Pathways

Metabolites of Tolcapone are predicted with biotransformer.

Tolfenamic acid is a nonsteroidal anti-inflammatory agent (NSAID) used to treat pain associated with the acute attack of migraine in adults. This drug binds as an antagonist to both prostaglandin G/H synthase 1 and prostaglandin G/H synthase 2 in the cyclooxygenase pathway. The cyclooxygenase pathway begins in the cytosol with phospholipids being converted into arachidonic acid by the action of phospholipase A2. The rest of the pathway occurs on the endoplasmic reticulum membrane, where prostaglandin G/H synthase 1 & 2 convert arachidonic acid into prostaglandin H2. Prostaglandin H2 can either be converted into thromboxane A2 via thromboxane A synthase, prostacyclin/prostaglandin I2 via prostacyclin synthase, or prostaglandin E2 via prostaglandin E synthase. COX-2 is an inducible enzyme, and during inflammation, it is responsible for prostaglandin synthesis. It leads to the formation of prostaglandin E2 which is responsible for contributing to the inflammatory response by activating immune cells and for increasing pain sensation by acting on pain fibers. The inhibition of both COX-1 and COX-2 by tolfenamic acid reduces the formation of prostaglandin H2 and therefore, prostaglandin E2 (PGE2). The low concentration of prostaglandin E2 attenuates the effect it has on stimulating immune cells and pain fibers, consequently reducing inflammation and pain. This drug is administered as an oral tablet.

Metabolites of Tolfenamic acid are predicted with biotransformer.

Toll-like receptors (TLRs) are part of the innate immune system. These receptors recognize pathogen-associated molecular patterns from different microbes. TLR2 recognizes a variety of PAMPs including lipoproteins, peptidoglycans, lipotechoic acids, and mannan. TLR3 recognizes viral double-stranded RNA, small interfering RNAsa, and self-RNAs. TLR4 recognizes lipopolysaccharides. TLR7 recognizes single-stranded RNA. TLR9 recognizes bacterial and viral DNA with unmethylated CpG-DNA motifs. TLRs are synthesized in the endoplasmic reticulum, moved to the Golgi, and then recruited to the cell surface or intracellular compartments. TLRs recruit adaptor molecules such as MYD88, TRIF, TIRAP, or TRAM leading to the activation of transcription factors NF-kappa-B causing innate immune responses. MYD88 is recruited by all TLRs. Adaptor TIRAP recruits MYD88 to cell surface TLRs, including TLR2 and TLR4. TLR signaling molecule IRAK1 activation activates TRAF6 causing the activation of IKK complex then NF-kappa-B and kinases. Activated TRAF6 promotes polyubiquination of TRAF6 and TAK1, TAB1, TAB2 complex. TAK1 activates pathways causing activation of IKK complex and NF-kappa-B and MAPK pathways. The IKK complex phosphorylates and activates IKK-beta. IKK complex also phosphorylates I-kappa-B-alpha allowing dissociation and translocation of NF-kappa-B to the nucleus resulting in proinflammatory gene expression. Activated TAK1 complex also activates p38 and JNK, regulating the activation of AP-1 transcription factors to regulate inflammatory responses. Many transmembrane molecules, such as glycophosphatidylinositol-anchored protein CD14, also regulate TLR signaling pathways.

Toll-like receptors (TLRs) are part of the innate immune system. These receptors recognize pathogen-associated molecular patterns from different microbes. TLR2 recognizes a variety of PAMPs including lipoproteins, peptidoglycans, lipotechoic acids, and mannan. TLR3 recognizes viral double-stranded RNA, small interfering RNAsa, and self-RNAs. TLR4 recognizes lipopolysaccharides. TLR7 recognizes single-stranded RNA. TLR9 recognizes bacterial and viral DNA with unmethylated CpG-DNA motifs. TLRs are synthesized in the endoplasmic reticulum, moved to the Golgi, and then recruited to the cell surface or intracellular compartments. TLRs recruit adaptor molecules such as MYD88, TRIF, TIRAP, or TRAM leading to the activation of transcription factors NF-kappa-B causing innate immune responses. MYD88 is recruited by all TLRs. Adaptor TIRAP recruits MYD88 to cell surface TLRs, including TLR2 and TLR4. TLR signaling molecule IRAK1 activation activates TRAF6 causing the activation of IKK complex then NF-kappa-B and kinases. Activated TRAF6 promotes polyubiquination of TRAF6 and TAK1, TAB1, TAB2 complex. TAK1 activates pathways causing activation of IKK complex and NF-kappa-B and MAPK pathways. The IKK complex phosphorylates and activates IKK-beta. IKK complex also phosphorylates I-kappa-B-alpha allowing dissociation and translocation of NF-kappa-B to the nucleus resulting in proinflammatory gene expression. Activated TAK1 complex also activates p38 and JNK, regulating the activation of AP-1 transcription factors to regulate inflammatory responses. Many transmembrane molecules, such as glycophosphatidylinositol-anchored protein CD14, also regulate TLR signaling pathways.

Toll-like receptors (TLRs) are part of the innate immune system. These receptors recognize pathogen-associated molecular patterns from different microbes. TLR2 recognizes a variety of PAMPs including lipoproteins, peptidoglycans, lipotechoic acids, and mannan. TLR3 recognizes viral double-stranded RNA, small interfering RNAsa, and self-RNAs. TLR4 recognizes lipopolysaccharides. TLR7 recognizes single-stranded RNA. TLR9 recognizes bacterial and viral DNA with unmethylated CpG-DNA motifs. TLRs are synthesized in the endoplasmic reticulum, moved to the Golgi, and then recruited to the cell surface or intracellular compartments. TLRs recruit adaptor molecules such as MYD88, TRIF, TIRAP, or TRAM leading to the activation of transcription factors NF-kappa-B causing innate immune responses. MYD88 is recruited by all TLRs. Adaptor TIRAP recruits MYD88 to cell surface TLRs, including TLR2 and TLR4. TLR signaling molecule IRAK1 activation activates TRAF6 causing the activation of IKK complex then NF-kappa-B and kinases. Activated TRAF6 promotes polyubiquination of TRAF6 and TAK1, TAB1, TAB2 complex. TAK1 activates pathways causing activation of IKK complex and NF-kappa-B and MAPK pathways. The IKK complex phosphorylates and activates IKK-beta. IKK complex also phosphorylates I-kappa-B-alpha allowing dissociation and translocation of NF-kappa-B to the nucleus resulting in proinflammatory gene expression. Activated TAK1 complex also activates p38 and JNK, regulating the activation of AP-1 transcription factors to regulate inflammatory responses. Many transmembrane molecules, such as glycophosphatidylinositol-anchored protein CD14, also regulate TLR signaling pathways.

Toll-like receptors (TLRs) are part of the innate immune system. These receptors recognize pathogen-associated molecular patterns from different microbes. TLR2 recognizes a variety of PAMPs including lipoproteins, peptidoglycans, lipotechoic acids, and mannan. TLR3 recognizes viral double-stranded RNA, small interfering RNAsa, and self-RNAs. TLR4 recognizes lipopolysaccharides. TLR7 recognizes single-stranded RNA. TLR9 recognizes bacterial and viral DNA with unmethylated CpG-DNA motifs. TLRs are synthesized in the endoplasmic reticulum, moved to the Golgi, and then recruited to the cell surface or intracellular compartments. TLRs recruit adaptor molecules such as MYD88, TRIF, TIRAP, or TRAM leading to the activation of transcription factors NF-kappa-B causing innate immune responses. MYD88 is recruited by all TLRs. Adaptor TIRAP recruits MYD88 to cell surface TLRs, including TLR2 and TLR4. TLR signaling molecule IRAK1 activation activates TRAF6 causing the activation of IKK complex then NF-kappa-B and kinases. Activated TRAF6 promotes polyubiquination of TRAF6 and TAK1, TAB1, TAB2 complex. TAK1 activates pathways causing activation of IKK complex and NF-kappa-B and MAPK pathways. The IKK complex phosphorylates and activates IKK-beta. IKK complex also phosphorylates I-kappa-B-alpha allowing dissociation and translocation of NF-kappa-B to the nucleus resulting in proinflammatory gene expression. Activated TAK1 complex also activates p38 and JNK, regulating the activation of AP-1 transcription factors to regulate inflammatory responses. Many transmembrane molecules, such as glycophosphatidylinositol-anchored protein CD14, also regulate TLR signaling pathways.

Toll-like receptors (TLRs) are a type of pattern recognition receptor that spans the cell membrane and recognizes conserved microbial molecules. TLRs get their name from the toll gene in Drosophila, which produces a protein that is similar in structure to TLR proteins. Each TLR is able to recognize specific unique molecules associated with pathogens, including lipoproteins, lipopolysaccharides, double stranded RNA, flagellin and others. Recognition of pathogen molecules allows the immune system to detect extracellular pathogens. TLR2 can form heterodimers on the surface of the cell's plasma membrane with either TLR1 or TLR6. These dimers, along with another protein known as CD14 as a cofactor, can detect different microbial lipoproteins. Following binding of lipoproteins to these complexes, they activate a protein known as myeloid differentiation primary response protein (MyD88). MyD88 then joins with interleukin-1 receptor-associated kinase 1 (IRAK1) to form a complex. TLR4 is another TLR that detects lipopolysaccharides (LPS) that make up the outer membrane of Gram-negative bacteria. It associates with two other proteins, monocyte differentiation antigen CD14, and lymphocyte antigen 96 (MD2), which allow it to better bind LPS. Once LPS has bound to the complex, it activates signalling to the toll/interleukin-1 receptor domain-containing adaptor protein (TIRAP) and Toll-interacting protein (TOLLIP), which then recruit MyD99 and IRAK1 to the TLR on the cell surface. Other TLRs have slightly more simple pathways, including TLR9, which recognizes CpG-DNA, which is a section of DNA with a cytosine followed by a guanine and are found commonly in pathogen genomes. TLRs 3 and 8 both recognize double stranded RNA, which is found in some viruses. TLR7 recognizes single stranded RNA from internalized viral genomes, and can also be activated by the drug Imiquimod, sold as Aldara. Imiquimod is used to treat genital warts , actinic keratosis and basal cell carcinoma by activating the immune system in the area it was applied. Finally, TLR5 recognizes the bacterial flagellin proteins. When any of these substances bind their respective TLRs, the TLRs signal to the MyD88 and IRAK1 complex. After any of these activation mechanisms occurs, the IRAK protein, which is a kinase, phosphorylates and activates TNF receptor-associated factor 6 (TRAF6). TRAF6 then interacts with the evolutionarily conserved signaling intermediate in Toll pathway (ECSIT). ECSIT then activates mitogen-activated protein kinase kinase kinase 1 (MAP3K1). This then phosphorylates the IKK complex, comprised of inhibitors of nuclear factor kappa-B kinase subunits alpha and beta (IKKA and IKKB), as well as its regulatory subunit, NF-kappa-B essential modulator (NEMO). Another pathway starting with the activation of TRAF6 leads to this same point. First, TRAF6 activates a complex consisting of mitogen-activated protein kinase kinase kinase 7 (MAP3K7), as well as TGF-beta-activated kinase 1 (TAK1) and MAP3K7-binding proteins 1, 2 and 3. This complex can then activate dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4), which then phosphorylates mitogen-activated protein kinase 8 (MAPK8) in the cell nucleus. Alternately, the TAK1 and MAP3K7-binding complex can phosphorylate and activate mitogen-activated protein kinase 14 (MAPK14), which then phosphorylates the IKK complex. NF-kappa-B is a transcription factor that is inhibited by NF-kappa-B inhibitor alpha, which binds to it and blocks its nuclear localization sequence, holding it in the cytoplasm rather than allowing it to enter the nucleus and transcribe the DNA. However, the IKK complex is able to phosphorylate the inhibitor, removing it and allowing nuclear factor NF-kappa-B p105 subunit and transcription factor p65 to enter the nucleus to transcribe DNA and allow the appropriate immune response for the stimulus to be activated.

Toll-like receptors (TLRs) are a type of pattern recognition receptor that spans the cell membrane and recognizes conserved microbial molecules. TLRs get their name from the toll gene in Drosophila, which produces a protein that is similar in structure to TLR proteins. Each TLR is able to recognize specific unique molecules associated with pathogens, including lipoproteins, lipopolysaccharides, double stranded RNA, flagellin and others. Recognition of pathogen molecules allows the immune system to detect extracellular pathogens. TLR2 can form heterodimers on the surface of the cell's plasma membrane with either TLR1 or TLR6. These dimers, along with another protein known as CD14 as a cofactor, can detect different microbial lipoproteins. Following binding of lipoproteins to these complexes, they activate a protein known as myeloid differentiation primary response protein (MyD88). MyD88 then joins with interleukin-1 receptor-associated kinase 1 (IRAK1) to form a complex. TLR4 is another TLR that detects lipopolysaccharides (LPS) that make up the outer membrane of Gram-negative bacteria. It associates with two other proteins, monocyte differentiation antigen CD14, and lymphocyte antigen 96 (MD2), which allow it to better bind LPS. Once LPS has bound to the complex, it activates signalling to the toll/interleukin-1 receptor domain-containing adaptor protein (TIRAP) and Toll-interacting protein (TOLLIP), which then recruit MyD99 and IRAK1 to the TLR on the cell surface. Other TLRs have slightly more simple pathways, including TLR9, which recognizes CpG-DNA, which is a section of DNA with a cytosine followed by a guanine and are found commonly in pathogen genomes. TLRs 3 and 8 both recognize double stranded RNA, which is found in some viruses. TLR7 recognizes single stranded RNA from internalized viral genomes, and can also be activated by the drug Imiquimod, sold as Aldara. Imiquimod is used to treat genital warts , actinic keratosis and basal cell carcinoma by activating the immune system in the area it was applied. Finally, TLR5 recognizes the bacterial flagellin proteins. When any of these substances bind their respective TLRs, the TLRs signal to the MyD88 and IRAK1 complex. After any of these activation mechanisms occurs, the IRAK protein, which is a kinase, phosphorylates and activates TNF receptor-associated factor 6 (TRAF6). TRAF6 then interacts with the evolutionarily conserved signaling intermediate in Toll pathway (ECSIT). ECSIT then activates mitogen-activated protein kinase kinase kinase 1 (MAP3K1). This then phosphorylates the IKK complex, comprised of inhibitors of nuclear factor kappa-B kinase subunits alpha and beta (IKKA and IKKB), as well as its regulatory subunit, NF-kappa-B essential modulator (NEMO). Another pathway starting with the activation of TRAF6 leads to this same point. First, TRAF6 activates a complex consisting of mitogen-activated protein kinase kinase kinase 7 (MAP3K7), as well as TGF-beta-activated kinase 1 (TAK1) and MAP3K7-binding proteins 1, 2 and 3. This complex can then activate dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4), which then phosphorylates mitogen-activated protein kinase 8 (MAPK8) in the cell nucleus. Alternately, the TAK1 and MAP3K7-binding complex can phosphorylate and activate mitogen-activated protein kinase 14 (MAPK14), which then phosphorylates the IKK complex. NF-kappa-B is a transcription factor that is inhibited by NF-kappa-B inhibitor alpha, which binds to it and blocks its nuclear localization sequence, holding it in the cytoplasm rather than allowing it to enter the nucleus and transcribe the DNA. However, the IKK complex is able to phosphorylate the inhibitor, removing it and allowing nuclear factor NF-kappa-B p105 subunit and transcription factor p65 to enter the nucleus to transcribe DNA and allow the appropriate immune response for the stimulus to be activated.