Multiple steps determine the overall rate of the reduction of 5α-dihydrotestosterone catalyzed by human type 3 3α-hydroxysteroid dehydrogenase: implications for the elimination of androgens
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Human type 3 3alpha-hydroxysteroid dehydrogenase, or aldo-keto reductase (AKR) 1C2, eliminates the androgen signal in human prostate by reducing 5alpha-dihydrotestosterone (DHT, potent androgen) to form 3alpha-androstanediol (inactive androgen), thereby depriving the androgen receptor of its ligand. The k(cat) for the NADPH-dependent reduction of DHT catalyzed by AKR1C2 is 0.033 s(-1). We employed transient kinetics and kinetic isotope effects to dissect the contribution of discrete steps to this low k(cat) value. Stopped-flow experiments to measure the formation of the AKR1C2.NADP(H) binary complex indicated that two slow isomerization events occur to yield a tight complex. A small primary deuterium isotope effect on k(cat) (1.5) and a slightly larger effect on k(cat)/K(m) (2.1) were observed in the steady state. In the transient state, the maximum rate constant for the single turnover of DHT (k(trans)) was determined to be 0.11 s(-1) for the NADPH-dependent reaction, which was approximately 4-fold greater than the corresponding k(cat) x k(trans) was significantly reduced when NADPD was substituted for NADPH, resulting in an apparent (D)k(trans) of 3.5. Thus, the effects of isotopic substitution on the hydride transfer step were masked by slow events that follow or precede the chemical transformation. Transient multiple-turnover reactions generated curvilinear reaction traces, consistent with the product formation and release occurring at comparable rates. Global fitting analysis of the transient kinetic data enabled the estimate of the rate constants for the three-step cofactor binding/release model and for the minimal ordered bi-bi turnover mechanism. Results were consistent with a kinetic mechanism in which a series of slow events, including the chemical step (0.12 s(-1)), the release of the steroid product (0.081 s(-1)), and the release of the cofactor product (0.21 s(-1)), combine to yield the overall observed low turnover number.
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All AKR1 enzymes use a sequential ordered bi bi kinetic mechanism in which cofactor must bind before steroid substrate.
“All AKR1 enzymes catalyze a sequential ordered bi bi kinetic mechanism in which there is an obligatory requirement for the cofactor to bind before the steroid substrate can bind to form the central complex.”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [28]
After the chemical step, steroid product leaves followed by oxidized cofactor, and different steps can be rate-limiting depending on substrate.
“Following the chemical step, steroid product then leaves followed by the oxidized cofactor. Different steps of the reaction can be rate-limiting depending upon the substrate.”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [28]
With high-turnover substrates, NADP+ release limits the reaction rate, and release is a two-step process involving isomerization from a tight to a loose E.NADP+ complex.
“However, with substrates with high turnover numbers the rate of release of the NADP+ cofactor places an upper limit on the rate of reaction. The release of the NADP+ cofactor is a two step process in which an isomerisation event occurs to convert a E.NADP+ tight complex to form a E.NADP+ loose complex”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [28]
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The Aldo-Keto Reductase Superfamily
Penning, T. M. (2024) · Elsevier eBooks · doi:10.1016/b978-0-323-95488-4.00010-3
Self-citationReduction of secondary 3-keto bile acids by aldo-keto reductase 1C1 and 1C4
Green, K. D., Thomason, G. K., & Czuba, L. C. (2026) · Drug Metabolism and Disposition · doi:10.1016/j.dmd.2026.100340
BindingDB Entry 50011297: Overview of AKR1C3: Inhibitor Achievements and Disease Insights.
BindingDB (2022) · UC San Diego · doi:10.7270/q23b63qx
- Authors
- Jin, Y., & Penning, T. M.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Penning, Trevor M.
- ORCID
- Penning, Trevor M.
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2006-10-01
- Volume
- 45
- Issue
- 43
- Pages
- 13054-13063
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- PMC
- PMC2597410
- OpenAlex
- W1971511316
- Cited by
- 60
- References
- 43
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 2 · 2016: 1 · 2015: 3 · 2014: 11 · 2013: 5 · 2012: 3
- FWCI
- 1.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-47015, R01DK047015)
- National Institute of Environmental Health Sciences (P30ES013508)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Reaction Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Keywords
- AKR1C2, 3α-hydroxysteroid dehydrogenase, dihydrotestosterone, androgen metabolism, enzyme kinetics, kinetic isotope effects, transient kinetics, hydride transfer, NADPH binding, product launch, prostate, androgen receptor
- MeSH terms
- Androgens, Humans, Kinetics, NADP, Oxidation-Reduction, Receptors, Androgen, Dihydrotestosterone, Molecular Structure, 3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
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