Caffeine (T3D2712)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (19)XML
Targets (19)
Record Information
Version2.0
Creation Date2009-07-21 20:26:17 UTC
Update Date2014-12-24 20:25:50 UTC
Accession NumberT3D2712
Identification
Common NameCaffeine
ClassSmall Molecule
DescriptionCaffeine is the most widely consumed psychostimulant drug in the world that mostly is consumed in the form of coffee. Whether caffeine and/or coffee consumption contribute to the development of cardiovascular disease (CVD), the single leading cause of death in the US, is unclear. The literature indicates a strong relationship between boiled, unfiltered coffee consumption and elevated cholesterol levels; however, there is a critical gap in the literature regarding the effects of coffee or caffeine consumption on fibrinogen or CRP, which is an independent predictor of CVD risk. Available studies are limited by small samples sizes, inclusion of only men (or few women) and unrepresented age or ethnic groups. There is a critical need for controlled laboratory and epidemiological studies that include fibrinogen and CRP markers of CVD risk before conclusions can be drawn regarding the health effects of caffeine and/or coffee in a normal, healthy population of men and women. (19). The relationship between caffeine consumption and various illnesses such as cardiovascular disease and cancer remains equivocal. Prudence might dictate that pregnant women and chronically ill individuals exercise restraint in their use of caffeine, although research suggests relatively low or nonexistent levels of risk associated with moderate caffeine consumption. (7). There is extensive evidence that caffeine at dietary doses increases blood pressure (BP). However, concern that the drug may contribute to cardiovascular disease appears to have been dampened by (1) the belief that habitual use leads to the development of tolerance, and (2) confusion regarding relevant epidemiologic findings. When considered comprehensively, findings from experimental and epidemiologic studies converge to show that BP remains reactive to the pressor effects of caffeine in the diet. Overall, the impact of dietary caffeine on population BP levels is likely to be modest, probably in the region of 4/2 mm Hg. At these levels, however, population studies of BP indicate that caffeine use could account for premature deaths in the region of 14% for coronary heart disease and 20% for stroke. (8). Caffeine is a purine alkaloid that occurs naturally in coffee beans. At intake levels associated with coffee consumption, caffeine appears to exert most of its biological effects through the antagonism of the A1 and A2A subtypes of the adenosine receptor. Adenosine is an endogenous neuromodulator with mostly inhibitory effects, and adenosine antagonism by caffeine results in effects that are generally stimulatory. Some physiological effects associated with caffeine administration include central nervous system stimulation, acute elevation of blood pressure, increased metabolic rate, and diuresis. Caffeine concentrations in coffee beverages can be quite variable. A standard cup of coffee is often assumed to provide 100 mg of caffeine, but a recent analysis of 14 different specialty coffees purchased at coffee shops in the US found that the amount of caffeine in 8 oz (=240 ml) of brewed coffee ranged from 72 to 130 mg.Caffeine in espresso coffees ranged from 58 to 76 mg in a single shot. (9). Caffeine is a member of the methylxanthine family of drugs, and is the most widely consumed behaviourally active substance in the western world. A number of in vitro and in vivo studies have demonstrated that caffeine modulates both innate and adaptive immune responses. For instance studies indicate that caffeine and its major metabolite paraxanthine suppress neutrophil and monocyte chemotaxis, and also suppress production of the pro-inflammatory cytokine tumor necrosis factor (TNF) alpha from human blood. Caffeine has also been reported to suppress human lymphocyte function as indicated by reduced T-cell proliferation and impaired production of Th1 (interleukin [IL]-2 and interferon [IFN]-gamma), Th2 (IL-4, IL-5) and Th3 (IL-10) cytokines. Studies also indicate that caffeine suppresses antibody production. The evidence suggests that at least some of the immunomodulatory actions of caffeine are mediated via inhibition of cyclic adenosine monophosphate (cAMP)-phosphodiesterase (PDE), and consequential increase in intracellular cAMP concentrations. Overall, these studies indicate that caffeine, like other members of the methylxanthine family, is largely anti-inflammatory in nature, and based on the pharmacokinetics of caffeine, many of its immunomodulatory effects occur at concentrations that are relevant to normal human consumption. (10).
Compound Type
  • Amide
  • Anorexigenic Agent
  • Appetite Depressant
  • Central Nervous System Stimulant
  • Drug
  • Food Toxin
  • Household Toxin
  • Metabolite
  • Natural Compound
  • Organic Compound
  • Phosphodiesterase Inhibitor
  • Purinergic P1 Receptor Antagonist
Chemical Structure
Thumb
MOLSDFPDBSMILESInChI
Synonyms
Synonym
1,3,7-Trimethyl-2,6-dioxopurine
1,3,7-Trimethyl-3,7-dihydro-1H-purine-2,6-dione
1,3,7-trimethylpurine-2,6-dione
1,3,7-Trimethylxanthine
1-Methyl-Theobromine
1-methyltheobromine
3,7-Dihydro-1,3,7-trimethyl-1H-purin-2,6-dion
3,7-Dihydro-1,3,7-trimethyl-1H-purine-2,6-dione
7-Methyl Theophylline
7-methyltheophylline
Anhydrous caffeine
Anhydrous caffeine (JP15)
Cafcit
Cafeína
Caféine
Caffedrine
Coffein
Dexitac
Durvitan
Enerjets
Guaranine
Hycomine
Koffein
Lanorinal
Mateína
Methyltheobromide
Methyltheobromine
Methylxanthine theophylline
Monohydrate Caffeine
No-Doz
Pep-Back
Quick Pep
Teina
Thein
Theine
Vivarin
Wake-Up
Chemical FormulaC8H10N4O2
Average Molecular Mass194.191 g/mol
Monoisotopic Mass194.080 g/mol
CAS Registry Number58-08-2
IUPAC Name1,3,7-trimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione
Traditional Namecaffeine
SMILESCN1C=NC2=C1C(=O)N(C)C(=O)N2C
InChI IdentifierInChI=1S/C8H10N4O2/c1-10-4-9-6-5(10)7(13)12(3)8(14)11(6)2/h4H,1-3H3
InChI KeyInChIKey=RYYVLZVUVIJVGH-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as xanthines. These are purine derivatives with a ketone group conjugated at carbons 2 and 6 of the purine moiety.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassImidazopyrimidines
Sub ClassPurines and purine derivatives
Direct ParentXanthines
Alternative Parents
Substituents
  • Xanthine
  • Purinone
  • 6-oxopurine
  • Alkaloid or derivatives
  • Pyrimidone
  • Pyrimidine
  • N-substituted imidazole
  • Heteroaromatic compound
  • Vinylogous amide
  • Imidazole
  • Azole
  • Urea
  • Lactam
  • Azacycle
  • Organic nitrogen compound
  • Organic oxygen compound
  • Organopnictogen compound
  • Organic oxide
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
Biofluid LocationsNot Available
Tissue Locations
  • Kidney
  • Liver
  • Prostate
  • Skin
Pathways
NameSMPDB LinkKEGG Link
Caffeine MetabolismSMP00028 map00232
Applications
Biological Roles
Chemical Roles
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point238°C
Boiling PointNot Available
Solubility2.16E+004 mg/L (at 25°C)
LogP-0.07
Predicted Properties
PropertyValueSource
Water Solubility11 g/LALOGPS
logP-0.24ALOGPS
logP-0.55ChemAxon
logS-1.2ALOGPS
pKa (Strongest Basic)-0.92ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area58.44 ŲChemAxon
Rotatable Bond Count0ChemAxon
Refractivity49.83 m³·mol⁻¹ChemAxon
Polarizability18.95 ųChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
GC-MSGC-MS Spectrum - GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies) (0 TMS)splash10-0536-3900000000-a9e112713ffae6dabdaa2014-06-16View Spectrum
GC-MSGC-MS Spectrum - GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies) (0 TMS)splash10-0536-2900000000-8cdcd005b2e7622a02a32014-06-16View Spectrum
GC-MSGC-MS Spectrum - GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies) (Non-derivatized)splash10-052f-0900000000-f1084acfddb2406960732014-06-16View Spectrum
GC-MSGC-MS Spectrum - GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies) (Non-derivatized)splash10-05nf-6900000000-8670a644cee5d9de78d42014-06-16View Spectrum
GC-MSGC-MS Spectrum - GC-MS (Non-derivatized)splash10-0536-3900000000-4430852b279a72e348222014-06-16View Spectrum
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-0006-0900000000-51898e93480e848d7da12017-09-12View Spectrum
GC-MSGC-MS Spectrum - CI-B (Non-derivatized)splash10-0002-0900000000-2aed5d425b6a95add5db2017-09-12View Spectrum
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-0a4l-4900000000-3ff72dace6687d242f1f2017-09-12View Spectrum
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-0006-1900000000-2ba1fae6e27c7b8369842017-09-12View Spectrum
GC-MSGC-MS Spectrum - CI-B (Non-derivatized)splash10-0002-0900000000-fd859aeb416e320d63792017-09-12View Spectrum
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-0536-3900000000-a9e112713ffae6dabdaa2017-09-12View Spectrum
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-0536-2900000000-8cdcd005b2e7622a02a32017-09-12View Spectrum
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-052f-0900000000-f1084acfddb2406960732017-09-12View Spectrum
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-05nf-6900000000-8670a644cee5d9de78d42017-09-12View Spectrum
GC-MSGC-MS Spectrum - GC-MS (Non-derivatized)splash10-0536-3900000000-4430852b279a72e348222017-09-12View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-052r-0900000000-41f36d541d34d20889642017-07-27View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 10V, Positive (Annotated)splash10-0006-0900000000-447fc72b2c709e2e18a92012-07-24View Spectrum
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 25V, Positive (Annotated)splash10-000i-1900000000-5e3b29de16ad91c79fe02012-07-24View Spectrum
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 40V, Positive (Annotated)splash10-0006-9100000000-d6f6c52ac36c8f25a5002012-07-24View Spectrum
LC-MS/MSLC-MS/MS Spectrum - EI-B (HITACHI M-80) , Positivesplash10-0006-0900000000-cddd24399d942b1ac97c2012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - CI-B (Unknown) , Positivesplash10-0002-0900000000-2aed5d425b6a95add5db2012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - EI-B (HITACHI M-60) , Positivesplash10-0a4l-4900000000-3ff72dace6687d242f1f2012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - EI-B (HITACHI M-68) , Positivesplash10-0006-1900000000-2ba1fae6e27c7b8369842012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - CI-B (HITACHI M-60) , Positivesplash10-0002-0900000000-63b9ef42a3e8d59e99972012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, Positivesplash10-0002-0900000000-185b3d97d8857a0f269d2012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, Positivesplash10-0002-0900000000-f8a0c0dd9f5c4a272eaf2012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 30V, Positivesplash10-000i-1900000000-dd8e35226d0704aa657d2012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 40V, Positivesplash10-01x9-9800000000-70e3b0eb52481c39d1912012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 50V, Positivesplash10-001l-9100000000-6d428a5571beb0e3fed42012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF (UPLC Q-Tof Premier, Waters) , Positivesplash10-0002-0900000000-98bec16f898808c3de682012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF (UPLC Q-Tof Premier, Waters) 30V, Positivesplash10-0002-0900000000-b112e4e059e1ecf98c5f2012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - DI-ESI-qTof , Positivesplash10-00dr-0900000000-42c6f8fc7b924e9c64f32017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-qTof , Positivesplash10-000i-4900000000-a60a480f1340558740a22017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-000i-0900000000-695d910d49fc0beb1d542017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0002-0900000000-094879886a2e72bf0c562017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0002-0900000000-fa38c865089a3a05f2872017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-000b-0900000000-0e82732a924c974dd0c82017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-000i-0900000000-bfc94c8091471847482b2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-000i-1900000000-c8fcf16986c4948982032017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-000i-3900000000-9569e0552abb7ebd145a2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0002-0900000000-3a924abd44877050c1c92017-09-14View Spectrum
MSMass Spectrum (Electron Ionization)splash10-052f-8900000000-68b5e9aa3404fb3d8d3a2014-09-20View Spectrum
1D NMR1H NMR Spectrum (1D, 500 MHz, CDCl3, experimental)Not Available2012-12-04View Spectrum
1D NMR1H NMR Spectrum (1D, 90 MHz, CDCl3, experimental)Not Available2014-09-20View Spectrum
1D NMR13C NMR Spectrum (1D, 25.16 MHz, CDCl3, experimental)Not Available2014-09-23View Spectrum
1D NMR1H NMR Spectrum (1D, 100 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR13C NMR Spectrum (1D, 100 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR1H NMR Spectrum (1D, 200 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR13C NMR Spectrum (1D, 200 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR1H NMR Spectrum (1D, 300 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR13C NMR Spectrum (1D, 300 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR1H NMR Spectrum (1D, 400 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR13C NMR Spectrum (1D, 400 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR1H NMR Spectrum (1D, 500 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR13C NMR Spectrum (1D, 500 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR1H NMR Spectrum (1D, 600 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR13C NMR Spectrum (1D, 600 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR1H NMR Spectrum (1D, 700 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR13C NMR Spectrum (1D, 700 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR1H NMR Spectrum (1D, 800 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR13C NMR Spectrum (1D, 800 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR1H NMR Spectrum (1D, 900 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR13C NMR Spectrum (1D, 900 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR1H NMR Spectrum (1D, 1000 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR13C NMR Spectrum (1D, 1000 MHz, D2O, predicted)Not Available2021-09-16View Spectrum
1D NMR1H NMR Spectrum (1D, 500 MHz, CDCl3, experimental)Not Available2021-10-10View Spectrum
2D NMR[1H, 1H]-TOCSY. Unexported temporarily by An Chi on Oct 15, 2021 until json or nmrML file is generated. 2D NMR Spectrum (experimental)Not Available2012-12-04View Spectrum
2D NMR[1H, 13C]-HSQC NMR Spectrum (2D, 600 MHz, CDCl3, experimental)Not Available2012-12-05View Spectrum
Toxicity Profile
Route of ExposureReadily absorbed after oral or parenteral administration. The peak plasma level for caffeine range from 6-10mg/L and the mean time to reach peak concentration ranged from 30 minutes to 2 hours.
Mechanism of ToxicityCaffeine stimulates medullary, vagal, vasomotor, and respiratory centers, promoting bradycardia, vasoconstriction, and increased respiratory rate. This action was previously believed to be due primarily to increased intracellular cyclic 3′,5′-adenosine monophosphate (cyclic AMP) following inhibition of phosphodiesterase, the enzyme that degrades cyclic AMP. It is now thought that xanthines such as caffeine act as antagonists at adenosine-receptors within the plasma membrane of virtually every cell. As adenosine acts as an autocoid, inhibiting the release of neurotransmitters from presynaptic sites but augmenting the actions of norepinephrine or angiotensin, antagonism of adenosine receptors promotes neurotransmitter release. This explains the stimulatory effects of caffeine. Blockade of the adenosine A1 receptor in the heart leads to the accelerated, pronounced "pounding" of the heart upon caffeine intake.
MetabolismHepatic cytochrome P450 1A2 (CYP 1A2) is involved in caffeine biotransformation. About 80% of a dose of caffeine is metabolized to paraxanthine (1,7-dimethylxanthine), 10% to theobromine (3,7-dimethylxanthine), and 4% to theophylline (1,3-dimethylxanthine). Route of Elimination: In young infants, the elimination of caffeine is much slower than that in adults due to immature hepatic and/or renal function. Half Life: 3 to 7 hours in adults, 65 to 130 hours in neonates
Toxicity ValuesLD50: 127 mg/kg (Oral, Mouse) (6)
Lethal DoseNot Available
Carcinogenicity (IARC Classification)3, not classifiable as to its carcinogenicity to humans. (23)
Uses/SourcesCaffeine is a central nervous system (CNS) stimulant, having the effect of temporarily warding off drowsiness and restoring alertness. For management of fatigue, orthostatic hypotension, and for the short term treatment of apnea of prematurity in infants.
Minimum Risk LevelNot Available
Health EffectsCaffeine may increase rates of miscarriage and low birth weight. Caffeine withdrawal symptoms include fatigue, headache, nausea and irritability. Using large amounts of these drugs can result in a condition known as amphetamine psychosis -- which can result in auditory, visual and tactile hallucinations, intense paranoia, irrational thoughts and beliefs, delusions, and mental confusion.
SymptomsHigh doses may cause nausea, diarrhea, insomnia, headaches, nervousness or agitation, and the shakes.
TreatmentConvulsions may be treated with IV administration of diazepam or a barbiturate such as pentobarbital sodium. (22)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00201
HMDB IDHMDB01847
PubChem Compound ID2519
ChEMBL IDCHEMBL113
ChemSpider ID2424
KEGG IDC07481
UniProt IDNot Available
OMIM ID
ChEBI ID27732
BioCyc ID1-3-7-TRIMETHYLXANTHINE
CTD IDNot Available
Stitch IDCaffeine
PDB IDCFF
ACToR ID235
Wikipedia LinkCaffeine
References
Synthesis Reference

Kaspar Bott, “Preparation of caffeine.” U.S. Patent US4380631, issued December, 1976.

MSDSLink
General References
  1. Nathanson JA: Caffeine and related methylxanthines: possible naturally occurring pesticides. Science. 1984 Oct 12;226(4671):184-7. [6207592 ]
  2. Haskell CF, Kennedy DO, Wesnes KA, Milne AL, Scholey AB: A double-blind, placebo-controlled, multi-dose evaluation of the acute behavioural effects of guarana in humans. J Psychopharmacol. 2007 Jan;21(1):65-70. Epub 2006 Mar 13. [16533867 ]
  3. Smit HJ, Gaffan EA, Rogers PJ: Methylxanthines are the psycho-pharmacologically active constituents of chocolate. Psychopharmacology (Berl). 2004 Nov;176(3-4):412-9. Epub 2004 May 5. [15549276 ]
  4. Benjamin LT Jr, Rogers AM, Rosenbaum A: Coca-Cola, caffeine, and mental deficiency: Harry Hollingworth and the Chattanooga trial of 1911. J Hist Behav Sci. 1991 Jan;27(1):42-55. [2010614 ]
  5. Nehlig A, Daval JL, Debry G: Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain Res Brain Res Rev. 1992 May-Aug;17(2):139-70. [1356551 ]
  6. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
  7. Lamarine RJ: Selected health and behavioral effects related to the use of caffeine. J Community Health. 1994 Dec;19(6):449-66. [7844249 ]
  8. James JE: Critical review of dietary caffeine and blood pressure: a relationship that should be taken more seriously. Psychosom Med. 2004 Jan-Feb;66(1):63-71. [14747639 ]
  9. Higdon JV, Frei B: Coffee and health: a review of recent human research. Crit Rev Food Sci Nutr. 2006;46(2):101-23. [16507475 ]
  10. Horrigan LA, Kelly JP, Connor TJ: Immunomodulatory effects of caffeine: friend or foe? Pharmacol Ther. 2006 Sep;111(3):877-92. Epub 2006 Mar 15. [16540173 ]
  11. Miyake Y, Sakaguchi K, Iwasaki Y, Ikeda H, Makino Y, Kobashi H, Araki Y, Ando M, Kita K, Shiratori Y: New prognostic scoring model for liver transplantation in patients with non-acetaminophen-related fulminant hepatic failure. Transplantation. 2005 Oct 15;80(7):930-6. [16249741 ]
  12. Wilkinson SC, Maas WJ, Nielsen JB, Greaves LC, van de Sandt JJ, Williams FM: Interactions of skin thickness and physicochemical properties of test compounds in percutaneous penetration studies. Int Arch Occup Environ Health. 2006 May;79(5):405-13. Epub 2006 Jan 25. [16435152 ]
  13. Spiller HA, Winter ML, Klein-Schwartz W, Bangh SA: Efficacy of activated charcoal administered more than four hours after acetaminophen overdose. J Emerg Med. 2006 Jan;30(1):1-5. [16434328 ]
  14. Ayotte P, Dewailly E, Lambert GH, Perkins SL, Poon R, Feeley M, Larochelle C, Pereg D: Biomarker measurements in a coastal fish-eating population environmentally exposed to organochlorines. Environ Health Perspect. 2005 Oct;113(10):1318-24. [16203240 ]
  15. Shah S, Budev M, Blazey H, Fairbanks K, Mehta A: Hepatic veno-occlusive disease due to tacrolimus in a single-lung transplant patient. Eur Respir J. 2006 May;27(5):1066-8. [16707401 ]
  16. Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, Reisch JS, Schiodt FV, Ostapowicz G, Shakil AO, Lee WM: Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005 Dec;42(6):1364-72. [16317692 ]
  17. Septer S, Thompson ES, Willemsen-Dunlap A: Anesthesia concerns for children with tuberous sclerosis. AANA J. 2006 Jun;74(3):219-25. [16786916 ]
  18. Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, Laxman B, Mehra R, Lonigro RJ, Li Y, Nyati MK, Ahsan A, Kalyana-Sundaram S, Han B, Cao X, Byun J, Omenn GS, Ghosh D, Pennathur S, Alexander DC, Berger A, Shuster JR, Wei JT, Varambally S, Beecher C, Chinnaiyan AM: Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature. 2009 Feb 12;457(7231):910-4. doi: 10.1038/nature07762. [19212411 ]
  19. Rodrigues IM, Klein LC: Boiled or filtered coffee? Effects of coffee and caffeine on cholesterol, fibrinogen and C-reactive protein. Toxicol Rev. 2006;25(1):55-69. [16856769 ]
  20. Drugs.com [Link]
  21. About.com (2009). Health Effects of Drug Use. [Link]
  22. RxList: The Internet Drug Index (2009). [Link]
  23. International Agency for Research on Cancer (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [Link]
Gene Regulation
Up-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails
Down-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails

Targets

Target Details
1. Adenosine receptor A2a
General Function:
Identical protein binding
Specific Function:
Receptor for adenosine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
Gene Name:
ADORA2A
Uniprot ID:
P29274
Molecular Weight:
44706.925 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory5.01187 uMNot AvailableBindingDB 10849
Inhibitory18.1 uMNot AvailableBindingDB 10849
Inhibitory23.4 uMNot AvailableBindingDB 10849
Inhibitory48 uMNot AvailableBindingDB 10849
AC504.62 uMNVS_GPCR_hAdoRA2aNovascreen
References
  1. Riksen NP, Franke B, van den Broek P, Smits P, Rongen GA: The 1976C>T polymorphism in the adenosine A2A receptor gene does not affect the vasodilator response to adenosine in humans in vivo. Pharmacogenet Genomics. 2007 Jul;17(7):551-4. [17558310 ]
  2. Zhao G, Messina E, Xu X, Ochoa M, Sun HL, Leung K, Shryock J, Belardinelli L, Hintze TH: Caffeine attenuates the duration of coronary vasodilation and changes in hemodynamics induced by regadenoson (CVT-3146), a novel adenosine A2A receptor agonist. J Cardiovasc Pharmacol. 2007 Jun;49(6):369-75. [17577101 ]
  3. Cornelis MC, El-Sohemy A, Campos H: Genetic polymorphism of the adenosine A2A receptor is associated with habitual caffeine consumption. Am J Clin Nutr. 2007 Jul;86(1):240-4. [17616786 ]
  4. Zhukov A, Andrews SP, Errey JC, Robertson N, Tehan B, Mason JS, Marshall FH, Weir M, Congreve M: Biophysical mapping of the adenosine A2A receptor. J Med Chem. 2011 Jul 14;54(13):4312-23. doi: 10.1021/jm2003798. Epub 2011 Jun 10. [21661720 ]
  5. Ishiyama H, Ohshita K, Abe T, Nakata H, Kobayashi J: Synthesis of eudistomin D analogues and its effects on adenosine receptors. Bioorg Med Chem. 2008 Apr 1;16(7):3825-30. doi: 10.1016/j.bmc.2008.01.041. Epub 2008 Jan 30. [18262425 ]
  6. Ishiyama H, Nakajima H, Nakata H, Kobayashi J: Synthesis of hybrid analogues of caffeine and eudistomin D and its affinity for adenosine receptors. Bioorg Med Chem. 2009 Jul 1;17(13):4280-4. doi: 10.1016/j.bmc.2009.05.036. Epub 2009 May 18. [19481943 ]
  7. Drabczynska A, Yuzlenko O, Kose M, Paskaleva M, Schiedel AC, Karolak-Wojciechowska J, Handzlik J, Karcz T, Kuder K, Muller CE, Kiec-Kononowicz K: Synthesis and biological activity of tricyclic cycloalkylimidazo-, pyrimido- and diazepinopurinediones. Eur J Med Chem. 2011 Sep;46(9):3590-607. doi: 10.1016/j.ejmech.2011.05.023. Epub 2011 May 23. [21664729 ]
  8. Franchetti P, Messini L, Cappellacci L, Grifantini M, Lucacchini A, Martini C, Senatore G: 8-Azaxanthine derivatives as antagonists of adenosine receptors. J Med Chem. 1994 Sep 2;37(18):2970-5. [8071944 ]
  9. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
Target Details
2. Adenosine receptor A1
General Function:
Purine nucleoside binding
Specific Function:
Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase.
Gene Name:
ADORA1
Uniprot ID:
P30542
Molecular Weight:
36511.325 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory29 uMNot AvailableBindingDB 10849
Inhibitory44.9 uMNot AvailableBindingDB 10849
Inhibitory49 uMNot AvailableBindingDB 10849
Inhibitory100 uMNot AvailableBindingDB 10849
Inhibitory>100 uMNot AvailableBindingDB 10849
Dissociation45 uMNot AvailableBindingDB 10849
References
  1. Gaytan SP, Saadani-Makki F, Bodineau L, Frugiere A, Larnicol N, Pasaro R: Effect of postnatal exposure to caffeine on the pattern of adenosine A1 receptor distribution in respiration-related nuclei of the rat brainstem. Auton Neurosci. 2006 Jun 30;126-127:339-46. Epub 2006 May 15. [16702031 ]
  2. Wang SJ: Caffeine facilitation of glutamate release from rat cerebral cortex nerve terminals (synaptosomes) through activation protein kinase C pathway: an interaction with presynaptic adenosine A1 receptors. Synapse. 2007 Jun;61(6):401-11. [17372967 ]
  3. Rieg T, Schnermann J, Vallon V: Adenosine A1 receptors determine effects of caffeine on total fluid intake but not caffeine appetite. Eur J Pharmacol. 2007 Jan 26;555(2-3):174-7. Epub 2006 Oct 25. [17126319 ]
  4. Mustafa S, Venkatesh P, Pasha K, Mullangi R, Srinivas NR: Altered intravenous pharmacokinetics of topotecan in rats with acute renal failure (ARF) induced by uranyl nitrate: do adenosine A1 antagonists (selective/non-selective) normalize the altered topotecan kinetics in ARF? Xenobiotica. 2006 Dec;36(12):1239-58. [17162470 ]
  5. Listos J, Malec D, Fidecka S: Adenosine receptor antagonists intensify the benzodiazepine withdrawal signs in mice. Pharmacol Rep. 2006 Sep-Oct;58(5):643-51. [17085856 ]
  6. Gilli P, Gilli G, Borea PA, Varani K, Scatturin A, Dalpiaz A: Binding thermodynamics as a tool to investigate the mechanisms of drug-receptor interactions: thermodynamics of cytoplasmic steroid/nuclear receptors in comparison with membrane receptors. J Med Chem. 2005 Mar 24;48(6):2026-35. [15771445 ]
  7. Ingkaninan K, IJzerman AP, Verpoorte R: Luteolin, a compound with adenosine A(1) receptor-binding activity, and chromone and dihydronaphthalenone constituents from Senna siamea. J Nat Prod. 2000 Mar;63(3):315-7. [10757709 ]
  8. Drabczynska A, Yuzlenko O, Kose M, Paskaleva M, Schiedel AC, Karolak-Wojciechowska J, Handzlik J, Karcz T, Kuder K, Muller CE, Kiec-Kononowicz K: Synthesis and biological activity of tricyclic cycloalkylimidazo-, pyrimido- and diazepinopurinediones. Eur J Med Chem. 2011 Sep;46(9):3590-607. doi: 10.1016/j.ejmech.2011.05.023. Epub 2011 May 23. [21664729 ]
  9. Ishiyama H, Ohshita K, Abe T, Nakata H, Kobayashi J: Synthesis of eudistomin D analogues and its effects on adenosine receptors. Bioorg Med Chem. 2008 Apr 1;16(7):3825-30. doi: 10.1016/j.bmc.2008.01.041. Epub 2008 Jan 30. [18262425 ]
  10. Ishiyama H, Nakajima H, Nakata H, Kobayashi J: Synthesis of hybrid analogues of caffeine and eudistomin D and its affinity for adenosine receptors. Bioorg Med Chem. 2009 Jul 1;17(13):4280-4. doi: 10.1016/j.bmc.2009.05.036. Epub 2009 May 18. [19481943 ]
  11. Suzuki F, Shimada J, Mizumoto H, Karasawa A, Kubo K, Nonaka H, Ishii A, Kawakita T: Adenosine A1 antagonists. 2. Structure-activity relationships on diuretic activities and protective effects against acute renal failure. J Med Chem. 1992 Aug 7;35(16):3066-75. [1501234 ]
  12. Shimada J, Suzuki F, Nonaka H, Ishii A: 8-Polycycloalkyl-1,3-dipropylxanthines as potent and selective antagonists for A1-adenosine receptors. J Med Chem. 1992 Mar 6;35(5):924-30. [1548682 ]
  13. Shimada J, Suzuki F, Nonaka H, Ishii A, Ichikawa S: (E)-1,3-dialkyl-7-methyl-8-(3,4,5-trimethoxystyryl)xanthines: potent and selective adenosine A2 antagonists. J Med Chem. 1992 Jun 12;35(12):2342-5. [1613758 ]
  14. Shimada J, Suzuki F, Nonaka H, Karasawa A, Mizumoto H, Ohno T, Kubo K, Ishii A: 8-(Dicyclopropylmethyl)-1,3-dipropylxanthine: a potent and selective adenosine A1 antagonist with renal protective and diuretic activities. J Med Chem. 1991 Jan;34(1):466-9. [1992150 ]
Target Details
3. Adenosine receptor A2b
General Function:
G-protein coupled adenosine receptor activity
Specific Function:
Receptor for adenosine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
Gene Name:
ADORA2B
Uniprot ID:
P29275
Molecular Weight:
36332.655 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory10.4 uMNot AvailableBindingDB 10849
Inhibitory20.5 uMNot AvailableBindingDB 10849
Inhibitory33.8 uMNot AvailableBindingDB 10849
References
  1. Kim SA, Marshall MA, Melman N, Kim HS, Muller CE, Linden J, Jacobson KA: Structure-activity relationships at human and rat A2B adenosine receptors of xanthine derivatives substituted at the 1-, 3-, 7-, and 8-positions. J Med Chem. 2002 May 23;45(11):2131-8. [12014951 ]
  2. Borrmann T, Hinz S, Bertarelli DC, Li W, Florin NC, Scheiff AB, Muller CE: 1-alkyl-8-(piperazine-1-sulfonyl)phenylxanthines: development and characterization of adenosine A2B receptor antagonists and a new radioligand with subnanomolar affinity and subtype specificity. J Med Chem. 2009 Jul 9;52(13):3994-4006. doi: 10.1021/jm900413e. [19569717 ]
  3. Cheng F, Xu Z, Liu G, Tang Y: Insights into binding modes of adenosine A(2B) antagonists with ligand-based and receptor-based methods. Eur J Med Chem. 2010 Aug;45(8):3459-71. doi: 10.1016/j.ejmech.2010.04.039. Epub 2010 May 7. [20537438 ]
  4. Drabczynska A, Yuzlenko O, Kose M, Paskaleva M, Schiedel AC, Karolak-Wojciechowska J, Handzlik J, Karcz T, Kuder K, Muller CE, Kiec-Kononowicz K: Synthesis and biological activity of tricyclic cycloalkylimidazo-, pyrimido- and diazepinopurinediones. Eur J Med Chem. 2011 Sep;46(9):3590-607. doi: 10.1016/j.ejmech.2011.05.023. Epub 2011 May 23. [21664729 ]
  5. Scheiff AB, Yerande SG, El-Tayeb A, Li W, Inamdar GS, Vasu KK, Sudarsanam V, Muller CE: 2-Amino-5-benzoyl-4-phenylthiazoles: Development of potent and selective adenosine A1 receptor antagonists. Bioorg Med Chem. 2010 Mar 15;18(6):2195-203. doi: 10.1016/j.bmc.2010.01.072. Epub 2010 Feb 4. [20188574 ]
Target Details
4. Adenosine receptor A3
General Function:
G-protein coupled adenosine receptor activity
Specific Function:
Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibits adenylyl cyclase. Possible role in reproduction.
Gene Name:
ADORA3
Uniprot ID:
P0DMS8
Molecular Weight:
36184.175 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory13.3 uMNot AvailableBindingDB 10849
Inhibitory>100 uMNot AvailableBindingDB 10849
References
  1. Muller CE, Thorand M, Qurishi R, Diekmann M, Jacobson KA, Padgett WL, Daly JW: Imidazo[2,1-i]purin-5-ones and related tricyclic water-soluble purine derivatives: potent A(2A)- and A(3)-adenosine receptor antagonists. J Med Chem. 2002 Aug 1;45(16):3440-50. [12139454 ]
  2. Ishiyama H, Ohshita K, Abe T, Nakata H, Kobayashi J: Synthesis of eudistomin D analogues and its effects on adenosine receptors. Bioorg Med Chem. 2008 Apr 1;16(7):3825-30. doi: 10.1016/j.bmc.2008.01.041. Epub 2008 Jan 30. [18262425 ]
  3. Scheiff AB, Yerande SG, El-Tayeb A, Li W, Inamdar GS, Vasu KK, Sudarsanam V, Muller CE: 2-Amino-5-benzoyl-4-phenylthiazoles: Development of potent and selective adenosine A1 receptor antagonists. Bioorg Med Chem. 2010 Mar 15;18(6):2195-203. doi: 10.1016/j.bmc.2010.01.072. Epub 2010 Feb 4. [20188574 ]
  4. Drabczynska A, Yuzlenko O, Kose M, Paskaleva M, Schiedel AC, Karolak-Wojciechowska J, Handzlik J, Karcz T, Kuder K, Muller CE, Kiec-Kononowicz K: Synthesis and biological activity of tricyclic cycloalkylimidazo-, pyrimido- and diazepinopurinediones. Eur J Med Chem. 2011 Sep;46(9):3590-607. doi: 10.1016/j.ejmech.2011.05.023. Epub 2011 May 23. [21664729 ]
Target Details
5. Serine-protein kinase ATM
General Function:
Protein serine/threonine kinase activity
Specific Function:
Serine/threonine protein kinase which activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates 'Ser-139' of histone variant H2AX/H2AFX at double strand breaks (DSBs), thereby regulating DNA damage response mechanism. Also plays a role in pre-B cell allelic exclusion, a process leading to expression of a single immunoglobulin heavy chain allele to enforce clonality and monospecific recognition by the B-cell antigen receptor (BCR) expressed on individual B-lymphocytes. After the introduction of DNA breaks by the RAG complex on one immunoglobulin allele, acts by mediating a repositioning of the second allele to pericentromeric heterochromatin, preventing accessibility to the RAG complex and recombination of the second allele. Also involved in signal transduction and cell cycle control. May function as a tumor suppressor. Necessary for activation of ABL1 and SAPK. Phosphorylates DYRK2, CHEK2, p53/TP53, FANCD2, NFKBIA, BRCA1, CTIP, nibrin (NBN), TERF1, RAD9 and DCLRE1C. May play a role in vesicle and/or protein transport. Could play a role in T-cell development, gonad and neurological function. Plays a role in replication-dependent histone mRNA degradation. Binds DNA ends. Phosphorylation of DYRK2 in nucleus in response to genotoxic stress prevents its MDM2-mediated ubiquitination and subsequent proteasome degradation. Phosphorylates ATF2 which stimulates its function in DNA damage response.
Gene Name:
ATM
Uniprot ID:
Q13315
Molecular Weight:
350684.105 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50200 uMNot AvailableBindingDB 10849
References
  1. Sarkaria JN, Busby EC, Tibbetts RS, Roos P, Taya Y, Karnitz LM, Abraham RT: Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. Cancer Res. 1999 Sep 1;59(17):4375-82. [10485486 ]
  2. Blasina A, Price BD, Turenne GA, McGowan CH: Caffeine inhibits the checkpoint kinase ATM. Curr Biol. 1999 Oct 7;9(19):1135-8. [10531013 ]
  3. Charrier JD, Durrant SJ, Golec JM, Kay DP, Knegtel RM, MacCormick S, Mortimore M, O'Donnell ME, Pinder JL, Reaper PM, Rutherford AP, Wang PS, Young SC, Pollard JR: Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents. J Med Chem. 2011 Apr 14;54(7):2320-30. doi: 10.1021/jm101488z. Epub 2011 Mar 17. [21413798 ]
6. Cyclic nucleotide phosphodiesterase (Protein Group)
General Function:
Metal ion binding
Specific Function:
Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. Has a higher affinity for cGMP than for cAMP.
Included Proteins:
P54750 , Q01064 , Q14123 , Q9Y233 , P27815 , Q07343 , Q08493 , Q08499 , Q9NP56 , O00408 , Q14432 , Q13370 , O76074 , P51160 , Q9HCR9 , Q13946 , O60658 , O95263 , O76083 , P16499 , P35913
References
  1. Ribeiro JA, Sebastiao AM: Caffeine and adenosine. J Alzheimers Dis. 2010;20 Suppl 1:S3-15. doi: 10.3233/JAD-2010-1379. [20164566 ]
  2. Essayan DM: Cyclic nucleotide phosphodiesterases. J Allergy Clin Immunol. 2001 Nov;108(5):671-80. [11692087 ]
Target Details
7. cAMP-specific 3',5'-cyclic phosphodiesterase 4B
General Function:
Metal ion binding
Specific Function:
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in mediating central nervous system effects of therapeutic agents ranging from antidepressants to antiasthmatic and anti-inflammatory agents.
Gene Name:
PDE4B
Uniprot ID:
Q07343
Molecular Weight:
83342.695 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]
Target Details
8. Amine oxidase [flavin-containing] B
General Function:
Primary amine oxidase activity
Specific Function:
Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues. MAOB preferentially degrades benzylamine and phenylethylamine.
Gene Name:
MAOB
Uniprot ID:
P27338
Molecular Weight:
58762.475 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory3600 uMNot AvailableBindingDB 10849
References
  1. Van der Walt EM, Milczek EM, Malan SF, Edmondson DE, Castagnoli N Jr, Bergh JJ, Petzer JP: Inhibition of monoamine oxidase by (E)-styrylisatin analogues. Bioorg Med Chem Lett. 2009 May 1;19(9):2509-13. doi: 10.1016/j.bmcl.2009.03.030. Epub 2009 Mar 14. [19342233 ]
Target Details
9. Chitotriosidase-1
General Function:
Endochitinase activity
Specific Function:
Degrades chitin, chitotriose and chitobiose. May participate in the defense against nematodes and other pathogens. Isoform 3 has no enzymatic activity.
Gene Name:
CHIT1
Uniprot ID:
Q13231
Molecular Weight:
51680.985 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50257 uMNot AvailableBindingDB 10849
References
  1. Rao FV, Andersen OA, Vora KA, Demartino JA, van Aalten DM: Methylxanthine drugs are chitinase inhibitors: investigation of inhibition and binding modes. Chem Biol. 2005 Sep;12(9):973-80. [16183021 ]
Target Details
10. DNA-dependent protein kinase catalytic subunit
General Function:
Transcription factor binding
Specific Function:
Serine/threonine-protein kinase that acts as a molecular sensor for DNA damage. Involved in DNA non-homologous end joining (NHEJ) required for double-strand break (DSB) repair and V(D)J recombination. Must be bound to DNA to express its catalytic properties. Promotes processing of hairpin DNA structures in V(D)J recombination by activation of the hairpin endonuclease artemis (DCLRE1C). The assembly of the DNA-PK complex at DNA ends is also required for the NHEJ ligation step. Required to protect and align broken ends of DNA. May also act as a scaffold protein to aid the localization of DNA repair proteins to the site of damage. Found at the ends of chromosomes, suggesting a further role in the maintenance of telomeric stability and the prevention of chromosomal end fusion. Also involved in modulation of transcription. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates 'Ser-139' of histone variant H2AX/H2AFX, thereby regulating DNA damage response mechanism. Phosphorylates DCLRE1C, c-Abl/ABL1, histone H1, HSPCA, c-jun/JUN, p53/TP53, PARP1, POU2F1, DHX9, SRF, XRCC1, XRCC1, XRCC4, XRCC5, XRCC6, WRN, MYC and RFA2. Can phosphorylate C1D not only in the presence of linear DNA but also in the presence of supercoiled DNA. Ability to phosphorylate p53/TP53 in the presence of supercoiled DNA is dependent on C1D. Contributes to the determination of the circadian period length by antagonizing phosphorylation of CRY1 'Ser-588' and increasing CRY1 protein stability, most likely through an indirect machanism. Interacts with CRY1 and CRY2; negatively regulates CRY1 phosphorylation.
Gene Name:
PRKDC
Uniprot ID:
P78527
Molecular Weight:
469084.155 Da
References
  1. Foukas LC, Daniele N, Ktori C, Anderson KE, Jensen J, Shepherd PR: Direct effects of caffeine and theophylline on p110 delta and other phosphoinositide 3-kinases. Differential effects on lipid kinase and protein kinase activities. J Biol Chem. 2002 Oct 4;277(40):37124-30. Epub 2002 Jul 26. [12145276 ]
Target Details
11. Glycogen phosphorylase, muscle form
General Function:
Pyridoxal phosphate binding
Specific Function:
Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties.
Gene Name:
PYGM
Uniprot ID:
P11217
Molecular Weight:
97091.265 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50114 uMNot AvailableBindingDB 10849
References
  1. Wen X, Sun H, Liu J, Wu G, Zhang L, Wu X, Ni P: Pentacyclic triterpenes. Part 1: the first examples of naturally occurring pentacyclic triterpenes as a new class of inhibitors of glycogen phosphorylases. Bioorg Med Chem Lett. 2005 Nov 15;15(22):4944-8. [16169219 ]
Target Details
12. Guanine deaminase
General Function:
Zinc ion binding
Specific Function:
Catalyzes the hydrolytic deamination of guanine, producing xanthine and ammonia.
Gene Name:
GDA
Uniprot ID:
Q9Y2T3
Molecular Weight:
51002.565 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory10.2 uMNot AvailableBindingDB 10849
References
  1. Fernandez JR, Sweet ES, Welsh WJ, Firestein BL: Identification of small molecule compounds with higher binding affinity to guanine deaminase (cypin) than guanine. Bioorg Med Chem. 2010 Sep 15;18(18):6748-55. doi: 10.1016/j.bmc.2010.07.054. Epub 2010 Jul 27. [20716488 ]
13. Inositol 1,4,5-trisphosphate receptor (Protein Group)
General Function:
Phosphatidylinositol binding
Specific Function:
Intracellular channel that mediates calcium release from the endoplasmic reticulum following stimulation by inositol 1,4,5-trisphosphate. Involved in the regulation of epithelial secretion of electrolytes and fluid through the interaction with AHCYL1 (By similarity). Plays a role in ER stress-induced apoptosis. Cytoplasmic calcium released from the ER triggers apoptosis by the activation of CaM kinase II, eventually leading to the activation of downstream apoptosis pathways (By similarity).
Included Proteins:
Q14643 , Q14571 , Q14573
References
  1. Parker I, Ivorra I: Caffeine inhibits inositol trisphosphate-mediated liberation of intracellular calcium in Xenopus oocytes. J Physiol. 1991 Feb;433:229-40. [1844813 ]
Target Details
14. Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
General Function:
Protein serine/threonine kinase activity
Specific Function:
Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation in breast cancer cells through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. Has also serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS.
Gene Name:
PIK3CA
Uniprot ID:
P42336
Molecular Weight:
124283.025 Da
References
  1. Foukas LC, Daniele N, Ktori C, Anderson KE, Jensen J, Shepherd PR: Direct effects of caffeine and theophylline on p110 delta and other phosphoinositide 3-kinases. Differential effects on lipid kinase and protein kinase activities. J Biol Chem. 2002 Oct 4;277(40):37124-30. Epub 2002 Jul 26. [12145276 ]
Target Details
15. Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform
General Function:
Phosphatidylinositol-4,5-bisphosphate 3-kinase activity
Specific Function:
Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Involved in the activation of AKT1 upon stimulation by G-protein coupled receptors (GPCRs) ligands such as CXCL12, sphingosine 1-phosphate, and lysophosphatidic acid. May also act downstream receptor tyrosine kinases. Required in different signaling pathways for stable platelet adhesion and aggregation. Plays a role in platelet activation signaling triggered by GPCRs, alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) and ITAM (immunoreceptor tyrosine-based activation motif)-bearing receptors such as GP6. Regulates the strength of adhesion of ITGA2B/ ITGB3 activated receptors necessary for the cellular transmission of contractile forces. Required for platelet aggregation induced by F2 (thrombin) and thromboxane A2 (TXA2). Has a role in cell survival. May have a role in cell migration. Involved in the early stage of autophagosome formation. Modulates the intracellular level of PtdIns3P (Phosphatidylinositol 3-phosphate) and activates PIK3C3 kinase activity. May act as a scaffold, independently of its lipid kinase activity to positively regulate autophagy. May have a role in insulin signaling as scaffolding protein in which the lipid kinase activity is not required. May have a kinase-independent function in regulating cell proliferation and in clathrin-mediated endocytosis. Mediator of oncogenic signal in cell lines lacking PTEN. The lipid kinase activity is necessary for its role in oncogenic transformation. Required for the growth of ERBB2 and RAS driven tumors.
Gene Name:
PIK3CB
Uniprot ID:
P42338
Molecular Weight:
122761.225 Da
References
  1. Foukas LC, Daniele N, Ktori C, Anderson KE, Jensen J, Shepherd PR: Direct effects of caffeine and theophylline on p110 delta and other phosphoinositide 3-kinases. Differential effects on lipid kinase and protein kinase activities. J Biol Chem. 2002 Oct 4;277(40):37124-30. Epub 2002 Jul 26. [12145276 ]
Target Details
16. Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
General Function:
Phosphatidylinositol-4,5-bisphosphate 3-kinase activity
Specific Function:
Phosphoinositide-3-kinase (PI3K) that phosphorylates PftdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Mediates immune responses. Plays a role in B-cell development, proliferation, migration, and function. Required for B-cell receptor (BCR) signaling. Mediates B-cell proliferation response to anti-IgM, anti-CD40 and IL4 stimulation. Promotes cytokine production in response to TLR4 and TLR9. Required for antibody class switch mediated by TLR9. Involved in the antigen presentation function of B-cells. Involved in B-cell chemotaxis in response to CXCL13 and sphingosine 1-phosphate (S1P). Required for proliferation, signaling and cytokine production of naive, effector and memory T-cells. Required for T-cell receptor (TCR) signaling. Mediates TCR signaling events at the immune synapse. Activation by TCR leads to antigen-dependent memory T-cell migration and retention to antigenic tissues. Together with PIK3CG participates in T-cell development. Contributes to T-helper cell expansion and differentiation. Required for T-cell migration mediated by homing receptors SELL/CD62L, CCR7 and S1PR1 and antigen dependent recruitment of T-cells. Together with PIK3CG is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in NK cell receptor activation. Have a role in NK cell maturation and cytokine production. Together with PIK3CG is involved in neutrophil chemotaxis and extravasation. Together with PIK3CG participates in neutrophil respiratory burst. Have important roles in mast-cell development and mast cell mediated allergic response. Involved in stem cell factor (SCF)-mediated proliferation, adhesion and migration. Required for allergen-IgE-induced degranulation and cytokine release. The lipid kinase activity is required for its biological function. Isoform 2 may be involved in stabilizing total RAS levels, resulting in increased ERK phosphorylation and increased PI3K activity.
Gene Name:
PIK3CD
Uniprot ID:
O00329
Molecular Weight:
119478.065 Da
References
  1. Foukas LC, Daniele N, Ktori C, Anderson KE, Jensen J, Shepherd PR: Direct effects of caffeine and theophylline on p110 delta and other phosphoinositide 3-kinases. Differential effects on lipid kinase and protein kinase activities. J Biol Chem. 2002 Oct 4;277(40):37124-30. Epub 2002 Jul 26. [12145276 ]
Target Details
17. Ryanodine receptor 1
General Function:
Voltage-gated calcium channel activity
Specific Function:
Calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm and thereby plays a key role in triggering muscle contraction following depolarization of T-tubules. Repeated very high-level exercise increases the open probability of the channel and leads to Ca(2+) leaking into the cytoplasm. Can also mediate the release of Ca(2+) from intracellular stores in neurons, and may thereby promote prolonged Ca(2+) signaling in the brain. Required for normal embryonic development of muscle fibers and skeletal muscle. Required for normal heart morphogenesis, skin development and ossification during embryogenesis (By similarity).
Gene Name:
RYR1
Uniprot ID:
P21817
Molecular Weight:
565170.715 Da
References
  1. Daly JW: Caffeine analogs: biomedical impact. Cell Mol Life Sci. 2007 Aug;64(16):2153-69. [17514358 ]
Target Details
18. Serine/threonine-protein kinase ATR
General Function:
Protein serine/threonine kinase activity
Specific Function:
Serine/threonine protein kinase which activates checkpoint signaling upon genotoxic stresses such as ionizing radiation (IR), ultraviolet light (UV), or DNA replication stalling, thereby acting as a DNA damage sensor. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates BRCA1, CHEK1, MCM2, RAD17, RPA2, SMC1 and p53/TP53, which collectively inhibit DNA replication and mitosis and promote DNA repair, recombination and apoptosis. Phosphorylates 'Ser-139' of histone variant H2AX/H2AFX at sites of DNA damage, thereby regulating DNA damage response mechanism. Required for FANCD2 ubiquitination. Critical for maintenance of fragile site stability and efficient regulation of centrosome duplication.
Gene Name:
ATR
Uniprot ID:
Q13535
Molecular Weight:
301363.675 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC501100 uMNot AvailableBindingDB 10849
References
  1. Charrier JD, Durrant SJ, Golec JM, Kay DP, Knegtel RM, MacCormick S, Mortimore M, O'Donnell ME, Pinder JL, Reaper PM, Rutherford AP, Wang PS, Young SC, Pollard JR: Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents. J Med Chem. 2011 Apr 14;54(7):2320-30. doi: 10.1021/jm101488z. Epub 2011 Mar 17. [21413798 ]
Target Details
19. Serine/threonine-protein kinase mTOR
General Function:
Tfiiic-class transcription factor binding
Specific Function:
Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals. MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins. Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2). Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E). Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote protein synthesis by modulating the activity of their downstream targets including ribosomal protein S6, eukaryotic translation initiation factor EIF4B, and the inhibitor of translation initiation PDCD4. Stimulates the pyrimidine biosynthesis pathway, both by acute regulation through RPS6KB1-mediated phosphorylation of the biosynthetic enzyme CAD, and delayed regulation, through transcriptional enhancement of the pentose phosphate pathway which produces 5-phosphoribosyl-1-pyrophosphate (PRPP), an allosteric activator of CAD at a later step in synthesis, this function is dependent on the mTORC1 complex. Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor. In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1. To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A. mTORC1 also negatively regulates autophagy through phosphorylation of ULK1. Under nutrient sufficiency, phosphorylates ULK1 at 'Ser-758', disrupting the interaction with AMPK and preventing activation of ULK1. Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP. mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor. Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules. As part of the mTORC2 complex MTOR may regulate other cellular processes including survival and organization of the cytoskeleton. Plays a critical role in the phosphorylation at 'Ser-473' of AKT1, a pro-survival effector of phosphoinositide 3-kinase, facilitating its activation by PDK1. mTORC2 may regulate the actin cytoskeleton, through phosphorylation of PRKCA, PXN and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B. mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422'. Regulates osteoclastogensis by adjusting the expression of CEBPB isoforms (By similarity).
Gene Name:
MTOR
Uniprot ID:
P42345
Molecular Weight:
288889.05 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50400 uMNot AvailableBindingDB 10849
References
  1. Charrier JD, Durrant SJ, Golec JM, Kay DP, Knegtel RM, MacCormick S, Mortimore M, O'Donnell ME, Pinder JL, Reaper PM, Rutherford AP, Wang PS, Young SC, Pollard JR: Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents. J Med Chem. 2011 Apr 14;54(7):2320-30. doi: 10.1021/jm101488z. Epub 2011 Mar 17. [21413798 ]