Characterization of disease-related 5β-reductase (AKR1D1) mutations reveals their potential to cause bile acid deficiency
Open accessAbstract
Bile acid deficiency is a serious syndrome in newborns that can result in death if untreated. 5beta-Reductase deficiency is one form of bile acid deficiency and is characterized by dramatically decreased levels of physiologically active 5beta-reduced bile acids. AKR1D1 (aldo-keto reductase 1D1) is the only known human enzyme that stereo-specifically reduces the Delta(4) double bond in 3-keto steroids and sterols to yield the 5beta-hydrogenated product. Analysis of the AKR1D1 gene in five patients with 5beta-reductase deficiency revealed five different mutations resulting in an amino acid substitution in the protein. To investigate a causal role for these observed point mutations in AKR1D1 in 5beta-reductase deficiency, we characterized their effect on enzymatic properties. Attempts to purify mutant enzymes by overexpression in Escherichia coli only yielded sufficient amounts of the P133R mutant for further characterization. This enzyme displayed a highly reduced K(m) and V(max) reminiscent of uncompetitive kinetics with 4-cholesten-7alpha-ol-3-one as substrate. In addition, this mutant displayed no change in cofactor affinity but was more thermolabile in the absence of NADPH as judged by CD spectroscopy. All mutants were compared following expression in HEK 293 cells. Although these enzymes were equally expressed based on mRNA levels, protein expression and functional activity were dramatically reduced. Cycloheximide treatment also revealed that several of the expressed mutants were less stable. Our findings show that the reported mutations in AKR1D1 in patients with 5beta-reductase lead to significantly decreased levels of active enzyme and could be causal in the development of bile acid deficiency syndrome.
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The mutants showed lower 5β-reductase activity than wild type, in agreement with clinical observations of bile acid deficiency.
“The mutants thus showed lower 5β-reductase activity as compared to wild type which is in agreement with clinical observations of bile acid deficiency [98, 101].”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [101]
Recombinant mutant Pro133Arg showed a 12-fold decreased catalytic efficiency for testosterone reduction.
“Mutant Pro133Arg was prepared in a recombinant form and showed a 12-fold decreased catalytic efficiency for testosterone reduction [101].”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [101]
HEK293 expression of Pro198Leu and Gly223Glu mutants showed lower enzymatic activity and expression levels.
“and lower enzymatic activity and expression levels of both Pro198Leu and Gly223Glu.”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [101]
With the exception of Pro133Arg, the mutations lie in regions conserved among AKR1D1 homologues and do not participate in catalysis, coenzyme binding, or substrate binding.
“Except Pro133Arg, these mutations reside in domains highly conserved across AKR1D1 homologues and are not involved in catalysis, coenzyme or substrate binding [21, 101].”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [101]
Pro133Arg had a 10-fold higher estimated Km and about 2-fold lower Vmax than wild-type enzyme for 7α-hydroxy-cholesten-3-one.
“The estimated Km value for Pro133Arg was 10-fold higher and Vmax about 2-fold lower as compared to the wild type enzyme for the bile acid precursor, 7α-hydroxy-cholesten-3-one [101].”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [101]
HEK293 expression of Leu106Phe and Arg261Cys mutants showed lower expression levels, probably due to decreased stability.
“Expression of the mutated enzymes in HEK293 cells revealed lower expression levels of Leu106Phe, and Arg261Cys probably due to decreased stability”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [101]
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- Authors
- Drury, J. E., Mindnich, R., & Penning, T. M.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Penning, Trevor M.
- ORCID
- Penning, Trevor M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2010-08
- Volume
- 285
- Issue
- 32
- Pages
- 24529-24537
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2915689
- OpenAlex
- W2069962157
- Cited by
- 51
- References
- 32
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 4 · 2023: 7 · 2022: 3 · 2021: 3 · 2019: 5 · 2018: 5 · 2017: 1 · 2016: 3 · 2015: 2 · 2014: 4 · 2013: 5 · 2012: 2
- FWCI
- 1.81
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (ES013508)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK47015, R01DK047015)
- National Institute of Environmental Health Sciences (P30ES013508)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal Health and Biochemistry
- Keywords
- AKR1D1, bile acid deficiency, point mutations, enzyme kinetics, uncompetitive inhibition, NADPH cofactor, protein stability, protein expression
- MeSH terms
- Bile Acids and Salts, Cell Line, Circular Dichroism, Cycloheximide, Genetic Vectors, Humans, Kinetics, Models, Molecular, Molecular Conformation, Mutation, NADP, Oxidoreductases, Protein Synthesis Inhibitors, Spectrometry, Fluorescence, Point Mutation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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