Tubulin in molecular biology can refer either to the tubulin protein superfamily of globular proteins, or one of the member proteins of that superfamily. Α- and β-tubulins polymerize into microtubules, a major component of the eukaryotic cytoskeleton. Microtubules function in many essential cellular processes, including mitosis. Tubulin-binding drugs kill cancerous cells by inhibiting microtubule dynamics, which are required for DNA segregation and therefore cell division. In eukaryotes there are six members of the tubulin superfamily, although not all are present in all species. Both α and β tubulins have a mass of around 50 kDa and are thus in a similar range compared to actin. In contrast, tubulin polymers tend to be much bigger than actin filaments due to their cylindrical nature. Tubulin was long thought to be specific to eukaryotes. More however, several prokaryotic proteins have been shown to be related to tubulin. Tubulin is characterized by GTPase protein domain; this GTPase protein domain is found in all eukaryotic tubulin chains, as well as the bacterial protein TubZ, the archaeal protein CetZ, the FtsZ protein family widespread in Bacteria and Archaea.
Α- and β-tubulin polymerize into dynamic microtubules. In eukaryotes, microtubules are one of the major components of the cytoskeleton, function in many processes, including structural support, intracellular transport, DNA segregation. Microtubules are assembled from dimers of α- and β-tubulin; these subunits are acidic with an isoelectric point between 5.2 and 5.8. Each has a molecular weight of 50 kDa. To form microtubules, the dimers of α- and β-tubulin bind to GTP and assemble onto the ends of microtubules while in the GTP-bound state; the β-tubulin subunit is exposed on the plus end of the microtubule while the α-tubulin subunit is exposed on the minus end. After the dimer is incorporated into the microtubule, the molecule of GTP bound to the β-tubulin subunit hydrolyzes into GDP through inter-dimer contacts along the microtubule protofilament. Whether the β-tubulin member of the tubulin dimer is bound to GTP or GDP influences the stability of the dimer in the microtubule. Dimers bound to GTP tend to assemble into microtubules, while dimers bound to GDP tend to fall apart.
Homologs of α- and β-tubulin have been identified in the Prosthecobacter genus of bacteria. They are designated BtubB to identify them as bacterial tubulins. Both exhibit homology to both α- and β-tubulin. While structurally similar to eukaryotic tubulins, they have several unique features, including chaperone-free folding and weak dimerization. Cryogenic electron microscopy showed that BtubA/B forms microtubules in vivo, suggested that these microtubules comprise only five protofilaments, in contrast to eukaryotic microtubules, which contain 13. Subsequent in vitro studies have shown that BtubA/B forms four-stranded'mini-microtubules'. FtsZ is found in nearly all Bacteria and Archaea, where it functions in cell division, localizing to a ring in the middle of the dividing cell and recruiting other components of the divisome, the group of proteins that together constrict the cell envelope to pinch off the cell, yielding two daughter cells. FtsZ can polymerize into tubes and rings in vitro, forms dynamic filaments in vivo.
TubZ functions in segregating low copy-number plasmids during bacterial cell division. The protein forms a structure unusual for a tubulin homolog; this may reflect an optimal structure for this role since the unrelated plasmid-partitioning protein ParM exhibits a similar structure. CetZ functions in cell shape changes in pleomorphic Haloarchaea. In Haloferax volcanii, CetZ forms dynamic cytoskeletal structures required for differentiation from a plate-shaped cell form into a rod-shaped form that exhibits swimming motility; the tubulin superfamily contains six families. Human α-tubulin subtypes include: All drugs that are known to bind to human tubulin bind to β-tubulin; these include paclitaxel and the vinca alkaloids, each of which have a distinct binding site on β-tubulin. Class III β-tubulin is a microtubule element expressed in neurons, is a popular identifier specific for neurons in nervous tissue, it binds colchicine much more than other isotypes of β-tubulin.β1-tubulin, sometimes called class VI β-tubulin, is the most divergent at the amino acid sequence level.
It is expressed in megakaryocytes and platelets in humans and appears to play an important role in the formation of platelets. When class VI β-tubulin were expressed in mammalian cells, they cause disruption of microtubule network, microtubule fragment formation, can cause marginal-band like structures present in megakaryocytes and platelets. Katanin is a protein complex that severs microtubules at β-tubulin subunits, is necessary for rapid microtubule transport in neurons and in higher plants. Human β-tubulins subtypes include: γ-Tubulin, another member of the tubulin family, is important in the nucleation and polar orientation of microtubules, it is found in centrosomes and spindle pole bodies, since these are the areas of most abundant microtubule nucleation. In these organelles, several γ-tubulin and other protein molecules are found in complexes known as γ-tubulin ring complexes, which chemically mimic the end of a microtubule and thus allow microtubules to bind. Γ-tubulin has been isolated as a dimer and as a part of a γ-tubulin small complex, intermedi
Deoxyribonucleic acid is a molecule composed of two chains that coil around each other to form a double helix carrying the genetic instructions used in the growth, development and reproduction of all known organisms and many viruses. DNA and ribonucleic acid are nucleic acids; the two DNA strands are known as polynucleotides as they are composed of simpler monomeric units called nucleotides. Each nucleotide is composed of one of four nitrogen-containing nucleobases, a sugar called deoxyribose, a phosphate group; the nucleotides are joined to one another in a chain by covalent bonds between the sugar of one nucleotide and the phosphate of the next, resulting in an alternating sugar-phosphate backbone. The nitrogenous bases of the two separate polynucleotide strands are bound together, according to base pairing rules, with hydrogen bonds to make double-stranded DNA; the complementary nitrogenous bases are divided into two groups and purines. In DNA, the pyrimidines are cytosine. Both strands of double-stranded DNA store the same biological information.
This information is replicated as and when the two strands separate. A large part of DNA is non-coding, meaning that these sections do not serve as patterns for protein sequences; the two strands of DNA are thus antiparallel. Attached to each sugar is one of four types of nucleobases, it is the sequence of these four nucleobases along the backbone. RNA strands are created using DNA strands as a template in a process called transcription. Under the genetic code, these RNA strands specify the sequence of amino acids within proteins in a process called translation. Within eukaryotic cells, DNA is organized into long structures called chromosomes. Before typical cell division, these chromosomes are duplicated in the process of DNA replication, providing a complete set of chromosomes for each daughter cell. Eukaryotic organisms store most of their DNA inside the cell nucleus as nuclear DNA, some in the mitochondria as mitochondrial DNA, or in chloroplasts as chloroplast DNA. In contrast, prokaryotes store their DNA only in circular chromosomes.
Within eukaryotic chromosomes, chromatin proteins, such as histones and organize DNA. These compacting structures guide the interactions between DNA and other proteins, helping control which parts of the DNA are transcribed. DNA was first isolated by Friedrich Miescher in 1869, its molecular structure was first identified by Francis Crick and James Watson at the Cavendish Laboratory within the University of Cambridge in 1953, whose model-building efforts were guided by X-ray diffraction data acquired by Raymond Gosling, a post-graduate student of Rosalind Franklin. DNA is used by researchers as a molecular tool to explore physical laws and theories, such as the ergodic theorem and the theory of elasticity; the unique material properties of DNA have made it an attractive molecule for material scientists and engineers interested in micro- and nano-fabrication. Among notable advances in this field are DNA origami and DNA-based hybrid materials. DNA is a long polymer made from repeating units called nucleotides.
The structure of DNA is dynamic along its length, being capable of coiling into tight loops and other shapes. In all species it is composed of two helical chains, bound to each other by hydrogen bonds. Both chains are coiled around the same axis, have the same pitch of 34 angstroms; the pair of chains has a radius of 10 angstroms. According to another study, when measured in a different solution, the DNA chain measured 22 to 26 angstroms wide, one nucleotide unit measured 3.3 Å long. Although each individual nucleotide is small, a DNA polymer can be large and contain hundreds of millions, such as in chromosome 1. Chromosome 1 is the largest human chromosome with 220 million base pairs, would be 85 mm long if straightened. DNA does not exist as a single strand, but instead as a pair of strands that are held together; these two long strands coil in the shape of a double helix. The nucleotide contains both a segment of the backbone of a nucleobase. A nucleobase linked to a sugar is called a nucleoside, a base linked to a sugar and to one or more phosphate groups is called a nucleotide.
A biopolymer comprising multiple linked nucleotides is called a polynucleotide. The backbone of the DNA strand is made from alternating sugar residues; the sugar in DNA is 2-deoxyribose, a pentose sugar. The sugars are joined together by phosphate groups that form phosphodiester bonds between the third and fifth carbon atoms of adjacent sugar rings; these are known as the 3′-end, 5′-end carbons, the prime symbol being used to distinguish these carbon atoms from those of the base to which the deoxyribose forms a glycosidic bond. When imagining DNA, each phosphoryl is considered to "belong" to the nucleotide whose 5′ carbon forms a bond therewith. Any DNA strand therefore has one end at which there is a phosphoryl attached to the 5′ carbon of a ribose and another end a
A polymer is a large molecule, or macromolecule, composed of many repeated subunits. Due to their broad range of properties, both synthetic and natural polymers play essential and ubiquitous roles in everyday life. Polymers range from familiar synthetic plastics such as polystyrene to natural biopolymers such as DNA and proteins that are fundamental to biological structure and function. Polymers, both natural and synthetic, are created via polymerization of many small molecules, known as monomers, their large molecular mass relative to small molecule compounds produces unique physical properties, including toughness, a tendency to form glasses and semicrystalline structures rather than crystals. The terms polymer and resin are synonymous with plastic; the term "polymer" derives from the Greek word πολύς and μέρος, refers to a molecule whose structure is composed of multiple repeating units, from which originates a characteristic of high relative molecular mass and attendant properties. The units composing polymers derive or conceptually, from molecules of low relative molecular mass.
The term was coined in 1833 by Jöns Jacob Berzelius, though with a definition distinct from the modern IUPAC definition. The modern concept of polymers as covalently bonded macromolecular structures was proposed in 1920 by Hermann Staudinger, who spent the next decade finding experimental evidence for this hypothesis. Polymers are studied in the fields of biophysics and macromolecular science, polymer science. Products arising from the linkage of repeating units by covalent chemical bonds have been the primary focus of polymer science. Polyisoprene of latex rubber is an example of a natural/biological polymer, the polystyrene of styrofoam is an example of a synthetic polymer. In biological contexts all biological macromolecules—i.e. Proteins, nucleic acids, polysaccharides—are purely polymeric, or are composed in large part of polymeric components—e.g. Isoprenylated/lipid-modified glycoproteins, where small lipidic molecules and oligosaccharide modifications occur on the polyamide backbone of the protein.
The simplest theoretical models for polymers are ideal chains. Polymers are of two types: occurring and synthetic or man made. Natural polymeric materials such as hemp, amber, wool and natural rubber have been used for centuries. A variety of other natural polymers exist, such as cellulose, the main constituent of wood and paper; the list of synthetic polymers in order of worldwide demand, includes polyethylene, polystyrene, polyvinyl chloride, synthetic rubber, phenol formaldehyde resin, nylon, polyacrylonitrile, PVB, many more. More than 330 million tons of these polymers are made every year. Most the continuously linked backbone of a polymer used for the preparation of plastics consists of carbon atoms. A simple example is polyethylene. Many other structures do exist. Oxygen is commonly present in polymer backbones, such as those of polyethylene glycol, DNA. Polymerization is the process of combining many small molecules known as monomers into a covalently bonded chain or network. During the polymerization process, some chemical groups may be lost from each monomer.
This happens in the polymerization of PET polyester. The monomers are terephthalic acid and ethylene glycol but the repeating unit is —OC—C6H4—COO—CH2—CH2—O—, which corresponds to the combination of the two monomers with the loss of two water molecules; the distinct piece of each monomer, incorporated into the polymer is known as a repeat unit or monomer residue. Laboratory synthetic methods are divided into two categories, step-growth polymerization and chain-growth polymerization; the essential difference between the two is that in chain growth polymerization, monomers are added to the chain one at a time only, such as in polyethylene, whereas in step-growth polymerization chains of monomers may combine with one another directly, such as in polyester. Newer methods, such as plasma polymerization do not fit neatly into either category. Synthetic polymerization reactions may be carried out without a catalyst. Laboratory synthesis of biopolymers of proteins, is an area of intensive research. There are three main classes of biopolymers: polysaccharides and polynucleotides.
In living cells, they may be synthesized by enzyme-mediated processes, such as the formation of DNA catalyzed by DNA polymerase. The synthesis of proteins involves multiple enzyme-mediated processes to transcribe genetic information from the DNA to RNA and subsequently translate that information to synthesize the specified protein from amino acids; the protein may be modified further following translation in order to provide appropriate structure and functioning. There are other biopolymers such as rubber, suberin and lignin. Occurring polymers such as cotton and rubber were familiar materials for years before synthetic polymers such as polyethene and perspex appeared on the market. Many commercially important polymers are synthesized by chemical modification of occurring polymers. Prominent examples inclu
Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to the cytoplasm of eukaryotic cells, some bacteria and some archaea. A microtubule can grow as long as 50 micrometres and are dynamic; the outer diameter of a microtubule is about 24 nm. They are formed by the polymerization of a dimer of two globular proteins and beta tubulin into protofilaments that can associate laterally to form a hollow tube, the microtubule; the most common form of a microtubule consists of 13 protofilaments in the tubular arrangement. Microtubules are important in a number of cellular processes, they are involved in maintaining the structure of the cell and, together with microfilaments and intermediate filaments, they form the cytoskeleton. They make up the internal structure of cilia and flagella, they provide platforms for intracellular transport and are involved in a variety of cellular processes, including the movement of secretory vesicles and intracellular macromolecular assemblies.
They are involved in cell division and are the major constituents of mitotic spindles, which are used to pull eukaryotic chromosomes apart. Microtubules are nucleated and organized by microtubule organizing centers, such as the centrosome found in the center of many animal cells or the basal bodies found in cilia and flagella, or the spindle pole bodies found in most fungi. There are many proteins that bind to microtubules, including the motor proteins kinesin and dynein, severing proteins like katanin, other proteins important for regulating microtubule dynamics. An actin-like protein has been found in a gram-positive bacterium Bacillus thuringiensis, which forms a microtubule-like structure and is involved in plasmid segregation. Tubulin and microtubule-mediated processes, like cell locomotion, were seen by early microscopists, like Leeuwenhoek. However, the fibrous nature of flagella and other structures were discovered two centuries with improved light microscopes, confirmed in the 20th century with the electron microscope and biochemical studies.
Microtubule in vitro assays for motor proteins such as dynein and kinesin are researched by fluorescently tagging a microtubule and fixing either the microtubule or motor proteins to a microscope slide visualizing the slide with video-enhanced microscopy to record the travel of the microtubule motor proteins. This allows the movement of the motor proteins along the microtubule or the microtubule moving across the motor proteins; some microtubule processes can be determined by kymograph. In eukaryotes, microtubules are long, hollow cylinders made up of polymerised α- and β-tubulin dimers; the inner space of the hollow microtubule cylinders is referred to as the lumen. The α and β-tubulin subunits are 50% identical at the amino acid level, each have a molecular weight of 50 kDa; these α/β-tubulin dimers polymerize end-to-end into linear protofilaments that associate laterally to form a single microtubule, which can be extended by the addition of more α/β-tubulin dimers. Microtubules are formed by the parallel association of thirteen protofilaments, although microtubules composed of fewer or more protofilaments have been observed in vitro.
Microtubules have a distinct polarity, critical for their biological function. Tubulin polymerizes end to end, with the β-subunits of one tubulin dimer contacting the α-subunits of the next dimer. Therefore, in a protofilament, one end will have the α-subunits exposed while the other end will have the β-subunits exposed; these ends are designated ends, respectively. The protofilaments bundle parallel to one another with the same polarity, so, in a microtubule, there is one end, the end, with only β-subunits exposed, while the other end, the end, has only α-subunits exposed. While microtubule elongation can occur at both the and ends, it is more rapid at the end; the lateral association of the protofilaments generates a pseudo-helical structure, with one turn of the helix containing 13 tubulin dimers, each from a different protofilament. In the most common "13-3" architecture, the 13th tubulin dimer interacts with the next tubulin dimer with a vertical offset of 3 tubulin monomers due to the helicity of the turn.
There are other alternative architectures, such as 11-3, 12-3, 14-3, 15-4, or 16-4, that have been detected at a much lower occurrence. Microtubules can morph into other forms such as helical filaments, which are observed in protist organisms like foraminifera. There are two distinct types of interactions that can occur between the subunits of lateral protofilaments within the microtubule called the A-type and B-type lattices. In the A-type lattice, the lateral associations of protofilaments occur between adjacent α and β-tubulin subunits. In the B-type lattice, the α and β-tubulin subunits from one protofilament interact with the α and β-tubulin subunits from an adjacent protofilament, respectively. Experimental studies have shown that the B-type lattice is the primary arrangement within microtubules. However, in most microtubules there is a seam in which tubulin subunits interact α-β; some species of Prosthecobacter contain microtubules. The structure of these bacterial microtubules is similar to that of eukaryotic microtubules, consisting of a hollow tube of protofilaments assembled from heterodimers of bacterial tubulin A and bacterial tubulin B.
Both BtubA and BtubB share features of both α- and β-tubulin. Unlike eukar
A kinesin is a protein belonging to a class of motor proteins found in eukaryotic cells. Kinesins move along microtubule filaments, are powered by the hydrolysis of adenosine triphosphate; the active movement of kinesins supports several cellular functions including mitosis and transport of cellular cargo, such as in axonal transport. Most kinesins walk towards the positive end of a microtubule, which, in most cells, entails transporting cargo such as protein and membrane components from the centre of the cell towards the periphery; this form of transport is known as anterograde transport. In contrast, dyneins are motor proteins that move toward the negative end of a microtubule in retrograde transport. Kinesins were discovered as MT-based anterograde intracellular transport motors; the founding member of this superfamily, kinesin-1, was isolated as a heterotetrameric fast axonal organelle transport motor consisting of 2 identical motor subunits and 2 "light chains" via microtubule affinity purification from neuronal cell extracts.
Subsequently, a different, heterotrimeric plus-end-directed MT-based motor named kinesin-2, consisting of 2 distinct KHC-related motor subunits and an accessory "KAP" subunit, was purified from echinoderm egg/embryo extracts and is best known for its role in transporting protein complexes along axonemes during cilium biogenesis. Molecular genetic and genomic approaches have led to the recognition that the kinesins form a diverse superfamily of motors that are responsible for multiple intracellular motility events in eukaryotic cells. For example, the genomes of mammals encode more than 40 kinesin proteins, organized into at least 14 families named kinesin-1 through kinesin-14. Members of the kinesin superfamily vary in shape but the prototypical kinesin-1 is a heterotetramer whose motor subunits form a protein dimer that binds two light chains; the heavy chain of kinesin-1 comprises a globular head at the amino terminal end connected via a short, flexible neck linker to the stalk – a long, central alpha-helical coiled coil domain – that ends in a carboxy terminal tail domain which associates with the light-chains.
The stalks of two KHCs intertwine to form a coiled coil. In most cases transported cargo binds to the kinesin light chains, at the TPR motif sequence of the KLC, but in some cases cargo binds to the C-terminal domains of the heavy chains; the head is the signature of kinesin and its amino acid sequence is well conserved among various kinesins. Each head has two separate binding sites: one for the microtubule and the other for ATP. ATP binding and hydrolysis as well as ADP release change the conformation of the microtubule-binding domains and the orientation of the neck linker with respect to the head. Several structural elements in the Head, including a central beta-sheet domain and the Switch I and II domains, have been implicated as mediating the interactions between the two binding sites and the neck domain. Kinesins are structurally related to G proteins, which hydrolyze GTP instead of ATP. Several structural elements are shared between the two families, notably the Switch I and Switch II domains.
In the cell, small molecules, such as gases and glucose, diffuse to. Large molecules synthesised in the cell body, intracellular components such as vesicles and organelles such as mitochondria are too large to be able to diffuse to their destinations. Motor proteins fulfill the role of transporting large cargo about the cell to their required destinations. Kinesins are motor proteins that transport such cargo by walking unidirectionally along microtubule tracks hydrolysing one molecule of adenosine triphosphate at each step, it was thought that ATP hydrolysis powered each step, the energy released propelling the head forwards to the next binding site. However, it has been proposed that the head diffuses forward and the force of binding to the microtubule is what pulls the cargo along. In addition viruses, HIV for example, exploit kinesins to allow virus particle shuttling after assembly. There is significant evidence. Motor proteins travel in a specific direction along a microtubule. Microtubules are polar.
It has been known that kinesin move cargo towards the positive end of a microtubule known as anterograde transport/orthograde transport. However, it has been discovered that in budding yeast cells kinesin Cin8 can move toward the negative end as well, or retrograde transport; this means, kinesin has the novel ability to switch directionality. Kinesin, so far, has only been shown to move toward the negative end when in a group, with motors sliding in the antiparallel direction in an attempt to separate microtubules; this dual directionality has been observed in identical conditions where free Cin8 molecules move towards the minus end, but cross-linking Cin8 move toward the plus ends of each cross-linked microtubule. One specific study tested the speed at which Cin8 motors moved, their results yielded a range of about 25-55nm/s, in the direction of the spindle poles. On an individual basis it has been found that through the use of ionic conditions Cin8 motors can become as fast as 380nm/s, a notable jump.
This tells us that Cin 8 can change directions on a microtubule, in turn led to the plus end movement of kinesin on a microtubule. It is suggested that this unique ability
Cyclin-dependent kinases are a family of protein kinases first discovered for their role in regulating the cell cycle. They are involved in regulating transcription, mRNA processing, the differentiation of nerve cells, they are present in all known eukaryotes, their regulatory function in the cell cycle has been evolutionarily conserved. In fact, yeast cells can proliferate when their CDK gene has been replaced with the homologous human gene. CDKs are small proteins, with molecular weights ranging from 34 to 40 kDa, contain little more than the kinase domain. By definition, a CDK binds. Without cyclin, CDK has little kinase activity. CDKs phosphorylate their substrates on serines and threonines, so they are serine-threonine kinases; the consensus sequence for the phosphorylation site in the amino acid sequence of a CDK substrate is PX, where S/T* is the phosphorylated serine or threonine, P is proline, X is any amino acid, K is lysine, R is arginine. Most of the known cyclin-CDK complexes regulate the progression through the cell cycle.
Animal cells contain at least nine CDKs, four of which, CDK1, 2, 3, 4, are directly involved in cell cycle regulation. In mammalian cells, CDK1, with its partners cyclin A2 and B1, alone can drive the cell cycle. Another one, CDK7, is involved indirectly as the CDK-activating kinase. Cyclin-CDK complexes phosphorylate substrates appropriate for the particular cell cycle phase. Cyclin-CDK complexes of earlier cell-cycle phase help activate cyclin-CDK complexes in phase. A list of CDKs with their regulator protein, cyclin or other: CDK1. See CDKL5. CDK6. Most knowledge of CDK structure and function is based on CDKs of S. pombe, S. cerevisiae, vertebrates. The four major mechanisms of CDK regulation are cyclin binding, CAK phosphorylation, regulatory inhibitory phosphorylation, binding of CDK inhibitory subunits; the active site, or ATP-binding site, of all kinases is a cleft between a small amino-terminal lobe and a larger carboxy-terminal lobe. The structure of human Cdk2 revealed that CDKs have a modified ATP-binding site that can be regulated by cyclin binding.
Phosphorylation by CDK-activating kinase at Thr 161 on the T-loop increases the complex activity. Without cyclin, a flexible loop called the activation loop or T-loop blocks the cleft, the position of several key amino acid residues is not optimal for ATP-binding. With cyclin, two alpha helices change position to permit ATP binding. One of them, the L12 helix that comes just before the T-loop in the primary sequence, becomes a beta strand and helps rearrange the T-loop, so it no longer blocks the active site; the other alpha helix called the PSTAIRE helix rearranges and helps change the position of the key amino acid residues in the active site. There is considerable specificity in which cyclin binds with CDK. Furthermore, cyclin binding determines the specificity of the cyclin-CDK complex for particular substrates. Cyclins can directly bind the substrate or localize the CDK to a subcellular area where the substrate is found. Substrate specificity of S cyclins is imparted by the hydrophobic batch, which has affinity for substrate proteins that contain a hydrophobic RXL motif.
Cyclin B1 and B2 can localize Cdk1 to the nucleus and the Golgi through a localization sequence outside the CDK-binding region. Full kinase activity requires an activating phosphorylation on a threonine adjacent to the active site; the identity of the CDK-activating kinase that performs this phosphorylation varies across the model organisms. The timing of this phosphorylation varies as well. In mammalian cells, the activating phosphorylation occurs after cyclin binding. In yeast cells, it occurs before cyclin binding. CAK activity is not regulated by known cell-cycle pathways and cyclin binding is the limiting step for CDK activation. Unlike activating phosphorylation, CDK inhibitory phosphorylation is vital for regulation of the cell cycle. Various kinases and phosphatases regulate their phosphorylation state. One of the kinases that place the tyrosine phosphate is a kinase conserved in all eukaryotes. Fission yeast contains a second kinase Mik1 that can phosphorylate the tyrosine. Vertebrates contain a different second kinase called Myt1, related to Wee1 but can phosphorylate both the threonine and the tyrosine.
Phosphatases from the Cdc25 family dephosphorylate both the tyrosine. A cyclin-dependent kinase inhibitor is a protein that interacts with a cyclin-CDK complex to block kinase activity during G1 or in response to signals from the environment or from damaged DNA. In animal cells, there are two major CKI families: the CIP/KIP family; the INK4 family proteins are inhibitory and bind CDK monomers. Crystal structures of CDK6-INK4 complexes show that INK4 binding twists the CDK to distort cyclin binding and kinase activity; the CIP/KIP family proteins bind both the cyclin and the CDK of a complex and can be inhibitory or activating. CIP/KIP family proteins activate CDK4 or CDK6 complexes by enhancing complex formation. In yeast and Drosophila, CKIs are strong inhibitors of S - and do not inhibit G1/S-CDKs. During G1, high levels of CKIs prevent ce
In biology, poisons are substances that cause disturbances in organisms by chemical reaction or other activity on the molecular scale, when an organism absorbs a sufficient quantity. The fields of medicine and zoology distinguish a poison from a toxin, from a venom. Toxins are poisons produced by organisms in nature, venoms are toxins injected by a bite or sting; the difference between venom and other poisons is the delivery method. Industry and other sectors employ poisonous substances for reasons other than their toxicity. Most poisonous industrial compounds have associated material safety data sheets and are classed as hazardous substances. Hazardous substances are subject to extensive regulation on production and use in overlapping domains of occupational safety and health, public health, drinking water quality standards, air pollution and environmental protection. Due to the mechanics of molecular diffusion, many poisonous compounds diffuse into biological tissues, water, or soil on a molecular scale.
By the principle of entropy, chemical contamination is costly or infeasible to reverse, unless specific chelating agents or micro-filtration processes are available. Chelating agents are broader in scope than the acute target, therefore their ingestion necessitates careful medical or veterinarian supervision. Pesticides are one group of substances whose toxicity to various insects and other animals deemed to be pests is their prime purpose. Natural pesticides have been used for this purpose for thousands of years. Bioaccumulation of chemically-prepared agricultural insecticides is a matter of concern for the many species birds, which consume insects as a primary food source. Selective toxicity, controlled application, controlled biodegradation are major challenges in herbicide and pesticide development and in chemical engineering as all lifeforms on earth share an underlying biochemistry. A poison which enters the food chain—whether of industrial, agricultural, or natural origin—might not be toxic to the first organism that ingests the toxin, but can become further concentrated in predatory organisms further up the food chain carnivores and omnivores concerning fat soluble poisons which tend to become stored in biological tissue rather than excreted in urine or other water-based effluents.
Two common cases of acute natural poisoning are theobromine poisoning of dogs and cats, mushroom poisoning in humans. Dogs and cats are not natural herbivores, but a chemical defense developed by Theobroma cacao can be incidentally fatal nevertheless. Many omnivores, including humans consume edible fungi, thus many fungi have evolved to become decisively inedible, in this case as a direct defense. Apart from food, many poisons enter the body through the skin and lungs. Hydrofluoric acid is a notorious contact poison, in addition to its corrosive damage. Occurring sour gas is a notorious, fast-acting atmospheric poison. Plant-based contact irritants, such as that possessed by poison ivy or poison oak, are classed as allergens rather than poisons. Poison can enter the body through the teeth, faulty medical implants, or by injection. In 2013, 3.3 million cases of unintentional human poisonings occurred. This resulted in 98,000 deaths worldwide, down from 120,000 deaths in 1990. In modern society, cases of suspicious death elicit the attention of the Coroner's office and forensic investigators.
While arsenic is a occurring environmental poison, its artificial concentrate was once nicknamed inheritance powder. In Medieval Europe, it was common for monarchs to employ personal food tasters to thwart royal assassination, in the dawning age of the Apothecary. Of increasing concern since the isolation of natural radium by Marie and Pierre Curie in 1898—and the subsequent advent of nuclear physics and nuclear technologies—are radiological poisons; these are associated with ionizing radiation, a mode of toxicity quite distinct from chemically active poisons. In mammals, chemical poisons are passed from mother to offspring through the placenta during gestation, or through breast milk during nursing. In contrast, radiological damage can be passed from mother or father to offspring through genetic mutation, which—if not fatal in miscarriage or childhood, or a direct cause of infertility—can be passed along again to a subsequent generation. Atmospheric radon is a natural radiological poison of increasing impact since humans moved from hunter-gatherer lifestyles though cave dwelling to enclosed structures able to contain radon in dangerous concentrations.
The 2006 poisoning of Alexander Litvinenko was a novel use of radiological assassination meant to evade the normal investigation of chemical poisons. Poisons dispersed into the environment are known as pollution; these are of human origin, but pollution can include unwanted biological processes such as toxic red tide, or acute changes to the natural chemical environment attributed to invasive species, which are toxic or detrimental to the prior ecology (especially if the prior ecology was associated with human economic valu