Molecular Endocrinology of Hydroxysteroid Dehydrogenases1
Trevor M. Penning
Department of Pharmacology, University of Pennsylvania School of
Medicine, Philadelphia, Pennsylvania 19104-6084
I. Introduction
II. 3ß-Hydroxysteroid Dehydrogenase/KetosteroidIsomerase
(3ß-HSD/KSI)
A. Physiological and pharmacologicalsignificance
B. Cloning and expression of the 3ß-HSD/KSIcDNAs
C. Structure, regulation, and tissue-specific expressionofthe
3ß-HSD/KSI genes
D. 3ß-HSD deficiencies
III. 17ß-Hydroxysteroid Dehydrogenases
A. Physiologicaland pharmacological significance
B. Cloning and expressionof the 17ß-HSD cDNAs
C. Structure, regulation, and tissue-specificexpression ofthe 17ß-HSD
genes
D. 17ß-HSD deficiency
IV. 11ß-Hydroxysteroid Dehydrogenases
A. Physiologicaland pharmacological significance
B. Cloning and expressionof the 11ß-HSD cDNAs
C. Structure, regulation, and tissue-specificexpression ofthe 11ß-HSD
genes
D. 11ß-HSD deficiency
V. 3-Hydroxysteroid Dehydrogenases
A. Physiological andpharmacological significance
B. Cloning and expression ofthe 3-HSD cDNAs
C. Structure, regulation, and tissue-specificexpression ofthe 3-HSD
genes
D. 3-HSD deficiencies
VI.20-Hydroxysteroid Dehydrogenases
A. Physiological and pharmacologicalsignificance
B. Cloning and expression of the 20-HSD cDNAs
C. Structure, regulation, and tissue-specific expression ofthe 20-HSD
genes
VII. HSDs Belong to Two Protein Families
A. HSDs that belong to the SDR superfamily
B. HSDs thatbelong to the AKR superfamily
VIII. Structure/Function ofHSDs
A. Kinetic mechanism of HSDs
B. Catalytic mechanismof HSDs
C. x-Ray crystal structures of HSDs in the SDR superfamily
D. Site-directed mutagenesis on HSDs that are SDR members
E. x-Ray crystal structures of HSDs in the AKR superfamily
F. Site-directed mutagenesis on HSDs that are AKR members
G. Convergent evolution to a common reaction mechanism
H.Engineering alternate substrate specificity
IX. Conclusions
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October 1, 2002;
67(4):
1080 - 1086.
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November 1, 2001;
142(11):
4652 - 4662.
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142(3):
1341 - 1348.
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February 1, 2001;
142(2):
778 - 787.
[Abstract][Full Text][PDF]
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October 12, 2000;
(2000)
220412297.
[Abstract][Full Text]
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Endocrinology,
August 1, 2000;
141(8):
2786 - 2794.
[Abstract][Full Text][PDF]
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Endocr. Rev.,
June 1, 2000;
21(3):
245 - 291.
[Abstract][Full Text]
W.-C. Song and M. H. Melner Editorial: Steroid Transformation Enzymes as Critical Regulators of Steroid Action in Vivo
Endocrinology,
May 1, 2000;
141(5):
1587 - 1589.
[Full Text][PDF]
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September 28, 1999;
96(20):
11161 - 11166.
[Abstract][Full Text][PDF]
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Endocrinology,
August 1, 1999;
140(8):
3478 - 3487.
[Abstract][Full Text]
C. H. Tsai-Morris, A. Khanum, P.-Z. Tang, and M. L. Dufau The Rat 17{beta}-Hydroxysteroid Dehydrogenase Type III: Molecular Cloning and Gonadotropin Regulation
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August 1, 1999;
140(8):
3534 - 3542.
[Abstract][Full Text]
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June 1, 1999;
47(6):
731 - 738.
[Abstract][Full Text]
E. Y. Adashi and J. D. Hennebold Single-Gene Mutations Resulting in Reproductive Dysfunction in Women
N. Engl. J. Med.,
March 4, 1999;
340(9):
709 - 718.
[Full Text][PDF]
A. G. Mensah-Nyagan, J.-L. Do-Rego, D. Beaujean, V. Luu-The, G. Pelletier, and H. Vaudry Neurosteroids: Expression of Steroidogenic Enzymes and Regulation of Steroid Biosynthesis in the Central Nervous System
Pharmacol. Rev.,
March 1, 1999;
51(1):
63 - 82.
[Abstract][Full Text][PDF]
O. Levalle, C. Zylbersztein, S. Aszpis, D. Aquilano, C. Terradas, M. Colombani, C. Aranda, and H. Scaglia Recombinant Human Follicle-Stimulating Hormone Administration Increases Testosterone Production in Men, Possibly by a Sertoli Cell-Secreted Nonsteroid Factor
J. Clin. Endocrinol. Metab.,
November 1, 1998;
83(11):
3973 - 3976.
[Abstract][Full Text]
P.-Z. Tang, C. H. Tsai-Morris, and M. L. Dufau Regulation of 3{beta}-Hydroxysteroid Dehydrogenase in Gonadotropin-Induced Steroidogenic Desensitization of Leydig Cells
Endocrinology,
November 1, 1998;
139(11):
4496 - 4505.
[Abstract][Full Text][PDF]
R.-S. Ge and M. P. Hardy Variation in the End Products of Androgen Biosynthesis and Metabolism during Postnatal Differentiation of Rat Leydig Cells
Endocrinology,
September 1, 1998;
139(9):
3787 - 3795.
[Abstract][Full Text][PDF]
W. H. Gough, S. VanOoteghem, T. Sint, and N. Y. Kedishvili cDNA Cloning and Characterization of a New Human Microsomal NAD+-dependent Dehydrogenase that Oxidizes All-trans-retinol and 3alpha -Hydroxysteroids
J. Biol. Chem.,
July 31, 1998;
273(31):
19778 - 19785.
[Abstract][Full Text][PDF]
Y. Qian, C. Deng, and W.-C. Song Expression of Estrogen Sulfotransferase in MCF-7 Cells by cDNA Transfection Suppresses the Estrogen Response: Potential Role of the Enzyme in Regulating Estrogen-Dependent Growth of Breast Epithelial Cells
J. Pharmacol. Exp. Ther.,
July 1, 1998;
286(1):
555 - 560.
[Abstract][Full Text]
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J. Biol. Chem.,
January 19, 2001;
276(4):
2890 - 2897.
[Abstract][Full Text][PDF]
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J. Biol. Chem.,
May 11, 2001;
276(20):
16767 - 16771.
[Abstract][Full Text][PDF]
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97(22):
12256 - 12259.
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-Hydroxysteroid Dehydrogenases 
