1.
Leukotriene
–
Leukotrienes use lipid signaling to convey information to either the cell producing them or neighboring cells in order to regulate immune responses. Leukotriene production is accompanied by the production of histamine and prostaglandins. One of their roles is to trigger contractions in the smooth muscles lining the bronchioles, their overproduction is a cause of inflammation in asthma. Leukotriene antagonists are used to treat these disorders by inhibiting the production or activity of leukotrienes, the name leukotriene, introduced by Swedish biochemist Bengt Samuelsson in 1979, comes from the words leukocyte and triene. What would be later named leukotriene C, slow reaction smooth muscle-stimulating substance was originally described between 1938 and 1940 by Feldberg and Kellaway, the researchers isolated SRS from lung tissue after a prolonged period following exposure to snake venom and histamine. Leukotrienes are commercially available to the research community, LTC4, LTD4, LTE4 and LTF4 are often called cysteinyl leukotrienes due to the presence of the amino acid cysteine in their structure. The cysteinyl leukotrienes make up the substance of anaphylaxis. LTF4, like LTD4, is a metabolite of LTC4, but, unlike LTD4, LTB4 is synthesized in vivo from LTA4 by the enzyme LTA4 hydrolase. Its primary function is to recruit neutrophils to areas of tissue damage, drugs that block the actions of LTB4 have shown some efficacy in slowing the progression of neutrophil-mediated diseases. There has also postulated the existence of LTG4, a metabolite of LTE4 in which the cysteinyl moiety has been oxidized to an alpha-keto-acid. Very little is known about this putative leukotriene, leukotrienes originating from the omega-3 class eicosapentanoic acid have diminished inflammatory effects. Leukotrienes are synthesized in the cell from arachidonic acid by arachidonate 5-lipoxygenase, the catalytic mechanism involves the insertion of an oxygen moiety at a specific position in the arachidonic acid backbone. The lipoxygenase pathway is active in leukocytes and other immunocompetent cells, including mast cells, eosinophils, neutrophils, monocytes, when such cells are activated, arachidonic acid is liberated from cell membrane phospholipids by phospholipase A2, and donated by the 5-lipoxygenase-activating protein to 5-lipoxygenase. 5-Lipoxygenase uses FLAP to convert arachidonic acid into 5-hydroperoxyeicosatetraenoic acid, which reduces to 5-hydroxyeicosatetraenoic acid. The enzyme 5-LO acts again on 5-HETE to convert it into leukotriene A4, in cells that express LTC4 synthase, such as mast cells and eosinophils, LTA4 is conjugated with the tripeptide glutathione to form the first of the cysteinyl-leukotrienes, LTC4. Outside the cell, LTC4 can be converted by enzymes to form successively LTD4 and LTE4. Both LTB4 and the cysteinyl-leukotrienes are partly degraded in local tissues, leukotrienes act principally on a subfamily of G protein-coupled receptors. They may also act upon peroxisome proliferator-activated receptors, leukotrienes are involved in asthmatic and allergic reactions and act to sustain inflammatory reactions
2.
Cell signaling
–
Cell signaling is part of any communication process that governs basic activities of cells and coordinates all cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, errors in signaling interactions and cellular information processing are responsible for diseases such as cancer, autoimmunity, and diabetes. By understanding cell signaling, diseases may be treated effectively and, theoretically. Traditional work in biology has focused on studying individual parts of cell signaling pathways, systems biology research helps us to understand the underlying structure of cell signaling networks and how changes in these networks may affect the transmission and flow of information. Such networks are complex systems in their organization and may exhibit a number of emergent properties including bistability and ultrasensitivity, analysis of cell signaling networks requires a combination of experimental and theoretical approaches including the development and analysis of simulations and modeling. Long-range allostery is often a significant component of signaling events. Cell signaling has been most extensively studied in the context of human diseases, however, cell signaling may also occur between the cells of two different organisms. In many mammals, early embryo cells exchange signals with cells of the uterus, in the human gastrointestinal tract, bacteria exchange signals with each other and with human epithelial and immune system cells. For the yeast Saccharomyces cerevisiae during mating, some cells send a signal into their environment. The mating factor peptide may bind to a surface receptor on other yeast cells. Cell signaling can be classified to be mechanical and biochemical based on the type of the signal, mechanical signals are the forces exerted on the cell and the forces produced by the cell. These forces can both be sensed and responded by the cells, biochemical signals are the biochemical molecules such as proteins, lipids, ions and gases. These signals can be categorized based on the distance between signaling and responder cells, Signaling within, between, and amongst cells is subdivided into the following classifications, Intracrine signals are produced by the target cell that stay within the target cell. Autocrine signals are produced by the cell, are secreted. Sometimes autocrine cells can target cells close by if they are the type of cell as the emitting cell. An example of this are immune cells and these signals are transmitted along cell membranes via protein or lipid components integral to the membrane and are capable of affecting either the emitting cell or cells immediately adjacent. Paracrine signals target cells in the vicinity of the emitting cell, endocrine cells produce hormones that travel through the blood to reach all parts of the body. Cells communicate with each other via direct contact, over short distances, some cell–cell communication requires direct cell–cell contact
3.
Receptor (biochemistry)
–
In biochemistry and pharmacology, a receptor is a protein molecule that receives chemical signals from outside a cell. When such chemical signals bind to a receptor, they cause some form of cellular/tissue response, however, sometimes in pharmacology, the term is also used to include other proteins that are drug targets, such as enzymes, transporters and ion channels. Receptor proteins can be classified by their location, transmembrane receptors include ion channel-linked receptors, G protein-linked hormone receptors, and enzyme-linked hormone receptors. Intracellular receptors are found inside the cell, and include cytoplasmic receptors. The endogenously designated -molecule for a receptor is referred to as its endogenous ligand. E. g. the endogenous ligand for the acetylcholine receptor is acetylcholine but the receptor can also be activated by nicotine. Each receptor is linked to a specific cellular biochemical pathway, while numerous receptors are found in most cells, each receptor will only bind with ligands of a particular structure, much like how locks will only accept specifically shaped keys. When a ligand binds to its receptor, it activates or inhibits the receptors associated biochemical pathway. The ligand-binding cavities are located at the interface between the subunits, type 2, G protein-coupled receptors – This is the largest family of receptors and includes the receptors for several hormones and slow transmitters e. g. dopamine, metabotropic glutamate. They are composed of seven transmembrane alpha helices, the loops connecting the alpha helices form extracellular and intracellular domains. The aforementioned receptors are coupled to different intracellular effector systems via G proteins, the insulin receptor is an example. Type 4, Nuclear receptors – While they are called nuclear receptors, they are located in the cytoplasm. They are composed of a C-terminal ligand-binding region, a core DNA-binding domain, the core region has two zinc fingers that are responsible for recognizing the DNA sequences specific to this receptor. The N terminus interacts with other transcription factors in a ligand-independent manner. Steroid and thyroid-hormone receptors are examples of such receptors, membrane receptors may be isolated from cell membranes by complex extraction procedures using solvents, detergents, and/or affinity purification. The structures and actions of receptors may be studied by using methods such as X-ray crystallography, NMR, circular dichroism. Computer simulations of the behavior of receptors have been used to gain understanding of their mechanisms of action. Ligand binding is an equilibrium process, ligands bind to receptors and dissociate from them according to the law of mass action
4.
Ligand (biochemistry)
–
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In protein-ligand binding, the ligand is usually a molecule which produces a signal by binding to a site on a target protein, the binding typically results in a change of conformation of the target protein. In DNA-ligand binding studies, the ligand can be a molecule, ion. The relationship between ligand and binding partner is a function of charge, hydrophobicity, and molecular structure, the instance of binding occurs over an infinitesimal range of time and space, so the rate constant is usually a very small number. Binding occurs by intermolecular forces, such as bonds, hydrogen bonds. The association of docking is actually reversible through dissociation, measurably irreversible covalent bonding between a ligand and target molecule is atypical in biological systems. In contrast to the definition of ligand in metalorganic and inorganic chemistry, in biochemistry it is whether the ligand generally binds at a metal site. In general, the interpretation of ligand is contextual with regards to what sort of binding has been observed, the etymology stems from ligare, which means to bind. Ligand binding to a receptor protein alters the chemical conformation by affecting the shape orientation. The conformation of a receptor protein composes the functional state, ligands include substrates, inhibitors, activators, and neurotransmitters. The rate of binding is called affinity, and this measurement typifies a tendency or strength of the effect, binding affinity is actualized not only by host-guest interactions, but also by solvent effects that can play a dominant, steric role which drives non-covalent binding in solution. The solvent provides an environment for the ligand and receptor to adapt. Radioligands are radioisotope labeled compounds are used in vivo as tracers in PET studies, the interaction of most ligands with their binding sites can be characterized in terms of a binding affinity. In general, high-affinity binding results in a degree of occupancy for the ligand at its receptor binding site than is the case for low-affinity binding. A ligand that can bind to a receptor, alter the function of the receptor, high-affinity ligand binding implies that a relatively low concentration of a ligand is adequate to maximally occupy a ligand-binding site and trigger a physiological response. The lower the Ki concentration is, the more likely there will be a reaction between the pending ion and the receptive antigen. In the example shown to the right, two different ligands bind to the receptor binding site. Only one of the agonists shown can maximally stimulate the receptor and, thus, an agonist that can only partially activate the physiological response is called a partial agonist
5.
12-Hydroxyeicosatetraenoic acid
–
It was first found as a product of arachidonic acid metabolism made by human and bovine platelets through their 12S-lipoxygenase enzyme. The two isomers, either directly or after being metabolized, have been suggested to be involved in a variety of human physiological and pathological reactions. In these roles, they may amplify or dampen, expand or contract cellular, in humans, Arachidonate 12-lipoxygenase is encoded by the ALOX12 gene and expressed primarily in platelets and skin. ALOX12 metabolizes arachidonic acid almost exclusively to 12-hydroperoxy-5Z, 8Z, 10E, Arachidonate 12-lipoxygenase, 12R type, also termed 12RLOX and encoded by the ALOX12B gene, is expressed primarily in skin and cornea, it metabolizes arachidonic acid to 12-HpETE. Mice also express an epidermal type 15-lipoxygenase which has 50. 8% amino acid identity to human 15-LOX-2 and 49. 3% sequence indetity to mouse Arachidonate 8-lipoxygenase. Mouse e-12LO metabolizes arachidonic acid predominantly to 12-HETE and to a lesser extent 15-HETE, in human skin epidermis, 12-HpETE is metabolized by Epidermis-type lipoxygenase, i. e. These decompositions may occur during tissue isolation procedures, in other tissues and animal species, numerous hepoxilins form but the hepoxilin synthase activity responsible for their formation is variable. The majority of reports on hepoxilin formation have not defined the pathways evolved, human and other mammalian cytochome P450 enzymes convert 12-HpETE to 12-oxo-ETE. 12-HETE, 12-HETE, 12-oxo-ETE, hepoxilin B3, and trioxilin B3 are found in the position of phospholipids isolated from normal human epidermis. These acylation reactions may sequester and thereby inactivate or store the metabolites for release during cell stimulation, GPR31 mRNA is expressed at low levels in several human cell lines including K562 cells, Jurkat cells, Hut78 cells, HEK293 cells, MCF7 cells, and EJ cells. Studies have not yet determined the role, if any, in GPR31 receptor in the action of 12-HETE in other cell types, a G protein-coupled receptor for the 5, 12-dihydroxy metabolite of aracidonic acid, Leukotriene B4, vis. Leukotriene B4 receptor 2, but not its Leukotriene B4 receptor 1, mediates responses to 12-HETE, 12-HETE, and 12-oxo-ETE in many cell types. The BLT2 receptor, in contrast to the GPR31 receptor, appears to be expressed at a level in a wide range of tissues including neutrophils, eosinophils, monocytes, spleen, liver. Ultimately, both receptors and all three ligands may prove to be responsible for some tissue responses in vivo, 12-HETE and 12-HETE bind to and act as Competitive antagonists of the Thromboxane receptor which mediates the actions of Thromboxane A2 and Prostaglandin H2. This antagonistic activity was responsible for the ability of 12-HETE and 12-HETE to relax mouse mesenteric arteries pre-constricted with a thromboxane A2 mimetic, 12-HETE binds with high affinity to a 50 kilodalton subunit of a 650 kDa cytosolic and nuclear protein complex. Since it mediates 12-HETE-induced itching in the model, BLT2 rather than GPR31 may mediate human itch in these reactions. These results suggest that the 12-HETE made by prostate cancer tissues serves to promote the growth, further studies in animal models suggest that the 12S-HETE made by pancreatic beta cells orchestrate a local immune response that results in the injury and, when extreme, death of beta cells. These results suggest that the 12-lipoxygenase-12S-HETE pathway is one contributing to immunity-based type I diabetes as well as low insulin output type II diabetes
