title: 17β-Hydroxysteroid dehydrogenases (17β-HSDs) as therapeutic targets: protein structures, functions, and recent progress in inhibitor development.
abstract: 17β-Hydroxysteroid dehydrogenases (17β-HSDs) are oxidoreductases, which play a key role in estrogen and androgen steroid metabolism by catalyzing final steps of the steroid biosynthesis. Up to now, 14 different subtypes have been identified in mammals, which catalyze NAD(P)H or NAD(P)(+) dependent reductions/oxidations at the 17-position of the steroid. Depending on their reductive or oxidative activities, they modulate the intracellular concentration of inactive and active steroids. As the genomic mechanism of steroid action involves binding to a steroid nuclear receptor, 17β-HSDs act like pre-receptor molecular switches. 17β-HSDs are thus key enzymes implicated in the different functions of the reproductive tissues in both males and females. The crucial role of estrogens and androgens in the genesis and development of hormone dependent diseases is well recognized. Considering the pivotal role of 17β-HSDs in steroid hormone modulation and their substrate specificity, these proteins are promising therapeutic targets for diseases like breast cancer, endometriosis, osteoporosis, and prostate cancer. The selective inhibition of the concerned enzymes might provide an effective treatment and a good alternative to the existing endocrine therapies. Herein, we give an overview of functional and structural aspects for the different 17β-HSDs. We focus on steroidal and non-steroidal inhibitors recently published for each subtype and report on existing animal models for the different 17β-HSDs and the respective diseases. Article from the Special issue on Targeted Inhibitors.
authors.affiliation: Saarland University, Pharmaceutical and Medicinal Chemistry, PO Box 15 11 50, 66041 Saarbrücken, Germany.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marchais-Oberwinkler
authors.forename: Claudia
authors.initials: C
authors.lastname: Henn
authors.forename: Gabriele
authors.initials: G
authors.lastname: Möller
authors.forename: Tobias
authors.initials: T
authors.lastname: Klein
authors.forename: Matthias
authors.initials: M
authors.lastname: Negri
authors.forename: Alexander
authors.initials: A
authors.lastname: Oster
authors.forename: Alessandro
authors.initials: A
authors.lastname: Spadaro
authors.forename: Ruth
authors.initials: R
authors.lastname: Werth
authors.forename: Marie
authors.initials: M
authors.lastname: Wetzel
authors.forename: Kuiying
authors.initials: K
authors.lastname: Xu
authors.forename: Martin
authors.initials: M
authors.lastname: Frotscher
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000145:classification / Q000378:metabolism*; D000595:Amino Acid Sequence; D000728:Androgens / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism*; D004967:Estrogens / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry* / Q000145:classification / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010802:Phylogeny; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology; D011487:Protein Conformation; D016415:Sequence Alignment
chemical_list: D000728:Androgens; D004791:Enzyme Inhibitors; D004967:Estrogens; D007527:Isoenzymes; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase