A cofactor is a non-protein chemical compound or metallic ion that is required for a proteins biological activity to happen. These proteins are enzymes, and cofactors can be considered helper molecules that assist in biochemical transformations. A coenzyme that is tightly or even covalently bound is termed a prosthetic group, the two subcategories under coenzyme are cosubstrates and prosthetic groups. Cosubstrates are transiently bound to the protein and will be released at some point, the prosthetic groups, on the other hand, are bound permanently to the protein. Both of them have the function, which is to facilitate the reaction of enzymes. Additionally, some sources limit the use of the cofactor to inorganic substances. An inactive enzyme without the cofactor is called an apoenzyme, while the enzyme with cofactor is called a holoenzyme. Some enzymes or enzyme complexes require several cofactors, organic cofactors are often vitamins or made from vitamins. Many contain the nucleotide adenosine monophosphate as part of their structures, such as ATP, coenzyme A, FAD and this common structure may reflect a common evolutionary origin as part of ribozymes in an ancient RNA world.
It has been suggested that the AMP part of the molecule can be considered to be a kind of handle by which the enzyme can grasp the coenzyme to switch it between different catalytic centers. Cofactors can be divided into two groups, organic cofactors, such as flavin or heme, and inorganic cofactors, such as the metal ions Mg2+, Cu+, Mn2+. Organic cofactors are sometimes divided into coenzymes and prosthetic groups. The term coenzyme refers specifically to enzymes and, as such, on the other hand, prosthetic group emphasizes the nature of the binding of a cofactor to a protein and, refers to a structural property. Different sources give different definitions of coenzymes, cofactors. It should be noted that terms are often used loosely. However, the author could not arrive at a single all-encompassing definition of a coenzyme, the study of these cofactors falls under the area of bioinorganic chemistry. In nutrition, the list of essential trace elements reflects their role as cofactors, in humans this list commonly includes iron, manganese, copper and molybdenum.
Although chromium deficiency causes impaired glucose tolerance, no human enzyme that uses this metal as a cofactor has been identified, iodine is an essential trace element, but this element is used as part of the structure of thyroid hormones rather than as an enzyme cofactor
Membrane transport protein
A membrane transport protein is a membrane protein involved in the movement of ions, small molecules, or macromolecules, such as another protein, across a biological membrane. Transport proteins are transmembrane proteins, that is they exist permanently within. The proteins may assist in the movement of substances by facilitated diffusion or active transport, the two main types of proteins involved in such transport are broadly categorized as either channels or carriers. A carrier is not open simultaneously to both the extracellular and intracellular environments, either its inner gate is open, or outer gate is open. In contrast, a channel can be open to both environments at the time, allowing the solutes it transports to diffuse without interruption. Carriers have binding sites, but pores and channels do not, when a channel is opened, millions of ions can pass through the membrane per second, but only 100 to 1000 molecules typically pass through a carrier molecule in the same time. Each carrier protein is designed to only one substance or one group of very similar substances.
Research has correlated defects in carrier proteins with specific diseases. Active transport is the movement of a substance across a membrane against its concentration gradient and this is usually to accumulate high concentrations of molecules that a cell needs, such as glucose or amino acids. When the lipid bilayer is impermeable to the molecule needing transport, if the process uses chemical energy, such as adenosine triphosphate, it is called primary active transport. Secondary active transport involves the use of a gradient. A carrier protein is required to move particles from areas of low concentration to areas of high concentration and these carrier proteins have receptors that bind to a specific molecule needing transport. The molecule or ion to be transported must first bind at a site at the carrier molecule. The carrier protein substrate is released at that site, according to its binding affinity there, facilitated diffusion is the passage of molecules or ions across a biological membrane through specific transport proteins and requires no energy input.
The type of proteins used in facilitated diffusion is slightly different from those used in active transport. They are still transmembrane carrier proteins, but these are gated transmembrane channels, meaning they do not internally translocate, the substrate is taken in one side of the gated carrier, and without using ATP the substrate is released into the cell. Facilitated diffusion occurs in and out of the membrane via channels/pores. Note, Channels are either in state or closed state
A receptor antagonist is a type of receptor ligand or drug that blocks or dampens agonist-mediated responses rather than provoking a biological response itself upon binding to a receptor. They are sometimes called blockers, examples include alpha blockers, beta blockers, antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex, which, in turn, depends on the nature of antagonist–receptor binding. The majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally defined binding sites on receptors, biochemical receptors are large protein molecules that can be activated by the binding of a ligand. Receptors can be membrane-bound, occurring on the membrane, or intracellular. Binding occurs as a result of noncovalent interaction between the receptor and its ligand, at locations called the site on the receptor. A receptor may contain one or more binding sites for different ligands, binding to the active site on the receptor regulates receptor activation directly.
The activity of receptors can be regulated by the binding of a ligand to other sites on the receptor, antagonists mediate their effects through receptor interactions by preventing agonist-induced responses. This may be accomplished by binding to the site or the allosteric site. In addition, antagonists may interact at unique binding sites not normally involved in the regulation of the receptors activity to exert their effects. The term antagonist was originally coined to describe different profiles of drug effects, the biochemical definition of a receptor antagonist was introduced by Ariens and Stephenson in the 1950s. The current accepted definition of receptor antagonist is based on the receptor occupancy model and it narrows the definition of antagonism to consider only those compounds with opposing activities at a single receptor. Agonists were thought to turn on a cellular response by binding to the receptor. Antagonists were thought to turn off that response by blocking the receptor from the agonist and this definition remains in use for physiological antagonists, substances that have opposing physiological actions, but act at different receptors.
Our understanding of the mechanism of drug-induced receptor activation and receptor theory, the two-state model of receptor activation has given way to multistate models with intermediate conformational states. This means efficacy may actually depend on where that receptor is expressed, by definition, antagonists display no efficacy to activate the receptors they bind. Antagonists do not maintain the ability to activate a receptor, once bound, antagonists inhibit the function of agonists, inverse agonists, and partial agonists. In functional antagonist assays, a dose-response curve measures the effect of the ability of a range of concentrations of antagonists to reverse the activity of an agonist, the potency of an antagonist is usually defined by its half maximal inhibitory concentration IC50 value. This can be calculated for a given antagonist by determining the concentration of antagonist needed to elicit half inhibition of the biological response of an agonist
Not to be confused with, Ion Television or Ion implantation. Ion channels are present in the membranes of all cells, Ion channels are one of the two classes of ionophoric proteins, along with ion transporters. Their classification as molecules is referred to as channelomics, there are two distinctive features of ion channels that differentiate them from other types of ion transporter proteins, The rate of ion transport through the channel is very high. Ions pass through channels down their electrochemical gradient, which is a function of ion concentration and membrane potential, Ion channels are located within the membrane of most cells and of many intracellular organelles. They are often described as narrow, water-filled tunnels that allow only ions of a certain size and/or charge to pass through and this characteristic is called selective permeability. The archetypal channel pore is just one or two atoms wide at its narrowest point and is selective for specific species of ion, such as sodium or potassium.
However, some channels may be permeable to the passage of more than one type of ion, typically sharing a common charge, ions often move through the segments of the channel pore in single file nearly as quickly as the ions move through free solution. In many ion channels, passage through the pore is governed by a gate, Ion channels are integral membrane proteins, typically formed as assemblies of several individual proteins. Such multi-subunit assemblies usually involve an arrangement of identical or homologous proteins closely packed around a water-filled pore through the plane of the membrane or lipid bilayer. For most voltage-gated ion channels, the pore-forming subunit are called the α subunit, while the auxiliary subunits are denoted β, γ, because channels underlie the nerve impulse and because transmitter-activated channels mediate conduction across the synapses, channels are especially prominent components of the nervous system. Indeed, numerous toxins that organisms have evolved for shutting down the nervous systems of predators, in the search for new drugs, ion channels are a frequent target.
There are over 300 types of ion channels in a living cell, Ion channels may be classified by the nature of their gating, the species of ions passing through those gates, the number of gates and localization of proteins. Further heterogeneity of ion channels arises when channels with different constitutive subunits give rise to a kind of current. Absence or mutation of one or more of the types of channel subunits can result in loss of function and, potentially. Ion channels may be classified by gating, i. e. what opens, Voltage-gated ion channels open or close depending on the voltage gradient across the plasma membrane, while ligand-gated ion channels open or close depending on binding of ligands to the channel. Voltage-gated ion channels open and close in response to membrane potential, Voltage-gated sodium channels, This family contains at least 9 members and is largely responsible for action potential creation and propagation. The pore-forming α subunits are very large and consist of four repeat domains each comprising six transmembrane segments for a total of 24 transmembrane segments.
The members of family coassemble with auxiliary β subunits
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, sometimes in pharmacology, the term is used to include other proteins that are drug targets, such as enzymes 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 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, 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
Enzymes /ˈɛnzaɪmz/ are macromolecular biological catalysts. Enzymes accelerate, or catalyze, chemical reactions, the molecules at the beginning of the process upon which enzymes may act are called substrates and the enzyme converts these into different molecules, called products. Almost all metabolic processes in the cell need enzymes in order to occur at rates fast enough to sustain life, the set of enzymes made in a cell determines which metabolic pathways occur in that cell. The study of enzymes is called enzymology, enzymes are known to catalyze more than 5,000 biochemical reaction types. Most enzymes are proteins, although a few are catalytic RNA molecules, enzymes specificity comes from their unique three-dimensional structures. Like all catalysts, enzymes increase the rate of a reaction by lowering its activation energy, some enzymes can make their conversion of substrate to product occur many millions of times faster. An extreme example is orotidine 5-phosphate decarboxylase, which allows a reaction that would take millions of years to occur in milliseconds.
Chemically, enzymes are like any catalyst and are not consumed in chemical reactions, enzymes differ from most other catalysts by being much more specific. Enzyme activity can be affected by other molecules, inhibitors are molecules that decrease enzyme activity, many drugs and poisons are enzyme inhibitors. An enzymes activity decreases markedly outside its optimal temperature and pH, some enzymes are used commercially, for example, in the synthesis of antibiotics. French chemist Anselme Payen was the first to discover an enzyme, diastase and he wrote that alcoholic fermentation is an act correlated with the life and organization of the yeast cells, not with the death or putrefaction of the cells. In 1877, German physiologist Wilhelm Kühne first used the term enzyme, the word enzyme was used to refer to nonliving substances such as pepsin, and the word ferment was used to refer to chemical activity produced by living organisms. Eduard Buchner submitted his first paper on the study of yeast extracts in 1897, in a series of experiments at the University of Berlin, he found that sugar was fermented by yeast extracts even when there were no living yeast cells in the mixture.
He named the enzyme that brought about the fermentation of sucrose zymase, in 1907, he received the Nobel Prize in Chemistry for his discovery of cell-free fermentation. Following Buchners example, enzymes are usually named according to the reaction they carry out, the biochemical identity of enzymes was still unknown in the early 1900s. Sumner showed that the enzyme urease was a protein and crystallized it. These three scientists were awarded the 1946 Nobel Prize in Chemistry, the discovery that enzymes could be crystallized eventually allowed their structures to be solved by x-ray crystallography. This high-resolution structure of lysozyme marked the beginning of the field of structural biology, an enzymes name is often derived from its substrate or the chemical reaction it catalyzes, with the word ending in -ase
Retigabine or ezogabine is an anticonvulsant used as an adjunctive treatment for partial epilepsies in treatment-experienced adult patients. The drug was developed by Valeant Pharmaceuticals and GlaxoSmithKline and it was approved by the European Medicines Agency under the trade name Trobalt on March 28,2011, and by the United States Food and Drug Administration, under the trade name Potiga, on June 10,2011. Production will be discontinued after June 2017, and the product no longer be commercially available. Retigabine works primarily as a potassium channel opener—that is, by activating a certain family of voltage-gated potassium channels in the brain. This mechanism of action is unique among antiepileptic drugs, and may hold promise for the treatment of other conditions, including tinnitus, migraine. The adverse effects found in the Phase II trial mainly affected the central nervous system, the most common adverse effects were drowsiness, dizziness and vertigo, and slurred speech. Less common side effects included tremor, memory loss, gait disturbances, in 2013 FDA warned the public that, Potiga can cause blue skin discoloration and eye abnormalities characterized by pigment changes in the retina. FDA does not currently know if these changes are reversible, FDA is working with the manufacturer to gather and evaluate all available information to better understand these events. FDA will update the public when more information is available, psychiatric symptoms and difficulty urinating have been reported, with most cases occurring in the first 2 months of treatment.
Retigabine appears to be free of interactions with most commonly used anticonvulsants. It may increase metabolism of lamotrigine, whereas phenytoin and carbamazepine increase the clearance of retigabine, concomitant use of retigabine and digoxin may increase serum concentration of the latter. In vitro studies suggest that the metabolite of retigabine acts as a P-glycoprotein inhibitor. Retigabine acts as a neuronal KCNQ/Kv7 potassium channel opener, a mechanism of action different from that of any current anticonvulsants. This mechanism of action is similar to that of the chemically-similar flupirtine, Retigabine is quickly absorbed, and reaches maximum plasma concentrations between half an hour and 2 hours after a single oral dose. It has a high oral bioavailability, a high volume of distribution. Retigabine requires thrice-daily dosing due to its short half-life, Retigabine is metabolized in the liver, by N-glucuronidation and acetylation. The cytochrome P450 system is not involved and its metabolites are excreted almost completely by the kidneys.
Among the newer anticonvulsants, retigabine was one of the most widely studied in the preclinical setting, researchers hoped this wide-ranging activity would translate to studies in humans as well
An agonist is a chemical that binds to a receptor and activates the receptor to produce a biological response. Whereas an agonist causes an action, an antagonist blocks the action of the agonist, receptors can be activated by either endogenous or exogenous agonists, resulting in a biological response. A physiological agonist is a substance that creates the same bodily responses but does not bind to the same receptor, an endogenous agonist for a particular receptor is a compound naturally produced by the body that binds to and activates that receptor. For example, the endogenous agonist for serotonin receptors is serotonin, a superagonist is a compound that is capable of producing a greater maximal response than the endogenous agonist for the target receptor, and thus has an efficacy of more than 100%. Full agonists bind and activate a receptor, producing full efficacy at that receptor, one example of a drug that acts as a full agonist is isoproterenol, which mimics the action of adrenaline at β adrenoreceptors.
Another example is morphine, which mimics the actions of endorphins at μ-opioid receptors throughout the nervous system. Partial agonists bind and activate a receptor, but have only partial efficacy at the receptor relative to a full agonist. Agents like buprenorphine are used to treat opiate dependence for this reason, as they produce milder effects on the receptor with lower dependence. An inverse agonist is an agent that binds to the same receptor binding-site as an agonist for that receptor, inverse agonists exert the opposite pharmacological effect of a receptor agonist, not merely an absence of the agonist effect as seen with antagonist. An example is the inverse agonist rimonabant. A co-agonist works with other co-agonists to produce the desired effect together, NMDA receptor activation requires the binding of both glutamate, glycine and D-serine co-agonists. An irreversible agonist is a type of agonist that binds permanently to a receptor through the formation of covalent bonds, a few of these have been described. A selective agonist is selective for a type of receptor. E. g. buspirone is a selective agonist for serotonin 5-HT1A, terms that describe this phenomenon are functional selectivity, protean agonism, or selective receptor modulators.
Potency is the amount of agonist needed to elicit a desired response, the potency of an agonist is inversely related to its EC50 value. The EC50 can be measured for a given agonist by determining the concentration of agonist needed to elicit half of the biological response of the agonist. The EC50 value is useful for comparing the potency of drugs with similar efficacies producing physiologically similar effects, the smaller the EC50 value, the greater the potency of the agonist, the lower the concentration of drug that is required to elicit the maximum biological response. This relationship, termed the index, is defined as the ratio TD50, ED50
Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group that is connected to an aromatic ring by a two-carbon chain. All monoamines are derived from amino acids like phenylalanine, tryptophan. Drugs used to increase the effect of monoamine are sometimes used to treat patients with psychiatric disorders, including depression, after release into the synaptic cleft, monoamine neurotransmitter action is ended by reuptake into the presynaptic terminal. There, they can be repackaged into synaptic vesicles or degraded by the enzyme oxidase, which is a target of monoamine oxidase inhibitors. As demonstrated by the existence of monoamine transmitters, an organisms ability to modify its behavior is advantageous to its survival. This system is found in species such as nematodes, desert locusts, mice. Disorders of monoamine neurotransmitters exist, part of a number of neurotransmitter disorders identified. Such disorders are responsible for degradation and difficulty in transporting neurotransmitters such as dopamine, epinephrine.
Monoamine neurotransmitter disorders mimic the symptoms of other more prevalent neurological disorders and thus are frequently misdiagnosed
A drug is any substance that, when inhaled, smoked, absorbed via a patch on the skin, or dissolved under the tongue, causes a physiological change in the body. In pharmacology, a drug, called a medication or medicine, is a chemical substance used to treat, prevent. Traditionally drugs were obtained through extraction from plants, but more recently by organic synthesis. Pharmaceutical drugs may be used for a duration, or on a regular basis for chronic disorders. Another major classification system is the Biopharmaceutics Classification System and this classifies drugs according to their solubility and permeability or absorption properties. Psychoactive drugs are chemical substances that affect the function of the nervous system, altering perception. They include alcohol, a depressant, and the nicotine and caffeine. These three are the most widely consumed psychoactive drugs worldwide and are considered recreational drugs since they are used for rather than medicinal purposes. Other recreational drugs include hallucinogens and amphetamines and some of these are used in spiritual or religious settings.
Some drugs can cause addiction and all drugs can have side effects, excessive use of stimulants can promote stimulant psychosis. Many recreational drugs are illicit and international such as the Single Convention on Narcotic Drugs exist for the purpose of their prohibition. The transitive verb to drug arose and invokes the psychoactive rather than properties of a substance. A medication or medicine is a drug taken to cure or ameliorate any symptoms of an illness or medical condition, the use may be as preventive medicine that has future benefits but does not treat any existing or pre-existing diseases or symptoms. In the United Kingdom, behind-the-counter medicines are called pharmacy medicines which can only be sold in registered pharmacies and these medications are designated by the letter P on the label. The range of medicines available without a prescription varies from country to country, medications are typically produced by pharmaceutical companies and are often patented to give the developer exclusive rights to produce them.
Those that are not patented are called generic drugs since they can be produced by other companies without restrictions or licenses from the patent holder, pharmaceutical drugs are usually categorised into drug classes. A group of drugs will share a chemical structure, or have the same mechanism of action. Another major classification system is the Biopharmaceutics Classification System and this groups drugs according to their solubility and permeability or absorption properties
Reuptake, or re-uptake, is the reabsorption of a neurotransmitter by a neurotransmitter transporter of a pre-synaptic neuron after it has performed its function of transmitting a neural impulse. Because neurotransmitters are too large and hydrophilic to diffuse through the membrane, much research, both biochemical and structural, has been performed to obtain clues about the mechanism of reuptake. The first primary sequence of a protein was published in 1990. After separation, it was realized that there were similarities between the two DNA sequences. The members of new family include transporters for dopamine, serotonin, proline. They were called Na+/Cl− dependent neurotransmitter transporters and Chloride ion dependence will be discussed in the mechanism of action. Using the commonalities among sequences and hydropathy plot analyses, it was predicted that there are 12 hydrophobic membrane spanning regions in the ‘Classical’ transporter family, in addition to this, the N- and C-termini exist in the intracellular space.
These proteins all have an extracellular loop between the third and fourth transmembrane sequences. Site-directed chemical labeling experiments verified the predicted topological organization of the serotonin transporter, in addition to neurotransmitter transporters, many other proteins in both animals and prokaryotes were found with similar sequences, indicating a larger family of Neurotransmitter, Sodium Symporters. They found that the transmembrane helices 1 and 6 contained unwound segments in the middle of the membrane, along with these two helices, TM helices 3 and 8 and the areas surrounding the unwound sections of 1 and 6 formed the substrate and sodium ion binding sites. The crystal structure revealed pseudo-symmetry in LeuT, in which the structure of TM helices 1-5 is reflected in the structure of helices 6-10, there is an extracellular cavity in the protein, into which protrudes a helical hairpin formed by extracellular loop EL4. In TM1, an aspartate distinguishes monoamine NSS transporters from amino acid transporters which contain a glycine at the same position and internal “gates” were assigned to pairs of negatively and positively charged residues in the extracellular cavity and near the cytoplasmic ends of TM helices 1 and 8.
The classic transporter proteins use transmembrane ion gradients and electrical potential to transport neurotransmitter across the membrane of the presynaptic neuron, typical neurotransmitter sodium symport transporters, which are Na+ and Cl− ion dependent, take advantage of both Na+ and Cl− gradients, inwardly directed across the membrane. The ions flow down their concentration gradients, in many cases leading to transmembrane charge movement that is enhanced by the membrane potential and these forces pull the neurotransmitter substrate into the cell, even against its own concentration gradient. At a molecular level, Na+ ions stabilize amino acid binding at the substrate site, the role of the Cl− ion in the symport mechanism has been proposed to be for stabilizing the charge of the symported Na+. After ion and substrate binding have taken place, some conformational change must occur and this increases neurotransmitter binding to pre- and postsynaptic neurotransmitter receptors. Depending on the system in question, a reuptake inhibitor can have drastic effects on cognition.
Non-competitive inhibition of the bacterial homologue LeuT by tricyclic antidepressants resulted from binding of inhibitors in the extracellular permeation pathway