested at physiological pH, indicating AKR1D1 is the only enzyme necessary for all the 5β-steroid metabolites present in humans. Substrate inhibition was observed with C18 to C21 steroids provided that the C11 position was unsubstituted. This structure activity relationship can be explained by the existence of a small alternative substrate binding pocket revealed by the AKR1D1 crystal structure. Non-steroidal anti-inflammatory drugs which are potent inhibitors of the related AKR1C enzymes do not inhibit AKR1D1. By contrast chenodeoxycholate and ursodeoxycholate were found to be potent non-competitive inhibitors suggesting that bile-acids may regulate their own synthesis at the level of AKR1D1 inhibition.
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AKR1D1 has broad substrate specificity, reducing C18, C19, C21 and C27 Δ4-ketosteroids and some synthetic drugs.
“AKR1D1 has broad substrate specificity; it catalyzes the reduction of C18, C19, C21 and C27 Δ4-ketosteroids and some synthetic drugs”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [23]
A proposed mechanism for AKR1D1 5β-reduction has Tyr58 as general acid and Glu120 as a superacid facilitating enolization of the Δ4 double bond.
“A mechanism of AKR1D1 catalyzed 5β-reduction has been proposed, in which Tyr58 acts as a general acid and Glu120 facilitates enolization of the Δ4 double bond by acting as a superacid”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [23]
AKR1D1 has high catalytic efficiency for reducing Δ4-androstene-3,17-dione and testosterone to 5β-androstane-3,17-dione and 5β-DHT.
“AKR1D1 has a high catalytic efficiency for the reduction of Δ4-androstene-3,17-dione and testosterone to form 5β-androstane-3,17-dione and 5β-DHT, respectively”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [23]
AKR1D1 catalyzes 5β-reduction of 7α-hydroxy-4-cholestene-3-one and 7α,12α-dihydroxy-4-cholestene-3-one to their respective 5β products, and AKR1C4 reduces the 3-keto group.
“AKR1D1 catalyzes 5β-reduction of bile acid precursors 7α-hydroxy-4-cholestene-3-one and 7α,12α-dihydroxy-4-cholestene-3-one to yield 7α-hydroxy-5β-cholestan-3-one and 7α,12α-dihydroxy-5β-cholestan-3-one, respectively and AKR1C4 catalyzes the further reduction of 3-keto group”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [23]
In liver and some peripheral tissues such as placenta and myometrium, AKR1D1 reduces progesterone to 5β-DHP, while SRD5A1 and SRD5A2 form 5α-DHP.
“In liver and some peripheral tissues (e.g. placenta and myometrium) AKR1D1 catalyzes reduction of progesterone to 5β-dihydroprogesterone (5β-DHP) while the 5α-reductases SRD5A1 and SRD5A2 form 5α-dihydroprogesterone (5α-DHP)”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [23]
SRD5As and AKR1D1 exhibit different catalytic efficiencies towards structurally different steroids.
“SRD5As and AKR1D1 exhibit different catalytic efficiencies towards structurally different steroids [57,100]”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [100]
AKR1D1 is the only human enzyme catalyzing the 5β-reduction of 3-keto-Δ4 steroids and bile acids.
“It is the only human enzyme catalyzing the 5β-reduction of 3-keto-Δ4 steroids and bile acids [100].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [100]
Androgens and precursors that escape tissue-specific activation via 5α-reduction are metabolized within the liver, which expresses both 5α- and 5β-reductases.
“Those androgens and precursors that escape the tissue specific activation via 5α-reduction are metabolized within the liver, which expresses both 5α- and 5β-reductases [54,94,100].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [100]
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- Authors
- Chen, M., Drury, J. E., & Penning, T. M.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Penning, Trevor M.
- Venue
- Steroids
- Publisher
- Elsevier BV
- Published
- 2011-04
- Volume
- 76
- Issue
- 5
- Pages
- 484-490
- ISSN
- 0039-128X (ISSN-L)
- PMC
- PMC3056882
- OpenAlex
- W2064449254
- Cited by
- 53
- References
- 35
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 5 · 2023: 5 · 2022: 1 · 2021: 7 · 2020: 3 · 2019: 3 · 2018: 2 · 2017: 2 · 2016: 4 · 2015: 2 · 2014: 6 · 2013: 3 · 2012: 2
- FWCI
- 1.84
- 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 Institute of Diabetes and Digestive and Kidney Diseases (1R01-DK47015, R01DK047015)
- National Institute of Environmental Health Sciences (P30ES13508, P30ES013508)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- AKR1D1, substrate specificity, substrate inhibition, bile acid synthesis, chenodeoxycholic acid, ursodeoxycholic acid, non-competitive inhibition, structure-activity relationship, steroid metabolism
- MeSH terms
- Bile Acids and Salts, Binding Sites, Humans, Hydrogen-Ion Concentration, Ketosteroids, Kinetics, Oxidoreductases, Structure-Activity Relationship, Substrate Specificity, Crystallography, X-Ray
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