Browsing Pathways

The ubiquitin-proteasome pathway is the pathway in which molecules, specifically proteins, are broken down into smaller molecules in the cytosol or in the nucleus.This pathway subsequently has effects in many other pathways and processes. This pathway uses 2 distinct steps. The first step is that the protein being broken down is tagged by multiple ubiquitin units attaching to the protein. The second step is that the protein that has been tagged degrades as it is catalyzed by the 26S proteasome. This pathway is important for DNA repair, regulating the amount of proteins, and the creation of antigen-peptide.

The lectin-induced complement pathway, also known as the MBL pathway, is a complement activation pathway that is triggered by mannose-binding lectin binding to sugars found on carbohydrates found on pathogens. Unlike other complement pathways, this pathways components do not bind directly to the antibodies attached to the pathogen. The bacteria that MBL binds to include listeria, salmonella, and HIV-1.

The classical complement pathway is a pathway that is responsible for activating the complement system within the immune system. This pathway begins with the activation of antibodies IgM and IgG. Protein C3 is created, and after a series of reactions, cleaves the C5 protein. This brings phagocytes to the infected area and sets the stage for the coming together of the membrane attack complex (MAC). This complex targets the cell and creates an opening in the membrane, which leads to cell lysis and death.

Perforin protein forms pores in the membrane to allow for granzyme B to enter the cell. Granzymes induce apoptosis by activating caspases. D4-GDP dissociation inhibitor (D4-GDI) is a negative regulator of ras-related Rho Family of GTPases. D4-GDI binds Rho GTPases to keep the Rho protein in a GDP-bound and inactivate state. Caspase 3 cleaves D4-GDI into two fragments of 5 kDa and 23 kDa size. The 23 kDa fragment translocates to the nucleus to activate Jun kinase, a regulator of apoptosis. Poly (ADP-ribose) polymerase-1 (PARP) is a substrate for caspase-3. Caspase-3 cleaves PARP into various fragments, this is a hallmark of apoptosis. PARP functions to detect and repair DNA damage. Cleavage of PARP by caspase prevents DNA repair, contributing to cell death. RHO GTPases become activated when released from D4-GDI upon cleavage by caspase-3. RHO GTPases mediate cytoskeleton changes leading to apoptosis and cell death. .

The complement system includes three separate pathways that lead to complement's activation. These pathways all have different molecules that trigger their activation, but all of them lead to a response by phagocytes as part of a response by the innate immune system. In the alternative pathway, complement factor C3 can spontaneously hydrolyze to form a complex with water. Complement factor D is a protease that can work at the same time, and it cleaves complement factor B into factors Ba and Bb. the C3(H2O) complex can bind to factor Bb, which is a C3 convertase, and works to cleave factor C3 into C3a and C3b more quickly. The C3(H2O)Bb complex also binds factor B, leading to easier cleavage into Ba and Bb by factor D. Following this, complement factor C3b can bind to the surface of cells, and on host cells, proteins on the cell membrane can bind to C3b, preventing it from forming complement factor C5 convertase. However, on pathogen cells, these proteins do not exist, complement factor Bb can bind to two molecules of C3b, forming a C5-convertase which is the end point of the other two pathways. In the lectin pathway, mannan-binding lectin serine proteases (MASP) 1 and 2, as well as mannose-binding protein C bind to carbohydrates, specifically mannose, glucose and sugars with specific hydroxide group placements. These sugars are found in the cell walls of bacteria such as salmonella and listeria, as well as some viruses, including HIV-1, and fungal pathogens, such as candida. After the sugar is bound by the proteins, it activates the serine proteases, which then can cleave complement C2 and C4 into C2a, C2b, C4a and C4b respectively. Factors C4b and C2a (sometimes called C2b) can interact to form C3 convertase, which is identical in function to the C3 convertase formed by the alternative pathway, and it works to cleave C3 into C3a and C3b more quickly. Finally for this pathway, a molecule of C3b interacts with the preexisting C3 convertase complex, forming the C5 convertase complex that cleaves factor C5 into C5a and C5b. The final pathway that leads to this point is the classical complement pathway. This pathway is activated by the binding of aggregated antibody-antigen complexes, as well as components of viral and bacterial cells such as lipopolysaccharides, to the C1q protein. C1q is part of the C1 complex, which also includes C1s and C1r. Binding of a substance to C1q causes a conformational change in C1r and C1s, allowing C1s to become an active protease, which then is able to cleave complement factors C2 and C4 into their a and b fragments, as in the lectin pathway. The remainder of the pathway is identical to that of the lectin pathway. Finally, after cleavage of C5 into C5a and C5b by any of the pathways, complement componenets C6, 7, 8 and 9 can interact with component C5b in order to form the membrane attack complex. This complex attaches to the plasma membrane of pathogen cells, forming a hole in the membrane and allowing diffusion of molecules in the cell, and eventually cell death if enough attack complex form.

Protein synthesis is an essential life process that builds the important large amino acid macromolecules that function as enzymes, antibodies, and cellular structural components. Although synthesis begins with the transcription of DNA into RNA, this pathway depicts the reactions that occur during translation. Transcribed messenger RNA (mRNA), which contains the genetic code to direct protein synthesis, is transported out of the nucleus and becomes bound to ribosomes in the cytoplasm or endoplasmic reticulum. The amino acids required to assemble polypeptide chains are delivered to the ribosomes using transfer RNA (tRNA). Each tRNA molecule has both a binding site for a specific amino acid and a three-nucleotide sequence called the anticodon that forms three complementary base pairs with an mRNA codon. Charging or loading the appropriate amino acid onto its tRNA is carried out by an aminoacyl-tRNA synthetase (aaRS or ARS), also called tRNA-ligase. This enzyme catalyzes the esterification of an amino acid to one of all its compatible tRNAs to form an aminoacyl-tRNA. Each of the twenty amino acids has a corresponding aa-tRNA made by a specific aminoacyl-tRNA synthetase. Ribosomes match the anticodons of the charged tRNA molecules with successive codons of the mRNA. After a match is found, the ribosome transfers the amino acid from the matching tRNA onto the growing peptide chain via a reaction termed peptide condensation, and the tRNAs, no longer carrying amino acids, are released.

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.

Vatalanib is an anti-VEGFR molecule in the treatment of cancer. Cancer cells tend to overexpress VEGF, which stimulates angiogenesis, facilitating cancer growth and metastasis. The majority of VEGF’s effects are mediated through its binding to the VEGFR-2 receptor on endothelial cell surfaces. Upon binding, the receptor autophosphorylates and initiates a signalling cascade, starting with the activation of CSK. CSK phosphorylates Raf-1, which subsequently phosphorylates MAP kinase kinase, which phosphorylates MAP kinase. The activated MAP kinase enters the nucleus and stimulates the expression of angiogenic factors resulting in increased cell proliferation, migration, permeability, invasion, and survival. Binding of VEGF to VEGFR-2 also activates phospholipase C PIP2 into DAG and IP3. DAG may be involved in the activation of Raf-1 leading to angiogenesis, while IP3 activates PI3K and triggers calcium release from the endoplasmic reticulum. This ultimately leads to the activation of nitric oxide synthase and the production of nitric oxide, which stimulates vasodilation and increases vascular permeability. In cancer, VEGF has also been shown to bind to the VEGFR-1 receptor. However, its effects on angiogenesis are unclear at the moment. There are some evidence to show that VEGFR-1 may cross-talk with VEGFR-2 and initiate the signalling cascades described above. Vatalanib exerts its effect by binding to intracellular tyrosine kinase domain of VEGFR-2 and preventing receptor autophosphorylation and activation of downstream pathways, resulting in suppression of angiogenesis.

Losartan (also named Cozaar) is an active metabolite of angiotensin II receptor blockers (ARBs). Losartan competes with angiotensin II to bind type-1 angiotensin II receptor (AT1) in many tissues (e.g. vascular smooth muscle, the adrenal glands, etc.) to prevent increasing sodium, water reabsorption and peripheral resistance (that will lead to increasing blood pressure) via aldosterone secretion that is caused by angiotensin II. Therefore, action of losartan binding to AT1 will result in decreasing blood pressure. For more information on the effects of aldosterone on electrolyte and water excretion, refer to the description of the \spironolactone\:http://pathman.smpdb.ca/pathways/SMP00134/pathway or \triamterene\:http://pathman.smpdb.ca/pathways/SMP00132/pathway pathway, which describes the mechanism of direct aldosterone antagonists. Losartan is an effective agent for reducing blood pressure and may be used to treat essential hypertension and heart failure.

Procaine exerts its local anaesthetic effect by blocking voltage-gated sodium channels in peripheral neurons. Procaine diffuses across the neuronal plasma membrane in its uncharged base form. Once inside the cytoplasm, it is protonated and this protonated form enters and blocks the pore of the voltage-gated sodium channel from the cytoplasmic side. For this to happen, the sodium channel must first become active so that so that gating mechanism is in the open state. Therefore procaine preferentially inhibits neurons that are actively firing.