Expression and Characterization of Recombinant Type 2 3α-Hydroxysteroid Dehydrogenase (HSD) from Human Prostate: Demonstration of Bifunctional 3α/17β-HSD Activity and Cellular Distribution
Abstract
In androgen target tissues, 3α-hydroxysteroid dehydrogenase (3α-HSD) may regulate occupancy of the androgen receptor (AR) by catalyzing the interconversion of 5α-dihydrotestosterone (5α-DHT) (a potent androgen) and 3α-androstanediol (a weak androgen). In this study, a 3α-HSD cDNA (1170 bp) was isolated from a human prostate cDNA library. The human prostatic 3α-HSD cDNA encodes a 323-amino acid protein with 69.9%, 84.1%, 99.4%, and 87.9% sequence identity to rat liver 3α-HSD and human type 1, type 2, and type 3 3α-HSDs, respectively, and is a member of the aldo-keto reductase superfamily. The close homology with human type 2 3α-HSD suggests that it is either identical to this enzyme or a structural allele. Surprisingly, when the recombinant protein was expressed and purified from Escherichia coli, the enzyme did not oxidize androsterone when measured spectrophotometrically, an activity previously assigned to recombinant type 2 3α-HSD using this assay. Complete kinetic characterization of the purified protein using spectrophotometric, fluorometric, and radiometric assays showed that the catalytic efficiency favored 3α-androstanediol oxidation over 5α-DHT reduction. Using[ 14C]-5α-DHT as substrate, TLC analysis confirmed that the reaction product was[ 14C]-3α-androstanediol. However, in the reverse reaction, [3H]-3α-androstanediol was oxidized first to [3H]-androsterone and then to [3H]-androstanedione, revealing that the expressed protein possessed both 3α- and 17β-HSD activities. The 17β-HSD activity accounted for the higher catalytic efficiency observed with 3α-androstanediol. These findings indicate that, in the prostate, type 2 3α-HSD does not interconvert 5α-DHT and 3α-androstanediol but inactivates 5α-DHT through its 3-ketosteroid reductase activity. Levels of 3α-HSD mRNA were measured in primary cultures of human prostatic cells and were higher in epithelial cells than stromal cells. In addition, elevated levels of 3α-HSD mRNA were observed in epithelial cells derived from benign prostatic hyperplasia and prostate carcinoma tissues. Expression of 3α-HSD was not prostate specific, since high levels of mRNA were also found in liver, small intestine, colon, lung, and kidney. This study is the first complete characterization of recombinant type 2 3α-HSD demonstrating dual activity and cellular distribution in the human prostate.
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17βHSD5 catalyzes the reduction of androstenedione to testosterone.
“17HSD5 catalyzes the reduction of androstenedione to testosterone (524, 526), and is expressed in both steroidogenic and nonsteroidogenic tissues (525,526).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [524]
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Wang, S., Yang, Q., Fung, K.-M. A., & Lin, H. (2008) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2008.04.004 · Cited by 65 · see citing works
“, 1998) and AKR1C3 (Lin et al., 1997) cDNAs into the pcDNA3”
BackgroundInfluentialSelf-citationKonings, G. F. J., Brentjens, L. S., Delvoux, B., Linnanen, T., Cornel, K. M. C., Koskimies, P., Bongers, M. Y., Kruitwagen, R. F. P. M., Xanthoulea, S., & Romano, A. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00940 · Cited by 65 · see citing works
Penning, T. M. (2015) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2015.05.010 · Cited by 55 · see citing works
“Overexpression of Type 5 17β-HSD or AKR1C3—AKR1C3 (type 5 17βhydroxysteroid dehydrogenase) plays an essential role in the formation of T and DHT in the prostate irrespective of the pathway used [35-38].”
BackgroundSelf-citationLin, S., Shi, R., Qiu, W., Azzi, A., Zhu, D.-W., Dabbagh, H., & Zhou, M. (2006) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2005.11.035 · Cited by 52 · see citing works
Iino, T., 真由子, 田., Takikawa, S.-I., Sawada, H., Shintaku, H., Ishikura, S., & Hara, A. (2003) · Archives of Biochemistry and Biophysics · doi:10.1016/s0003-9861(03)00295-9 · Cited by 48 · see citing works
Du, X., Rosenfield, R. L., & Qin, K. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0139 · Cited by 67 · see citing works
New frontiers in androgen biosynthesis and metabolism
Penning, T. M. (2010) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0b013e3283381a31 · Cited by 51 · see citing works
Self-citationOxidative 3α-hydroxysteroid dehydrogenase activity of human type 10 17β-hydroxysteroid dehydrogenase
He, X., Yang, Y., Peehl, D. M., Lauderdale, A., Schulz, H., & Yang, S. (2003) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2003.07.007 · Cited by 53 · see citing works
Self-citationJin, Y., Duan, L., Lee, S. H., Kloosterboer, H. J., Blair, I. A., & Penning, T. M. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m809465200 · Cited by 50 · see citing works
Self-citationAdeniji, A. O., Twenter, B. M., Byrns, M. C., Jin, Y., Winkler, J. D., & Penning, T. M. (2011) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2011.01.010 · Cited by 50 · see citing works
Self-citationPelletier, G., Luu-The, V., Elalfy, M., Li, S., & Labrie, F. (2001) · Journal of Molecular Endocrinology · doi:10.1677/jme.0.0260011 · Cited by 49 · see citing works
“So far, six types of 17-HSD have been characterized in the human (Jarabak et al. 1962, Peltoketo et al. 1988, Luu-The et al. 1989a ,W uet al. 1993, Geissler et al. 1994, Adamski et al. 1995, Lin et al. 1997, Nokelainen et al. 1998, Dufort et al. 1999, Krazeisen et al. 1999).”
BackgroundInfluentialMa, H., & Penning, T. M. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.20.11161 · Cited by 52 · see citing works
Self-citationPirog, E. C., & Collins, D. C. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.9.5963 · Cited by 45 · see citing works
Vitamin A and Retinoids: An Update of Biological Aspects and Clinical Applications
Livrea, M. (2000) · Birkhäuser Basel eBooks · doi:10.1007/978-3-0348-8454-9 · Cited by 56 · see citing works
Bumke‐Vogt, C., Bähr, V., Diederich, S., Herrmann, S.-M., Anagnostopoulos, I., Oelkers, W., & Quinkler, M. O. (2002) · Journal of Endocrinology · doi:10.1677/joe.0.1750349 · Cited by 39 · see citing works
“Our sequencing data show 99·5% homology to the CDS of HAKRb (Qin et al. 1993); 99·8% homology was found to the sequence of a recombinant 3-HSD type 2 with 17-HSD activity ( Lin et al. 1997 ), identified as 17-HSD type 5 (Penning 1999).”
MethodGe, R., Hardy, D. O., Catterall, J. F., & Hardy, M. P. (1999) · Biology of Reproduction · doi:10.1095/biolreprod60.4.855 · Cited by 42 · see citing works
Adeniji, A. O., Uddin, M. J., Zang, T., Tamae, D., Wangtrakuldee, P., Marnett, L. J., & Penning, T. M. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00160 · Cited by 45 · see citing works
Self-citationAndrogen biosynthesis in castration-resistant prostate cancer
Penning, T. M. (2014) · Endocrine Related Cancer · doi:10.1530/erc-14-0109 · Cited by 44 · see citing works
“AKR1C3 catalyzes the NADPH-dependent reduction of D4-AD to testosterone, the reduction of Adione to DHT, and the reduction of androsterone to 3a-Adiol (Lin et al. 1997, Penning et al. 2000).”
Self-citationCrucial role of cytokines in sex steroid formation in normal and tumoral tissues
Simard, J., & Gingras, S. (2001) · Molecular and Cellular Endocrinology · doi:10.1016/s0303-7207(00)00387-7 · Cited by 40 · see citing works
Mantel, A., Carpenter-Mendini, A. B., VanBuskirk, J., Benedetto, A. D., Beck, L. A., & Pentland, A. P. (2011) · Journal of Investigative Dermatology · doi:10.1038/jid.2011.412 · Cited by 40 · see citing works
“In contrast, AKR1C3, also known as type 5 17βhydroxysteroid dehydrogenase (17β-HSD) (Lin et al., 1997) and prostaglandin F synthase (Matsuura et al.”
InfluentialRiboflavin deficiency induces a significant change in proteomic profiles in HepG2 cells
Xin, Z.-H., Pu, L., Gao, W.-N., Wang, Y.-W., Wei, J.-Y., Shi, T.-L., Yao, Z., & Guo, C. (2017) · Scientific Reports · doi:10.1038/srep45861 · Cited by 39 · see citing works
Zhang, A., Zhang, J., Plymate, S. R., & Mostaghel, E. A. (2016) · Hormones and Cancer · doi:10.1007/s12672-016-0250-9 · Cited by 42 · see citing works
Blomquist, C. H., Bonenfant, M., McGinley, D. M., Pósalaky, Z., LAKATUA, D. J., Tuli-Puri, S., Bealka, D. G., & Tremblay, Y. (2002) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/s0960-0760(02)00117-6 · Cited by 34 · see citing works
Initial Testing of the Hypoxia-Activated Prodrug PR-104 by the Pediatric Preclinical Testing Program
Houghton, P. J., Lock, R., Carol, H., Morton, C. L., Phelps, D., Gorlick, R., Kolb, E., Keir, S., Reynolds, C., Kang, M., et al. (2010) · Pediatric Blood & Cancer · doi:10.1002/pbc.22921 · Cited by 37
Antineoplastic Effects of Gamma Linolenic Acid on Hepatocellular Carcinoma Cell Lines
Itoh, S., Taketomi, A., Harimoto, N., Tsujita, E., Rikimaru, T., Shirabe, K., Shimada, M., & Maehara, Y. (2010) · Journal of Clinical Biochemistry and Nutrition · doi:10.3164/jcbn.10-24 · Cited by 36 · see citing works
“Human AKR1 family (C1-C4) are plastic enzymes and display 3-, 17- and 20-ketosteroid reductase activity and 3α-, 17β- and 20α-hydroxysteroid oxidase activity [31, 32].”
Background
- Authors
- Lin, H.-K., Jez, J. M., Schlegel, B. P., Peehl, D. M., Pachter, J. A., & Penning, T. M.
- Affiliations
- University of Pennsylvania (US)
- Stanford Medicine (US)
- Schering-Plough Research Institute (J.A.P.) Kenilworth, New Jersey 07033
- Corresponding author
- Penning, Trevor M.
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 1997-12-01
- Volume
- 11
- Issue
- 13
- Pages
- 1971-1984
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- OpenAlex
- W2115131467
- Cited by
- 194
- References
- 0
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 2 · 2022: 5 · 2021: 2 · 2020: 3 · 2019: 4 · 2018: 8 · 2017: 5 · 2016: 7 · 2015: 3 · 2014: 12 · 2013: 10 · 2012: 6
- FWCI
- 9.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ca055711-07)
- National Cancer Institute (CA 39504, CA-55711, R01CA039504)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-47015, R01DK047015)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- 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
- Keywords
- 3α-hydroxysteroid dehydrogenase, 17β-hydroxysteroid dehydrogenase, dihydrotestosterone, 3α-androstanediol, androgen metabolism, androgen receptor, prostate, aldo-keto reductase superfamily, enzyme kinetic characterization
- MeSH terms
- Amino Acid Sequence, Base Sequence, Cells, Cultured, Cloning, Molecular, Enzyme Activation, Humans, Kinetics, Male, Molecular Sequence Data, Multienzyme Complexes, Organ Specificity, Prostate, Recombinant Proteins, 17-Hydroxysteroid Dehydrogenases, 3-Hydroxysteroid Dehydrogenases, Blotting, Northern, DNA, Complementary
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