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
