Mammalian 3 alpha-hydroxysteroid dehydrogenases.
Mammalian 3 alpha-hydroxysteroid dehydrogenases (3 alpha-HSDs) regulate steroid hormone levels. For example, hepatic 3 alpha-HSDs inactivate circulating androgens, progestins, and glucocorticoids. In target tissues they regulate access of steroid hormones to steroid hormone receptors. For example, in the prostate 3 alpha-HSD acts as a molecular switch and controls the amount of 5 alpha-dihydrotestosterone that can bind to the androgen receptor, while in the brain 3 alpha-HSD can regulate the amount of tetrahydrosteroids that can alter GABAa receptor function. Molecular cloning indicates that these mammalian 3 alpha-HSDs belong to the aldo-keto reductase superfamily and that they are highly homologous proteins. Using the three-dimensional structure of rat liver 3 alpha-HSD as a template for site-directed mutagenesis, details regarding structure function relationships, including catalysis and cofactor and steroid hormone recognition have been elucidated. These details may be relevant to all mammalian 3 alpha-HSDs.
Penning
T M
TM
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104-6084, USA.
Pawlowski
J E
JE
Schlegel
B P
BP
Jez
J M
JM
Lin
H K
HK
Hoog
S S
SS
Bennett
M J
MJ
Lewis
M
M
D015096:3-Hydroxysteroid Dehydrogenases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000201:enzymology; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D005544:Forecasting; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011467:Prostate / Q000201:enzymology; D011487:Protein Conformation; D011817:Rabbits; D051381:Rats; D017386:Sequence Homology, Amino Acid; D013256:Steroids / Q000378:metabolism; D013379:Substrate Specificity
D013256:Steroids; D015096:3-Hydroxysteroid Dehydrogenases; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)