(-)-Gossypol
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Basic Info
| Common Name | (-)-Gossypol(F04795) |
| 2D Structure | |
| Description | (-)-Gossypol is found in fats and oils. (-)-Gossypol is a constituent of Gossypium hirsutum (cotton). (-)-gossypol has been shown to exhibit anti-tumor, anti-cancer and anti-proliferative functions (A7832, A7833, A7834). |
| FRCD ID | F04795 |
| CAS Number | 90141-22-3 |
| PubChem CID | 3503 |
| Formula | C30H30O8 |
| IUPAC Name | 7-(8-formyl-1,6,7-trihydroxy-3-methyl-5-propan-2-ylnaphthalen-2-yl)-2,3,8-trihydroxy-6-methyl-4-propan-2-ylnaphthalene-1-carbaldehyde |
| InChI Key | QBKSWRVVCFFDOT-UHFFFAOYSA-N |
| InChI | InChI=1S/C30H30O8/c1-11(2)19-15-7-13(5)21(27(35)23(15)17(9-31)25(33)29(19)37)22-14(6)8-16-20(12(3)4)30(38)26(34)18(10-32)24(16)28(22)36/h7-12,33-38H,1-6H3 |
| Canonical SMILES | CC1=C(C(=C2C(=C1)C(=C(C(=C2C=O)O)O)C(C)C)O)C3=C(C=C4C(=C3O)C(=C(C(=C4C(C)C)O)O)C=O)C |
| Isomeric SMILES | CC1=C(C(=C2C(=C1)C(=C(C(=C2C=O)O)O)C(C)C)O)C3=C(C=C4C(=C3O)C(=C(C(=C4C(C)C)O)O)C=O)C |
| Synonyms |
gossypol
303-45-7
(-)-Gossypol
(+)-Gossypol
Pogosin
90141-22-3
Tash 1
racemic-Gossypol
(R)-(-)-Gossypol
(R)-Gossypol
|
| Classifies |
Plant Toxin
|
| Update Date | Nov 13, 2018 17:07 |
Chemical Taxonomy
| Kingdom | Organic compounds |
| Superclass | Lipids and lipid-like molecules |
| Class | Prenol lipids |
| Subclass | Sesquiterpenoids |
| Intermediate Tree Nodes | Not available |
| Direct Parent | Sesquiterpenoids |
| Alternative Parents | |
| Molecular Framework | Aromatic homopolycyclic compounds |
| Substituents | Cadinane sesquiterpenoid - Sesquiterpenoid - 2-naphthol - 1-naphthol - Naphthalene - Aryl-aldehyde - 1-hydroxy-4-unsubstituted benzenoid - Benzenoid - Vinylogous acid - Polyol - Organic oxygen compound - Organooxygen compound - Aldehyde - Hydrocarbon derivative - Organic oxide - Aromatic homopolycyclic compound |
| Description | This compound belongs to the class of organic compounds known as sesquiterpenoids. These are terpenes with three consecutive isoprene units. |
Properties
| Property Name | Property Value |
|---|---|
| Molecular Weight | 518.562 |
| Hydrogen Bond Donor Count | 6 |
| Hydrogen Bond Acceptor Count | 8 |
| Rotatable Bond Count | 5 |
| Complexity | 780 |
| Monoisotopic Mass | 518.194 |
| Exact Mass | 518.194 |
| XLogP | 6.9 |
| Formal Charge | 0 |
| Heavy Atom Count | 38 |
| Defined Atom Stereocenter Count | 0 |
| Undefined Atom Stereocenter Count | 0 |
| Defined Bond Stereocenter Count | 0 |
| Undefined Bond Stereocenter Count | 0 |
| Isotope Atom Count | 0 |
| Covalently-Bonded Unit Count | 1 |
ADMET
| Model | Result | Probability |
|---|---|---|
| Absorption | ||
| Blood-Brain Barrier | BBB- | 0.7849 |
| Human Intestinal Absorption | HIA+ | 0.9958 |
| Caco-2 Permeability | Caco2+ | 0.5253 |
| P-glycoprotein Substrate | Substrate | 0.5933 |
| P-glycoprotein Inhibitor | Non-inhibitor | 0.7920 |
| Non-inhibitor | 0.7525 | |
| Renal Organic Cation Transporter | Non-inhibitor | 0.9484 |
| Distribution | ||
| Subcellular localization | Mitochondria | 0.8961 |
| Metabolism | ||
| CYP450 2C9 Substrate | Non-substrate | 0.7799 |
| CYP450 2D6 Substrate | Non-substrate | 0.8456 |
| CYP450 3A4 Substrate | Substrate | 0.5073 |
| CYP450 1A2 Inhibitor | Inhibitor | 0.9107 |
| CYP450 2C9 Inhibitor | Inhibitor | 0.6711 |
| CYP450 2D6 Inhibitor | Non-inhibitor | 0.9231 |
| CYP450 2C19 Inhibitor | Non-inhibitor | 0.9026 |
| CYP450 3A4 Inhibitor | Non-inhibitor | 0.9115 |
| CYP Inhibitory Promiscuity | Low CYP Inhibitory Promiscuity | 0.7843 |
| Excretion | ||
| Toxicity | ||
| Human Ether-a-go-go-Related Gene Inhibition | Weak inhibitor | 0.9871 |
| Non-inhibitor | 0.8141 | |
| AMES Toxicity | Non AMES toxic | 0.9133 |
| Carcinogens | Non-carcinogens | 0.8317 |
| Fish Toxicity | High FHMT | 0.9989 |
| Tetrahymena Pyriformis Toxicity | High TPT | 0.9969 |
| Honey Bee Toxicity | High HBT | 0.6737 |
| Biodegradation | Not ready biodegradable | 0.9801 |
| Acute Oral Toxicity | III | 0.8060 |
| Carcinogenicity (Three-class) | Non-required | 0.5419 |
| Model | Value | Unit |
|---|---|---|
| Absorption | ||
| Aqueous solubility | -3.8490 | LogS |
| Caco-2 Permeability | 0.5810 | LogPapp, cm/s |
| Distribution | ||
| Metabolism | ||
| Excretion | ||
| Toxicity | ||
| Rat Acute Toxicity | 2.3811 | LD50, mol/kg |
| Fish Toxicity | -0.0891 | pLC50, mg/L |
| Tetrahymena Pyriformis Toxicity | 1.2742 | pIGC50, ug/L |
References
| Title | Journal | Date | Pubmed ID |
|---|---|---|---|
| Development of an RP-UHPLC-PDA method for quantification of free gossypol in cottonseed cake and fungal-treated cottonseed cake. | PLoS One | 2018 | 29791447 |
| Metabolic Characterization of Dairy Cows Treated with Gossypol by BloodBiochemistry and Body Fluid Untargeted Metabolome Analyses. | J Agric Food Chem | 2017 Oct 25 | 28965405 |
| The aldehyde group of gossypol induces mitochondrial apoptosis via ROS-SIRT1-p53-PUMA pathway in male germline stem cell. | Oncotarget | 2017 Nov 21 | 29245965 |
| Gossypol inhibits LH-induced steroidogenesis in bovine theca cells. | Anim Sci J | 2017 Jan | 27128796 |
| Effects of gossypol from cottonseed cake on the blood profile in sheep. | Trop Anim Health Prod | 2016 Jun | 27098313 |
| Application of low-gossypol cottonseed meal in laying hens' diet. | Poult Sci | 2015 Oct | 26287003 |
| Gossypol Content of Cotton Free Commercial Feed for Dairy Cows. | Ital J Food Saf | 2015 May 28 | 27800399 |
| The response of meat ducks from 15 to 35 d of age to gossypol from cottonseedmeal. | Poult Sci | 2015 Jun | 25834247 |
| First discovery of acetone extract from cottonseed oil sludge as a novelantiviral agent against plant viruses. | PLoS One | 2015 Feb 23 | 25705894 |
| A new synthetic allotetraploid (A1A1G2G2) between Gossypium herbaceum and G.australe: bridging for simultaneously transferring favorable genes from these twodiploid species into upland cotton. | PLoS One | 2015 Apr 16 | 25879660 |
| Effect of cottonseed oilcake as a protein source on production of breeding ostriches. | Br Poult Sci | 2015 | 25735889 |
| Indirect multi-trophic interactions mediated by induced plant resistance: impact of caterpillar feeding on aphid parasitoids. | Biol Lett | 2014 Feb | 24522627 |
| Effects of dietary gossypol concentration on growth performance, blood profiles, and hepatic histopathology in meat ducks. | Poult Sci | 2014 Aug | 24902707 |
| Aphid honeydew quality as a food source for parasitoids is maintained in Bt cotton. | PLoS One | 2014 | 25226521 |
| Gossypol toxicity from cottonseed products. | ScientificWorldJournal | 2014 | 24895646 |
| Effect of feeding of calcium hydroxide-treated or vitamin E-supplementedcottonseed meal on plasma gossypol levels, blood parameters, and performance ofBikaneri lambs. | Trop Anim Health Prod | 2013 Aug | 23345064 |
| RNAi-mediated Ultra-low gossypol cottonseed trait: performance of transgenic lines under field conditions. | Plant Biotechnol J | 2013 Apr | 23078138 |
| Transcriptome sequencing and differential gene expression analysis of delayed gland morphogenesis in Gossypium australe during seed germination. | PLoS One | 2013 | 24073262 |
| Alleviation of reproductive toxicity of gossypol using selenium supplementationin rams. | J Anim Sci | 2012 Sep | 22585803 |
| Effects of different sources and levels of dietary gossypol on gossypol residues in plasma and milk of lactating cows. | J Dairy Sci | 2012 Sep | 22916918 |
Targets
- General Function:
- Zinc ion binding
- Specific Function:
- Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that is involved in positive and negative regulation of cell proliferation, apoptosis, differentiation, migration and adhesion, tumorigenesis, cardiac hypertrophy, angiogenesis, platelet function and inflammation, by directly phosphorylating targets such as RAF1, BCL2, CSPG4, TNNT2/CTNT, or activating signaling cascade involving MAPK1/3 (ERK1/2) and RAP1GAP. Involved in cell proliferation and cell growth arrest by positive and negative regulation of the cell cycle. Can promote cell growth by phosphorylating and activating RAF1, which mediates the activation of the MAPK/ERK signaling cascade, and/or by up-regulating CDKN1A, which facilitates active cyclin-dependent kinase (CDK) complex formation in glioma cells. In intestinal cells stimulated by the phorbol ester PMA, can trigger a cell cycle arrest program which is associated with the accumulation of the hyper-phosphorylated growth-suppressive form of RB1 and induction of the CDK inhibitors CDKN1A and CDKN1B. Exhibits anti-apoptotic function in glioma cells and protects them from apoptosis by suppressing the p53/TP53-mediated activation of IGFBP3, and in leukemia cells mediates anti-apoptotic action by phosphorylating BCL2. During macrophage differentiation induced by macrophage colony-stimulating factor (CSF1), is translocated to the nucleus and is associated with macrophage development. After wounding, translocates from focal contacts to lamellipodia and participates in the modulation of desmosomal adhesion. Plays a role in cell motility by phosphorylating CSPG4, which induces association of CSPG4 with extensive lamellipodia at the cell periphery and polarization of the cell accompanied by increases in cell motility. Is highly expressed in a number of cancer cells where it can act as a tumor promoter and is implicated in malignant phenotypes of several tumors such as gliomas and breast cancers. Negatively regulates myocardial contractility and positively regulates angiogenesis, platelet aggregation and thrombus formation in arteries. Mediates hypertrophic growth of neonatal cardiomyocytes, in part through a MAPK1/3 (ERK1/2)-dependent signaling pathway, and upon PMA treatment, is required to induce cardiomyocyte hypertrophy up to heart failure and death, by increasing protein synthesis, protein-DNA ratio and cell surface area. Regulates cardiomyocyte function by phosphorylating cardiac troponin T (TNNT2/CTNT), which induces significant reduction in actomyosin ATPase activity, myofilament calcium sensitivity and myocardial contractility. In angiogenesis, is required for full endothelial cell migration, adhesion to vitronectin (VTN), and vascular endothelial growth factor A (VEGFA)-dependent regulation of kinase activation and vascular tube formation. Involved in the stabilization of VEGFA mRNA at post-transcriptional level and mediates VEGFA-induced cell proliferation. In the regulation of calcium-induced platelet aggregation, mediates signals from the CD36/GP4 receptor for granule release, and activates the integrin heterodimer ITGA2B-ITGB3 through the RAP1GAP pathway for adhesion. During response to lipopolysaccharides (LPS), may regulate selective LPS-induced macrophage functions involved in host defense and inflammation. But in some inflammatory responses, may negatively regulate NF-kappa-B-induced genes, through IL1A-dependent induction of NF-kappa-B inhibitor alpha (NFKBIA/IKBA). Upon stimulation with 12-O-tetradecanoylphorbol-13-acetate (TPA), phosphorylates EIF4G1, which modulates EIF4G1 binding to MKNK1 and may be involved in the regulation of EIF4E phosphorylation. Phosphorylates KIT, leading to inhibition of KIT activity. Phosphorylates ATF2 which promotes cooperation between ATF2 and JUN, activating transcription.
- Gene Name:
- PRKCA
- Uniprot ID:
- P17252
- Molecular Weight:
- 76749.445 Da
- Mechanism of Action:
- Gossypol inhibits protein kinase C.
References
- Wikipedia. Gossypol. Last Updated 9 July 2009. : http://en.wikipedia.org/wiki/Gossypol
- General Function:
- Translation initiation factor activity
- Specific Function:
- Component of the protein complex eIF4F, which is involved in the recognition of the mRNA cap, ATP-dependent unwinding of 5'-terminal secondary structure and recruitment of mRNA to the ribosome.
- Gene Name:
- EIF4G1
- Uniprot ID:
- Q04637
- Molecular Weight:
- 175489.41 Da
References
- Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK: BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Res. 2007 Jan;35(Database issue):D198-201. Epub 2006 Dec 1. [17145705 ]
- General Function:
- Protein kinase binding
- Specific Function:
- Potent inhibitor of cell death. Inhibits activation of caspases. Appears to regulate cell death by blocking the voltage-dependent anion channel (VDAC) by binding to it and preventing the release of the caspase activator, CYC1, from the mitochondrial membrane. Also acts as a regulator of G2 checkpoint and progression to cytokinesis during mitosis.Isoform Bcl-X(L) also regulates presynaptic plasticity, including neurotransmitter release and recovery, number of axonal mitochondria as well as size and number of synaptic vesicle clusters. During synaptic stimulation, increases ATP availability from mitochondria through regulation of mitochondrial membrane ATP synthase F(1)F(0) activity and regulates endocytic vesicle retrieval in hippocampal neurons through association with DMN1L and stimulation of its GTPase activity in synaptic vesicles. May attenuate inflammation impairing NLRP1-inflammasome activation, hence CASP1 activation and IL1B release (PubMed:17418785).Isoform Bcl-X(S) promotes apoptosis.
- Gene Name:
- BCL2L1
- Uniprot ID:
- Q07817
- Molecular Weight:
- 26048.8 Da
References
- Wei J, Stebbins JL, Kitada S, Dash R, Placzek W, Rega MF, Wu B, Cellitti J, Zhai D, Yang L, Dahl R, Fisher PB, Reed JC, Pellecchia M: BI-97C1, an optically pure Apogossypol derivative as pan-active inhibitor of antiapoptotic B-cell lymphoma/leukemia-2 (Bcl-2) family proteins. J Med Chem. 2010 May 27;53(10):4166-76. doi: 10.1021/jm1001265. [20443627 ]
- General Function:
- Protein kinase binding
- Specific Function:
- Motor protein required for establishing a bipolar spindle. Blocking of KIF11 prevents centrosome migration and arrest cells in mitosis with monoastral microtubule arrays.
- Gene Name:
- KIF11
- Uniprot ID:
- P52732
- Molecular Weight:
- 119158.025 Da
References
- El-Nassan HB: Advances in the discovery of kinesin spindle protein (Eg5) inhibitors as antitumor agents. Eur J Med Chem. 2013 Apr;62:614-31. doi: 10.1016/j.ejmech.2013.01.031. Epub 2013 Feb 5. [23434636 ]
- General Function:
- Glyceraldehyde oxidoreductase activity
- Specific Function:
- Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols with a broad range of catalytic efficiencies.
- Gene Name:
- AKR1B1
- Uniprot ID:
- P15121
- Molecular Weight:
- 35853.125 Da
References
- Deck LM, Vander Jagt DL, Royer RE: Gossypol and derivatives: a new class of aldose reductase inhibitors. J Med Chem. 1991 Nov;34(11):3301-5. [1956050 ]
- General Function:
- Protein homodimerization activity
- Specific Function:
- Promotes cell survival. Blocks dexamethasone-induced apoptosis. Mediates survival of postmitotic Sertoli cells by suppressing death-promoting activity of BAX.
- Gene Name:
- BCL2L2
- Uniprot ID:
- Q92843
- Molecular Weight:
- 20746.24 Da
References
- Xing C, Wang L, Tang X, Sham YY: Development of selective inhibitors for anti-apoptotic Bcl-2 proteins from BHI-1. Bioorg Med Chem. 2007 Mar 1;15(5):2167-76. Epub 2006 Dec 14. [17227711 ]
- General Function:
- Protein kinase binding
- Specific Function:
- Promotes cell death. Successfully competes for the binding to Bcl-X(L), Bcl-2 and Bcl-W, thereby affecting the level of heterodimerization of these proteins with BAX. Can reverse the death repressor activity of Bcl-X(L), but not that of Bcl-2 (By similarity). Appears to act as a link between growth factor receptor signaling and the apoptotic pathways.
- Gene Name:
- BAD
- Uniprot ID:
- Q92934
- Molecular Weight:
- 18391.765 Da
References
- Janssen CO, Lim S, Lo EP, Wan KF, Yu VC, Lee MA, Ng SB, Everett MJ, Buss AD, Lane DP, Boyce RS: Interaction of kendomycin and semi-synthetic analogues with the anti-apoptotic protein Bcl-xl. Bioorg Med Chem Lett. 2008 Nov 1;18(21):5771-3. doi: 10.1016/j.bmcl.2008.09.071. Epub 2008 Sep 23. [18845435 ]
- General Function:
- Protein domain specific binding
- Specific Function:
- Regulatory subunit of calcineurin, a calcium-dependent, calmodulin stimulated protein phosphatase. Confers calcium sensitivity.
- Gene Name:
- PPP3R1
- Uniprot ID:
- P63098
- Molecular Weight:
- 19299.785 Da
- Mechanism of Action:
- Gossypol inhibits calcineurin.
References
- Wikipedia. Gossypol. Last Updated 9 July 2009. : http://en.wikipedia.org/wiki/Gossypol
- General Function:
- Calcium ion binding
- Specific Function:
- Regulatory subunit of calcineurin, a calcium-dependent, calmodulin stimulated protein phosphatase. Confers calcium sensitivity (By similarity).
- Gene Name:
- PPP3R2
- Uniprot ID:
- Q96LZ3
- Molecular Weight:
- 19533.065 Da
- Mechanism of Action:
- Gossypol inhibits calcineurin.
References
- Wikipedia. Gossypol. Last Updated 9 July 2009. : http://en.wikipedia.org/wiki/Gossypol
- Uniprot ID:
- P62158
- Mechanism of Action:
- Gossypol binds to calmodulin.
References
- Wikipedia. Gossypol. Last Updated 9 July 2009. : http://en.wikipedia.org/wiki/Gossypol
- General Function:
- Protein serine/threonine kinase activity
- Specific Function:
- Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays contrasting roles in cell death and cell survival by functioning as a pro-apoptotic protein during DNA damage-induced apoptosis, but acting as an anti-apoptotic protein during cytokine receptor-initiated cell death, is involved in tumor suppression as well as survival of several cancers, is required for oxygen radical production by NADPH oxidase and acts as positive or negative regulator in platelet functional responses. Negatively regulates B cell proliferation and also has an important function in self-antigen induced B cell tolerance induction. Upon DNA damage, activates the promoter of the death-promoting transcription factor BCLAF1/Btf to trigger BCLAF1-mediated p53/TP53 gene transcription and apoptosis. In response to oxidative stress, interact with and activate CHUK/IKKA in the nucleus, causing the phosphorylation of p53/TP53. In the case of ER stress or DNA damage-induced apoptosis, can form a complex with the tyrosine-protein kinase ABL1 which trigger apoptosis independently of p53/TP53. In cytosol can trigger apoptosis by activating MAPK11 or MAPK14, inhibiting AKT1 and decreasing the level of X-linked inhibitor of apoptosis protein (XIAP), whereas in nucleus induces apoptosis via the activation of MAPK8 or MAPK9. Upon ionizing radiation treatment, is required for the activation of the apoptosis regulators BAX and BAK, which trigger the mitochondrial cell death pathway. Can phosphorylate MCL1 and target it for degradation which is sufficient to trigger for BAX activation and apoptosis. Is required for the control of cell cycle progression both at G1/S and G2/M phases. Mediates phorbol 12-myristate 13-acetate (PMA)-induced inhibition of cell cycle progression at G1/S phase by up-regulating the CDK inhibitor CDKN1A/p21 and inhibiting the cyclin CCNA2 promoter activity. In response to UV irradiation can phosphorylate CDK1, which is important for the G2/M DNA damage checkpoint activation. Can protect glioma cells from the apoptosis induced by TNFSF10/TRAIL, probably by inducing increased phosphorylation and subsequent activation of AKT1. Is highly expressed in a number of cancer cells and promotes cell survival and resistance against chemotherapeutic drugs by inducing cyclin D1 (CCND1) and hyperphosphorylation of RB1, and via several pro-survival pathways, including NF-kappa-B, AKT1 and MAPK1/3 (ERK1/2). Can also act as tumor suppressor upon mitogenic stimulation with PMA or TPA. In N-formyl-methionyl-leucyl-phenylalanine (fMLP)-treated cells, is required for NCF1 (p47-phox) phosphorylation and activation of NADPH oxidase activity, and regulates TNF-elicited superoxide anion production in neutrophils, by direct phosphorylation and activation of NCF1 or indirectly through MAPK1/3 (ERK1/2) signaling pathways. May also play a role in the regulation of NADPH oxidase activity in eosinophil after stimulation with IL5, leukotriene B4 or PMA. In collagen-induced platelet aggregation, acts a negative regulator of filopodia formation and actin polymerization by interacting with and negatively regulating VASP phosphorylation. Downstream of PAR1, PAR4 and CD36/GP4 receptors, regulates differentially platelet dense granule secretion; acts as a positive regulator in PAR-mediated granule secretion, whereas it negatively regulates CD36/GP4-mediated granule release. Phosphorylates MUC1 in the C-terminal and regulates the interaction between MUC1 and beta-catenin. The catalytic subunit phosphorylates 14-3-3 proteins (YWHAB, YWHAZ and YWHAH) in a sphingosine-dependent fashion (By similarity).
- Gene Name:
- PRKCD
- Uniprot ID:
- Q05655
- Molecular Weight:
- 77504.445 Da
- Mechanism of Action:
- Gossypol inhibits protein kinase C.
References
- Wikipedia. Gossypol. Last Updated 9 July 2009. : http://en.wikipedia.org/wiki/Gossypol
- General Function:
- Signal transducer activity
- Specific Function:
- Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays essential roles in the regulation of multiple cellular processes linked to cytoskeletal proteins, such as cell adhesion, motility, migration and cell cycle, functions in neuron growth and ion channel regulation, and is involved in immune response, cancer cell invasion and regulation of apoptosis. Mediates cell adhesion to the extracellular matrix via integrin-dependent signaling, by mediating angiotensin-2-induced activation of integrin beta-1 (ITGB1) in cardiac fibroblasts. Phosphorylates MARCKS, which phosphorylates and activates PTK2/FAK, leading to the spread of cardiomyocytes. Involved in the control of the directional transport of ITGB1 in mesenchymal cells by phosphorylating vimentin (VIM), an intermediate filament (IF) protein. In epithelial cells, associates with and phosphorylates keratin-8 (KRT8), which induces targeting of desmoplakin at desmosomes and regulates cell-cell contact. Phosphorylates IQGAP1, which binds to CDC42, mediating epithelial cell-cell detachment prior to migration. In HeLa cells, contributes to hepatocyte growth factor (HGF)-induced cell migration, and in human corneal epithelial cells, plays a critical role in wound healing after activation by HGF. During cytokinesis, forms a complex with YWHAB, which is crucial for daughter cell separation, and facilitates abscission by a mechanism which may implicate the regulation of RHOA. In cardiac myocytes, regulates myofilament function and excitation coupling at the Z-lines, where it is indirectly associated with F-actin via interaction with COPB1. During endothelin-induced cardiomyocyte hypertrophy, mediates activation of PTK2/FAK, which is critical for cardiomyocyte survival and regulation of sarcomere length. Plays a role in the pathogenesis of dilated cardiomyopathy via persistent phosphorylation of troponin I (TNNI3). Involved in nerve growth factor (NFG)-induced neurite outgrowth and neuron morphological change independently of its kinase activity, by inhibition of RHOA pathway, activation of CDC42 and cytoskeletal rearrangement. May be involved in presynaptic facilitation by mediating phorbol ester-induced synaptic potentiation. Phosphorylates gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2), which reduces the response of GABA receptors to ethanol and benzodiazepines and may mediate acute tolerance to the intoxicating effects of ethanol. Upon PMA treatment, phosphorylates the capsaicin- and heat-activated cation channel TRPV1, which is required for bradykinin-induced sensitization of the heat response in nociceptive neurons. Is able to form a complex with PDLIM5 and N-type calcium channel, and may enhance channel activities and potentiates fast synaptic transmission by phosphorylating the pore-forming alpha subunit CACNA1B (CaV2.2). In prostate cancer cells, interacts with and phosphorylates STAT3, which increases DNA-binding and transcriptional activity of STAT3 and seems to be essential for prostate cancer cell invasion. Downstream of TLR4, plays an important role in the lipopolysaccharide (LPS)-induced immune response by phosphorylating and activating TICAM2/TRAM, which in turn activates the transcription factor IRF3 and subsequent cytokines production. In differentiating erythroid progenitors, is regulated by EPO and controls the protection against the TNFSF10/TRAIL-mediated apoptosis, via BCL2. May be involved in the regulation of the insulin-induced phosphorylation and activation of AKT1.
- Gene Name:
- PRKCE
- Uniprot ID:
- Q02156
- Molecular Weight:
- 83673.2 Da
- Mechanism of Action:
- Gossypol inhibits protein kinase C.
References
- Wikipedia. Gossypol. Last Updated 9 July 2009. : http://en.wikipedia.org/wiki/Gossypol
- General Function:
- Protein kinase c activity
- Specific Function:
- Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that is involved in the regulation of cell differentiation in keratinocytes and pre-B cell receptor, mediates regulation of epithelial tight junction integrity and foam cell formation, and is required for glioblastoma proliferation and apoptosis prevention in MCF-7 cells. In keratinocytes, binds and activates the tyrosine kinase FYN, which in turn blocks epidermal growth factor receptor (EGFR) signaling and leads to keratinocyte growth arrest and differentiation. Associates with the cyclin CCNE1-CDK2-CDKN1B complex and inhibits CDK2 kinase activity, leading to RB1 dephosphorylation and thereby G1 arrest in keratinocytes. In association with RALA activates actin depolymerization, which is necessary for keratinocyte differentiation. In the pre-B cell receptor signaling, functions downstream of BLNK by up-regulating IRF4, which in turn activates L chain gene rearrangement. Regulates epithelial tight junctions (TJs) by phosphorylating occludin (OCLN) on threonine residues, which is necessary for the assembly and maintenance of TJs. In association with PLD2 and via TLR4 signaling, is involved in lipopolysaccharide (LPS)-induced RGS2 down-regulation and foam cell formation. Upon PMA stimulation, mediates glioblastoma cell proliferation by activating the mTOR pathway, the PI3K/AKT pathway and the ERK1-dependent phosphorylation of ELK1. Involved in the protection of glioblastoma cells from irradiation-induced apoptosis by preventing caspase-9 activation. In camptothecin-treated MCF-7 cells, regulates NF-kappa-B upstream signaling by activating IKBKB, and confers protection against DNA damage-induced apoptosis. Promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria. Phosphorylates ATF2 which promotes its nuclear retention and transcriptional activity and negatively regulates its mitochondrial localization.
- Gene Name:
- PRKCH
- Uniprot ID:
- P24723
- Molecular Weight:
- 77827.96 Da
- Mechanism of Action:
- Gossypol inhibits protein kinase C.
References
- Wikipedia. Gossypol. Last Updated 9 July 2009. : http://en.wikipedia.org/wiki/Gossypol
- General Function:
- Zinc ion binding
- Specific Function:
- Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays diverse roles in neuronal cells and eye tissues, such as regulation of the neuronal receptors GRIA4/GLUR4 and GRIN1/NMDAR1, modulation of receptors and neuronal functions related to sensitivity to opiates, pain and alcohol, mediation of synaptic function and cell survival after ischemia, and inhibition of gap junction activity after oxidative stress. Binds and phosphorylates GRIA4/GLUR4 glutamate receptor and regulates its function by increasing plasma membrane-associated GRIA4 expression. In primary cerebellar neurons treated with the agonist 3,5-dihyidroxyphenylglycine, functions downstream of the metabotropic glutamate receptor GRM5/MGLUR5 and phosphorylates GRIN1/NMDAR1 receptor which plays a key role in synaptic plasticity, synaptogenesis, excitotoxicity, memory acquisition and learning. May be involved in the regulation of hippocampal long-term potentiation (LTP), but may be not necessary for the process of synaptic plasticity. May be involved in desensitization of mu-type opioid receptor-mediated G-protein activation in the spinal cord, and may be critical for the development and/or maintenance of morphine-induced reinforcing effects in the limbic forebrain. May modulate the functionality of mu-type-opioid receptors by participating in a signaling pathway which leads to the phosphorylation and degradation of opioid receptors. May also contributes to chronic morphine-induced changes in nociceptive processing. Plays a role in neuropathic pain mechanisms and contributes to the maintenance of the allodynia pain produced by peripheral inflammation. Plays an important role in initial sensitivity and tolerance to ethanol, by mediating the behavioral effects of ethanol as well as the effects of this drug on the GABA(A) receptors. During and after cerebral ischemia modulate neurotransmission and cell survival in synaptic membranes, and is involved in insulin-induced inhibition of necrosis, an important mechanism for minimizing ischemic injury. Required for the elimination of multiple climbing fibers during innervation of Purkinje cells in developing cerebellum. Is activated in lens epithelial cells upon hydrogen peroxide treatment, and phosphorylates connexin-43 (GJA1/CX43), resulting in disassembly of GJA1 gap junction plaques and inhibition of gap junction activity which could provide a protective effect against oxidative stress (By similarity). Phosphorylates p53/TP53 and promotes p53/TP53-dependent apoptosis in response to DNA damage. Involved in the phase resetting of the cerebral cortex circadian clock during temporally restricted feeding. Stabilizes the core clock component ARNTL/BMAL1 by interfering with its ubiquitination, thus suppressing its degradation, resulting in phase resetting of the cerebral cortex clock (By similarity).
- Gene Name:
- PRKCG
- Uniprot ID:
- P05129
- Molecular Weight:
- 78447.23 Da
- Mechanism of Action:
- Gossypol inhibits protein kinase C.
References
- Wikipedia. Gossypol. Last Updated 9 July 2009. : http://en.wikipedia.org/wiki/Gossypol
- General Function:
- Protein serine/threonine kinase activity
- Specific Function:
- Calcium- and diacylglycerol-independent serine/ threonine-protein kinase that plays a general protective role against apoptotic stimuli, is involved in NF-kappa-B activation, cell survival, differentiation and polarity, and contributes to the regulation of microtubule dynamics in the early secretory pathway. Is necessary for BCR-ABL oncogene-mediated resistance to apoptotic drug in leukemia cells, protecting leukemia cells against drug-induced apoptosis. In cultured neurons, prevents amyloid beta protein-induced apoptosis by interrupting cell death process at a very early step. In glioblastoma cells, may function downstream of phosphatidylinositol 3-kinase (PI(3)K) and PDPK1 in the promotion of cell survival by phosphorylating and inhibiting the pro-apoptotic factor BAD. Can form a protein complex in non-small cell lung cancer (NSCLC) cells with PARD6A and ECT2 and regulate ECT2 oncogenic activity by phosphorylation, which in turn promotes transformed growth and invasion. In response to nerve growth factor (NGF), acts downstream of SRC to phosphorylate and activate IRAK1, allowing the subsequent activation of NF-kappa-B and neuronal cell survival. Functions in the organization of the apical domain in epithelial cells by phosphorylating EZR. This step is crucial for activation and normal distribution of EZR at the early stages of intestinal epithelial cell differentiation. Forms a protein complex with LLGL1 and PARD6B independently of PARD3 to regulate epithelial cell polarity. Plays a role in microtubule dynamics in the early secretory pathway through interaction with RAB2A and GAPDH and recruitment to vesicular tubular clusters (VTCs). In human coronary artery endothelial cells (HCAEC), is activated by saturated fatty acids and mediates lipid-induced apoptosis.
- Gene Name:
- PRKCI
- Uniprot ID:
- P41743
- Molecular Weight:
- 68261.855 Da
- Mechanism of Action:
- Gossypol inhibits protein kinase C.
References
- Wikipedia. Gossypol. Last Updated 9 July 2009. : http://en.wikipedia.org/wiki/Gossypol
- General Function:
- Ubiquitin-protein transferase activity
- Specific Function:
- Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that mediates non-redundant functions in T-cell receptor (TCR) signaling, including T-cells activation, proliferation, differentiation and survival, by mediating activation of multiple transcription factors such as NF-kappa-B, JUN, NFATC1 and NFATC2. In TCR-CD3/CD28-co-stimulated T-cells, is required for the activation of NF-kappa-B and JUN, which in turn are essential for IL2 production, and participates to the calcium-dependent NFATC1 and NFATC2 transactivation. Mediates the activation of the canonical NF-kappa-B pathway (NFKB1) by direct phosphorylation of CARD11 on several serine residues, inducing CARD11 association with lipid rafts and recruitment of the BCL10-MALT1 complex, which then activates IKK complex, resulting in nuclear translocation and activation of NFKB1. May also play an indirect role in activation of the non-canonical NF-kappa-B (NFKB2) pathway. In the signaling pathway leading to JUN activation, acts by phosphorylating the mediator STK39/SPAK and may not act through MAP kinases signaling. Plays a critical role in TCR/CD28-induced NFATC1 and NFATC2 transactivation by participating in the regulation of reduced inositol 1,4,5-trisphosphate generation and intracellular calcium mobilization. After costimulation of T-cells through CD28 can phosphorylate CBLB and is required for the ubiquitination and subsequent degradation of CBLB, which is a prerequisite for the activation of TCR. During T-cells differentiation, plays an important role in the development of T-helper 2 (Th2) cells following immune and inflammatory responses, and, in the development of inflammatory autoimmune diseases, is necessary for the activation of IL17-producing Th17 cells. May play a minor role in Th1 response. Upon TCR stimulation, mediates T-cell protective survival signal by phosphorylating BAD, thus protecting T-cells from BAD-induced apoptosis, and by up-regulating BCL-X(L)/BCL2L1 levels through NF-kappa-B and JUN pathways. In platelets, regulates signal transduction downstream of the ITGA2B, CD36/GP4, F2R/PAR1 and F2RL3/PAR4 receptors, playing a positive role in 'outside-in' signaling and granule secretion signal transduction. May relay signals from the activated ITGA2B receptor by regulating the uncoupling of WASP and WIPF1, thereby permitting the regulation of actin filament nucleation and branching activity of the Arp2/3 complex. May mediate inhibitory effects of free fatty acids on insulin signaling by phosphorylating IRS1, which in turn blocks IRS1 tyrosine phosphorylation and downstream activation of the PI3K/AKT pathway. Phosphorylates MSN (moesin) in the presence of phosphatidylglycerol or phosphatidylinositol. Phosphorylates PDPK1 at 'Ser-504' and 'Ser-532' and negatively regulates its ability to phosphorylate PKB/AKT1.
- Gene Name:
- PRKCQ
- Uniprot ID:
- Q04759
- Molecular Weight:
- 81864.145 Da
- Mechanism of Action:
- Gossypol inhibits protein kinase C.
References
- Wikipedia. Gossypol. Last Updated 9 July 2009. : http://en.wikipedia.org/wiki/Gossypol
- General Function:
- Sodium-independent organic anion transmembrane transporter activity
- Specific Function:
- Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostaglandin E2, thromboxane B2, leukotriene C3, leukotriene E4, thyroxine and triiodothyronine. Involved in the clearance of bile acids and organic anions from the liver.
- Gene Name:
- SLCO1B1
- Uniprot ID:
- Q9Y6L6
- Molecular Weight:
- 76447.99 Da
References
- De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP: Structure-based identification of OATP1B1/3 inhibitors. Mol Pharmacol. 2013 Jun;83(6):1257-67. doi: 10.1124/mol.112.084152. Epub 2013 Apr 9. [23571415 ]
- General Function:
- Sodium-independent organic anion transmembrane transporter activity
- Specific Function:
- Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotrexate and sulfobromophthalein (BSP). Involved in the clearance of bile acids and organic anions from the liver.
- Gene Name:
- SLCO1B3
- Uniprot ID:
- Q9NPD5
- Molecular Weight:
- 77402.175 Da
References
- De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP: Structure-based identification of OATP1B1/3 inhibitors. Mol Pharmacol. 2013 Jun;83(6):1257-67. doi: 10.1124/mol.112.084152. Epub 2013 Apr 9. [23571415 ]
- General Function:
- Protein homodimerization activity
- Specific Function:
- Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.
- Gene Name:
- MCL1
- Uniprot ID:
- Q07820
- Molecular Weight:
- 37336.975 Da
References
- Zhang Z, Song T, Li X, Wu Z, Feng Y, Xie F, Liu C, Qin J, Chen H: Novel soluble myeloid cell leukemia sequence 1 (Mcl-1) inhibitor (E,E)-2-(benzylaminocarbonyl)-3-styrylacrylonitrile (4g) developed using a fragment-based approach. Eur J Med Chem. 2013 Jan;59:141-9. doi: 10.1016/j.ejmech.2012.10.050. Epub 2012 Nov 7. [23220642 ]
- General Function:
- Ubiquitin protein ligase binding
- Specific Function:
- Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1). May attenuate inflammation by impairing NLRP1-inflammasome activation, hence CASP1 activation and IL1B release (PubMed:17418785).
- Gene Name:
- BCL2
- Uniprot ID:
- P10415
- Molecular Weight:
- 26265.66 Da
References
- Zhang Z, Liu C, Li X, Song T, Wu Z, Liang X, Zhao Y, Shen X, Chen H: Fragment-based design, synthesis, and biological evaluation of N-substituted-5-(4-isopropylthiophenol)-2-hydroxynicotinamide derivatives as novel Mcl-1 inhibitors. Eur J Med Chem. 2013 Feb;60:410-20. doi: 10.1016/j.ejmech.2012.12.016. Epub 2012 Dec 17. [23314054 ]
- General Function:
- Zinc ion binding
- Specific Function:
- Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3. Isoform 3 can bind to ERE and inhibit isoform 1.
- Gene Name:
- ESR1
- Uniprot ID:
- P03372
- Molecular Weight:
- 66215.45 Da
References
- Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK: BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Res. 2007 Jan;35(Database issue):D198-201. Epub 2006 Dec 1. [17145705 ]
- General Function:
- Zinc ion binding
- Specific Function:
- Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase involved in various cellular processes such as regulation of the B-cell receptor (BCR) signalosome, oxidative stress-induced apoptosis, androgen receptor-dependent transcription regulation, insulin signaling and endothelial cells proliferation. Plays a key role in B-cell activation by regulating BCR-induced NF-kappa-B activation. Mediates the activation of the canonical NF-kappa-B pathway (NFKB1) by direct phosphorylation of CARD11/CARMA1 at 'Ser-559', 'Ser-644' and 'Ser-652'. Phosphorylation induces CARD11/CARMA1 association with lipid rafts and recruitment of the BCL10-MALT1 complex as well as MAP3K7/TAK1, which then activates IKK complex, resulting in nuclear translocation and activation of NFKB1. Plays a direct role in the negative feedback regulation of the BCR signaling, by down-modulating BTK function via direct phosphorylation of BTK at 'Ser-180', which results in the alteration of BTK plasma membrane localization and in turn inhibition of BTK activity. Involved in apoptosis following oxidative damage: in case of oxidative conditions, specifically phosphorylates 'Ser-36' of isoform p66Shc of SHC1, leading to mitochondrial accumulation of p66Shc, where p66Shc acts as a reactive oxygen species producer. Acts as a coactivator of androgen receptor (ANDR)-dependent transcription, by being recruited to ANDR target genes and specifically mediating phosphorylation of 'Thr-6' of histone H3 (H3T6ph), a specific tag for epigenetic transcriptional activation that prevents demethylation of histone H3 'Lys-4' (H3K4me) by LSD1/KDM1A. In insulin signaling, may function downstream of IRS1 in muscle cells and mediate insulin-dependent DNA synthesis through the RAF1-MAPK/ERK signaling cascade. May participate in the regulation of glucose transport in adipocytes by negatively modulating the insulin-stimulated translocation of the glucose transporter SLC2A4/GLUT4. Under high glucose in pancreatic beta-cells, is probably involved in the inhibition of the insulin gene transcription, via regulation of MYC expression. In endothelial cells, activation of PRKCB induces increased phosphorylation of RB1, increased VEGFA-induced cell proliferation, and inhibits PI3K/AKT-dependent nitric oxide synthase (NOS3/eNOS) regulation by insulin, which causes endothelial dysfunction. Also involved in triglyceride homeostasis (By similarity). Phosphorylates ATF2 which promotes cooperation between ATF2 and JUN, activating transcription.
- Gene Name:
- PRKCB
- Uniprot ID:
- P05771
- Molecular Weight:
- 76868.45 Da
- Mechanism of Action:
- Gossypol inhibits protein kinase C.
References
- Wikipedia. Gossypol. Last Updated 9 July 2009. : http://en.wikipedia.org/wiki/Gossypol
- General Function:
- Protein serine/threonine kinase activity
- Specific Function:
- Calcium- and diacylglycerol-independent serine/threonine-protein kinase that functions in phosphatidylinositol 3-kinase (PI3K) pathway and mitogen-activated protein (MAP) kinase cascade, and is involved in NF-kappa-B activation, mitogenic signaling, cell proliferation, cell polarity, inflammatory response and maintenance of long-term potentiation (LTP). Upon lipopolysaccharide (LPS) treatment in macrophages, or following mitogenic stimuli, functions downstream of PI3K to activate MAP2K1/MEK1-MAPK1/ERK2 signaling cascade independently of RAF1 activation. Required for insulin-dependent activation of AKT3, but may function as an adapter rather than a direct activator. Upon insulin treatment may act as a downstream effector of PI3K and contribute to the activation of translocation of the glucose transporter SLC2A4/GLUT4 and subsequent glucose transport in adipocytes. In EGF-induced cells, binds and activates MAP2K5/MEK5-MAPK7/ERK5 independently of its kinase activity and can activate JUN promoter through MEF2C. Through binding with SQSTM1/p62, functions in interleukin-1 signaling and activation of NF-kappa-B with the specific adapters RIPK1 and TRAF6. Participates in TNF-dependent transactivation of NF-kappa-B by phosphorylating and activating IKBKB kinase, which in turn leads to the degradation of NF-kappa-B inhibitors. In migrating astrocytes, forms a cytoplasmic complex with PARD6A and is recruited by CDC42 to function in the establishment of cell polarity along with the microtubule motor and dynein. In association with FEZ1, stimulates neuronal differentiation in PC12 cells. In the inflammatory response, is required for the T-helper 2 (Th2) differentiation process, including interleukin production, efficient activation of JAK1 and the subsequent phosphorylation and nuclear translocation of STAT6. May be involved in development of allergic airway inflammation (asthma), a process dependent on Th2 immune response. In the NF-kappa-B-mediated inflammatory response, can relieve SETD6-dependent repression of NF-kappa-B target genes by phosphorylating the RELA subunit at 'Ser-311'. Necessary and sufficient for LTP maintenance in hippocampal CA1 pyramidal cells. In vein endothelial cells treated with the oxidant peroxynitrite, phosphorylates STK11 leading to nuclear export of STK11, subsequent inhibition of PI3K/Akt signaling, and increased apoptosis. Phosphorylates VAMP2 in vitro (PubMed:17313651).
- Gene Name:
- PRKCZ
- Uniprot ID:
- Q05513
- Molecular Weight:
- 67659.335 Da
- Mechanism of Action:
- Gossypol inhibits protein kinase C.
References
- Wikipedia. Gossypol. Last Updated 9 July 2009. : http://en.wikipedia.org/wiki/Gossypol