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Cell Jul 2002Brassinosteroids regulate plant growth and development through a protein complex that includes the leucine-rich repeat receptor-like protein kinase (LRR-RLK)...
Brassinosteroids regulate plant growth and development through a protein complex that includes the leucine-rich repeat receptor-like protein kinase (LRR-RLK) brassinosteroid-insensitive 1 (BRI1). Activation tagging was used to identify a dominant genetic suppressor of bri1, bak1-1D (bri1-associated receptor kinase 1-1Dominant), which encodes an LRR-RLK, distinct from BRI1. Overexpression of BAK1 results in elongated organ phenotypes, while a null allele of BAK1 displays a semidwarfed phenotype and has reduced sensitivity to brassinosteroids (BRs). BAK1 is a serine/threonine protein kinase, and BRI1 and BAK1 interact in vitro and in vivo. Expression of a dominant-negative mutant allele of BAK1 causes a severe dwarf phenotype, resembling the phenotype of null bri1 alleles. These results indicate BAK1 is a component of BR signaling.
Topics: Alleles; Arabidopsis; Arabidopsis Proteins; Brassinosteroids; Cholestanols; Enzyme Activation; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Plant; Hydroxysteroids; Membrane Proteins; Phenotype; Phosphorylation; Protein Kinases; Protein Serine-Threonine Kinases; Repressor Proteins; Signal Transduction; Steroids, Heterocyclic; Tissue Distribution
PubMed: 12150929
DOI: 10.1016/s0092-8674(02)00812-7 -
Molecular and Cellular Endocrinology Apr 2021This review briefly addresses the history of the discovery and elucidation of the three cloned 11β-hydroxysteroid dehydrogenase (11βHSD) enzymes in the human,... (Review)
Review
This review briefly addresses the history of the discovery and elucidation of the three cloned 11β-hydroxysteroid dehydrogenase (11βHSD) enzymes in the human, 11βHSD1, 11βHSD2 and 11βHSD3, an NADP-dependent dehydrogenase also called the 11βHSD1-like dehydrogenase (11βHSD1L), as well as evidence for yet identified 11βHSDs. Attention is devoted to more recently described aspects of this multi-functional family. The importance of 11βHSD substrates other than glucocorticoids including bile acids, 7-keto sterols, neurosteroids, and xenobiotics is discussed, along with examples of pathology when functions of these multi-tasking enzymes are disrupted. 11βHSDs modulate the intracellular concentration of glucocorticoids, thereby regulating the activation of the glucocorticoid and mineralocorticoid receptors, and 7β-27-hydroxycholesterol, an agonist of the retinoid-related orphan receptor gamma (RORγ). Key functions of this nuclear transcription factor include regulation of immune cell differentiation, cytokine production and inflammation at the cell level. 11βHSD1 expression and/or glucocorticoid reductase activity are inappropriately increased with age and in obesity and metabolic syndrome (MetS). Potential causes for disappointing results of the clinical trials of selective inhibitors of 11βHSD1 in the treatment of these disorders are discussed, as well as the potential for more targeted use of inhibitors of 11βHSD1 and 11βHSD2.
Topics: 11-beta-Hydroxysteroid Dehydrogenases; Animals; Cytokines; Enzyme Inhibitors; Humans; Reproduction; Transcription, Genetic
PubMed: 33607268
DOI: 10.1016/j.mce.2021.111210 -
Molecular and Cellular Endocrinology Jul 2011Aromatase, estrone sulfatase, and 17β-hydroxysteroid dehydrogenase type 1 are involved in the key steps of 17β-estradiol biosynthesis. Structure-function studies of... (Review)
Review
Aromatase, estrone sulfatase, and 17β-hydroxysteroid dehydrogenase type 1 are involved in the key steps of 17β-estradiol biosynthesis. Structure-function studies of aromatase, estrone sulfatase and 17β-hydroxysteroid dehydrogenase type 1 are important to evaluate the molecular basis of the interaction between these enzymes and their inhibitors. Selective and potent inhibitors of the three enzymes have been developed as antiproliferative agents in hormone-dependent breast carcinoma. New treatment strategies for hormone-dependent breast cancer are discussed.
Topics: 17-Hydroxysteroid Dehydrogenases; Animals; Aromatase; Drug Design; Enzyme Inhibitors; Humans; Structure-Activity Relationship; Sulfatases
PubMed: 20888390
DOI: 10.1016/j.mce.2010.09.012 -
Oncotarget May 2017Sex steroid hormones such as estrogens and androgens are involved in the development and differentiation of the breast tissue. The activity and concentration of sex... (Review)
Review
Estrogen and androgen-converting enzymes 17β-hydroxysteroid dehydrogenase and their involvement in cancer: with a special focus on 17β-hydroxysteroid dehydrogenase type 1, 2, and breast cancer.
Sex steroid hormones such as estrogens and androgens are involved in the development and differentiation of the breast tissue. The activity and concentration of sex steroids is determined by the availability from the circulation, and on local conversion. This conversion is primarily mediated by aromatase, steroid sulfatase, and 17β-hydroxysteroid dehydrogenases. In postmenopausal women, this is the primary source of estrogens in the breast. Up to 70-80% of all breast cancers express the estrogen receptor-α, responsible for promoting the growth of the tissue. Further, 60-80% express the androgen receptor, which has been shown to have tissue protective effects in estrogen receptor positive breast cancer, and a more ambiguous response in estrogen receptor negative breast cancers. In this review, we summarize the function and clinical relevance in cancer for 17β-hydroxysteroid dehydrogenases 1, which facilitates the reduction of estrone to estradiol, dehydroepiandrosterone to androstendiol and dihydrotestosterone to 3α- and 3β-diol as well as 17β-hydroxysteroid dehydrogenases 2 which mediates the oxidation of estradiol to estrone, testosterone to androstenedione and androstendiol to dehydroepiandrosterone. The expression of 17β-hydroxysteroid dehydrogenases 1 and 2 alone and in combination has been shown to predict patient outcome, and inhibition of 17β-hydroxysteroid dehydrogenases 1 has been proposed to be a prime candidate for inhibition in patients who develop aromatase inhibitor resistance or in combination with aromatase inhibitors as a first line treatment. Here we review the status of inhibitors against 17β-hydroxysteroid dehydrogenases 1. In addition, we review the involvement of 17β-hydroxysteroid dehydrogenases 4, 5, 7, and 14 in breast cancer.
Topics: 17-Hydroxysteroid Dehydrogenases; Androgens; Animals; Breast Neoplasms; Enzyme Inhibitors; Estrogens; Female; Gene Expression Regulation, Neoplastic; Humans; Multigene Family
PubMed: 28430630
DOI: 10.18632/oncotarget.15547 -
The Netherlands Journal of Medicine Apr 2005Glycyrrhetinic acid, the active constituent of liquorice, inhibits renal IIbeta-hydroxysteroid dehydrogenase. This allows cortisol to stimulate mineralocorticoid...
Glycyrrhetinic acid, the active constituent of liquorice, inhibits renal IIbeta-hydroxysteroid dehydrogenase. This allows cortisol to stimulate mineralocorticoid receptors, which can result in hypertension and hypokalaemia. Treatment options are based on pathophysiological understanding.
Topics: 11-beta-Hydroxysteroid Dehydrogenases; Candy; Glycyrrhetinic Acid; Glycyrrhiza; Humans; Hypertension; Hypokalemia; Receptors, Mineralocorticoid
PubMed: 15869038
DOI: No ID Found -
Endocrine Reviews Apr 2019Aldo-keto reductases (AKRs) are monomeric NAD(P)(H)-dependent oxidoreductases that play pivotal roles in the biosynthesis and metabolism of steroids in humans. AKR1C... (Review)
Review
Aldo-keto reductases (AKRs) are monomeric NAD(P)(H)-dependent oxidoreductases that play pivotal roles in the biosynthesis and metabolism of steroids in humans. AKR1C enzymes acting as 3-ketosteroid, 17-ketosteroid, and 20-ketosteroid reductases are involved in the prereceptor regulation of ligands for the androgen, estrogen, and progesterone receptors and are considered drug targets to treat steroid hormone-dependent malignancies and endocrine disorders. In contrast, AKR1D1 is the only known steroid 5β-reductase and is essential for bile-acid biosynthesis, the generation of ligands for the farnesoid X receptor, and the 5β-dihydrosteroids that have their own biological activity. In this review we discuss the crystal structures of these AKRs, their kinetic and catalytic mechanisms, AKR genomics (gene expression, splice variants, polymorphic variants, and inherited genetic deficiencies), distribution in steroid target tissues, roles in steroid hormone action and disease, and inhibitor design.
Topics: Aldo-Keto Reductases; Humans; Hydroxysteroid Dehydrogenases; Oxidoreductases; Steroids
PubMed: 30137266
DOI: 10.1210/er.2018-00089 -
Future Medicinal Chemistry Mar 2011Cortisol is synthesized by 11β-hydroxysteroid dehydrogenase type 1, inhibitors of which may treat disease associated with excessive cortisol levels. The crystal... (Review)
Review
Cortisol is synthesized by 11β-hydroxysteroid dehydrogenase type 1, inhibitors of which may treat disease associated with excessive cortisol levels. The crystal structures of 11β-hydroxysteroid dehydrogenase type 1 that have been released may aid drug discovery. The crystal structures have been analyzed in terms of the interactions between the protein and the ligands. Despite a variety of structurally different inhibitors the crystal structures of the proteins are quite similar. However, the differences are significant for drug discovery. The crystal structures can be of use in drug discovery, but care needs to be taken when selecting structures for use in virtual screening and ligand docking.
Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Animals; Binding Sites; Crystallography, X-Ray; Drug Discovery; Enzyme Inhibitors; Glutamate Dehydrogenase (NADP+); Guinea Pigs; Humans; Hydrocortisone; Hydrogen Bonding; Ligands; Metabolic Syndrome; Mice; Models, Molecular; Protein Conformation; Rats
PubMed: 21446847
DOI: 10.4155/fmc.10.282 -
The International Journal of... May 202211β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity is implicated as a moderator of the progression of multiple diseases and disorders in medicine and is...
11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity is implicated as a moderator of the progression of multiple diseases and disorders in medicine and is actively subject to investigation as a therapeutic target. Here we summarize the mechanisms of the enzyme and detail the novel agents under investigation. Such agents modulate peripheral cortisol and cortisone levels in hypertension, type 2 diabetes, metabolic disorders, and Alzheimer's disease models, but there is mixed evidence for transduction into symptom management. There is inchoate evidence that 11β-HSD1 modulators may be useful pharmacotherapies for clinical improvement in psychiatry and neurology; however, more research is required.
Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Diabetes Mellitus, Type 2; Glucocorticoids; Humans; Hydrocortisone; Hydroxysteroids; Mental Disorders
PubMed: 35143668
DOI: 10.1093/ijnp/pyac014 -
Steroids Sep 1996Mammalian 3 alpha-hydroxysteroid dehydrogenases (3 alpha-HSDs) regulate steroid hormone levels. For example, hepatic 3 alpha-HSDs inactivate circulating androgens,... (Review)
Review
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.
Topics: 3-Hydroxysteroid Dehydrogenases; 3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); Amino Acid Sequence; Animals; Brain; Cloning, Molecular; Crystallography, X-Ray; Forecasting; Humans; Kinetics; Liver; Male; Mice; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Prostate; Protein Conformation; Rabbits; Rats; Sequence Homology, Amino Acid; Steroids; Substrate Specificity
PubMed: 8883217
DOI: 10.1016/s0039-128x(96)00093-1 -
Molecular and Cellular Endocrinology Jun 2019Abnormal synthesis and metabolism of sex steroids is involved in the pathogenesis of various human diseases, such as endometriosis and cancers arising from the breast... (Review)
Review
Abnormal synthesis and metabolism of sex steroids is involved in the pathogenesis of various human diseases, such as endometriosis and cancers arising from the breast and uterus. Steroid biosynthesis is a multistep enzymatic process proceeding from cholesterol to highly active sex steroids via different intermediates. Human Hydroxysteroid (17beta) dehydrogenase 1 (HSD17B1) enzyme shows a high capacity to produce the highly active estrogen, estradiol, from a precursor hormone, estrone. However, the enzyme may also play a role in other steps of the steroid biosynthesis pathway. In this article, we have reviewed the literature on HSD17B1, and summarize the role of the enzyme in hormone-dependent diseases in women as evidenced by preclinical studies.
Topics: 17-Hydroxysteroid Dehydrogenases; Animals; Enzyme Inhibitors; Genitalia; Hormones; Humans; Models, Biological; Organ Specificity
PubMed: 30149044
DOI: 10.1016/j.mce.2018.08.004