Indomethacin (T3D2753)

General Function:

Zinc ion binding

Specific Function:

Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses. Plays a role in the regulation of cardiovascular circadian rhythms by regulating the transcription of ARNTL/BMAL1 in the blood vessels (By similarity).

Gene Name:

PPARG

Uniprot ID:

P37231

Molecular Weight:

57619.58 Da

References

1. Cho MC, Lee HS, Kim JH, Choe YK, Hong JT, Paik SG, Yoon DY: A simple ELISA for screening ligands of peroxisome proliferator-activated receptor-gamma. J Biochem Mol Biol. 2003 Mar 31;36(2):207-13. [12689521 ]
2. Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, Kliewer SA: Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem. 1997 Feb 7;272(6):3406-10. [9013583 ]
3. 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 ]

General Function:

Prostaglandin-endoperoxide synthase activity

Specific Function:

Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and brain, and in pathological conditions, such as in cancer. PTGS2 is responsible for production of inflammatory prostaglandins. Up-regulation of PTGS2 is also associated with increased cell adhesion, phenotypic changes, resistance to apoptosis and tumor angiogenesis. In cancer cells, PTGS2 is a key step in the production of prostaglandin E2 (PGE2), which plays important roles in modulating motility, proliferation and resistance to apoptosis.

Gene Name:

PTGS2

Uniprot ID:

P35354

Molecular Weight:

68995.625 Da

References

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General Function:

Prostaglandin-endoperoxide synthase activity

Specific Function:

Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gastric epithelial cells, it is a key step in the generation of prostaglandins, such as prostaglandin E2 (PGE2), which plays an important role in cytoprotection. In platelets, it is involved in the generation of thromboxane A2 (TXA2), which promotes platelet activation and aggregation, vasoconstriction and proliferation of vascular smooth muscle cells.

Gene Name:

PTGS1

Uniprot ID:

P23219

Molecular Weight:

68685.82 Da

References

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5. Kundu N, Walser TC, Ma X, Fulton AM: Cyclooxygenase inhibitors modulate NK activities that control metastatic disease. Cancer Immunol Immunother. 2005 Oct;54(10):981-7. Epub 2005 May 13. [15891886 ]
6. Larsson J, Gottfries J, Bohlin L, Backlund A: Expanding the ChemGPS chemical space with natural products. J Nat Prod. 2005 Jul;68(7):985-91. [16038536 ]
7. Prasit P, Wang Z, Brideau C, Chan CC, Charleson S, Cromlish W, Ethier D, Evans JF, Ford-Hutchinson AW, Gauthier JY, Gordon R, Guay J, Gresser M, Kargman S, Kennedy B, Leblanc Y, Leger S, Mancini J, O'Neill GP, Ouellet M, Percival MD, Perrier H, Riendeau D, Rodger I, Zamboni R, et al.: The discovery of rofecoxib, [MK 966, Vioxx, 4-(4'-methylsulfonylphenyl)-3-phenyl-2(5H)-furanone], an orally active cyclooxygenase-2-inhibitor. Bioorg Med Chem Lett. 1999 Jul 5;9(13):1773-8. [10406640 ]
8. Liedtke AJ, Adeniji AO, Chen M, Byrns MC, Jin Y, Christianson DW, Marnett LJ, Penning TM: Development of potent and selective indomethacin analogues for the inhibition of AKR1C3 (Type 5 17beta-hydroxysteroid dehydrogenase/prostaglandin F synthase) in castrate-resistant prostate cancer. J Med Chem. 2013 Mar 28;56(6):2429-46. doi: 10.1021/jm3017656. Epub 2013 Mar 13. [23432095 ]
9. Chen XY, Park SJ, Buschmann H, De Rosa M, Bolm C: Syntheses and biological activities of sulfoximine-based acyclic triaryl olefins. Bioorg Med Chem Lett. 2012 Jul 1;22(13):4307-9. doi: 10.1016/j.bmcl.2012.05.018. Epub 2012 May 11. [22652053 ]
10. Khan KM, Ambreen N, Mughal UR, Jalil S, Perveen S, Choudhary MI: 3-Formylchromones: potential antiinflammatory agents. Eur J Med Chem. 2010 Sep;45(9):4058-64. doi: 10.1016/j.ejmech.2010.05.065. Epub 2010 Jun 8. [20576329 ]
11. Liedtke AJ, Crews BC, Daniel CM, Blobaum AL, Kingsley PJ, Ghebreselasie K, Marnett LJ: Cyclooxygenase-1-selective inhibitors based on the (E)-2'-des-methyl-sulindac sulfide scaffold. J Med Chem. 2012 Mar 8;55(5):2287-300. doi: 10.1021/jm201528b. Epub 2012 Feb 14. [22263894 ]
12. Kakuta H, Zheng X, Oda H, Harada S, Sugimoto Y, Sasaki K, Tai A: Cyclooxygenase-1-selective inhibitors are attractive candidates for analgesics that do not cause gastric damage. design and in vitro/in vivo evaluation of a benzamide-type cyclooxygenase-1 selective inhibitor. J Med Chem. 2008 Apr 24;51(8):2400-11. doi: 10.1021/jm701191z. Epub 2008 Mar 26. [18363350 ]
13. Hashimoto H, Imamura K, Haruta J, Wakitani K: 4-(4-cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamides as selective cyclooxygenase-2 inhibitors: enhancement of the selectivity by introduction of a fluorine atom and identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522(1). J Med Chem. 2002 Mar 28;45(7):1511-7. [11906292 ]
14. Bridoux A, Millet R, Pommery J, Pommery N, Henichart JP: Synthesis and biological activity of N-aroyl-tetrahydro-gamma-carbolines. Bioorg Med Chem. 2010 Jun 1;18(11):3910-24. doi: 10.1016/j.bmc.2010.04.034. Epub 2010 Apr 18. [20451397 ]
15. Puig C, Crespo MI, Godessart N, Feixas J, Ibarzo J, Jimenez JM, Soca L, Cardelus I, Heredia A, Miralpeix M, Puig J, Beleta J, Huerta JM, Lopez M, Segarra V, Ryder H, Palacios JM: Synthesis and biological evaluation of 3,4-diaryloxazolones: A new class of orally active cyclooxygenase-2 inhibitors. J Med Chem. 2000 Jan 27;43(2):214-23. [10649977 ]
16. Bekhit AA, Ashour HM, Bekhit Ael-D, Abdel-Rahman HM, Bekhit SA: Synthesis of some pyrazolyl benzenesulfonamide derivatives as dual anti-inflammatory antimicrobial agents. J Enzyme Inhib Med Chem. 2009 Feb;24(1):296-309. doi: 10.1080/14756360802188404 . [18951238 ]
17. Wey SJ, Augustyniak ME, Cochran ED, Ellis JL, Fang X, Garvey DS, Janero DR, Letts LG, Martino AM, Melim TL, Murty MG, Richardson SK, Schroeder JD, Selig WM, Trocha AM, Wexler RS, Young DV, Zemtseva IS, Zifcak BM: Structure-based design, synthesis, and biological evaluation of indomethacin derivatives as cyclooxygenase-2 inhibiting nitric oxide donors. J Med Chem. 2007 Dec 13;50(25):6367-82. Epub 2007 Nov 10. [17994684 ]
18. Riendeau D, Percival MD, Boyce S, Brideau C, Charleson S, Cromlish W, Ethier D, Evans J, Falgueyret JP, Ford-Hutchinson AW, Gordon R, Greig G, Gresser M, Guay J, Kargman S, Leger S, Mancini JA, O'Neill G, Ouellet M, Rodger IW, Therien M, Wang Z, Webb JK, Wong E, Chan CC, et al.: Biochemical and pharmacological profile of a tetrasubstituted furanone as a highly selective COX-2 inhibitor. Br J Pharmacol. 1997 May;121(1):105-17. [9146894 ]

General Function:

Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase activity

Specific Function:

Catalyzes the conversion of aldehydes and ketones to alcohols. Catalyzes the reduction of prostaglandin (PG) D2, PGH2 and phenanthrenequinone (PQ) and the oxidation of 9-alpha,11-beta-PGF2 to PGD2. Functions as a bi-directional 3-alpha-, 17-beta- and 20-alpha HSD. Can interconvert active androgens, estrogens and progestins with their cognate inactive metabolites. Preferentially transforms androstenedione (4-dione) to testosterone.

Gene Name:

AKR1C3

Uniprot ID:

P42330

Molecular Weight:

36852.89 Da

References

1. Liedtke AJ, Adeniji AO, Chen M, Byrns MC, Jin Y, Christianson DW, Marnett LJ, Penning TM: Development of potent and selective indomethacin analogues for the inhibition of AKR1C3 (Type 5 17beta-hydroxysteroid dehydrogenase/prostaglandin F synthase) in castrate-resistant prostate cancer. J Med Chem. 2013 Mar 28;56(6):2429-46. doi: 10.1021/jm3017656. Epub 2013 Mar 13. [23432095 ]
2. Jamieson SM, Brooke DG, Heinrich D, Atwell GJ, Silva S, Hamilton EJ, Turnbull AP, Rigoreau LJ, Trivier E, Soudy C, Samlal SS, Owen PJ, Schroeder E, Raynham T, Flanagan JU, Denny WA: 3-(3,4-Dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic Acids: highly potent and selective inhibitors of the type 5 17-beta-hydroxysteroid dehydrogenase AKR1C3. J Med Chem. 2012 Sep 13;55(17):7746-58. doi: 10.1021/jm3007867. Epub 2012 Aug 21. [22877157 ]
3. Endo S, Matsunaga T, Kanamori A, Otsuji Y, Nagai H, Sundaram K, El-Kabbani O, Toyooka N, Ohta S, Hara A: Selective inhibition of human type-5 17beta-hydroxysteroid dehydrogenase (AKR1C3) by baccharin, a component of Brazilian propolis. J Nat Prod. 2012 Apr 27;75(4):716-21. doi: 10.1021/np201002x. Epub 2012 Apr 16. [22506594 ]
4. Lovering AL, Ride JP, Bunce CM, Desmond JC, Cummings SM, White SA: Crystal structures of prostaglandin D(2) 11-ketoreductase (AKR1C3) in complex with the nonsteroidal anti-inflammatory drugs flufenamic acid and indomethacin. Cancer Res. 2004 Mar 1;64(5):1802-10. [14996743 ]

General Function:

Prostaglandin j receptor activity

Specific Function:

Receptor for prostaglandin D2 (PGD2). Coupled to the G(i)-protein. Receptor activation may result in pertussis toxin-sensitive decreases in cAMP levels and Ca(2+) mobilization. PI3K signaling is also implicated in mediating PTGDR2 effects. PGD2 induced receptor internalization. CRTH2 internalization can be regulated by diverse kinases such as, PKC, PKA, ADRBK1/GRK2, GPRK5/GRK5 and GRK6. Receptor activation is responsible, at least in part, in immune regulation and allergic/inflammation responses.

Gene Name:

PTGDR2

Uniprot ID:

Q9Y5Y4

Molecular Weight:

43267.15 Da

References

1. Hata AN, Lybrand TP, Breyer RM: Identification of determinants of ligand binding affinity and selectivity in the prostaglandin D2 receptor CRTH2. J Biol Chem. 2005 Sep 16;280(37):32442-51. Epub 2005 Jul 19. [16030019 ]
2. Hata AN, Lybrand TP, Marnett LJ, Breyer RM: Structural determinants of arylacetic acid nonsteroidal anti-inflammatory drugs necessary for binding and activation of the prostaglandin D2 receptor CRTH2. Mol Pharmacol. 2005 Mar;67(3):640-7. Epub 2004 Nov 24. [15563582 ]
3. Mathiesen JM, Ulven T, Martini L, Gerlach LO, Heinemann A, Kostenis E: Identification of indole derivatives exclusively interfering with a G protein-independent signaling pathway of the prostaglandin D2 receptor CRTH2. Mol Pharmacol. 2005 Aug;68(2):393-402. Epub 2005 May 3. [15870392 ]
4. Sugimoto H, Shichijo M, Okano M, Bacon KB: CRTH2-specific binding characteristics of [3H]ramatroban and its effects on PGD2-, 15-deoxy-Delta12, 14-PGJ2- and indomethacin-induced agonist responses. Eur J Pharmacol. 2005 Nov 7;524(1-3):30-7. Epub 2005 Oct 27. [16256979 ]

General Function:

Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase activity

Specific Function:

Works in concert with the 5-alpha/5-beta-steroid reductases to convert steroid hormones into the 3-alpha/5-alpha and 3-alpha/5-beta-tetrahydrosteroids. Catalyzes the inactivation of the most potent androgen 5-alpha-dihydrotestosterone (5-alpha-DHT) to 5-alpha-androstane-3-alpha,17-beta-diol (3-alpha-diol). Has a high bile-binding ability.

Gene Name:

AKR1C2

Uniprot ID:

P52895

Molecular Weight:

36734.97 Da

References

1. Liedtke AJ, Adeniji AO, Chen M, Byrns MC, Jin Y, Christianson DW, Marnett LJ, Penning TM: Development of potent and selective indomethacin analogues for the inhibition of AKR1C3 (Type 5 17beta-hydroxysteroid dehydrogenase/prostaglandin F synthase) in castrate-resistant prostate cancer. J Med Chem. 2013 Mar 28;56(6):2429-46. doi: 10.1021/jm3017656. Epub 2013 Mar 13. [23432095 ]
2. Endo S, Matsunaga T, Kanamori A, Otsuji Y, Nagai H, Sundaram K, El-Kabbani O, Toyooka N, Ohta S, Hara A: Selective inhibition of human type-5 17beta-hydroxysteroid dehydrogenase (AKR1C3) by baccharin, a component of Brazilian propolis. J Nat Prod. 2012 Apr 27;75(4):716-21. doi: 10.1021/np201002x. Epub 2012 Apr 16. [22506594 ]
3. Jamieson SM, Brooke DG, Heinrich D, Atwell GJ, Silva S, Hamilton EJ, Turnbull AP, Rigoreau LJ, Trivier E, Soudy C, Samlal SS, Owen PJ, Schroeder E, Raynham T, Flanagan JU, Denny WA: 3-(3,4-Dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic Acids: highly potent and selective inhibitors of the type 5 17-beta-hydroxysteroid dehydrogenase AKR1C3. J Med Chem. 2012 Sep 13;55(17):7746-58. doi: 10.1021/jm3007867. Epub 2012 Aug 21. [22877157 ]

General Function:

Zinc ion binding

Specific Function:

Catalyzes the conversion of hemimercaptal, formed from methylglyoxal and glutathione, to S-lactoylglutathione. Involved in the regulation of TNF-induced transcriptional activity of NF-kappa-B. Required for normal osteoclastogenesis.

Gene Name:

GLO1

Uniprot ID:

Q04760

Molecular Weight:

20777.515 Da

References

1. Sato S, Kwon Y, Kamisuki S, Srivastava N, Mao Q, Kawazoe Y, Uesugi M: Polyproline-rod approach to isolating protein targets of bioactive small molecules: isolation of a new target of indomethacin. J Am Chem Soc. 2007 Jan 31;129(4):873-80. [17243824 ]
2. Yuan M, Luo M, Song Y, Xu Q, Wang X, Cao Y, Bu X, Ren Y, Hu X: Identification of curcumin derivatives as human glyoxalase I inhibitors: A combination of biological evaluation, molecular docking, 3D-QSAR and molecular dynamics simulation studies. Bioorg Med Chem. 2011 Feb 1;19(3):1189-96. doi: 10.1016/j.bmc.2010.12.039. Epub 2010 Dec 22. [21237663 ]
3. Liu M, Yuan M, Li Z, Cheng YK, Luo HB, Hu X: Structural investigation into the inhibitory mechanisms of indomethacin and its analogues towards human glyoxalase I. Bioorg Med Chem Lett. 2011 Jul 15;21(14):4243-7. doi: 10.1016/j.bmcl.2011.05.095. Epub 2011 Jun 1. [21689932 ]

General Function:

Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase activity

Specific Function:

Converts progesterone to its inactive form, 20-alpha-dihydroxyprogesterone (20-alpha-OHP). In the liver and intestine, may have a role in the transport of bile. May have a role in monitoring the intrahepatic bile acid concentration. Has a low bile-binding ability. May play a role in myelin formation.

Gene Name:

AKR1C1

Uniprot ID:

Q04828

Molecular Weight:

36788.02 Da

References

1. Endo S, Matsunaga T, Kanamori A, Otsuji Y, Nagai H, Sundaram K, El-Kabbani O, Toyooka N, Ohta S, Hara A: Selective inhibition of human type-5 17beta-hydroxysteroid dehydrogenase (AKR1C3) by baccharin, a component of Brazilian propolis. J Nat Prod. 2012 Apr 27;75(4):716-21. doi: 10.1021/np201002x. Epub 2012 Apr 16. [22506594 ]
2. Jamieson SM, Brooke DG, Heinrich D, Atwell GJ, Silva S, Hamilton EJ, Turnbull AP, Rigoreau LJ, Trivier E, Soudy C, Samlal SS, Owen PJ, Schroeder E, Raynham T, Flanagan JU, Denny WA: 3-(3,4-Dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic Acids: highly potent and selective inhibitors of the type 5 17-beta-hydroxysteroid dehydrogenase AKR1C3. J Med Chem. 2012 Sep 13;55(17):7746-58. doi: 10.1021/jm3007867. Epub 2012 Aug 21. [22877157 ]

General Function:

Retinal dehydrogenase activity

Specific Function:

Catalyzes the transformation of the potent androgen dihydrotestosterone (DHT) into the less active form, 5-alpha-androstan-3-alpha,17-beta-diol (3-alpha-diol). Also has some 20-alpha-hydroxysteroid dehydrogenase activity. The biotransformation of the pesticide chlordecone (kepone) to its corresponding alcohol leads to increased biliary excretion of the pesticide and concomitant reduction of its neurotoxicity since bile is the major excretory route.

Gene Name:

AKR1C4

Uniprot ID:

P17516

Molecular Weight:

37066.52 Da

References

1. Endo S, Matsunaga T, Kanamori A, Otsuji Y, Nagai H, Sundaram K, El-Kabbani O, Toyooka N, Ohta S, Hara A: Selective inhibition of human type-5 17beta-hydroxysteroid dehydrogenase (AKR1C3) by baccharin, a component of Brazilian propolis. J Nat Prod. 2012 Apr 27;75(4):716-21. doi: 10.1021/np201002x. Epub 2012 Apr 16. [22506594 ]
2. Jamieson SM, Brooke DG, Heinrich D, Atwell GJ, Silva S, Hamilton EJ, Turnbull AP, Rigoreau LJ, Trivier E, Soudy C, Samlal SS, Owen PJ, Schroeder E, Raynham T, Flanagan JU, Denny WA: 3-(3,4-Dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic Acids: highly potent and selective inhibitors of the type 5 17-beta-hydroxysteroid dehydrogenase AKR1C3. J Med Chem. 2012 Sep 13;55(17):7746-58. doi: 10.1021/jm3007867. Epub 2012 Aug 21. [22877157 ]

General Function:

Prostaglandin e receptor activity

Specific Function:

Receptor for prostaglandin E2 (PGE2). The activity of this receptor is mediated by G(s) proteins that stimulate adenylate cyclase. The subsequent raise in intracellular cAMP is responsible for the relaxing effect of this receptor on smooth muscle.

Gene Name:

PTGER2

Uniprot ID:

P43116

Molecular Weight:

39759.945 Da

References

1. Chan CC, Boyce S, Brideau C, Charleson S, Cromlish W, Ethier D, Evans J, Ford-Hutchinson AW, Forrest MJ, Gauthier JY, Gordon R, Gresser M, Guay J, Kargman S, Kennedy B, Leblanc Y, Leger S, Mancini J, O'Neill GP, Ouellet M, Patrick D, Percival MD, Perrier H, Prasit P, Rodger I, et al.: Rofecoxib [Vioxx, MK-0966; 4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone]: a potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and biochemical profiles. J Pharmacol Exp Ther. 1999 Aug;290(2):551-60. [10411562 ]
2. Riendeau D, Percival MD, Brideau C, Charleson S, Dube D, Ethier D, Falgueyret JP, Friesen RW, Gordon R, Greig G, Guay J, Mancini J, Ouellet M, Wong E, Xu L, Boyce S, Visco D, Girard Y, Prasit P, Zamboni R, Rodger IW, Gresser M, Ford-Hutchinson AW, Young RN, Chan CC: Etoricoxib (MK-0663): preclinical profile and comparison with other agents that selectively inhibit cyclooxygenase-2. J Pharmacol Exp Ther. 2001 Feb;296(2):558-66. [11160644 ]

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

1. Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P: Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions. J Med Chem. 2012 May 24;55(10):4740-63. doi: 10.1021/jm300212s. Epub 2012 May 15. [22541068 ]
2. Riendeau D, Percival MD, Brideau C, Charleson S, Dube D, Ethier D, Falgueyret JP, Friesen RW, Gordon R, Greig G, Guay J, Mancini J, Ouellet M, Wong E, Xu L, Boyce S, Visco D, Girard Y, Prasit P, Zamboni R, Rodger IW, Gresser M, Ford-Hutchinson AW, Young RN, Chan CC: Etoricoxib (MK-0663): preclinical profile and comparison with other agents that selectively inhibit cyclooxygenase-2. J Pharmacol Exp Ther. 2001 Feb;296(2):558-66. [11160644 ]

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

1. Cerelli MJ, Curtis DL, Dunn JP, Nelson PH, Peak TM, Waterbury LD: Antiinflammatory and aldose reductase inhibitory activity of some tricyclic arylacetic acids. J Med Chem. 1986 Nov;29(11):2347-51. [3097317 ]

General Function:

Iron ion binding

Specific Function:

Catalyzes the first step in leukotriene biosynthesis, and thereby plays a role in inflammatory processes.

Gene Name:

ALOX5

Uniprot ID:

P09917

Molecular Weight:

77982.595 Da

References

1. Kolasa T, Brooks CD, Rodriques KE, Summers JB, Dellaria JF, Hulkower KI, Bouska J, Bell RL, Carter GW: Nonsteroidal anti-inflammatory drugs as scaffolds for the design of 5-lipoxygenase inhibitors. J Med Chem. 1997 Feb 28;40(5):819-24. [9057869 ]

General Function:

Toxic substance binding

Specific Function:

Bifunctional enzyme. The C-terminal domain has epoxide hydrolase activity and acts on epoxides (alkene oxides, oxiranes) and arene oxides. Plays a role in xenobiotic metabolism by degrading potentially toxic epoxides. Also determines steady-state levels of physiological mediators. The N-terminal domain has lipid phosphatase activity, with the highest activity towards threo-9,10-phosphonooxy-hydroxy-octadecanoic acid, followed by erythro-9,10-phosphonooxy-hydroxy-octadecanoic acid, 12-phosphonooxy-octadec-9Z-enoic acid, 12-phosphonooxy-octadec-9E-enoic acid, and p-nitrophenyl phospate.

Gene Name:

EPHX2

Uniprot ID:

P34913

Molecular Weight:

62615.22 Da

References

1. Hwang SH, Wagner KM, Morisseau C, Liu JY, Dong H, Wecksler AT, Hammock BD: Synthesis and structure-activity relationship studies of urea-containing pyrazoles as dual inhibitors of cyclooxygenase-2 and soluble epoxide hydrolase. J Med Chem. 2011 Apr 28;54(8):3037-50. doi: 10.1021/jm2001376. Epub 2011 Apr 5. [21434686 ]

General Function:

Organic anion transmembrane transporter activity

Specific Function:

Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter.

Gene Name:

ABCC2

Uniprot ID:

Q92887

Molecular Weight:

174205.64 Da

References

1. Leyers S, Hacker HG, Wiendlocha J, Gutschow M, Wiese M: A 4-aminobenzoic acid derivative as novel lead for selective inhibitors of multidrug resistance-associated proteins. Bioorg Med Chem Lett. 2008 Sep 1;18(17):4761-3. doi: 10.1016/j.bmcl.2008.07.127. Epub 2008 Aug 3. [18707884 ]

General Function:

Testosterone dehydrogenase (nad+) activity

Specific Function:

3-alpha-hydroxysteroid dehydrogenase that converts 3-alpha-tetrahydroprogesterone (allopregnanolone) to dihydroxyprogesterone and 3-alpha-androstanediol to dihydroxyprogesterone. May play a role in the biosynthesis of retinoic acid from retinaldehyde, but seems to have low activity with retinoids. Can utilize both NADH and NADPH.

Gene Name:

DHRS9

Uniprot ID:

Q9BPW9

Molecular Weight:

35226.78 Da

References

1. Gebhardt P, Dornberger K, Gollmick FA, Grafe U, Hartl A, Gorls H, Schlegel B, Hertweck C: Quercinol, an anti-inflammatory chromene from the wood-rotting fungus Daedalea quercina (Oak Mazegill). Bioorg Med Chem Lett. 2007 May 1;17(9):2558-60. Epub 2007 Feb 7. [17346963 ]

General Function:

Interleukin-8 receptor binding

Specific Function:

IL-8 is a chemotactic factor that attracts neutrophils, basophils, and T-cells, but not monocytes. It is also involved in neutrophil activation. It is released from several cell types in response to an inflammatory stimulus. IL-8(6-77) has a 5-10-fold higher activity on neutrophil activation, IL-8(5-77) has increased activity on neutrophil activation and IL-8(7-77) has a higher affinity to receptors CXCR1 and CXCR2 as compared to IL-8(1-77), respectively.

Gene Name:

CXCL8

Uniprot ID:

P10145

Molecular Weight:

11097.98 Da

References

1. Sablone MR, Cesta MC, Moriconi A, Aramini A, Bizzarri C, Di Giacinto C, Di Bitondo R, Gloaguen I, Aschi M, Crucianelli M, Bertini R, Allegretti M: Structure-Activity Relationship of novel phenylacetic CXCR1 inhibitors. Bioorg Med Chem Lett. 2009 Aug 1;19(15):4026-30. doi: 10.1016/j.bmcl.2009.06.027. Epub 2009 Jun 13. [19560921 ]

General Function:

Monovalent cation:proton antiporter activity

Specific Function:

Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acyclovir, ganciclovir and also the zwitterionic cephalosporin, cephalexin and cephradin. Seems to also play a role in the uptake of oxaliplatin (a new platinum anticancer agent). Able to transport paraquat (PQ or N,N-dimethyl-4-4'-bipiridinium); a widely used herbicid. Responsible for the secretion of cationic drugs across the brush border membranes.

Gene Name:

SLC47A1

Uniprot ID:

Q96FL8

Molecular Weight:

61921.585 Da

References

1. Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, Morrissey KM, Sali A, Huang Y, Giacomini KM: Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling. J Med Chem. 2013 Feb 14;56(3):781-95. doi: 10.1021/jm301302s. Epub 2013 Jan 22. [23241029 ]

General Function:

Transporter activity

Specific Function:

Mediates export of organic anions and drugs from the cytoplasm. Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotrexate, antiviral drugs and other xenobiotics. Confers resistance to anticancer drugs. Hydrolyzes ATP with low efficiency.

Gene Name:

ABCC1

Uniprot ID:

P33527

Molecular Weight:

171589.5 Da

References

1. Leyers S, Hacker HG, Wiendlocha J, Gutschow M, Wiese M: A 4-aminobenzoic acid derivative as novel lead for selective inhibitors of multidrug resistance-associated proteins. Bioorg Med Chem Lett. 2008 Sep 1;18(17):4761-3. doi: 10.1016/j.bmcl.2008.07.127. Epub 2008 Aug 3. [18707884 ]

General Function:

Zinc ion binding

Specific Function:

Ligand-activated transcription factor. Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleylethanolamide, a naturally occurring lipid that regulates satiety. Receptor for peroxisome proliferators such as hypolipidemic drugs and fatty acids. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the ACOX1 and P450 genes. Transactivation activity requires heterodimerization with RXRA and is antagonized by NR2C2. May be required for the propagation of clock information to metabolic pathways regulated by PER2.

Gene Name:

PPARA

Uniprot ID:

Q07869

Molecular Weight:

52224.595 Da

References

1. Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, Kliewer SA: Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem. 1997 Feb 7;272(6):3406-10. [9013583 ]

General Function:

Prostaglandin-e synthase activity

Specific Function:

Catalyzes the oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2).

Gene Name:

PTGES

Uniprot ID:

O14684

Molecular Weight:

17102.135 Da

References

1. Elkady M, Niess R, Schaible AM, Bauer J, Luderer S, Ambrosi G, Werz O, Laufer SA: Modified acidic nonsteroidal anti-inflammatory drugs as dual inhibitors of mPGES-1 and 5-LOX. J Med Chem. 2012 Oct 25;55(20):8958-62. doi: 10.1021/jm3010543. Epub 2012 Oct 9. [22992107 ]

General Function:

15-oxoprostaglandin 13-oxidase activity

Specific Function:

Functions as 15-oxo-prostaglandin 13-reductase and acts on 15-keto-PGE1, 15-keto-PGE2, 15-keto-PGE1-alpha and 15-keto-PGE2-alpha with highest activity towards 15-keto-PGE2. Overexpression represses transcriptional activity of PPARG and inhibits adipocyte differentiation (By similarity).

Gene Name:

PTGR2

Uniprot ID:

Q8N8N7

Molecular Weight:

38498.74 Da

References

1. Wu YH, Ko TP, Guo RT, Hu SM, Chuang LM, Wang AH: Structural basis for catalytic and inhibitory mechanisms of human prostaglandin reductase PTGR2. Structure. 2008 Nov 12;16(11):1714-23. doi: 10.1016/j.str.2008.09.007. [19000823 ]

General Function:

Protein homodimerization activity

Specific Function:

Hydrolyzes the toxic metabolites of a variety of organophosphorus insecticides. Capable of hydrolyzing a broad spectrum of organophosphate substrates and lactones, and a number of aromatic carboxylic acid esters. Mediates an enzymatic protection of low density lipoproteins against oxidative modification and the consequent series of events leading to atheroma formation.

Gene Name:

PON1

Uniprot ID:

P27169

Molecular Weight:

39730.99 Da

References

1. Ekinci D, Beydemir S: Effect of some analgesics on paraoxonase-1 purified from human serum. J Enzyme Inhib Med Chem. 2009 Aug;24(4):1034-9. doi: 10.1080/14756360802608351. [19548782 ]

General Function:

Sodium-independent organic anion transmembrane transporter activity

Specific Function:

Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one molecule of endogenous dicarboxylic acid (glutarate, ketoglutarate, etc). Mediates the sodium-independent uptake of 2,3-dimercapto-1-propanesulfonic acid (DMPS) (By similarity). Mediates the sodium-independent uptake of p-aminohippurate (PAH), ochratoxin (OTA), acyclovir (ACV), 3'-azido-3-'deoxythymidine (AZT), cimetidine (CMD), 2,4-dichloro-phenoxyacetate (2,4-D), hippurate (HA), indoleacetate (IA), indoxyl sulfate (IS) and 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), cidofovir, adefovir, 9-(2-phosphonylmethoxyethyl) guanine (PMEG), 9-(2-phosphonylmethoxyethyl) diaminopurine (PMEDAP) and edaravone sulfate. PAH uptake is inhibited by p-chloromercuribenzenesulphonate (PCMBS), diethyl pyrocarbonate (DEPC), sulindac, diclofenac, carprofen, glutarate and okadaic acid (By similarity). PAH uptake is inhibited by benzothiazolylcysteine (BTC), S-chlorotrifluoroethylcysteine (CTFC), cysteine S-conjugates S-dichlorovinylcysteine (DCVC), furosemide, steviol, phorbol 12-myristate 13-acetate (PMA), calcium ionophore A23187, benzylpenicillin, furosemide, indomethacin, bumetamide, losartan, probenecid, phenol red, urate, and alpha-ketoglutarate.

Gene Name:

SLC22A6

Uniprot ID:

Q4U2R8

Molecular Weight:

61815.78 Da

References

1. Mulato AS, Ho ES, Cihlar T: Nonsteroidal anti-inflammatory drugs efficiently reduce the transport and cytotoxicity of adefovir mediated by the human renal organic anion transporter 1. J Pharmacol Exp Ther. 2000 Oct;295(1):10-5. [10991954 ]

General Function:

Sodium-independent organic anion transmembrane transporter activity

Specific Function:

Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenadine. Transports benzylpenicillin (PCG), estrone-3-sulfate (E1S), cimetidine (CMD), 2,4-dichloro-phenoxyacetate (2,4-D), p-amino-hippurate (PAH), acyclovir (ACV) and ochratoxin (OTA).

Gene Name:

SLC22A8

Uniprot ID:

Q8TCC7

Molecular Weight:

59855.585 Da

References

1. Takeda M, Khamdang S, Narikawa S, Kimura H, Hosoyamada M, Cha SH, Sekine T, Endou H: Characterization of methotrexate transport and its drug interactions with human organic anion transporters. J Pharmacol Exp Ther. 2002 Aug;302(2):666-71. [12130730 ]

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

1. Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P: Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions. J Med Chem. 2012 May 24;55(10):4740-63. doi: 10.1021/jm300212s. Epub 2012 May 15. [22541068 ]

General Function:

Sodium-independent organic anion transmembrane transporter activity

Specific Function:

Mediates the Na(+)-independent transport of organic anions such as taurocholate, the prostaglandins PGD2, PGE1, PGE2, leukotriene C4, thromboxane B2 and iloprost.

Gene Name:

SLCO2B1

Uniprot ID:

O94956

Molecular Weight:

76709.98 Da

References

1. Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P: Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions. J Med Chem. 2012 May 24;55(10):4740-63. doi: 10.1021/jm300212s. Epub 2012 May 15. [22541068 ]

General Function:

Monoamine transmembrane transporter activity

Specific Function:

Amine transporter. Terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals.

Gene Name:

SLC6A3

Uniprot ID:

Q01959

Molecular Weight:

68494.255 Da

References

1. 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 ]

General Function:

Phospholipid binding

Specific Function:

Thought to participate in the regulation of the phospholipid metabolism in biomembranes including eicosanoid biosynthesis. Catalyzes the calcium-dependent hydrolysis of the 2-acyl groups in 3-sn-phosphoglycerides.

Gene Name:

PLA2G2A

Uniprot ID:

P14555

Molecular Weight:

16082.525 Da