Research Summary
Steroid Hormone Transforming Aldo-Keto Reductases.
The aldo-keto reductase (AKR) superfamily contains mammalian hydroxysteroid dehydrogenases (HSDs). For each sex steroid there are a pair of HSDs, which by acting as reductases or oxidases can convert potent steroid hormones into their cognate inactive metabolites or vice versa. When found in steroid target tissues they can regulate the occupancy and trans-activation of steroid hormone receptors, providing a pre-receptor regulation of steroid hormone action. Many HSDs are considered therapeutic targets. For example, aldo-keto reductase AKR1C3 (type 5 17beta-hydroxysteroid dehydrogenase) catalyses the formation of the potent androgens, testosterone and 5alpha-dihydrotestosterone, in castrate resistant prostate cancer (CRPC). CRPC is dependent upon intratumoral androgen biosynthesis that reactivate the androgen receptor and is uniformly fatal. Structure-based inhibitor design is being used to develop selective AKR1C3 inhibitors for the treatment of CRPC. In another area structure-function studies on steroid 5beta-reductase (AKR1D1) are being pursued. This enzyme catalyzes a pivotal step in bile-acid biosynthesis and natural mutations are causal in bile-acid deficiency syndromes which are often neonatal fatal. In both areas we use the following techniques: site-directed mutagenesis, x-ray crystallography, transient and steady state kinetics, transfection studies and si-RNA.
Aldo-Keto Reductases and the Metabolic Activation of Chemical Carcinogens
Human AKRs are involved in the metabolic activation of pyrogenic, petrogenic and nitro-polycyclic aromatic hydrocarbons (PAH). For pyrogenic PAH his group identified a novel pathway of PAH activation involving the formation of redox-active o-quinones, which has become widely accepted as an alternative pathway to diol-epoxide formation. His work on petrogenic PAH has led to the identification of the first potential human biomarkers of oil exposure. In work on the metabolic activation of nitroarenes, his group showed that 3-nitrobenzanthrone is metabolically activated by both AKRs and NQO1, and that the metabolic activation is dependent on the Nrf2-Keap1 pathway using CRISPER/Cas9 gene editing. Methods include cell culture, high-resolution NMR, EPR, mass-spectrometry, PAH-DNA adduct chemistry, mutagenesis assays, and epigenetic signaling through the Nrf2 pathway.
Laboratory Personnel
Ms. Ling Duan, MS Laboratory Manager
Dr. Steven Eichelbaum, Research Specialist
Postdoctoral Fellows:
Dr. Catia Marques
Predoctoral Fellows:
Ms. Andrea Andress Huacachino
Selected Publications
Huacachino AA, Chung A, Sharp K, Penning TM.: Specific and potent inhibition of steroid hormone pre-receptor regulator AKR1C2 by perfluorooctanoic acid: Implications for androgen metabolism J Steroid Biochem Mol Biol. 246: 106641, Feb 2025.
Gardner S, Vogt A, Penning TM, Marmorstein, R
: Substrate specificity and kinetic mechanism of 3-hydroxy-Δ5-C27-steroid oxidoreductase J. Biol. Chem.
Page: Online ahead of print. Nov 2024.
Jonnalagadda SK, Duan L, Dow LF, Boligala GP, Kosmacek E, McCoy K, Oberley-Deegan R, Chhonker YS, Murry DJ, Reynolds CP, Maurer BJ, Penning TM, Trippier PC.: Coumarin-Based Aldo-Keto Reductase Family 1C (AKR1C) 2 and 3 Inhibitors. ChemMedChem. 19(21): e202400081, September 2024.
Carmona AV, Jonnalagadda S, Case AM, Maddeboina K, Jonnalagadda SK, Dow LF, Duan L, Penning TM, Trippier PC.: Discovery of an Aldo-Keto reductase 1C3 (AKR1C3) degrader. Commun Chem. 7(1): 95, April 2024.
Detlefsen AJ, Mesaros CA, Duan L, Penning TM.: AKR1C3 Converts Castrate and Post-Abiraterone DHEA-S into Testosterone to Stimulate Growth of Prostate Cancer Cells via 5-Androstene-3β,17β-Diol Cancer Res Commun. 3(1888-1898), Sep 2023.
Paulukinas RD, Penning TM.: Insulin-Induced AKR1C3 Induces Fatty Acid Synthase in a Model of Human PCOS Adipocytes Endocrinology 164(5): doi: 10.1210/endocr/bqad033. Mar 2023.
Su AL, Penning TM.: Role of Human Aldo-Keto Reductases and Nuclear Factor Erythroid 2-Related Factor 2 in the Metabolic Activation of 1-Nitropyrene via Nitroreduction in Human Lung Cells Chem Res Toxicol. 36(2): 270-280, Feb 2023.
Su AL, Mesaros CA, Krzeminski J, El-Bayoumy K, Penning TM.: Role of Human Aldo-Keto Reductases in the Nitroreduction of 1-Nitropyrene and 1,8-Dinitropyrene Chem Res Toxicol. 35(12): 2296-2309, Nov 2022.
Sakata Y, Cheng K, Mayama M, Seita Y, Detlefsen AJ, Mesaros CA, Penning TM, Shishikura K, Yang W, Auchus RJ, Strauss JF 3rd, Sasaki K.: Reconstitution of human adrenocortical specification and steroidogenesis using induced pluripotent stem cells. Dev Cell. 57(22): 2566-2583, Nov 2022.
Paulukinas RD, Mesaros CA, Penning TM.: Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes Endocrinology 163(7): doi: 10.1210/endocr/bqac068. Jul 2022.
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Last updated: 02/05/2025
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