Platelet-derived growth factor
Platelet-derived growth factor is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing blood vessel tissue, mitogenesis, i.e. proliferation, of mesenchymal cells such as fibroblasts, tenocytes, vascular smooth muscle cells and mesenchymal stem cells as well as chemotaxis, the directed migration, of mesenchymal cells. Platelet-derived growth factor is a dimeric glycoprotein that can be composed of two A subunits, two B subunits, or one of each. PDGF is a potent mitogen for cells of mesenchymal origin, including fibroblasts, smooth muscle cells and glial cells. In both mouse and human, the PDGF signalling network consists of five ligands, PDGF-AA through -DD, two receptors, PDGFRalpha and PDGFRbeta. All PDGFs function as secreted, disulphide-linked homodimers, but only PDGFA and B can form functional heterodimers. Though PDGF is synthesized and released by platelets upon activation, it is produced by other cells including smooth muscle cells, activated macrophages, endothelial cellsRecombinant PDGF is used in medicine to help heal chronic ulcers and in orthopedic surgery and periodontics as an alternative to bone autograft to stimulate bone regeneration and repair.
There are five different isoforms of PDGF that activate cellular response through two different receptors. Known ligands include A, B, C, D, an AB heterodimer and receptors alpha and beta. PDGF has few other members of the family, for example VEGF sub-family; the receptor for PDGF, PDGFR is classified as a receptor tyrosine kinase, a type of cell surface receptor. Two types of PDGFRs have been identified: alpha-type and beta-type PDGFRs; the alpha type binds to PDGF-AA, PDGF-BB and PDGF-AB, whereas the beta type PDGFR binds with high affinity to PDGF-BB and PDGF-AB. PDGF binds to the PDGFR ligand binding pocket located within the second and third immunoglobulin domains. Upon activation by PDGF, these receptors dimerise, are "switched on" by auto-phosphorylation of several sites on their cytosolic domains, which serve to mediate binding of cofactors and subsequently activate signal transduction, for example, through the PI3K pathway or through reactive oxygen species -mediated activation of the STAT3 pathway.
Downstream effects of this include regulation of the cell cycle. The role of PI3K has been investigated by several laboratories. Accumulating data suggests that, while this molecule is, in general, part of growth signaling complex, it plays a more profound role in controlling cell migration; the different ligand isoforms have variable affinities for the receptor isoforms, the receptor isoforms may variably form hetero- or homo- dimers. This leads to specificity of downstream signaling, it has been shown. PDGF-BB is the highest-affinity ligand for the PDGFR-beta. PDGFs are mitogenic during early developmental stages, driving the proliferation of undifferentiated mesenchyme and some progenitor populations. During maturation stages, PDGF signalling has been implicated in tissue remodelling and cellular differentiation, in inductive events involved in patterning and morphogenesis. In addition to driving mesenchymal proliferation, PDGFs have been shown to direct the migration and function of a variety of specialised mesenchymal and migratory cell types, both during development and in the adult animal.
Other growth factors in this family include vascular endothelial growth factors B and C which are active in angiogenesis and endothelial cell growth, placenta growth factor, active in angiogenesis. PDGF plays a role in embryonic development, cell proliferation, cell migration, angiogenesis. Over-expression of PDGF has been linked to several diseases such as atherosclerosis, fibrotic disorders and malignancies. Synthesis occurs due to external stimuli such as thrombin, low oxygen tension, or other cytokines and growth factors. PDGF is a required element in cellular division for fibroblasts, a type of connective tissue cell, prevalent in wound healing. In essence, the PDGFs allow a cell to skip the G1 checkpoints in order to divide, it has been shown that in monocytes-macrophages and fibroblasts, exogenously administered PDGF stimulates chemotaxis and gene expression and augmented the influx of inflammatory cells and fibroblasts, accelerating extracellular matrix and collagen formation and thus reducing the time for the healing process to occur.
In terms of osteogenic differentiation of mesenchymal stem cells, comparing PDGF to epidermal growth factor, implicated in stimulating cell growth and differentiation, MSCs were shown to have stronger osteogenic differentiation into bone-forming cells when stimulated by epidermal growth factor versus PDGF. However, comparing the signaling pathways between them reveals that the PI3K pathway is activated by PDGF, with EGF having no effect. Chemically inhibiting the PI3K pathway in PDGF-stimulated cells negates the differential effect between the two growth factors, gives PDGF an edge in osteogenic differentiation. Wortmannin is a PI3K-specific inhibitor, treatment of cells with Wortmannin in combination with PDGF resulted in enhanced osteoblast differentiation compared to just PDGF alone, as well as compared to EGF; these results indicate that the addition of Wortmannin can increas
Integrins are transmembrane receptors that facilitate cell-extracellular matrix adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, organization of the intracellular cytoskeleton, movement of new receptors to the cell membrane; the presence of integrins allows flexible responses to events at the cell surface. Several types of integrins exist, one cell may have multiple different types on its surface. Integrins are found in all animals. Integrins work alongside other receptors such as cadherins, the immunoglobulin superfamily cell adhesion molecules and syndecans, to mediate cell–cell and cell–matrix interaction. Ligands for integrins include fibronectin, vitronectin and laminin. Integrins are obligate heterodimers, meaning that they have two subunits: α and β. Integrins in mammals have twenty-four α and nine β subunits, in Drosophila five α and two β subunits, in Caenorhabditis nematodes two α subunits and one β subunit.
The α and β subunits each possess several cytoplasmic domains. Variants of some subunits are formed by differential RNA splicing. Through different combinations of the α and β subunits, around 24 unique integrins are generated. Integrin subunits have short cytoplasmic domains of 40 -- 70 amino acids; the exception is the beta-4 subunit, which has a cytoplasmic domain of 1,088 amino acids, one of the largest of any membrane protein. Outside the cell membrane, the α and β chains lie close together along a length of about 23 nm, they have been compared to lobster claws, although they don't "pinch" their ligand, they chemically interact with it at the insides of the "tips" of their "pinchers". The molecular mass of the integrin subunits can vary from 90 kDa to 160 kDa. Beta subunits have four cysteine-rich repeated sequences. Both α and β subunits bind several divalent cations; the role of divalent cations in the α subunit is unknown, but may stabilize the folds of the protein. The cations in the β subunits are more interesting: they are directly involved in coordinating at least some of the ligands that integrins bind.
Integrins can be categorized in multiple ways. For example, some α chains have an additional structural element inserted toward the N-terminal, the alpha-A domain. Integrins carrying this domain either bind to collagens, or act as cell-cell adhesion molecules; this α-I domain is the binding site for ligands of such integrins. Those integrins that don't carry this inserted domain have an A-domain in their ligand binding site, but this A-domain is found on the β subunit. In both cases, the A-domains carry up to three divalent cation binding sites. One is permanently occupied in physiological concentrations of divalent cations, carries either a calcium or magnesium ion, the principal divalent cations in blood at median concentrations of 1.4 mM and 0.8 mM. The other two sites become occupied by cations when ligands bind—at least for those ligands involving an acidic amino acid in their interaction sites. An acidic amino acid features in the integrin-interaction site of many ECM proteins, for example as part of the amino acid sequence Arginine-Glycine-Aspartic acid.
Despite many years of effort, discovering the high-resolution structure of integrins proved to be challenging, as membrane proteins are classically difficult to purify, as integrins are large and linked to many sugar trees. Low-resolution images of detergent extracts of intact integrin GPIIbIIIa, obtained using electron microscopy, data from indirect techniques that investigate the solution properties of integrins using ultracentrifugation and light scattering, were combined with fragmentary high-resolution crystallographic or NMR data from single or paired domains of single integrin chains, molecular models postulated for the rest of the chains; the X-ray crystal structure obtained for the complete extracellular region of one integrin, αvβ3, shows the molecule to be folded into an inverted V-shape that brings the ligand-binding sites close to the cell membrane. More the crystal structure was obtained for the same integrin bound to a small ligand containing the RGD-sequence, the drug cilengitide.
As detailed above, this revealed why divalent cations are critical for RGD-ligand binding to integrins. The interaction of such sequences with integrins is believed to be a primary switch by which ECM exerts its effects on cell behaviour; the structure poses many questions regarding ligand binding and signal transduction. The ligand binding site is directed towards the C-terminal of the integrin, the region where the molecule emerges from the cell membrane. If it emerges orthogonally from the membrane, the ligand binding site would be obstructed as integrin ligands are massive and well cross-linked components of the ECM. In fact, little is known about the angle that membrane proteins subtend to the plane of the membrane; the default assumption is that they emerge rather like little lollipops, but the evidence for thi
A cytoskeleton is present in the cytoplasm of all cells, including bacteria, archaea. It is a complex, dynamic network of interlinking protein filaments that extends from the cell nucleus to the cell membrane; the cytoskeletal systems of different organisms are composed of similar proteins. In eukaryotes, the cytoskeletal matrix is a dynamic structure composed of three main proteins, which are capable of rapid growth or disassembly dependent on the cell's requirements; the structure and dynamic behavior of the cytoskeleton can be different, depending on organism and cell type. Within one cell the cytoskeleton can change through association with other proteins and the previous history of the network. A multitude of functions can be performed by the cytoskeleton, its primary function is to give the cell its shape and mechanical resistance to deformation, through association with extracellular connective tissue and other cells it stabilizes entire tissues. The cytoskeleton can contract, thereby deforming the cell and the cell's environment and allowing cells to migrate.
Moreover, it is involved in many cell signaling pathways: in the uptake of extracellular material, segregates chromosomes during cellular division, is involved in cytokinesis, provides a scaffold to organize the contents of the cell in space and for intracellular transport. Furthermore, it forms specialized structures, such as flagella, cilia and podosomes. A large-scale example of an action performed by the cytoskeleton is muscle contraction; this is carried out by groups of specialized cells working together. A main component in the cytoskeleton that helps show the true function of this muscle contraction is the microfilament. Microfilaments are composed of the most abundant cellular protein known as actin. During contraction of a muscle, within each muscle cell, myosin molecular motors collectively exert forces on parallel actin filaments. Muscle contraction starts from nerve impulses which causes increased amounts of calcium to be released from the sarcoplasmic reticulum. Increases in calcium in the cytosol allows muscle contraction to begin with the help of two proteins and troponin.
Tropomyosin inhibits the interaction between actin and myosin, while troponin senses the increase in calcium and releases the inhibition. This action contracts the muscle cell, through the synchronous process in many muscle cells, the entire muscle. In 1903, Nikolai K. Koltsov proposed that the shape of cells was determined by a network of tubules that he termed the cytoskeleton; the concept of a protein mosaic that dynamically coordinated cytoplasmic biochemistry was proposed by Rudolph Peters in 1929 while the term was first introduced by French embryologist Paul Wintrebert in 1931. When the cytoskeleton was first introduced, it was thought to be an uninteresting gel-like substance that helps organelles stay in place. Much research took place to try to understand the purpose of its components. With the help of Stuart Hameroff and Roger Penrose, they discovered that microtubules vibrate within neurons in the brain which suggest that brain waves come from deeper microtubule vibrations; this discovery showed that the cytoskeleton is not just a gel like substance but it has a purpose.
It was thought that the cytoskeleton was exclusive to eukaryotes but in 1992, it was discovered to be present in prokaryotes as well. This discovery came after the realization that bacteria possess proteins that are homologous to tubulin and actin. Eukaryotic cells contain three main kinds of cytoskeletal filaments: microfilaments and intermediate filaments; each type is formed by the polymerization of a distinct type of protein subunit and has its own characteristic shape and intracellular distribution. Microfilaments are 7 nm in diameter. Microtubules are 25 nm in diameter. Intermediate filaments are composed of various proteins, depending on the type of cell in which they are found; the cytoskeleton provides the cell with structure and shape, by excluding macromolecules from some of the cytosol, it adds to the level of macromolecular crowding in this compartment. Cytoskeletal elements interact intimately with cellular membranes. Research into neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis indicate that the cytoskeleton is affected in these diseases.
Parkinson's disease is marked by the degradation of neurons, resulting in tremors and other non-motor symptoms. Research has shown that microtubule assembly and stability in the cytoskeleton is compromised causing the neurons to degrade over time. In Alzheimer's disease, tau proteins which stabilize microtubules, malfunction in the progression of the disease, causing pathology with the cytoskeleton. Excess glutamine in the Huntington protein, involved with linking vesicles to the cytoskeleton is proposed to be a factor in the development of Huntington's disease. Amyotrophic lateral sclerosis which results in a loss of movement caused by the degradation of motor neurons is seen to involve defects in the cytoskeleton. A number of small-molecule cytoskeletal drugs have been discovered that interact with actin and microtubules; these compounds have proven useful in studying the cytoskeleton and several have clinical applications. All filaments interact with accessory prote
Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin binds to other extracellular matrix proteins such as collagen and heparan sulfate proteoglycans. Fibronectin exists as a protein dimer, consisting of two nearly identical monomers linked by a pair of disulfide bonds; the fibronectin protein is produced from a single gene, but alternative splicing of its pre-mRNA leads to the creation of several isoforms. Two types of fibronectin are present in vertebrates: soluble plasma fibronectin is a major protein component of blood plasma and is produced in the liver by hepatocytes. Insoluble cellular fibronectin is a major component of the extracellular matrix, it is secreted by various cells fibroblasts, as a soluble protein dimer and is assembled into an insoluble matrix in a complex cell-mediated process. Fibronectin plays a major role in cell adhesion, growth and differentiation, it is important for processes such as wound healing and embryonic development.
Altered fibronectin expression and organization has been associated with a number of pathologies, including cancer and fibrosis. Fibronectin exists as a protein dimer, consisting of two nearly identical polypeptide chains linked by a pair of C-terminal disulfide bonds; each fibronectin subunit has a molecular weight of 230–250 kDa and contains three types of modules: type I, II, III. All three modules are composed of two anti-parallel β-sheets resulting in a Beta-sandwich; the absence of disulfide bonds in type III modules allows them to unfold under applied force. Three regions of variable splicing occur along the length of the fibronectin protomer. One or both of the "extra" type III modules may be present in cellular fibronectin, but they are never present in plasma fibronectin. A "variable" V-region exists between III14–15; the V-region structure is different from the type I, II, III modules, its presence and length may vary. The V-region contains the binding site for α4β1 integrins, it is present in most cellular fibronectin, but only one of the two subunits in a plasma fibronectin dimer contains a V-region sequence.
The modules are arranged into several functional and protein-binding domains along the length of a fibronectin monomer. There are four fibronectin-binding domains, allowing fibronectin to associate with other fibronectin molecules. One of these fibronectin-binding domains, I1–5, is referred to as the "assembly domain", it is required for the initiation of fibronectin matrix assembly. Modules III9–10 correspond to the "cell-binding domain" of fibronectin; the RGD sequence is located in III10 and is the site of cell attachment via α5β1 and αVβ3 integrins on the cell surface. The "synergy site" is in III9 and has a role in modulating fibronectin's association with α5β1 integrins. Fibronectin contains domains for fibrin-binding, collagen-binding, fibulin-1-binding, heparin-binding and syndecan-binding. Fibronectin has numerous functions, it is involved in cell adhesion, growth and differentiation. Cellular fibronectin is assembled into the extracellular matrix, an insoluble network that separates and supports the organs and tissues of an organism.
Fibronectin plays a crucial role in wound healing. Along with fibrin, plasma fibronectin is deposited at the site of injury, forming a blood clot that stops bleeding and protects the underlying tissue; as repair of the injured tissue continues and macrophages begin to remodel the area, degrading the proteins that form the provisional blood clot matrix and replacing them with a matrix that more resembles the normal, surrounding tissue. Fibroblasts secrete proteases, including matrix metalloproteinases, that digest the plasma fibronectin, the fibroblasts secrete cellular fibronectin and assemble it into an insoluble matrix. Fragmentation of fibronectin by proteases has been suggested to promote wound contraction, a critical step in wound healing. Fragmenting fibronectin further exposes its V-region, which contains the site for α4β1 integrin binding; these fragments of fibronectin are believed to enhance the binding of α4β1 integrin-expressing cells, allowing them to adhere to and forcefully contract the surrounding matrix.
Fibronectin is necessary for embryogenesis, inactivating the gene for fibronectin results in early embryonic lethality. Fibronectin is important for migration during embryonic development. In mammalian development, the absence of fibronectin leads to defects in mesodermal, neural tube, vascular development; the absence of a normal fibronectin matrix in developing amphibians causes defects in mesodermal patterning and inhibits gastrulation. Fibronectin is found in normal human saliva, which helps prevent colonization of the oral cavity and pharynx by pathogenic bacteria. Cellular fibronectin is assembled into an insoluble fibrillar matrix in a complex cell-mediated process. Fibronectin matrix assembly begins when soluble, compact fibronectin dimers are secreted from cells fibroblasts; these soluble dimers bind to α5β1 integrin receptors on the cell surface and aid in clustering the integrins. The local concentration of integrin-bound fibronectin increases, allowing bound fibronectin molecules to more interact with one another.
Short fibronectin fibrils the
In cell biology, the nucleus is a membrane-bound organelle found in eukaryotic cells. Eukaryotes have a single nucleus, but a few cell types, such as mammalian red blood cells, have no nuclei, a few others including osteoclasts have many; the cell nucleus contains all of the cell's genome, except for a small fraction of mitochondrial DNA, organized as multiple long linear DNA molecules in a complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these chromosomes are structured in such a way to promote cell function; the nucleus maintains the integrity of genes and controls the activities of the cell by regulating gene expression—the nucleus is, the control center of the cell. The main structures making up the nucleus are the nuclear envelope, a double membrane that encloses the entire organelle and isolates its contents from the cellular cytoplasm, the nuclear matrix, a network within the nucleus that adds mechanical support, much like the cytoskeleton, which supports the cell as a whole.
Because the nuclear envelope is impermeable to large molecules, nuclear pores are required to regulate nuclear transport of molecules across the envelope. The pores cross both nuclear membranes, providing a channel through which larger molecules must be transported by carrier proteins while allowing free movement of small molecules and ions. Movement of large molecules such as proteins and RNA through the pores is required for both gene expression and the maintenance of chromosomes. Although the interior of the nucleus does not contain any membrane-bound subcompartments, its contents are not uniform, a number of nuclear bodies exist, made up of unique proteins, RNA molecules, particular parts of the chromosomes; the best-known of these is the nucleolus, involved in the assembly of ribosomes. After being produced in the nucleolus, ribosomes are exported to the cytoplasm where they translate mRNA; the nucleus was the first organelle to be discovered. What is most the oldest preserved drawing dates back to the early microscopist Antonie van Leeuwenhoek.
He observed the nucleus, in the red blood cells of salmon. Unlike mammalian red blood cells, those of other vertebrates still contain nuclei; the nucleus was described by Franz Bauer in 1804 and in more detail in 1831 by Scottish botanist Robert Brown in a talk at the Linnean Society of London. Brown was studying orchids under the microscope when he observed an opaque area, which he called the "areola" or "nucleus", in the cells of the flower's outer layer, he did not suggest a potential function. In 1838, Matthias Schleiden proposed that the nucleus plays a role in generating cells, thus he introduced the name "cytoblast", he believed that he had observed new cells assembling around "cytoblasts". Franz Meyen was a strong opponent of this view, having described cells multiplying by division and believing that many cells would have no nuclei; the idea that cells can be generated de novo, by the "cytoblast" or otherwise, contradicted work by Robert Remak and Rudolf Virchow who decisively propagated the new paradigm that cells are generated by cells.
The function of the nucleus remained unclear. Between 1877 and 1878, Oscar Hertwig published several studies on the fertilization of sea urchin eggs, showing that the nucleus of the sperm enters the oocyte and fuses with its nucleus; this was the first time. This was in contradiction to Ernst Haeckel's theory that the complete phylogeny of a species would be repeated during embryonic development, including generation of the first nucleated cell from a "monerula", a structureless mass of primordial mucus. Therefore, the necessity of the sperm nucleus for fertilization was discussed for quite some time. However, Hertwig confirmed his observation in other animal groups, including amphibians and molluscs. Eduard Strasburger produced the same results for plants in 1884; this paved the way to assign the nucleus an important role in heredity. In 1873, August Weismann postulated the equivalence of the maternal and paternal germ cells for heredity; the function of the nucleus as carrier of genetic information became clear only after mitosis was discovered and the Mendelian rules were rediscovered at the beginning of the 20th century.
The nucleus is the largest organelle in animal cells. In mammalian cells, the average diameter of the nucleus is 6 micrometres, which occupies about 10% of the total cell volume; the contents of the nucleus are held in the nucleoplasm similar to the cytoplasm in the rest of the cell. The fluid component of this is termed the nucleosol, similar to the cytosol in the cytoplasm. In most types of granulocyte, a white blood cell, the nucleus is lobated and can be bi-lobed, tri-lobed or multi-lobed; the nuclear envelope, otherwise known as nuclear membrane, consists of two cellular membranes, an inner and an outer membrane, arranged parallel to one another and separated by 10 to 50 nanometres. The nuclear envelope encloses the nucleus and separates the cell's genetic material from the surrounding cytoplasm, serving as a barrier to prevent macromolecules from diffusing between the nucleoplasm and the cytoplasm; the outer nuclear membrane is continuous with the membrane of the rough endoplasmic reticulum, is studded with ribosomes.
The space between the membranes is called the perinuclear space and is continuous with the RER lumen. Nuclear pores, which provide aqueous cha
Catalysis is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst, not consumed in the catalyzed reaction and can continue to act repeatedly. Because of this, only small amounts of catalyst are required to alter the reaction rate in principle. In general, chemical reactions occur faster in the presence of a catalyst because the catalyst provides an alternative reaction pathway with a lower activation energy than the non-catalyzed mechanism. In catalyzed mechanisms, the catalyst reacts to form a temporary intermediate, which regenerates the original catalyst in a cyclic process. A substance which provides a mechanism with a higher activation energy does not decrease the rate because the reaction can still occur by the non-catalyzed route. An added substance which does reduce the reaction rate is not considered a catalyst but a reaction inhibitor. Catalysts may be classified as either heterogeneous. A homogeneous catalyst is one whose molecules are dispersed in the same phase as the reactant's molecules.
A heterogeneous catalyst is one whose molecules are not in the same phase as the reactant's, which are gases or liquids that are adsorbed onto the surface of the solid catalyst. Enzymes and other biocatalysts are considered as a third category. In the presence of a catalyst, less free energy is required to reach the transition state, but the total free energy from reactants to products does not change. A catalyst may participate in multiple chemical transformations; the effect of a catalyst may vary due to the presence of other substances known as inhibitors or poisons or promoters. Catalyzed reactions have a lower activation energy than the corresponding uncatalyzed reaction, resulting in a higher reaction rate at the same temperature and for the same reactant concentrations. However, the detailed mechanics of catalysis is complex. Catalysts may bind to the reagents to polarize bonds, e.g. acid catalysts for reactions of carbonyl compounds, or form specific intermediates that are not produced such as osmate esters in osmium tetroxide-catalyzed dihydroxylation of alkenes, or cause dissociation of reagents to reactive forms, such as chemisorbed hydrogen in catalytic hydrogenation.
Kinetically, catalytic reactions are typical chemical reactions. The catalyst participates in this slowest step, rates are limited by amount of catalyst and its "activity". In heterogeneous catalysis, the diffusion of reagents to the surface and diffusion of products from the surface can be rate determining. A nanomaterial-based catalyst is an example of a heterogeneous catalyst. Analogous events associated with substrate binding and product dissociation apply to homogeneous catalysts. Although catalysts are not consumed by the reaction itself, they may be inhibited, deactivated, or destroyed by secondary processes. In heterogeneous catalysis, typical secondary processes include coking where the catalyst becomes covered by polymeric side products. Additionally, heterogeneous catalysts can dissolve into the solution in a solid–liquid system or sublimate in a solid–gas system; the production of most industrially important chemicals involves catalysis. Most biochemically significant processes are catalysed.
Research into catalysis is a major field in applied science and involves many areas of chemistry, notably organometallic chemistry and materials science. Catalysis is relevant to many aspects of environmental science, e.g. the catalytic converter in automobiles and the dynamics of the ozone hole. Catalytic reactions are preferred in environmentally friendly green chemistry due to the reduced amount of waste generated, as opposed to stoichiometric reactions in which all reactants are consumed and more side products are formed. Many transition metals and transition metal complexes are used in catalysis as well. Catalysts called. A catalyst works by providing an alternative reaction pathway to the reaction product; the rate of the reaction is increased as this alternative route has a lower activation energy than the reaction route not mediated by the catalyst. The disproportionation of hydrogen peroxide creates oxygen, as shown below. 2 H2O2 → 2 H2O + O2This reaction is preferable in the sense that the reaction products are more stable than the starting material, though the uncatalysed reaction is slow.
In fact, the decomposition of hydrogen peroxide is so slow that hydrogen peroxide solutions are commercially available. This reaction is affected by catalysts such as manganese dioxide, or the enzyme peroxidase in organisms. Upon the addition of a small amount of manganese dioxide, the hydrogen peroxide reacts rapidly; this effect is seen by the effervescence of oxygen. The manganese dioxide is not consumed in the reaction, thus may be recovered unchanged, re-used indefinitely. Accordingly, manganese dioxide catalyses this reaction. Catalytic activity is denoted by the symbol z and measured in mol/s, a unit, called katal and defined the SI unit for catalytic activity since 1999. Catalytic activity is not a kind of reaction rate, but a property of the catalyst under certain conditions, in relation to a specific chemical reaction. Catalytic activity of one katal of a catalyst means one mole of that catalyst will catalyse 1 mole of the reactant to product in one second. A catalyst may and will have different catalytic activity for di
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most protein phosphorylation catalyzed by protein kinases, which results in a cellular response. Proteins responsible for detecting stimuli are termed receptors, although in some cases the term sensor is used; the changes elicited by ligand binding in a receptor give rise to a biochemical cascade, a chain of biochemical events as a signaling pathway. When signaling pathways interact with one another they form networks, which allow cellular responses to be coordinated by combinatorial signaling events. At the molecular level, such responses include changes in the transcription or translation of genes, post-translational and conformational changes in proteins, as well as changes in their location; these molecular events are the basic mechanisms controlling cell growth, proliferation and many other processes. In multicellular organisms, signal transduction pathways have evolved to regulate cell communication in a wide variety of ways.
Each component of a signaling pathway is classified according to the role it plays with respect to the initial stimulus. Ligands are termed first messengers, while receptors are the signal transducers, which activate primary effectors; such effectors are linked to second messengers, which can activate secondary effectors, so on. Depending on the efficiency of the nodes, a signal can be amplified, so that one signaling molecule can generate a response involving hundreds to millions of molecules; as with other signals, the transduction of biological signals is characterised by delay, signal feedback and feedforward and interference, which can range from negligible to pathological. With the advent of computational biology, the analysis of signaling pathways and networks has become an essential tool to understand cellular functions and disease, including signaling rewiring mechanisms underlying responses to acquired drug resistance; the basis for signal transduction is the transformation of a certain stimulus into a biochemical signal.
The nature of such stimuli can vary ranging from extracellular cues, such as the presence of EGF, to intracellular events, such as the DNA damage resulting from replicative telomere attrition. Traditionally, signals that reach the central nervous system are classified as senses; these are transmitted from neuron to neuron in a process called synaptic transmission. Many other intercellular signal relay mechanisms exist in multicellular organisms, such as those that govern embryonic development; the majority of signal transduction pathways involve the binding of signaling molecules, known as ligands, to receptors that trigger events inside the cell. The binding of a signaling molecule with a receptor causes a change in the conformation of the receptor, known as receptor activation. Most ligands are soluble molecules from the extracellular medium which bind to cell surface receptors; these include growth factors and neurotransmitters. Components of the extracellular matrix such as fibronectin and hyaluronan can bind to such receptors.
In addition, some molecules such as steroid hormones are lipid-soluble and thus cross the plasma membrane to reach nuclear receptors. In the case of steroid hormone receptors, their stimulation leads to binding to the promoter region of steroid-responsive genes. Not all classifications of signaling molecules take into account the molecular nature of each class member. For example, odorants belong to a wide range of molecular classes, as do neurotransmitters, which range in size from small molecules such as dopamine to neuropeptides such as endorphins. Moreover, some molecules may fit into more than one class, e.g. epinephrine is a neurotransmitter when secreted by the central nervous system and a hormone when secreted by the adrenal medulla. Some receptors such as HER2 are capable of ligand-independent activation when overexpressed or mutated; this leads to constituitive activation of the pathway, which may or may not be overturned by compensation mechanisms. In the case of HER2, which acts as a dimerization partner of other EGFRs, constituitive activation leads to hyperproliferation and cancer.
The prevalence of basement membranes in the tissues of Eumetazoans means that most cell types require attachment to survive. This requirement has led to the development of complex mechanotransduction pathways, allowing cells to sense the stiffness of the substratum; such signaling is orchestrated in focal adhesions, regions where the integrin-bound actin cytoskeleton detects changes and transmits them downstream through YAP1. Calcium-dependent cell adhesion molecules such as cadherins and selectins can mediate mechanotransduction. Specialised forms of mechanotransduction within the nervous system are responsible for mechanosensation: hearing, touch and balance. Cellular and systemic control of osmotic pressure is critical for homeostasis. There are three ways in which cells can detect osmotic stimuli: as changes in macromolecular crowding, ionic strength, changes in the properties of the plasma membrane or cytoskeleton; these changes are detected by proteins known as osmoreceptors. In humans, the best characterised osmosensors are transient receptor potential channels present in the primary cilium of human cells.
In yeast, the HOG pathway has been extensively characterised. The sensing of temperature in cells is known as thermoception and is mediated by transient receptor potential channels. Addi