Signal transduction: Difference between revisions

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<StructureSection load='' size='300' side='right' scene='Journal:JBSD:16/Cv/2' caption='Nicotinic Acetylcholine Receptor, PDB code [[2bg9]]'>
<StructureSection load='' size='300' side='right' scene='Journal:JBSD:16/Cv/2' caption='Nicotinic Acetylcholine Receptor, PDB code [[2bg9]]'>
'''Under development!'''
*[[Ligand]]
*[[Ligand]]
*[[Types of ligands]]
*[[Types of ligands]]
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*[[Growth factors]]
*[[Growth factors]]
*[[Neurotransmitters]]
*[[Neurotransmitters]]
*[[Neuropeptides]]
*[[Neuromodulators]]
*[[Receptor]]
*[[Receptor]]
*[[Ion channels]]
*[[Ion channels]]
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This large and diverse class of steroids are biosynthesized from isoprenoids and structurally resemble cholesterol. Mammalian steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestogens. Vitamin D derivatives are a sixth closely related hormone system with homologous receptors. They have some of the characteristics of true steroids as receptor ligands. For example, <scene name='89/895670/Cv/1'>estradiol</scene> is an important estrogen steroid hormone in both women and men. It is a typical steroid with core four-ring system (ABCD), composed of 17 carbon atoms.
This large and diverse class of steroids are biosynthesized from isoprenoids and structurally resemble cholesterol. Mammalian steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestogens. Vitamin D derivatives are a sixth closely related hormone system with homologous receptors. They have some of the characteristics of true steroids as receptor ligands. For example, <scene name='89/895670/Cv/1'>estradiol</scene> is an important estrogen steroid hormone in both women and men. It is a typical steroid with core four-ring system (ABCD), composed of 17 carbon atoms.


=[[Corticosteroids]]=
''[[Corticosteroids]]''
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, [[glucocorticoids]] and [[mineralocorticoids]], are involved in a wide range of physiological processes.
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, [[glucocorticoids]] and [[mineralocorticoids]], are involved in a wide range of physiological processes.


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<scene name='89/895670/Cv/2'>Cortisol</scene> (hydrocortisone) is a corticosteroid with both glucocorticoid and mineralocorticoid activity and effects.
<scene name='89/895670/Cv/2'>Cortisol</scene> (hydrocortisone) is a corticosteroid with both glucocorticoid and mineralocorticoid activity and effects.


==[[Glucocorticoids]]==
''[[Glucocorticoids]]''
Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor. <scene name='89/895670/Cv/3'>Dexamethasone</scene> is a glucocorticoid medication. It is the most potent glucocorticoid and it has not mineralocorticoid potency.   
Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor. <scene name='89/895670/Cv/3'>Dexamethasone</scene> is a glucocorticoid medication. It is the most potent glucocorticoid and it has not mineralocorticoid potency.   
*[[Glucocorticoid receptor]]. <scene name='89/895670/Cv/4'>Human glucocorticoid receptor ligand-binding domain bound to dexamethasone</scene> ([[1m2z]]).
*[[Glucocorticoid receptor]]. <scene name='89/895670/Cv/4'>Human glucocorticoid receptor ligand-binding domain bound to dexamethasone</scene> ([[1m2z]]).
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*Microsomal [[Prostaglandin E synthase]] (PGES) converts cyclooxygenase (COX)-derived prostaglandin to PGE2. It is membrane-associated and belongs to the microsomal glutathione S-transferase family. PGES is preferentially linked with the inducible COX-2<ref>PMID:12432931</ref> . PGES is induced by proinflammatory stimuli and down-regulated by anti-inflammatory '''glucocorticoids'''<ref>PMID:16336776</ref>. Microsomal ''Prostaglandin E synthase'' <scene name='77/778890/Cv/2'>is membrane-associated</scene> (coordinates are from [http://opm.phar.umich.edu/protein.php?extrapdb=4yl0 OPM database]. The <scene name='77/778890/Cv/6'>anti-inflammatory inhibitor binds to PGES in a pocket above the glutathione and interacts with various side-chains of a helix</scene><ref>PMID:25961169</ref>. Water molecules are shown as red spheres.
*Microsomal [[Prostaglandin E synthase]] (PGES) converts cyclooxygenase (COX)-derived prostaglandin to PGE2. It is membrane-associated and belongs to the microsomal glutathione S-transferase family. PGES is preferentially linked with the inducible COX-2<ref>PMID:12432931</ref> . PGES is induced by proinflammatory stimuli and down-regulated by anti-inflammatory '''glucocorticoids'''<ref>PMID:16336776</ref>. Microsomal ''Prostaglandin E synthase'' <scene name='77/778890/Cv/2'>is membrane-associated</scene> (coordinates are from [http://opm.phar.umich.edu/protein.php?extrapdb=4yl0 OPM database]. The <scene name='77/778890/Cv/6'>anti-inflammatory inhibitor binds to PGES in a pocket above the glutathione and interacts with various side-chains of a helix</scene><ref>PMID:25961169</ref>. Water molecules are shown as red spheres.


==[[Mineralocorticoids]]==
''[[Mineralocorticoids]]''
Mineralocorticoids are a class of corticosteroids. Mineralocorticoids are produced in the adrenal cortex and influence salt and water balances (electrolyte balance and fluid balance). The primary mineralocorticoid is <scene name='89/896192/Cv/1'>aldosterone</scene>.
Mineralocorticoids are a class of corticosteroids. Mineralocorticoids are produced in the adrenal cortex and influence salt and water balances (electrolyte balance and fluid balance). The primary mineralocorticoid is <scene name='89/896192/Cv/1'>aldosterone</scene>.
*[[Mineralocorticoid receptor]] (MR) in epithelial cells is activated by the mineralocorticoid hormone aldosterone promoting renal sodium retention and potassium excretion. It is [[Nuclear receptors|nuclear receptor]]. In non epithelial cells MR is activated by cortisol<ref>PMID:15199296</ref>.  MR is exposed to many steroids including cortisol, cortisone and progesterone, however, aldosterone and deoxycorticosterone are its physiological ligands. MR mutations are the principal cause of renal pseudohypoaldosteronism<ref>PMID:16972228</ref>. MR mutation S810L causes early-onset hypertension<ref>PMID:10884226</ref>. Inhibition of cardia MR prevents doxorubicin-induced cardiotoxicity<ref>PMID:28430882</ref>. MR is an important proadipogenic transcription factor that may mediate aldosterone and glucocorticoid effects on adipose tissue development and hence on obesity and development of metabolic syndrome<ref>PMID:17384139</ref>. The MR ligand aldosterone binds in a <scene name='78/781019/Cv/6'>fully enclosed pocket, contacting residues with six α-helices and a β-turn</scene> ({{Template:ColorKey_Helix}},{{Template:ColorKey_Strand}},{{Template:ColorKey_Loop}},{{Template:ColorKey_Turn}}). <scene name='78/781019/Cv/7'>It forms hydrogen bonds with 4 MR residues</scene><ref>PMID:15967794</ref>. <scene name='78/781019/Cv/8'>Whole binding site</scene>. Water molecules are shown as red spheres.
*[[Mineralocorticoid receptor]] (MR) in epithelial cells is activated by the mineralocorticoid hormone aldosterone promoting renal sodium retention and potassium excretion. It is [[Nuclear receptors|nuclear receptor]]. In non epithelial cells MR is activated by cortisol<ref>PMID:15199296</ref>.  MR is exposed to many steroids including cortisol, cortisone and progesterone, however, aldosterone and deoxycorticosterone are its physiological ligands. MR mutations are the principal cause of renal pseudohypoaldosteronism<ref>PMID:16972228</ref>. MR mutation S810L causes early-onset hypertension<ref>PMID:10884226</ref>. Inhibition of cardia MR prevents doxorubicin-induced cardiotoxicity<ref>PMID:28430882</ref>. MR is an important proadipogenic transcription factor that may mediate aldosterone and glucocorticoid effects on adipose tissue development and hence on obesity and development of metabolic syndrome<ref>PMID:17384139</ref>. The MR ligand aldosterone binds in a <scene name='78/781019/Cv/6'>fully enclosed pocket, contacting residues with six α-helices and a β-turn</scene> ({{Template:ColorKey_Helix}},{{Template:ColorKey_Strand}},{{Template:ColorKey_Loop}},{{Template:ColorKey_Turn}}). <scene name='78/781019/Cv/7'>It forms hydrogen bonds with 4 MR residues</scene><ref>PMID:15967794</ref>. <scene name='78/781019/Cv/8'>Whole binding site</scene>. Water molecules are shown as red spheres.
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*[[Hydroxysteroid dehydrogenase]]
*[[Hydroxysteroid dehydrogenase]]


*[[Lysophosphatidic acid receptor]]
'''[[Sex steroids]]'''
*[[GPR40]]
 
''[[Androgens]]''
An androgen is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. The major androgen in males is <scene name='89/895670/Cv/5'>testosterone</scene>. It is the primary sex hormone and anabolic steroid in males. It is a steroid from the androstane class. It exerts its action through binding to and activation of the [[androgen receptor]].
*[[Androgen receptor]]. Ligand binding domain (LBD) containing an <scene name='54/543362/Cv/3'>active site</scene> which binds intramolecularly the N-terminal FXXFL motif or coactivators with the same motif.<ref>PMID:18805694</ref> Water molecules are shown as red spheres. <scene name='89/895670/Cv/6'>Human androgen receptor bound to testosterone</scene> ([[2ylo]]).
*[[Heat shock factor]] (HSF) are transcriptional activators of heat shock genes. HSF bind to heat shock sequence elements throughout the genome with a consensus array of three oppositely oriented sequence AGGAN and activate transcription.  Each HSF monomer contains one C-terminal and 3 N-terminal leucine zippers. Two sequences flanking the N-terminal leucine zippers contain the consensus nuclear localization signal (NLS). The DNA-binding domain (DBD residues 193-281)  of HSF lies in the N-terminal of the first NLS region<ref>PMID:8441385</ref>. Depletion of HSF-1 is associated with accumulation of pathogenic [[androgen receptor]] in neurodegenerative diseases<ref>PMID:23360996</ref>.
*[[Cellular retinoic acid-binding protein]] (CRABP); Epididymal RABP (ERABP) is an '''androgen'''-dependent RABP present in the lumen of the epididymis believed to be involved in '''sperm''' maturation. ERABP binds specifically all-trans- and 9-cis-RA.
*[[Aromatase]]. The primary function of aromatase is to produce estrogens by aromatizing '''androgens'''. Aromatase is the only known enzyme in vertebrates capable of catalyzing the aromatization of a six-membered ring<ref name="structure"> Ghosh, D., Griswold, J., Erman, M., Pangborn, W. " X-ray Structure of Human Aromatase Reveals An Androgen-Specific Active Site" ''Journal of Steroid Biochemistry and Molecular Biology''. [Online] '''2010''',Vol. 118, Issue 4-5, p197-202[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826573/]</ref>.
*[[Student Project 1 for UMass Chemistry 423 Spring 2015]]. Protein kinase C related kinase 1 (PRK1) is a component of Rho-GTPase, histone demethylase, '''androgen''' receptor, and histone demethylase signaling pathways and is involved in ovary and prostate cancer. A lot of PRK1 is expressed in cases of ovarian serous carcinoma.
*[[Finasteride]]
*[[Zolinza (Vorinostat)]]
*[[Hydroxysteroid dehydrogenase]], 17-β HSD is involved in the conversion of androstenedione to testosterone.
*[[Aromatase]] converts androstenedione to estrogen and testosterone to estradiol.
*[[Lipids: structure and classification]]
*Cytochrome P450 3A4 ([[CYP3A4]])
 
''[[Estrogens]]''
 
There are three major endogenous estrogens that have estrogenic hormonal activity: estrone (E1), estradiol (E2), and estriol (E3). Estradiol, an estrane, is the most potent and prevalent. Another estrogen called estetrol (E4) is produced only during pregnancy.
*[[Estrogen receptor]]
<scene name='Estrogen_receptor/Cv/1'>Click here to see the difference between conformations</scene> of estrogen receptor α complexed with raloxifene and a corepressor peptide (morph was taken from [http://molmovdb.org/cgi-bin/movie.cgi Gallery of Morphs] of the [http://molmovdb.org Yale Morph Server]).
 
*[[Estrogen-related receptor]]
*[[Tamoxifen|Tamoxifen and the Estrogen Receptor/Tamoxifen and the Estrogen-related receptor]]
<scene name='50/501401/Cv/4'>Binding of nuclear receptor corepressor 2 peptide and 4-hydroxytamoxifen</scene> to human estrogen-related receptor γ. The chemotherapeutic drugs bisphenol and <scene name='50/501401/Cv/5'>tamoxifen</scene> are nestled between 4 alpha helices in the ERR active site.
* [[Estrogen sulfotransferase]]
*[[Aromatase]]
*[[Finasteride]]
 
'''Estrone'''
*[[Estrogen receptor 3D structures]]
*[[Estrone sulfatase]]
*[[Sulfatase 3D structures]]
*[[ABC transporter 3D structures]]
*[[ABCG2 multidrug transporter]]
Substrates, such as estrone sulfate, <scene name='83/832932/Cavity_1_-_use2/4'>form hydrogen bonds and stacking interactions</scene> with residues from each subunit in Cavity 1 of ABCG2 multidrug transporter.
*[[Hydroxysteroid dehydrogenase]]
*[[Hydroxysteroid dehydrogenase 3D structures]]
*[[Prostaglandin F synthase]]
 
'''Estradiol'''
*[[Lipids: structure and classification]]
*[[Estrogen receptor]]
*[[Ivan Koutsopatriy estrogen receptor]]
*[[Estradiol 17-beta-dehydrogenase]]
*[[Student Project 10 for UMass Chemistry 423 Spring 2015]]
*[[Aromatase]]
*[[Sulfotransferase]]
*[[ATPase family AAA domain-containing protein 2]]
*[[Hypoxia-Inducible Factors]]
 
'''Estriol'''
*[[Cytochrome P450 3D structures]]: [[1x8v]] - MtP450 CYP51 (mutant)+estriol<br />
 
'''Estetrol'''
*[[3l03]] - Crystal Structure of human Estrogen Receptor alpha Ligand-Binding Domain in complex with a Glucocorticoid Receptor Interacting Protein 1 Nr Box II peptide and Estetrol (Estra-1,3,5(10)-triene-3,15 alpha,16alpha,17beta-tetrol)
 
''[[Progestogens]]''
 
'''Progesterone'''
 
<scene name='89/895670/Cv/7'>Progesterone</scene> (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species.
*[[Progesterone receptor]]. <scene name='89/895670/Cv/8'>Human progesterone receptor ligand-binding domain bound with progesterone</scene> ([[1a28]]). Water molecules are shown as red spheres.
 
*Progesterone is a negative allosteric modulator of [[nicotinic acetylcholine receptors]], and a potent antagonist of the [[mineralocorticoid receptor]].
 
*[[Hydroxysteroid dehydrogenase]], 20-α HSD is involved in the control of progesterone level in pregnancy of mice. 17-β HSD is involved in the conversion of androstenedione to testosterone.
 
'''Vitamin D derivatives; secosteroids (open-ring steroids)'''
 
<scene name='89/895670/Cv/9'>Vitamin D</scene>.
 
<scene name='89/895670/Cv/10'>25-hydroxy-cholecalciferol (25-D3); 25-hydroxyvitamin D3</scene> ([[5ien]])
 
Calcitriol is the active form of vitamin D pro-hormone.
 
*[[Vitamin D receptor]] (also called calcitriol receptor)
<scene name='56/562378/Vit_d_receptor_3m7r/3'>Vitamin D receptor (VDR)</scene> is a transcription factor. Upon binding to vitamin D, VDR forms a heterodimer with retinoid-X receptor and binds to hormone response receptors on DNA causing gene expression. The <scene name='56/562378/Vit_d_receptor_ligand/1'>vitamin D hormone</scene> (green) binds to receptors in its target cells, controlling the synthesis of many different proteins involved in Ca transport and utilization.
<scene name='51/517370/Cv/2'>Vitamin D hormone binding site</scene>.
 
<scene name='51/517370/Cv/3'>Vitamin D hormone is located in deep pocket</scene>. VDR contains 2 domains: a <scene name='56/562378/Lbd/1'>ligand binding domain (LBD)</scene>, that binds to the hormone (grey) and <scene name='56/562378/Dbd/2'>DNA-binding domain (DBD)</scene> that binds to DNA (green and blue are 2 same VDR structures). It pairs up with a similar protein, 9-cis retinoic acid receptor (RXR), and together they bind to the DNA, activating synthesis in some cases and repressing it in others. When <scene name='56/562378/Serine_final/1'>serine</scene> is mutated it is replaced with a <scene name='56/562378/Glycine_final/1'>glycine</scene> which results in an inhibition of transcriptional activation. When transcription is inhibited it results in p53 accumulation, which activates and promotes p53 translocation into mitochondria leading to apoptosis. <scene name='56/562378/Serine_final/1'>Serine</scene> is replaced with <scene name='56/562378/Asparticacid_final/1'>aspartic acid</scene> when mutated creating a negative charge. The negative charge at the residue inhibits DNA binding which cause a downregulation of VDR activity. VDR needs DNA binding in order for it to be activated which is only possible with a serine residue.


'''Signaling Pathways:'''
The vitamin D nuclear receptor is a ligand-dependent transcription factor that controls multiple biological responses such as cell proliferation, immune responses, and bone mineralization. Numerous 1 α,25(OH)(2)D(3) analogues, which exhibit low calcemic side effects and/or antitumoral properties, have been synthesized. It was shown that <scene name='56/562378/3a3z/1'>the synthetic analogue (20S,23S)-epoxymethano-1α,25-dihydroxyvitamin D(3) (2a)</scene> acts as a 1α,25(OH)(2)D(3) superagonist and exhibits both antiproliferative and prodifferentiating properties in vitro. Using this information and on the basis of the crystal structures of human VDR ligand binding domain (hVDR LBD) bound to 1α,25(OH)(2)D(3), 2α-methyl-1α,25(OH)(2)D(3), or 2a, a novel analogue, 2α-methyl-(20S,23S)-epoxymethano-1α,25-dihydroxyvitamin D(3) (4a) was designed, in order to increase its transactivation potency.


''ABA Signaling Pathway''
''ABA Signaling Pathway''
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*[[Protein Phosphatase 2C]]
*[[Protein Phosphatase 2C]]
*[[ABA-regulated SNRK2 Protein Kinase]]
*[[ABA-regulated SNRK2 Protein Kinase]]
'''[[Signaling Pathways]]:'''
*[[Akt/PKB signaling pathway]]
*[[AMPK signaling pathway]]
*[[cAMP-dependent pathway]]
*[[Eph/ephrin signaling pathway]]
*[[Hedgehog signaling pathway]]
*[[Insulin signal transduction pathway]]
*[[JAK-STAT signaling pathway]]
*[[MAPK/ERK pathway]]
*[[mTOR signaling pathway]]
*[[Nodal signaling pathway]]
*[[Notch signaling pathway]]
*[[PI3K/AKT/mTOR signaling pathway]]
*[[TGF beta signaling pathway‎]]
*[[TLR signaling pathway]]
*[[VEGF signaling pathway]]
*[[Wnt signaling pathway]]
[[MAPK/ERK pathway]]
*[[Mitogen-activated protein kinase]]
*[[Mitogen-activated protein kinase kinase]]
*[[Mitogen-activated protein kinase kinase kinase]]
*[[Michael Roberts/BIOL115/ERK2]]
*[[UMass Chem 423 Student Projects 2011-2#p38 kinase|p38 MAPK (UMass Chem 423 Student Projects 2011-2)]]


'''[[Protein Kinases]]:'''
'''[[Protein Kinases]]:'''
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*[[Protein kinase C]]
*[[Protein kinase C]]
*The sensitization of [[TRPV1]] is thought to be connected to phosphorylation by [[protein kinase C]] and the cleavage of PIP2.
*The sensitization of [[TRPV1]] is thought to be connected to phosphorylation by [[protein kinase C]] and the cleavage of PIP2.
''MAPK''
*[[Mitogen-activated protein kinase]]
*[[Mitogen-activated protein kinase kinase]]
*[[Mitogen-activated protein kinase kinase kinase]]
*[[Michael Roberts/BIOL115/ERK2]]
*[[UMass Chem 423 Student Projects 2011-2#p38 kinase|p38 MAPK (UMass Chem 423 Student Projects 2011-2)]]


''CAMP-dependent protein kinase''
''CAMP-dependent protein kinase''
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*[[Inositol 1,4,5-Trisphosphate Receptor]]
*[[Inositol 1,4,5-Trisphosphate Receptor]]


Paracrine signaling: fibroblast growth factor (FGF) family, Hedgehog family, Wnt family, and TGF-β superfamily
'''[[Paracrine signaling]]:'''
Fibroblast growth factor (FGF) family, Hedgehog family, Wnt family, and TGF-β superfamily


[[Fibroblast growth factor]] and [[Fibroblast growth factor receptor]] (FGFR). FGFR belongs to Receptor tyrosine kinases, class V.
*[[Fibroblast growth factor]] and [[Fibroblast growth factor receptor]] (FGFR). FGFR belongs to Receptor tyrosine kinases, class V.
*[[Hedgehog signaling pathway]]
*[[TGF beta signaling pathway]]‎
*[[Wnt signaling pathway]]


'''Sonic Hedgehog'''
'''[[Intracrine signaling]]'''
*[[Sonic Hedgehog]]
*[[Protein patched homolog 1]] (Ptch1) acts as receptor of Sonic Hedgehog protein (Shh) which is involved in formation of embryonic structures.


'''Ca2+ signalling processes'''
'''[[Ca2+ signalling processes]]'''
*[[Inositol 1,4,5-Trisphosphate Receptor]]
*[[Inositol 1,4,5-Trisphosphate Receptor]]
*[[Calcium-dependent protein kinase]]
*[[Calcium-dependent protein kinase]]
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'''GTPase'''
'''GTPase'''
*[[GTPase HRas]].
*[[GTPase HRas]].
'''The Mitogen-activated protein kinase cascade'''
MAPKs are involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflammatory cytokines. They regulate cell functions including proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis.
*[[Mitogen-activated protein kinase]]
*[[Mitogen-activated protein kinase kinase]]
*[[Mitogen-activated protein kinase kinase kinase]]
*[[Michael Roberts/BIOL115/ERK2]]
*[[UMass Chem 423 Student Projects 2011-2#p38 kinase|p38 MAPK (UMass Chem 423 Student Projects 2011-2)]]


'''Inflammatory response'''
'''Inflammatory response'''

Latest revision as of 15:18, 22 June 2023

Lipid signaling:

Ceramide

  • Sphingomyelinase (SMase) or sphingomyelin phosphodiesterase is a hydrolase involved in sphingolipid metabolism. It catalyzes the breakdown of sphingomyelin (SM) to phosphocholine and ceramide[1].
  • Acid-beta-glucosidase or glucosylceramidase is a lysozomal enzyme (EC number 3.2.1.45), which cleaves glucosylceramide to glucose and ceramide. It catalyzes hydrolysis of the sphingolipid, , to at the acidic pH prevailing within the lysosome. .
  • The molecular function of galactosylceramidase is hydrolysis of a O-glycosyl bond to remove galactose from ceramide and other sphingolipids.

Sphingosine-1-Phosphate

Glucosylceramide

Phosphatidylinositol bisphosphate (PIP2)

Phosphatidylinositol 4,5-bisphosphate (PIP2) binds to and directly activates inwardly rectifying potassium channels. Inward rectifier KCh.

Prostaglandins

Endocannabinoids

Retinol derivatives

Retinal

Retinoic acid

Steroid Hormones and their receptors

This large and diverse class of steroids are biosynthesized from isoprenoids and structurally resemble cholesterol. Mammalian steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestogens. Vitamin D derivatives are a sixth closely related hormone system with homologous receptors. They have some of the characteristics of true steroids as receptor ligands. For example, is an important estrogen steroid hormone in both women and men. It is a typical steroid with core four-ring system (ABCD), composed of 17 carbon atoms.

Corticosteroids

Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involved in a wide range of physiological processes.

and its derivatives have some mineralocorticoid action in addition to the glucocorticoid effect.

(hydrocortisone) is a corticosteroid with both glucocorticoid and mineralocorticoid activity and effects.

Glucocorticoids

Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor. is a glucocorticoid medication. It is the most potent glucocorticoid and it has not mineralocorticoid potency.

  • Glucocorticoid receptor. (1m2z).
  • Forkhead box proteins (FOX) are transcription factors involved in regulation of gene expression.[3]. FOXO1 activation contributes to glucocorticoid-induced beta cell death[4]. FOX contain a DNA-binding motif (DBD) of 80-100 amino acids having a winged-helix shape.
    • .
    • . Water molecules shown as red spheres.
    • .
  • Nuclear receptor coactivator (NCOA) is a protein recruited by nuclear receptors in order to enhance or repress DNA transcription. NCOA is involved in coactivation with transcription factors[5]. NCOA1 shows histone acetyltransferase activity and is required for steroid hormone response. NCOA2 is a DNA transcription coactivator with glucocorticoid receptor.
    • .
    • .
    • . Water molecules are shown as red spheres.
    • .
    • .
  • Thioredoxin Reductase (TrxR) is an enzyme which reduces thioredoxin using NADPH[6]. Mutations in TrxR-2 are associated with familial glucocorticoid deficiency[7]. Thioredoxin Reductase (TrxR) is an enzyme which reduces thioredoxin using NADPH[8]. TrxR-2 is mitochondrial. For more details see User:Sarah Abdalla/Thioredoxin Reductase. TrxR and Trx form an [9]. . Water molecules are shown as red spheres.
  • Microsomal Prostaglandin E synthase (PGES) converts cyclooxygenase (COX)-derived prostaglandin to PGE2. It is membrane-associated and belongs to the microsomal glutathione S-transferase family. PGES is preferentially linked with the inducible COX-2[10] . PGES is induced by proinflammatory stimuli and down-regulated by anti-inflammatory glucocorticoids[11]. Microsomal Prostaglandin E synthase (coordinates are from OPM database. The [12]. Water molecules are shown as red spheres.

Mineralocorticoids

Mineralocorticoids are a class of corticosteroids. Mineralocorticoids are produced in the adrenal cortex and influence salt and water balances (electrolyte balance and fluid balance). The primary mineralocorticoid is .

  • Mineralocorticoid receptor (MR) in epithelial cells is activated by the mineralocorticoid hormone aldosterone promoting renal sodium retention and potassium excretion. It is nuclear receptor. In non epithelial cells MR is activated by cortisol[13]. MR is exposed to many steroids including cortisol, cortisone and progesterone, however, aldosterone and deoxycorticosterone are its physiological ligands. MR mutations are the principal cause of renal pseudohypoaldosteronism[14]. MR mutation S810L causes early-onset hypertension[15]. Inhibition of cardia MR prevents doxorubicin-induced cardiotoxicity[16]. MR is an important proadipogenic transcription factor that may mediate aldosterone and glucocorticoid effects on adipose tissue development and hence on obesity and development of metabolic syndrome[17]. The MR ligand aldosterone binds in a (Alpha Helices, Beta Strands , Loops ,Turns). [18]. . Water molecules are shown as red spheres.

Sex steroids

Androgens

An androgen is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. The major androgen in males is . It is the primary sex hormone and anabolic steroid in males. It is a steroid from the androstane class. It exerts its action through binding to and activation of the androgen receptor.

  • Androgen receptor. Ligand binding domain (LBD) containing an which binds intramolecularly the N-terminal FXXFL motif or coactivators with the same motif.[19] Water molecules are shown as red spheres. (2ylo).
  • Heat shock factor (HSF) are transcriptional activators of heat shock genes. HSF bind to heat shock sequence elements throughout the genome with a consensus array of three oppositely oriented sequence AGGAN and activate transcription. Each HSF monomer contains one C-terminal and 3 N-terminal leucine zippers. Two sequences flanking the N-terminal leucine zippers contain the consensus nuclear localization signal (NLS). The DNA-binding domain (DBD residues 193-281) of HSF lies in the N-terminal of the first NLS region[20]. Depletion of HSF-1 is associated with accumulation of pathogenic androgen receptor in neurodegenerative diseases[21].
  • Cellular retinoic acid-binding protein (CRABP); Epididymal RABP (ERABP) is an androgen-dependent RABP present in the lumen of the epididymis believed to be involved in sperm maturation. ERABP binds specifically all-trans- and 9-cis-RA.
  • Aromatase. The primary function of aromatase is to produce estrogens by aromatizing androgens. Aromatase is the only known enzyme in vertebrates capable of catalyzing the aromatization of a six-membered ring[22].
  • Student Project 1 for UMass Chemistry 423 Spring 2015. Protein kinase C related kinase 1 (PRK1) is a component of Rho-GTPase, histone demethylase, androgen receptor, and histone demethylase signaling pathways and is involved in ovary and prostate cancer. A lot of PRK1 is expressed in cases of ovarian serous carcinoma.
  • Finasteride
  • Zolinza (Vorinostat)
  • Hydroxysteroid dehydrogenase, 17-β HSD is involved in the conversion of androstenedione to testosterone.
  • Aromatase converts androstenedione to estrogen and testosterone to estradiol.
  • Lipids: structure and classification
  • Cytochrome P450 3A4 (CYP3A4)

Estrogens

There are three major endogenous estrogens that have estrogenic hormonal activity: estrone (E1), estradiol (E2), and estriol (E3). Estradiol, an estrane, is the most potent and prevalent. Another estrogen called estetrol (E4) is produced only during pregnancy.

of estrogen receptor α complexed with raloxifene and a corepressor peptide (morph was taken from Gallery of Morphs of the Yale Morph Server).

to human estrogen-related receptor γ. The chemotherapeutic drugs bisphenol and are nestled between 4 alpha helices in the ERR active site.

Estrone

Substrates, such as estrone sulfate, with residues from each subunit in Cavity 1 of ABCG2 multidrug transporter.

Estradiol

Estriol

Estetrol

  • 3l03 - Crystal Structure of human Estrogen Receptor alpha Ligand-Binding Domain in complex with a Glucocorticoid Receptor Interacting Protein 1 Nr Box II peptide and Estetrol (Estra-1,3,5(10)-triene-3,15 alpha,16alpha,17beta-tetrol)

Progestogens

Progesterone

(P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species.

  • Hydroxysteroid dehydrogenase, 20-α HSD is involved in the control of progesterone level in pregnancy of mice. 17-β HSD is involved in the conversion of androstenedione to testosterone.

Vitamin D derivatives; secosteroids (open-ring steroids)

.

(5ien)

Calcitriol is the active form of vitamin D pro-hormone.

is a transcription factor. Upon binding to vitamin D, VDR forms a heterodimer with retinoid-X receptor and binds to hormone response receptors on DNA causing gene expression. The (green) binds to receptors in its target cells, controlling the synthesis of many different proteins involved in Ca transport and utilization.

.

. VDR contains 2 domains: a , that binds to the hormone (grey) and that binds to DNA (green and blue are 2 same VDR structures). It pairs up with a similar protein, 9-cis retinoic acid receptor (RXR), and together they bind to the DNA, activating synthesis in some cases and repressing it in others. When is mutated it is replaced with a which results in an inhibition of transcriptional activation. When transcription is inhibited it results in p53 accumulation, which activates and promotes p53 translocation into mitochondria leading to apoptosis. is replaced with when mutated creating a negative charge. The negative charge at the residue inhibits DNA binding which cause a downregulation of VDR activity. VDR needs DNA binding in order for it to be activated which is only possible with a serine residue.

The vitamin D nuclear receptor is a ligand-dependent transcription factor that controls multiple biological responses such as cell proliferation, immune responses, and bone mineralization. Numerous 1 α,25(OH)(2)D(3) analogues, which exhibit low calcemic side effects and/or antitumoral properties, have been synthesized. It was shown that acts as a 1α,25(OH)(2)D(3) superagonist and exhibits both antiproliferative and prodifferentiating properties in vitro. Using this information and on the basis of the crystal structures of human VDR ligand binding domain (hVDR LBD) bound to 1α,25(OH)(2)D(3), 2α-methyl-1α,25(OH)(2)D(3), or 2a, a novel analogue, 2α-methyl-(20S,23S)-epoxymethano-1α,25-dihydroxyvitamin D(3) (4a) was designed, in order to increase its transactivation potency.

ABA Signaling Pathway

Signaling Pathways:

MAPK/ERK pathway

Protein Kinases:

Tyrosine kinase

  • Receptor tyrosine kinases
  • Tyrosine kinase
  • Janus kinase or tyrosine-protein kinase JAK (JAK) are nonreceptor tyrosine kinases which transduces cytokine-mediated signals via the JAK-STAT pathway. The JAK-STAT pathway transmits signals through the cell membrane to DNA promoters thus causing transcription.

Protein kinase C

CAMP-dependent protein kinase

Chemotaxis:

Mechanotransduction:

Thermoception

Transient receptor potential channels

Voltage-gated channels

Visual phototransduction

Light is detected by rhodopsin in rod and cone cells.

Photoreceptor pigments

Circadian clock

Protein phosphatases:

Second messengers

cAMP is second messenger

CAMP-dependent protein kinase

IP3 is second messenger

Receptors that activate this pathway (Phospholipase C) are mainly G protein-coupled receptors coupled to the Gαq subunit, including:

  • 5-HT2 serotonergic receptors (5-hydroxytryptamine receptor#Structural highlights/Specific Function of 5-HT2B).
  • α1 adrenergic receptors
  • Calcitonin receptors
  • Histamine H1 receptor. The H1 receptor is a histamine receptor belonging to the family of rhodopsin-like G-protein-coupled receptors. The H1 receptor is linked to an intracellular G-protein (Gq) that activates phospholipase C and the inositol triphosphate signaling pathway. When a ligand binds to a G protein-coupled receptor that is coupled to a Gq heterotrimeric G protein, the α-subunit of Gq can bind to and induce activity in the PLC isozyme PLC-β, which results in the cleavage of PIP2 into IP3 and DAG.
  • Metabotropic glutamate receptor 1 and metabotropic glutamate receptor 5 belong to group I and activate phospholipase C. For details see Metabotropic glutamate receptor 5.
  • M1, M3, and M5 muscarinic receptors. Muscarinic acetylcholine receptors (mAChR) contain 5 subtypes M1-M5. Subtypes M1, M3, M5 activate phospholipase C which leads to activation of protein kinase C.
  • Inositol 1,4,5-Trisphosphate Receptor

Paracrine signaling:

Fibroblast growth factor (FGF) family, Hedgehog family, Wnt family, and TGF-β superfamily

Intracrine signaling

Ca2+ signalling processes

H+/K+-ATPase signal pathway (acetylcholine, histamine, and gastrin) activates the pump in order to move the vesicles toward the lumen.

Proton pump

Signal transducing adaptor proteins (STAPs)

GTPase

Inflammatory response

Allostery

ATPase


Nicotinic Acetylcholine Receptor, PDB code 2bg9

Drag the structure with the mouse to rotate

ReferencesReferences

  1. ↑ Chatterjee S. Neutral sphingomyelinase: past, present and future. Chem Phys Lipids. 1999 Nov;102(1-2):79-96. PMID:11001563
  2. ↑ Barna TM, Khan H, Bruce NC, Barsukov I, Scrutton NS, Moody PC. Crystal structure of pentaerythritol tetranitrate reductase: "flipped" binding geometries for steroid substrates in different redox states of the enzyme. J Mol Biol. 2001 Jul 6;310(2):433-47. PMID:11428899 doi:10.1006/jmbi.2001.4779
  3. ↑ Tuteja G, Kaestner KH. SnapShot: forkhead transcription factors I. Cell. 2007 Sep 21;130(6):1160. PMID:17889656 doi:http://dx.doi.org/10.1016/j.cell.2007.09.005
  4. ↑ Kaiser G, Gerst F, Michael D, Berchtold S, Friedrich B, Strutz-Seebohm N, Lang F, Haring HU, Ullrich S. Regulation of forkhead box O1 (FOXO1) by protein kinase B and glucocorticoids: different mechanisms of induction of beta cell death in vitro. Diabetologia. 2013 Jul;56(7):1587-95. doi: 10.1007/s00125-013-2863-7. Epub 2013, Feb 23. PMID:23435785 doi:http://dx.doi.org/10.1007/s00125-013-2863-7
  5. ↑ Horwitz KB, Jackson TA, Bain DL, Richer JK, Takimoto GS, Tung L. Nuclear receptor coactivators and corepressors. Mol Endocrinol. 1996 Oct;10(10):1167-77. PMID:9121485 doi:http://dx.doi.org/10.1210/mend.10.10.9121485
  6. ↑ Arner ES, Holmgren A. Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem. 2000 Oct;267(20):6102-9. PMID:11012661
  7. ↑ Prasad R, Chan LF, Hughes CR, Kaski JP, Kowalczyk JC, Savage MO, Peters CJ, Nathwani N, Clark AJ, Storr HL, Metherell LA. Thioredoxin Reductase 2 (TXNRD2) mutation associated with familial glucocorticoid deficiency (FGD). J Clin Endocrinol Metab. 2014 Aug;99(8):E1556-63. doi: 10.1210/jc.2013-3844. Epub, 2014 Mar 6. PMID:24601690 doi:http://dx.doi.org/10.1210/jc.2013-3844
  8. ↑ Arner ES, Holmgren A. Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem. 2000 Oct;267(20):6102-9. PMID:11012661
  9. ↑ Fritz-Wolf K, Kehr S, Stumpf M, Rahlfs S, Becker K. Crystal structure of the human thioredoxin reductase-thioredoxin complex. Nat Commun. 2011 Jul 12;2:383. doi: 10.1038/ncomms1382. PMID:21750537 doi:10.1038/ncomms1382
  10. ↑ Murakami M, Nakatani Y, Tanioka T, Kudo I. Prostaglandin E synthase. Prostaglandins Other Lipid Mediat. 2002 Aug;68-69:383-99. PMID:12432931
  11. ↑ Kudo I, Murakami M. Prostaglandin E synthase, a terminal enzyme for prostaglandin E2 biosynthesis. J Biochem Mol Biol. 2005 Nov 30;38(6):633-8. PMID:16336776
  12. ↑ Luz JG, Antonysamy S, Kuklish SL, Condon B, Lee MR, Allison D, Yu XP, Chandrasekhar S, Backer R, Zhang A, Russell M, Chang SS, Harvey A, Sloan AV, Fisher MJ. Crystal Structures of mPGES-1 Inhibitor Complexes Form a Basis for the Rational Design of Potent Analgesic and Anti-Inflammatory Therapeutics. J Med Chem. 2015 May 20. PMID:25961169 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b00330
  13. ↑ Frey FJ, Odermatt A, Frey BM. Glucocorticoid-mediated mineralocorticoid receptor activation and hypertension. Curr Opin Nephrol Hypertens. 2004 Jul;13(4):451-8. PMID:15199296
  14. ↑ Pujo L, Fagart J, Gary F, Papadimitriou DT, Claes A, Jeunemaitre X, Zennaro MC. Mineralocorticoid receptor mutations are the principal cause of renal type 1 pseudohypoaldosteronism. Hum Mutat. 2007 Jan;28(1):33-40. PMID:16972228 doi:10.1002/humu.20371
  15. ↑ Geller DS, Farhi A, Pinkerton N, Fradley M, Moritz M, Spitzer A, Meinke G, Tsai FT, Sigler PB, Lifton RP. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science. 2000 Jul 7;289(5476):119-23. PMID:10884226
  16. ↑ Lother A, Bergemann S, Kowalski J, Huck M, Gilsbach R, Bode C, Hein L. Inhibition of the cardiac myocyte mineralocorticoid receptor ameliorates doxorubicin-induced cardiotoxicity. Cardiovasc Res. 2018 Feb 1;114(2):282-290. doi: 10.1093/cvr/cvx078. PMID:28430882 doi:http://dx.doi.org/10.1093/cvr/cvx078
  17. ↑ Caprio M, Feve B, Claes A, Viengchareun S, Lombes M, Zennaro MC. Pivotal role of the mineralocorticoid receptor in corticosteroid-induced adipogenesis. FASEB J. 2007 Jul;21(9):2185-94. doi: 10.1096/fj.06-7970com. Epub 2007 Mar 23. PMID:17384139 doi:http://dx.doi.org/10.1096/fj.06-7970com
  18. ↑ Bledsoe RK, Madauss KP, Holt JA, Apolito CJ, Lambert MH, Pearce KH, Stanley TB, Stewart EL, Trump RP, Willson TM, Williams SP. A ligand-mediated hydrogen bond network required for the activation of the mineralocorticoid receptor. J Biol Chem. 2005 Sep 2;280(35):31283-93. Epub 2005 Jun 20. PMID:15967794 doi:http://dx.doi.org/10.1074/jbc.M504098200
  19. ↑ Bohl CE, Wu Z, Chen J, Mohler ML, Yang J, Hwang DJ, Mustafa S, Miller DD, Bell CE, Dalton JT. Effect of B-ring substitution pattern on binding mode of propionamide selective androgen receptor modulators. Bioorg Med Chem Lett. 2008 Oct 15;18(20):5567-70. Epub 2008 Sep 5. PMID:18805694 doi:10.1016/j.bmcl.2008.09.002
  20. ↑ Sarge KD, Murphy SP, Morimoto RI. Activation of heat shock gene transcription by heat shock factor 1 involves oligomerization, acquisition of DNA-binding activity, and nuclear localization and can occur in the absence of stress. Mol Cell Biol. 1993 Mar;13(3):1392-407. PMID:8441385
  21. ↑ Kondo N, Katsuno M, Adachi H, Minamiyama M, Doi H, Matsumoto S, Miyazaki Y, Iida M, Tohnai G, Nakatsuji H, Ishigaki S, Fujioka Y, Watanabe H, Tanaka F, Nakai A, Sobue G. Heat shock factor-1 influences pathological lesion distribution of polyglutamine-induced neurodegeneration. Nat Commun. 2013;4:1405. doi: 10.1038/ncomms2417. PMID:23360996 doi:http://dx.doi.org/10.1038/ncomms2417
  22. ↑ Ghosh, D., Griswold, J., Erman, M., Pangborn, W. " X-ray Structure of Human Aromatase Reveals An Androgen-Specific Active Site" Journal of Steroid Biochemistry and Molecular Biology. [Online] 2010,Vol. 118, Issue 4-5, p197-202[1]

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