Crystal Structure of Human Liver Δ4-3-Ketosteroid 5β-Reductase (AKR1D1) and Implications for Substrate Binding and Catalysis
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AKR1D1 (steroid 5beta-reductase) reduces all Delta(4)-3-ketosteroids to form 5beta-dihydrosteroids, a first step in the clearance of steroid hormones and an essential step in the synthesis of all bile acids. The reduction of the carbon-carbon double bond in an alpha,beta-unsaturated ketone by 5beta-reductase is a unique reaction in steroid enzymology because hydride transfer from NADPH to the beta-face of a Delta(4)-3-ketosteroid yields a cis-A/B-ring configuration with an approximately 90 degrees bend in steroid structure. Here, we report the first x-ray crystal structure of a mammalian steroid hormone carbon-carbon double bond reductase, human Delta(4)-3-ketosteroid 5beta-reductase (AKR1D1), and its complexes with intact substrates. We have determined the structures of AKR1D1 complexes with NADP(+) at 1.79- and 1.35-A resolution (HEPES bound in the active site), NADP(+) and cortisone at 1.90-A resolution, NADP(+) and progesterone at 2.03-A resolution, and NADP(+) and testosterone at 1.62-A resolution. Complexes with cortisone and progesterone reveal productive substrate binding orientations based on the proximity of each steroid carbon-carbon double bond to the re-face of the nicotinamide ring of NADP(+). This orientation would permit 4-pro-(R)-hydride transfer from NADPH. Each steroid carbonyl accepts hydrogen bonds from catalytic residues Tyr(58) and Glu(120). The Y58F and E120A mutants are devoid of activity, supporting a role for this dyad in the catalytic mechanism. Intriguingly, testosterone binds nonproductively, thereby rationalizing the substrate inhibition observed with this particular steroid. The locations of disease-linked mutations thought to be responsible for bile acid deficiency are also revealed.
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AKR1D1 has an (α/β)8 barrel structure with cofactor and steroid substrate bound at the C-terminal end of the β-sheets.
“The AKR1D1 enzyme has the typical (α/β)8 barrel structure of the AKR superfamily with cofactor and the steroid substrate bound at the C-terminal end of the β-sheets”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [21]
Some Δ4 ketosteroids, such as testosterone, show substrate inhibition with AKR1D1, explained by productive and non-productive binding modes.
“some Δ4 ketosteroids show distinct substrate inhibition with AKR1D1 e.g. testosterone which can be explained by two binding modes for the steroid; productive and non-productive”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [21]
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 [21]
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- Authors
- Di Costanzo, L., Drury, J. E., Penning, T. M., & Christianson, D. W.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Penning, Trevor M.
- Christianson, David W.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-06
- Volume
- 283
- Issue
- 24
- Pages
- 16830-16839
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2423251
- OpenAlex
- W2005732363
- Cited by
- 79
- References
- 52
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 5 · 2023: 4 · 2022: 1 · 2021: 3 · 2020: 2 · 2019: 5 · 2018: 2 · 2016: 10 · 2015: 1 · 2014: 10 · 2013: 2 · 2012: 6
- FWCI
- 3.40
- 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 Institute of General Medical Sciences (R01 GM56838, R01GM056838)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK47015, R01DK047015)
- National Institute of Environmental Health Sciences (P30ES013508)
- Topics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- 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
- Keywords
- AKR1D1, bile acid synthesis, steroid hormone metabolism, substrate orientation, cortisone, progesterone, testosterone, substrate inhibition, catalytic dyad, enzyme crystal structure
- MeSH terms
- Binding Sites, Carbon, Catalysis, Cortisone, Humans, Kinetics, Liver, Models, Chemical, Molecular Conformation, Mutation, Progesterone, Protein Binding, Steroids, 3-Oxo-5-alpha-Steroid 4-Dehydrogenase, Crystallography, X-Ray
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