Browsing Pathways

Tamoxifen is a selective estrogen modulator (SERM) used in the treatment of estrogen-sensitive breast cancer. Tamoxifen itself only has weak anti-estrogen effects and must be converted into more active metabolites to have therapeutic activity. Metabolism takes place in the liver and is carried out primarily by cytochrome P450 enzymes. Tamoxifen is hydroxylated by CYP2D6 and demethylated by CYP3A4 and CYP3A5, producing the active metabolites 4-hydroxytamoxifen and endoxifen. These metabolites inhibit estrogen binding to estrogen receptors in breast cancer cells, which in turn inhibit tumour growth.

Erlotinib is an anti-EGFR drug used in the treatment of some cancers. EGFR is linked multiple signalling pathways involved in tumour growth and angiogenesis such as the Ras/Raf pathway and the PI3K/Akt pathways. These pathways ultimately lead to the activation of transcription factors such as Jun, Fos, and Myc, as well as cyclin D1, which stimulates cell growth and mitosis. Uncontrolled cell growth and mitosis leads to cancer. Erlotinib acts as an anticancer drug by binding to the intracellular tyrosine kinase domain of the EGFR and blocking its activity. This in turn inhibits downstream signalling and prevents tumour growth.

Gefitinib is an anti-EGFR drug used in the treatment of some cancers. EGFR is linked multiple signalling pathways involved in tumour growth and angiogenesis such as the Ras/Raf pathway and the PI3K/Akt pathways. These pathways ultimately lead to the activation of transcription factors such as Jun, Fos, and Myc, as well as cyclin D1, which stimulates cell growth and mitosis. Uncontrolled cell growth and mitosis leads to cancer. Gefitinib acts as an anticancer drug by binding to the intracellular tyrosine kinase domain of the EGFR and blocking its activity. This in turn inhibits downstream signalling and prevents tumour growth.

Cetuximab is an anti-EGFR drug used in the treatment of some cancers. EGFR is linked multiple signalling pathways involved in tumour growth and angiogenesis such as the Ras/Raf pathway and the PI3K/Akt pathways. These pathways ultimately lead to the activation of transcription factors such as Jun, Fos, and Myc, as well as cyclin D1, which stimulates cell growth and mitosis. Uncontrolled cell growth and mitosis leads to cancer. Cetuximab acts as an anticancer drug by binding to the extracellular domain of the EGFR and preventing its activation by epidermal growth factor. This in turn inhibits downstream signalling and prevents tumour growth.

Panitumumab is an anti-EGFR drug used in the treatment of some cancers. EGFR is linked multiple signalling pathways involved in tumour growth and angiogenesis such as the Ras/Raf pathway and the PI3K/Akt pathways. These pathways ultimately lead to the activation of transcription factors such as Jun, Fos, and Myc, as well as cyclin D1, which stimulates cell growth and mitosis. Uncontrolled cell growth and mitosis leads to cancer. Panitumumab acts as an anticancer drug by binding to the extracellular domain of the EGFR and preventing its activation by epidermal growth factor. This in turn inhibits downstream signalling and prevents tumour growth.

Trastuzumab is an anti-EGFR drug used in the treatment of HER2-positive breast cancer. EGFR is linked multiple signalling pathways involved in tumour growth and angiogenesis such as the Ras/Raf pathway and the PI3K/Akt pathways. These pathways ultimately lead to the activation of transcription factors such as Jun, Fos, and Myc, as well as cyclin D1, which stimulates cell growth and mitosis. Uncontrolled cell growth and mitosis leads to cancer. Trastuzumab acts as an anticancer drug by binding to the extracellular domain of the EGFR and preventing its activation by epidermal growth factor. This in turn inhibits downstream signalling and prevents tumour growth.

DNA is composed of two long and complementary strands, with a backbone on the outside and nucleotides in the middle. During replication the two strands of DNA separate; the resulting structure is called the replication fork. The replication fork forms because enzymes called helicases surround the DNA strands and break the hydrogen bonds which hold them together. The result is that two long branches, almost like fork prongs, each of which is a DNA strand. Replication of DNA has two main different processes. Because DNA is replicated in the 5' to 3' direction, and because both DNA strands in the replication fork are negative mirror images of each other, and because the replication fork is created on only one direction down the length of the DNA, two types of replication strands are formed: the leading and the lagging strand. These strands are so named by the way in which DNA polymerase reads the original DNA strand and attaches the complementary nucleotides as it makes its way along the chain. Because the direction of the movement of the replication fork, and the direction of the addition of nucleotides in the leading strand is the same, the process is continuous.That is, a polymerase is able to read the DNA and add the matching nucleotide bases to it continuously. In prokaryotes DNA polymerase III is responsible for creating the leading strand. The lagging strand is oriented in the opposite direction to the leading strand. Thus, replication of the lagging strand occurs in the opposing direction to that of the leading strand and the replication fork. As a result, replication of the lagging strand is a slower and more complicated process than that of the leading strand. Thus it is seen to lag behind the leading strand (hence the name).

In order to pass genetic information from one generation to the next, all organisms must accurately replicate their genomes during each cell division. This includes the nuclear genome and mitochondrial and chloroplast genomes. These are normally replicated with high fidelity that is achieved through the action of accurate DNA repair. Nucleotide Excision Repair is one os several mechanisms of DNA repair. Nucleotide excision repair (NER) operates on base damage caused by exogenous agents (such as mutagenic and carcinogenic chemicals and photoproducts generated by sunlight exposure) that cause alterations in the chemistry and structure of the DNA duplex . Such damage is recognized by a protein called XPC, which is stably bound to another protein called HHRAD23B (R23). The binding of the XPC–HHRAD23 heterodimeric subcomplex is followed by the binding of several other proteins (XPA, RPA, TFIIH and XPG). Of these, XPA and RPA are believed to facilitate specific recognition of base damage. TFIIH is a subcomplex of the RNA polymerase II transcription initiation machinery which also operates during NER. It consists of six subunits and contains two DNA helicase activities (XPB and XPD) that unwind the DNA duplex in the immediate vicinity of the base damage. This local denaturation generates a bubble in the DNA, the ends of which comprise junctions between duplex and single-stranded DNA. The subsequent binding of the ERCC1–XPF heterodimeric subcomplex generates a completely assembled NER multiprotein complex. XPG is a duplex/single-stranded DNA endonuclease that cuts the damaged strand at such junctions 3’ to the site of base damage. Conversely, the ERCC1–XPF heterodimeric protein is a duplex/single-stranded DNA endonuclease that cuts the damaged strand at such junctions 5’ to the site of base damage. This bimodal incision generates an oligonucleotide fragment 27–30 nucleotides in length which includes the damaged base. This fragment is excised from the genome, concomitant with restoring the potential 27–30 nucleotide gap by repair synthesis. Repair synthesis requires DNA polymerases or , as well as the accessory replication proteins PCNA, RPA and RFC. The covalent integrity of the damaged strand is then restored by DNA ligase. Collectively, these biochemical events return the damaged DNA to its native chemistry and configuration. ERCC1, excision repair cross-complementing 1; PCNA, proliferating cell nuclear antigen; POL, polymerase; RFC, replication factor C; RPA, replication protein A; TFIIH, transcription factor IIH; XP, xeroderma pigmentosum.

Plasmalogens are a class of phospholipids found in animals. Plasmalogens are thought to influence membrane dynamics and fatty acid levels, while also having roles in intracellular signalling and as antioxidants. Plasmalogens consist of a glycerol backbone with an vinyl-ether-linked alkyl chain at the sn-1 position, an ester-linked long-chain fatty acid at the sn-2 position, and a head group attached to the sn-3 position through a phosphodiester linkage. It is the vinyl-ether-linkage that separates plasmalogens from other phospholipids. Plasmalogen biosynthesis begins in the peroxisomes, where the integral membrane protein dihydroxyacetone phosphate acyltransferase (DHAPAT) catalyzes the esterification of the free hydroxyl group of dihydroxyacetone phosphate (DHAP) with a molecule any of long chain acyl CoA. Next, alkyl-DHAP synthase, a peroxisomal enzyme associated with DHAPAT, replaces the fatty acid on the DHAP with a long chain fatty alcohol. The third step of plasmalogen biosynthesis is catalyzed by the enzyme acyl/alkyl-DHAP reductase, which is found in the membrane of both the peroxisome and endoplasmic reticulum (ER). Acyl/alkyl-DHAP reductase uses NADPH as a cofactor to reduce the ketone of the 1-alkyl-DHAP using a classical hydride transfer mechanism. The remainder of plasmalogen synthesis occurs using enzymes in the ER. Lysophosphatidate acyltransferases (LPA-ATs) transfer the acyl component of a polyunsaturated acyl-CoA to the the 1-alkyl-DHAP, creating a 1-alkyl-2-acylglycerol 3-phosphate. The phosphate is then removed by lipid phosphate phosphohydrolase I (PAP-I), and the head group is attached by a choline/ethanolaminephosphotransferase. The majority of plasmalogens have either ethanolamine or choline as a headgroup, although a small amount of serine and inositol-linked ether-phospholipids can also be found. In the final step, the vinyl-ether linkage is created by plasmanylethanolamine desaturase, which catalyzes the formation of a double bond in the alkyl chain of the plasmalogen.

Beta-oxidation is the major degradative pathway for fatty acid esters in humans. Fatty acids and their CoA esters are found throughout the body, playing roles such as components of cellular lipids, regulators of enzymes and membrane channels, ligands for nuclear receptors, precursor molecules for hormones, and signalling molecules. Beta-oxidation occurs in the peroxisomes and mitochondria, the latter of which is depicted here. Whether beta-oxidation starts in the mitochondria or the peroxisome depends on the length of the fatty acid. Medium to long chain fatty acids go directly to the mitochondria, whereas very long chain fatty acids (>22 carbons) may be first metabolized down to octanyl-CoA in the peroxisomes and then transported to the mitochondria for the remainder of the oxidation. Beta-oxidation begins with fatty acids first being activated by an acyl-coenzyme A synthetase. This process uses ATP to produce a reactive fatty acyl adenylate which then reacts with coenzyme A to produce a fatty acyl-CoA. Short and medium chain fatty acids can enter the mitochondria directly via diffusion where they are activated in the mitochondrial matrix by acyl-coenzyme A synthetases. Long chain fatty acids must be activated in the outer mitochondrial membrane then transported as a carnatine complex into the mitochondria. A double bond is formed between C-2 and C-3 to produce trans-Δ2-enoyl-CoA which is catalyzed by acyl-CoA-dehydrogenases in the mitochondria. Enoyl CoA hydratase then hydrates the double bond between C-2 and C-3 to produce a L-beta-hydroxyacyl CoA which then has its hydroxyl group converted to a keto group to produce beta-ketoacyl CoA. Finally, the beta-ketoacyl CoA is cleaved by beta-ketothiolase and a thiol group is inserted between C-2 and C-3 to reduce the acyl-CoA and produce acetyl-CoA. Acetyl-CoA can then enter the citric acid cycle.