1.
Drugs.com
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Drugs. com is an online pharmaceutical encyclopedia which provides drug information for consumers and healthcare professionals primarily in the USA. The domain Drugs. com was registered by Bonnie Neubeck in 1994. In 1999 at the height of the boom, Eric MacIver purchased an option to buy the domain from Neubeck. com. Venture Frogs sold the drugs. com domain name to an investor in June 2001. The Drugs. com website is owned and operated by the Drugsite Trust, the Drugsite Trust is a privately held Trust administered by two New Zealand pharmacists, Karen Ann and Phillip James Thornton The Drugs. com website was officially launched in September 2001. Stedmans, AHFS, Harvard Health Publications, Mayoclinic, North American Compendiums, in March 2008, Drugs. com announced the release of Mednotes —an online personal medication record application which connected to Google Health. In May 2010, U. S. FDA announced a collaboration with Drugs. com to distribute consumer health updates on the Drugs. com website, Drugs. com is certified by the TRUSTe online privacy certification program and the HONcode Health on the Net Foundation
2.
Regulation of therapeutic goods
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The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the level by a single agency. In other jurisdictions they are regulated at the level, or at both state and national levels by various bodies, as is the case in Australia. The role of therapeutic goods regulation is designed mainly to protect the health, regulation is aimed at ensuring the safety, quality, and efficacy of the therapeutic goods which are covered under the scope of the regulation. In most jurisdictions, therapeutic goods must be registered before they are allowed to be marketed, there is usually some degree of restriction of the availability of certain therapeutic goods depending on their risk to consumers. Therapeutic goods in Australia are regulated by the Therapeutic Goods Administration, there are 5 main categories, Normal Medicines - Cough, cold and fever medicines, antiseptics, vitamins and others. Sold freely in pharmacies and some large supermarkets, red Stripe Medicines - These medicines are sold only with medical prescription. Antibiotics, Anti allergenics, Anti inflammatories, and other medicines, in Brazil, governmental control is loose on this type, it is not uncommon to buy this type of prescription medicine over the counter without a prescription. Red Stripe Psychoactive Medicines - These medicines are only with a Special Control white medical prescription with carbon copy. The original must be retained by the pharmacist after the sale, Drugs include anti-depressants, anti-convulsants, some sleep aids, anti-psychotics and other non-habit-inducing controlled medicines. Though some consider them habit inducing, anabolic steroids are also regulated under this category, black Stripe Medicines - These medicines are sold only with the Blue B Form medical prescription, which is valid for 30 days and must be retained by the pharmacist after the sale. Includes sedatives, some anorexic inducers and other habit-inducing controlled medicines, includes amphetamines and other stimulants, opioids and other strong habit-forming controlled medicines. In Canada, regulation of goods are governed by the Food and Drug Act. In addition, the Controlled Drugs and Substances Act requires additional regulatory requirements for controlled drugs, the regulation of drugs in Burma is governed by the Food and Drug Administration and Food and Drug Board of Authority. The regulation of drugs in China is governed by the China Food, Medicines for Human Use in the United Kingdom are regulated by the Medicines and Healthcare products Regulatory Agency. The availability of drugs is regulated by classification by the MHRA as part of marketing authorisation of a product, Medicines in the Republic of Ireland are regulated according to the Misuse of Drugs Regulations 1988. Controlled drugs are divided into five categories based on their potential for misuse, cD1, cannabis, lysergamide, coca leaf, etc. Use prohibited except in limited circumstances where a license has been granted, CD2, amphetamine, methadone, morphine, fentanyl, oxycodone, tapentadol, etc
3.
Over-the-counter drug
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In many countries, OTC drugs are selected by a regulatory agency to ensure that they are ingredients that are safe and effective when used without a physicians care. OTC drugs are regulated by active pharmaceutical ingredients, not final products. By regulating APIs instead of specific drug formulations, governments allow manufacturers freedom to formulate ingredients, or combinations of ingredients, into proprietary mixtures. The term over-the-counter may be somewhat counterintuitive, since, in many countries, in contrast, prescription drugs are almost always passed over a counter from the pharmacist to the customer. Some drugs may be classified as over-the-counter, but may only be dispensed by a pharmacist after an assessment of the patients needs or the provision of patient education. In many countries, a number of OTC drugs are available in establishments without a pharmacy, such as stores, supermarkets. Regulations detailing the establishments where drugs may be sold, who is authorized to dispense them, as of 2011, around a third of older adults in the U. S. reportedly use OTC drugs. In Canada, there are four drug schedules, Schedule 1, Schedule 2, Do not require a prescription, but require an assessment by a pharmacist prior to sale. These drugs are kept in an area of the pharmacy where there is no public access, Schedule 3, Do not require a prescription, but must be kept in an area under the supervision of a pharmacist. These drugs are kept in an area of the outlet where self-selection is possible. Unscheduled, Do not require a prescription and may be sold in any retail outlet, all medications outside of Schedule 1 may be considered an OTC drug, as they do not require prescriptions for sale. While the National Association of Pharmacy Regulatory Authorities provides recommendations on the scheduling of drugs for sale in Canada, due to this, the exact drugs found in each schedule may vary from province to province. The drug can be on the shelves like any other product, examples are domperidone,400 mg ibuprofen up to 50 tablets and dextromethorphan. The drugs are usually on the shelves and the store sells items like toys, gadgets, perfumes. The drugs in this category have limited risk and addiction potential, examples are naproxen and diclofenac in small amounts, cinnarizine,400 mg ibuprofen up to 20 tablets and also 500 mg paracetamol up to 50 tablets. In the United States, the manufacture and sale of OTC substances is regulated by the Food, the FDA requires that all new drugs obtain a New Drug Application before entering interstate commerce, but the act exempts any drugs generally recognized as safe and effective from this requirement. Thus, in the United States an OTC drug product is allowed to be marketed either pursuant to an FDA monograph, the Federal Trade Commission regulates advertising of OTC products. This is in contrast to prescription drug advertising, which is regulated by the FDA, the FDA requires that OTC products are labeled with an approved Drug Facts label to educate consumers about their medications
4.
Pharmacokinetics
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Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered to a living organism. The substances of interest include any chemical xenobiotic such as, pharmaceutical drugs, pesticides, food additives, cosmetic ingredients, etc. It attempts to analyze chemical metabolism and to discover the fate of a chemical from the moment that it is administered up to the point at which it is eliminated from the body. Pharmacokinetics is the study of how an organism affects a drug, both together influence dosing, benefit, and adverse effects, as seen in PK/PD models. Pharmacokinetic properties of chemicals are affected by the route of administration and these may affect the absorption rate. Models have been developed to simplify conceptualization of the processes that take place in the interaction between an organism and a chemical substance. The various compartments that the model is divided into are commonly referred to as the ADME scheme, absorption - the process of a substance entering the blood circulation. Distribution - the dispersion or dissemination of substances throughout the fluids, metabolism – the recognition by the organism that a foreign substance is present and the irreversible transformation of parent compounds into daughter metabolites. Excretion - the removal of the substances from the body, in rare cases, some drugs irreversibly accumulate in body tissue. The two phases of metabolism and excretion can also be grouped together under the title elimination, the study of these distinct phases involves the use and manipulation of basic concepts in order to understand the process dynamics. All these concepts can be represented through mathematical formulas that have a graphical representation. The model outputs for a drug can be used in industry or in the application of pharmacokinetic concepts. Clinical pharmacokinetics provides many performance guidelines for effective and efficient use of drugs for human-health professionals, in practice, it is generally considered that steady state is reached when a time of 4 to 5 times the half-life for a drug after regular dosing is started. Noncompartmental methods estimate the exposure to a drug by estimating the area under the curve of a concentration-time graph, compartmental methods estimate the concentration-time graph using kinetic models. Noncompartmental methods are more versatile in that they do not assume any specific compartmental model. The final outcome of the transformations that a drug undergoes in an organism, a number of functional models have been developed in order to simplify the study of pharmacokinetics. These models are based on a consideration of an organism as a number of related compartments, the simplest idea is to think of an organism as only one homogenous compartment. However, these models do not always reflect the real situation within an organism
5.
Drug metabolism
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Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. These pathways are a form of biotransformation present in all groups of organisms. These reactions often act to detoxify poisonous compounds, the study of drug metabolism is called pharmacokinetics. The metabolism of drugs is an important aspect of pharmacology. For example, the rate of metabolism determines the duration and intensity of a drugs pharmacologic action, the enzymes of xenobiotic metabolism, particularly the glutathione S-transferases are also important in agriculture, since they may produce resistance to pesticides and herbicides. Drug metabolism is divided into three phases, in phase I, enzymes such as cytochrome P450 oxidases introduce reactive or polar groups into xenobiotics. These modified compounds are conjugated to polar compounds in phase II reactions. These reactions are catalysed by enzymes such as glutathione S-transferases. Finally, in phase III, the conjugated xenobiotics may be processed, before being recognised by efflux transporters. Drug metabolism often converts lipophilic compounds into hydrophilic products that are readily excreted. The exact compounds an organism is exposed to will be unpredictable, and may differ widely over time. The solution that has evolved to address this problem is an elegant combination of physical barriers, all organisms use cell membranes as hydrophobic permeability barriers to control access to their internal environment. This selective uptake means that most hydrophilic molecules cannot enter cells, in contrast, the diffusion of hydrophobic compounds across these barriers cannot be controlled, and organisms, therefore, cannot exclude lipid-soluble xenobiotics using membrane barriers. However, the existence of a permeability barrier means that organisms were able to evolve detoxification systems that exploit the hydrophobicity common to membrane-permeable xenobiotics and these systems therefore solve the specificity problem by possessing such broad substrate specificities that they metabolise almost any non-polar compound. Useful metabolites are excluded since they are polar, and in general one or more charged groups. However, since these compounds are few in number, specific enzymes can recognize, the metabolism of xenobiotics is often divided into three phases, - modification, conjugation, and excretion. These reactions act in concert to detoxify xenobiotics and remove them from cells, in phase I, a variety of enzymes act to introduce reactive and polar groups into their substrates. One of the most common modifications is hydroxylation catalysed by the cytochrome P-450-dependent mixed-function oxidase system and these enzyme complexes act to incorporate an atom of oxygen into nonactivated hydrocarbons, which can result in either the introduction of hydroxyl groups or N-, O- and S-dealkylation of substrates
6.
PubChem
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PubChem is a database of chemical molecules and their activities against biological assays. The system is maintained by the National Center for Biotechnology Information, a component of the National Library of Medicine, PubChem can be accessed for free through a web user interface. Millions of compound structures and descriptive datasets can be downloaded via FTP. PubChem contains substance descriptions and small molecules with fewer than 1000 atoms and 1000 bonds, more than 80 database vendors contribute to the growing PubChem database. PubChem consists of three dynamically growing primary databases, as of 28 January 2016, Compounds,82.6 million entries, contains pure and characterized chemical compounds. Substances,198 million entries, contains also mixtures, extracts, complexes, bioAssay, bioactivity results from 1.1 million high-throughput screening programs with several million values. PubChem contains its own online molecule editor with SMILES/SMARTS and InChI support that allows the import and export of all common chemical file formats to search for structures and fragments. In the text search form the database fields can be searched by adding the name in square brackets to the search term. A numeric range is represented by two separated by a colon. The search terms and field names are case-insensitive, parentheses and the logical operators AND, OR, and NOT can be used. AND is assumed if no operator is used, example,0,5000,50,10 -5,5 PubChem was released in 2004. The American Chemical Society has raised concerns about the publicly supported PubChem database and they have a strong interest in the issue since the Chemical Abstracts Service generates a large percentage of the societys revenue. To advocate their position against the PubChem database, ACS has actively lobbied the US Congress, soon after PubChems creation, the American Chemical Society lobbied U. S. Congress to restrict the operation of PubChem, which they asserted competes with their Chemical Abstracts Service
7.
Guide to Pharmacology
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The IUPHAR/BPS Guide to PHARMACOLOGY is an open-access website, acting as a portal to information on the biological targets of licensed drugs and other small molecules. The Guide to PHARMACOLOGY is developed as a joint venture between the International Union of Basic and Clinical Pharmacology and the British Pharmacological Society and this replaces and expands upon the original 2009 IUPHAR Database. The information featured includes pharmacological data, target and gene nomenclature, overviews and commentaries on each target family are included, with links to key references. The Guide to PHARMACOLOGY was initially made available online in December 2011 with additional material released in July 2012 and its network of over 700 specialist advisors contribute expertise and data. The current PI and Grant holder of the GtoPdb project is Prof. Jamie A. Davies, the development and release of the first version of the GtoPdb in 2012 was described in an editorial published in the British Journal of Pharmacology entitled Guide to Pharmacology. org- an update. The IUPHAR-DB is no longer being developed and all the contained within this site is now available through the Guide to PHARMACOLOGY. A complete list of all the approved drugs included on the website is available via the ligand list. The Guide to PHARMACOLOGY is being expanded to include information on targets and ligands. Search features on the website include quick and advanced search options, other features include Hot topic news items and a recent receptor-ligand pairing list. A hard copy summary of the database is published as The Concise Guide to Pharmacology 2015/2016 as a series of papers as a bi-annual supplement to the British Journal of Pharmacology. The Guide to PHARMACOLOGY includes links to other relevant resources via target, many of these resources maintain reciprocal links with the relevant Guide to PHARMACOLOGY pages. As of November 2015 the Wellcome Trust is supporting a new project to develop the Guide to Immumopharmacology, the latter continues to be supported by the British Pharmacological Society
8.
DrugBank
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The DrugBank database is a comprehensive, freely accessible, online database containing information on drugs and drug targets. As both a bioinformatics and a resource, DrugBank combines detailed drug data with comprehensive drug target information. Because of its scope, comprehensive referencing and unusually detailed data descriptions. As a result, links to DrugBank are maintained for nearly all drugs listed in Wikipedia, DrugBank is widely used by the drug industry, medicinal chemists, pharmacists, physicians, students and the general public. Its extensive drug and drug-target data has enabled the discovery and repurposing of a number of existing drugs to treat rare, the latest release of the database contains 8227 drug entries including 2003 FDA-approved small molecule drugs,221 FDA-approved biotech drugs,93 nutraceuticals and over 6000 experimental drugs. Additionally,4270 non-redundant protein sequences are linked to these drug entries, each DrugCard entry contains more than 200 data fields with half of the information being devoted to drug/chemical data and the other half devoted to drug target or protein data. Four additional databases, HMDB, T3DB, SMPDB and FooDB are also part of a suite of metabolomic/cheminformatic databases. The first version of DrugBank was released in 2006 and this early release contained relatively modest information about 841 FDA-approved small molecule drugs and 113 biotech drugs. It also included information on 2133 drug targets, the second version of DrugBank was released in 2009. This greatly expanded and improved version of the database included 1344 approved small molecule drugs and 123 biotech drugs as well as 3037 unique drug targets. Version 2.0 also included, for the first time, withdrawn drugs and illicit drugs, version 3.0 was released in 2011. This version contained 1424 approved small molecule drugs and 132 biotech drugs as well as >4000 unique drug targets, version 3.0 also included drug transporter data, drug pathway data, drug pricing, patent and manufacturing data as well as data on >5000 experimental drugs. Version 4.0 was released in 2014 and this version included 1558 FDA-approved small molecule drugs,155 biotech drugs and 4200 unique drug targets. Version 4.0 also incorporated information on drug metabolites, drug taxonomy, drug spectra, drug binding constants. Table 1 provides a complete statistical summary of the history of DrugBank’s development. All data in DrugBank is non-proprietary or is derived from a non-proprietary source and it is freely accessible and available to anyone. In addition, nearly every item is fully traceable and explicitly referenced to the original source. DrugBank data is available through a web interface and downloads
9.
ChemSpider
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ChemSpider is a database of chemicals. ChemSpider is owned by the Royal Society of Chemistry, the database contains information on more than 50 million molecules from over 500 data sources including, Each chemical is given a unique identifier, which forms part of a corresponding URL. This is an approach to develop an online chemistry database. The search can be used to widen or restrict already found results, structure searching on mobile devices can be done using free apps for iOS and for the Android. The ChemSpider database has been used in combination with text mining as the basis of document markup. The result is a system between chemistry documents and information look-up via ChemSpider into over 150 data sources. ChemSpider was acquired by the Royal Society of Chemistry in May,2009, prior to the acquisition by RSC, ChemSpider was controlled by a private corporation, ChemZoo Inc. The system was first launched in March 2007 in a release form. ChemSpider has expanded the generic support of a database to include support of the Wikipedia chemical structure collection via their WiChempedia implementation. A number of services are available online. SyntheticPages is an interactive database of synthetic chemistry procedures operated by the Royal Society of Chemistry. Users submit synthetic procedures which they have conducted themselves for publication on the site and these procedures may be original works, but they are more often based on literature reactions. Citations to the published procedure are made where appropriate. They are checked by an editor before posting. The pages do not undergo formal peer-review like a journal article. The comments are moderated by scientific editors. The intention is to collect practical experience of how to conduct useful chemical synthesis in the lab, while experimental methods published in an ordinary academic journal are listed formally and concisely, the procedures in ChemSpider SyntheticPages are given with more practical detail. Comments by submitters are included as well, other publications with comparable amounts of detail include Organic Syntheses and Inorganic Syntheses
10.
ChEMBL
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ChEMBL or ChEMBLdb is a manually curated chemical database of bioactive molecules with drug-like properties. It is maintained by the European Bioinformatics Institute, of the European Molecular Biology Laboratory, based at the Wellcome Trust Genome Campus, Hinxton, the database, originally known as StARlite, was developed by a biotechnology company called Inpharmatica Ltd. later acquired by Galapagos NV. The data was acquired for EMBL in 2008 with an award from The Wellcome Trust, resulting in the creation of the ChEMBL chemogenomics group at EMBL-EBI, the ChEMBL database contains compound bioactivity data against drug targets. Bioactivity is reported in Ki, Kd, IC50, and EC50, data can be filtered and analyzed to develop compound screening libraries for lead identification during drug discovery. ChEMBL version 2 was launched in January 2010, including 2.4 million bioassay measurements covering 622,824 compounds and this was obtained from curating over 34,000 publications across twelve medicinal chemistry journals. ChEMBLs coverage of available bioactivity data has grown to become the most comprehensive ever seen in a public database, in October 2010 ChEMBL version 8 was launched, with over 2.97 million bioassay measurements covering 636,269 compounds. ChEMBL_10 saw the addition of the PubChem confirmatory assays, in order to integrate data that is comparable to the type, ChEMBLdb can be accessed via a web interface or downloaded by File Transfer Protocol. It is formatted in a manner amenable to computerized data mining, ChEMBL is also integrated into other large-scale chemistry resources, including PubChem and the ChemSpider system of the Royal Society of Chemistry. In addition to the database, the ChEMBL group have developed tools and these include Kinase SARfari, an integrated chemogenomics workbench focussed on kinases. The system incorporates and links sequence, structure, compounds and screening data, the primary purpose of ChEMBL-NTD is to provide a freely accessible and permanent archive and distribution centre for deposited data. July 2012 saw the release of a new data service, sponsored by the Medicines for Malaria Venture. The data in this service includes compounds from the Malaria Box screening set, myChEMBL, the ChEMBL virtual machine, was released in October 2013 to allow users to access a complete and free, easy-to-install cheminformatics infrastructure. In December 2013, the operations of the SureChem patent informatics database were transferred to EMBL-EBI, in a portmanteau, SureChem was renamed SureChEMBL. 2014 saw the introduction of the new resource ADME SARfari - a tool for predicting and comparing cross-species ADME targets
11.
European Chemicals Agency
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ECHA is the driving force among regulatory authorities in implementing the EUs chemicals legislation. ECHA helps companies to comply with the legislation, advances the safe use of chemicals, provides information on chemicals and it is located in Helsinki, Finland. The Agency, headed by Executive Director Geert Dancet, started working on 1 June 2007, the REACH Regulation requires companies to provide information on the hazards, risks and safe use of chemical substances that they manufacture or import. Companies register this information with ECHA and it is freely available on their website. So far, thousands of the most hazardous and the most commonly used substances have been registered, the information is technical but gives detail on the impact of each chemical on people and the environment. This also gives European consumers the right to ask whether the goods they buy contain dangerous substances. The Classification, Labelling and Packaging Regulation introduces a globally harmonised system for classifying and labelling chemicals into the EU. This worldwide system makes it easier for workers and consumers to know the effects of chemicals, companies need to notify ECHA of the classification and labelling of their chemicals. So far, ECHA has received over 5 million notifications for more than 100000 substances, the information is freely available on their website. Consumers can check chemicals in the products they use, Biocidal products include, for example, insect repellents and disinfectants used in hospitals. The Biocidal Products Regulation ensures that there is information about these products so that consumers can use them safely. ECHA is responsible for implementing the regulation, the law on Prior Informed Consent sets guidelines for the export and import of hazardous chemicals. Through this mechanism, countries due to hazardous chemicals are informed in advance and have the possibility of rejecting their import. Substances that may have effects on human health and the environment are identified as Substances of Very High Concern 1. These are mainly substances which cause cancer, mutation or are toxic to reproduction as well as substances which persist in the body or the environment, other substances considered as SVHCs include, for example, endocrine disrupting chemicals. Companies manufacturing or importing articles containing these substances in a concentration above 0 and they are required to inform users about the presence of the substance and therefore how to use it safely. Consumers have the right to ask the retailer whether these substances are present in the products they buy, once a substance has been officially identified in the EU as being of very high concern, it will be added to a list. This list is available on ECHA’s website and shows consumers and industry which chemicals are identified as SVHCs, Substances placed on the Candidate List can then move to another list
12.
Chemical formula
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These are limited to a single typographic line of symbols, which may include subscripts and superscripts. A chemical formula is not a name, and it contains no words. Although a chemical formula may imply certain simple chemical structures, it is not the same as a full chemical structural formula. Chemical formulas can fully specify the structure of only the simplest of molecules and chemical substances, the simplest types of chemical formulas are called empirical formulas, which use letters and numbers indicating the numerical proportions of atoms of each type. Molecular formulas indicate the numbers of each type of atom in a molecule. For example, the formula for glucose is CH2O, while its molecular formula is C6H12O6. This is possible if the relevant bonding is easy to show in one dimension, an example is the condensed molecular/chemical formula for ethanol, which is CH3-CH2-OH or CH3CH2OH. For reasons of structural complexity, there is no condensed chemical formula that specifies glucose, chemical formulas may be used in chemical equations to describe chemical reactions and other chemical transformations, such as the dissolving of ionic compounds into solution. A chemical formula identifies each constituent element by its chemical symbol, in empirical formulas, these proportions begin with a key element and then assign numbers of atoms of the other elements in the compound, as ratios to the key element. For molecular compounds, these numbers can all be expressed as whole numbers. For example, the formula of ethanol may be written C2H6O because the molecules of ethanol all contain two carbon atoms, six hydrogen atoms, and one oxygen atom. Some types of compounds, however, cannot be written with entirely whole-number empirical formulas. An example is boron carbide, whose formula of CBn is a variable non-whole number ratio with n ranging from over 4 to more than 6.5. When the chemical compound of the consists of simple molecules. These types of formulas are known as molecular formulas and condensed formulas. A molecular formula enumerates the number of atoms to reflect those in the molecule, so that the formula for glucose is C6H12O6 rather than the glucose empirical formula. However, except for very simple substances, molecular chemical formulas lack needed structural information, for simple molecules, a condensed formula is a type of chemical formula that may fully imply a correct structural formula. For example, ethanol may be represented by the chemical formula CH3CH2OH
13.
Jmol
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Jmol is computer software for molecular modelling chemical structures in 3-dimensions. Jmol returns a 3D representation of a molecule that may be used as a teaching tool and it is written in the programming language Java, so it can run on the operating systems Windows, macOS, Linux, and Unix, if Java is installed. It is free and open-source software released under a GNU Lesser General Public License version 2.0, a standalone application and a software development kit exist that can be integrated into other Java applications, such as Bioclipse and Taverna. A popular feature is an applet that can be integrated into web pages to display molecules in a variety of ways, for example, molecules can be displayed as ball-and-stick models, space-filling models, ribbon diagrams, etc. Jmol supports a range of chemical file formats, including Protein Data Bank, Crystallographic Information File, MDL Molfile. There is also a JavaScript-only version, JSmol, that can be used on computers with no Java, the Jmol applet, among other abilities, offers an alternative to the Chime plug-in, which is no longer under active development. While Jmol has many features that Chime lacks, it does not claim to reproduce all Chime functions, most notably, Chime requires plug-in installation and Internet Explorer 6.0 or Firefox 2.0 on Microsoft Windows, or Netscape Communicator 4.8 on Mac OS9. Jmol requires Java installation and operates on a variety of platforms. For example, Jmol is fully functional in Mozilla Firefox, Internet Explorer, Opera, Google Chrome, fast and Scriptable Molecular Graphics in Web Browsers without Java3D
14.
Simplified molecular-input line-entry system
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The simplified molecular-input line-entry system is a specification in form of a line notation for describing the structure of chemical species using short ASCII strings. SMILES strings can be imported by most molecule editors for conversion back into two-dimensional drawings or three-dimensional models of the molecules, the original SMILES specification was initiated in the 1980s. It has since modified and extended. In 2007, a standard called OpenSMILES was developed in the open-source chemistry community. Other linear notations include the Wiswesser Line Notation, ROSDAL and SLN, the original SMILES specification was initiated by David Weininger at the USEPA Mid-Continent Ecology Division Laboratory in Duluth in the 1980s. The Environmental Protection Agency funded the project to develop SMILES. It has since modified and extended by others, most notably by Daylight Chemical Information Systems. In 2007, a standard called OpenSMILES was developed by the Blue Obelisk open-source chemistry community. Other linear notations include the Wiswesser Line Notation, ROSDAL and SLN, in July 2006, the IUPAC introduced the InChI as a standard for formula representation. SMILES is generally considered to have the advantage of being slightly more human-readable than InChI, the term SMILES refers to a line notation for encoding molecular structures and specific instances should strictly be called SMILES strings. However, the term SMILES is also used to refer to both a single SMILES string and a number of SMILES strings, the exact meaning is usually apparent from the context. The terms canonical and isomeric can lead to confusion when applied to SMILES. The terms describe different attributes of SMILES strings and are not mutually exclusive, typically, a number of equally valid SMILES strings can be written for a molecule. For example, CCO, OCC and CC all specify the structure of ethanol, algorithms have been developed to generate the same SMILES string for a given molecule, of the many possible strings, these algorithms choose only one of them. This SMILES is unique for each structure, although dependent on the algorithm used to generate it. These algorithms first convert the SMILES to a representation of the molecular structure. A common application of canonical SMILES is indexing and ensuring uniqueness of molecules in a database, there is currently no systematic comparison across commercial software to test if such flaws exist in those packages. SMILES notation allows the specification of configuration at tetrahedral centers, and these are structural features that cannot be specified by connectivity alone and SMILES which encode this information are termed isomeric SMILES
15.
International Chemical Identifier
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Initially developed by IUPAC and NIST from 2000 to 2005, the format and algorithms are non-proprietary. The continuing development of the standard has supported since 2010 by the not-for-profit InChI Trust. The current version is 1.04 and was released in September 2011, prior to 1.04, the software was freely available under the open source LGPL license, but it now uses a custom license called IUPAC-InChI Trust License. Not all layers have to be provided, for instance, the layer can be omitted if that type of information is not relevant to the particular application. InChIs can thus be seen as akin to a general and extremely formalized version of IUPAC names and they can express more information than the simpler SMILES notation and differ in that every structure has a unique InChI string, which is important in database applications. Information about the 3-dimensional coordinates of atoms is not represented in InChI, the InChI algorithm converts input structural information into a unique InChI identifier in a three-step process, normalization, canonicalization, and serialization. The InChIKey, sometimes referred to as a hashed InChI, is a fixed length condensed digital representation of the InChI that is not human-understandable. The InChIKey specification was released in September 2007 in order to facilitate web searches for chemical compounds and it should be noted that, unlike the InChI, the InChIKey is not unique, though collisions can be calculated to be very rare, they happen. In January 2009 the final 1.02 version of the InChI software was released and this provided a means to generate so called standard InChI, which does not allow for user selectable options in dealing with the stereochemistry and tautomeric layers of the InChI string. The standard InChIKey is then the hashed version of the standard InChI string, the standard InChI will simplify comparison of InChI strings and keys generated by different groups, and subsequently accessed via diverse sources such as databases and web resources. Every InChI starts with the string InChI= followed by the version number and this is followed by the letter S for standard InChIs. The remaining information is structured as a sequence of layers and sub-layers, the layers and sub-layers are separated by the delimiter / and start with a characteristic prefix letter. The six layers with important sublayers are, Main layer Chemical formula and this is the only sublayer that must occur in every InChI. The atoms in the formula are numbered in sequence, this sublayer describes which atoms are connected by bonds to which other ones. Describes how many hydrogen atoms are connected to each of the other atoms, the condensed,27 character standard InChIKey is a hashed version of the full standard InChI, designed to allow for easy web searches of chemical compounds. Most chemical structures on the Web up to 2007 have been represented as GIF files, the full InChI turned out to be too lengthy for easy searching, and therefore the InChIKey was developed. With all databases currently having below 50 million structures, such duplication appears unlikely at present, a recent study more extensively studies the collision rate finding that the experimental collision rate is in agreement with the theoretical expectations. Example, Morphine has the structure shown on the right, as the InChI cannot be reconstructed from the InChIKey, an InChIKey always needs to be linked to the original InChI to get back to the original structure
16.
Nucleoside
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Nucleosides are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nucleobase and a sugar, whereas a nucleotide is composed of a nucleobase, a five-carbon sugar. In a nucleoside, the base is bound to either ribose or deoxyribose via a beta-glycosidic linkage, examples of nucleosides include cytidine, uridine, adenosine, guanosine, thymidine and inosine. While a nucleoside is a linked to a sugar, a nucleotide is composed of a nucleoside. Thus, nucleosides can be phosphorylated by specific kinases in the cell on the primary alcohol group to produce nucleotides. Nucleotides are the molecular building-blocks of DNA and RNA, the nucleosides, in turn, are subsequently broken down, in the lumen of the digestive system by nucleosidases into nucleobases and ribose or deoxyribose. In addition, nucleotides can be broken down, inside the cell into nitrogenous bases, in medicine several nucleoside analogues are used as antiviral or anticancer agents. The viral polymerase incorporates these compounds with non-canonical bases and these compounds are activated in the cells by being converted into nucleotides. They are administered as nucleosides since charged nucleotides cannot easily cross cell membranes, in molecular biology, several analogues of the sugar backbone exist. Due to the low stability of RNA, which is prone to hydrolysis and this is achieved by using a different backbone sugar. These analogues include LNA, morpholino, PNA and these nucleotides possess the non-canonical sugar dideoxyribose, which lacks 3 hydroxyl group. It therefore cannot bond with the base and terminates the chain. Arabinosyl nucleosides Nucleobase Synthesis of nucleosides
17.
Ribose
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Ribose is a carbohydrate with the formula C5H10O5, specifically, it is a pentose monosaccharide with linear form H−−4−H, which has all the hydroxyl groups on the same side in the Fischer projection. The term may refer to either of two enantiomers, the term usually indicates D-ribose, which occurs widely in nature and is discussed here. Its synthetic mirror image, L-ribose, is not found in nature, d-Ribose was first reported in 1891 by Emil Fischer. It is a C-2 carbon epimer of the sugar D-arabinose and ribose itself is named as a rearrangement of letters in the word arabinose. The ribose β-D-ribofuranose forms part of the backbone of RNA and it is related to deoxyribose, which is found in DNA. Phosphorylated derivatives of such as ATP and NADH play central roles in metabolism. CAMP and cGMP, formed from ATP and GTP, serve as messengers in some signalling pathways. Ribose is an aldopentose that, in its open form, has an aldehyde functional group at one end. In the conventional numbering scheme for monosaccharides, the atoms are numbered from C1 to C5. The deoxyribose derivative found in DNA differs from ribose by having a hydrogen atom in place of the group at C2. This hydroxyl group performs a function in RNA splicing, the beta-ribopyranose form predominates in aqueous solution. The “D-” in the name D-ribose refers to the stereochemistry of the carbon atom farthest away from the aldehyde group. In D-ribose, as in all D-sugars, this carbon atom has the configuration as in D-glyceraldehyde. Relative abundance of different forms of ribose in solution, β-D-ribopyranose, α-D-ribopyranose, β-D-ribofuranose, α-D-ribofuranose, in biology, D-ribose must be phosphorylated by the cell before it can be used. Ribokinase catalyzes this reaction by converting D-ribose to D-ribose 5-phosphate, once converted, D-ribose-5-phosphate is available for the manufacturing of the amino acids tryptophan and histidine, or for use in the pentose phosphate pathway. The absorption of D-ribose is 88–100% in the small intestines
18.
Glycosidic bond
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In chemistry, a glycosidic bond or glycosidic linkage is a type of covalent bond that joins a carbohydrate molecule to another group, which may or may not be another carbohydrate. A glycosidic bond is formed between the hemiacetal or hemiketal group of a saccharide and the group of some compound such as an alcohol. A substance containing a glycosidic bond is a glycoside, glycosidic bonds of the form discussed above are known as O-glycosidic bonds, in reference to the glycosidic oxygen that links the glycoside to the aglycone or reducing end sugar. In analogy, one also considers S-glycosidic bonds, where the oxygen of the bond is replaced with a sulfur atom. In the same way, N-glycosidic bonds, have the glycosidic oxygen replaced with nitrogen. Substances containing N-glycosidic bonds are known as glycosylamines. C-glycosyl bonds have the oxygen replaced by a carbon, the term C-glycoside is considered a misnomer by IUPAC and is discouraged. All of these modified glycosidic bonds have different susceptibility to hydrolysis, one distinguishes between α- and β-glycosidic bonds based on the relative stereochemistry of the anomeric position and the stereocenter furthest from C1 in the saccharide. An α-glycosidic bond is formed when both carbons have the same stereochemistry, whereas a β-glycosidic bond occurs when the two carbons have different stereochemistry. One complicating issue is that the alpha and beta conformations were originally defined based on the orientation of the major constituents in a Haworth projection. In this case, for D-sugars, a beta conformation would see the major constituent at each carbon drawn above the plane of the ring, for L-sugars, the definitions would then, necessarily, reverse. This is worth noting as these older definitions still permeate the literature, pharmacologists often join substances to glucuronic acid via glycosidic bonds in order to increase their water solubility, this is known as glucuronidation. Many other glycosides have important physiological functions, Nüchter et al. have shown a new approach to Fischer Glycosylation. Employing a microwave oven equipped with refluxing apparatus in a reactor with pressure bombs, Nüchter et al. were able to achieve 100% yield of α-. This method can be performed on a multi-kilogram scale, ondruschka, and W. Lautenschläger, Synthetic Communications 31,1277. Vishal Y Joshis method Joshi et al, d-glucose is first protected by forming the peracetate by addition of acetic anhydride in acetic acid, and then addition of hydrogen bromide which brominates at the 5-position. On addition of the alcohol ROH and lithium carbonate, the OR replaces the bromine and it was suggested by Joshi et al. that lithium acts as the nucleophile that attacks the carbon at the 5-position and through a transition state the alcohol is substituted for the bromine group. Glycoside hydrolases, are enzymes that break glycosidic bonds, glycoside hydrolases typically can act either on α- or on β-glycosidic bonds, but not on both
19.
Transfer RNA
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A transfer RNA is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length, that serves as the physical link between the mRNA and the amino acid sequence of proteins. It does this by carrying an amino acid to the protein synthetic machinery of a cell as directed by a sequence in a messenger RNA. As such, tRNAs are a component of translation, the biological synthesis of new proteins in accordance with the genetic code. The mRNA encodes a protein as a series of contiguous codons, one end of the tRNA matches the genetic code in a three-nucleotide sequence called the anticodon. The anticodon forms three base pairs with a codon in mRNA during protein biosynthesis, on the other end of the tRNA is a covalent attachment to the amino acid that corresponds to the anticodon sequence. Each type of molecule can be attached to only one type of amino acid. Because the genetic code contains multiple codons that specify the amino acid. The covalent attachment to the tRNA 3’ end is catalyzed by enzymes called aminoacyl tRNA synthetases, a large number of the individual nucleotides in a tRNA molecule may be chemically modified, often by methylation or deamidation. These unusual bases sometimes affect the interaction with ribosomes and sometimes occur in the anticodon to alter base-pairing properties. The structure of tRNA can be decomposed into its structure, its secondary structure. The cloverleaf structure becomes the 3D L-shaped structure through coaxial stacking of the helices, the lengths of each arm, as well as the loop diameter, in a tRNA molecule vary from species to species. The tRNA structure consists of the following, A 5-terminal phosphate group, the acceptor stem is a 7- to 9-base pair stem made by the base pairing of the 5-terminal nucleotide with the 3-terminal nucleotide. The acceptor stem may contain non-Watson-Crick base pairs, the CCA tail is a cytosine-cytosine-adenine sequence at the 3 end of the tRNA molecule. The amino acid loaded onto the tRNA by aminoacyl tRNA synthetases and this sequence is important for the recognition of tRNA by enzymes and critical in translation. In prokaryotes, the CCA sequence is transcribed in some tRNA sequences, in most prokaryotic tRNAs and eukaryotic tRNAs, the CCA sequence is added during processing and therefore does not appear in the tRNA gene. The D arm is a 4- to 6-bp stem ending in a loop that often contains dihydrouridine, the anticodon arm is a 5-bp stem whose loop contains the anticodon. The tRNA 5-to-3 primary structure contains the anticodon but in reverse order, the T arm is a 4- to 5- bp stem containing the sequence TΨC where Ψ is pseudouridine, a modified uridine. Bases that have modified, especially by methylation, occur in several positions throughout the tRNA
20.
Wobble base pair
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A wobble base pair is a pairing between two nucleotides in RNA molecules that does not follow Watson-Crick base pair rules. The four main wobble base pairs are guanine-uracil, hypoxanthine-uracil, hypoxanthine-adenine, the thermodynamic stability of a wobble base pair is comparable to that of a Watson-Crick base pair. Wobble base pairs are fundamental in RNA secondary structure and are critical for the translation of the genetic code. In the genetic code, there are 43 =64 possible codons, for translation, each of these codons requires a tRNA molecule with a complementary anticodon. If each tRNA molecule paired with its complementary mRNA codon using canonical Watson-Crick base pairing, in the standard genetic code, three of these 64 mRNA codons are stop codons. These terminate translation by binding to release factors rather than tRNA molecules, since most organisms have fewer than 45 species of tRNA, some tRNA species must pair with more than one codon. In 1966, Francis Crick proposed the Wobble Hypothesis to account for this. He postulated that the 5 base on the anticodon, which binds to the 3 base on the mRNA, was not as confined as the other two bases, and could, thus, have non-standard base pairing. Crick creatively named it for the amount of play that occurs at this third codon position. Movement of the base in the 5 anticodon position is necessary for small conformational adjustments that affect the overall pairing geometry of anticodons of tRNA, as an example, yeast tRNAPhe has the anticodon 5-GmAA-3 and can recognize the codons 5-UUC-3 and 5-UUU-3. It is, therefore, possible for non-Watson–Crick base pairing to occur at the codon position, i. e. the 3 nucleotide of the mRNA codon. These notions led Francis Crick to the creation of the wobble hypothesis, the first two bases in the codon create the coding specificity, for they form strong Watson-Crick base pairs and bond strongly to the anticodon of the tRNA. When reading 5 to 3 the first nucleotide in the anticodon determines how many nucleotides the tRNA actually distinguishes. If the first nucleotide in the anticodon is a C or an A pairing is specific and acknowledges original Watson-Crick pairing, if the first nucleotide is U or G, the pairing is less specific and in fact two bases can be interchangeably recognized by the tRNA. Inosine displays the qualities of wobble, in that if that is the first nucleotide in the anticodon then any of three bases in the original codon can be matched with the tRNA. The minimum requirement to all possible codons is 32 tRNAS. That is 31 tRNAs for the amino acids and one initiation codon, the original wobble pairing rules, as proposed by Crick. In fact, in a study of E. colis tRNA for alanine there is a base pair that determines whether the tRNA will be aminoacylated
21.
Guanine
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Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine. In DNA, guanine is paired with cytosine, the guanine nucleoside is called guanosine. With the formula C5H5N5O, guanine is a derivative of purine, being unsaturated, the bicyclic molecule is planar. Guanine, along with adenine and cytosine, is present in both DNA and RNA, whereas thymine is usually only in DNA, and uracil only in RNA. Guanine has two forms, the major keto form and rare enol form. It binds to cytosine through three hydrogen bonds, in cytosine, the amino group acts as the hydrogen bond donor and the C-2 carbonyl and the N-3 amine as the hydrogen-bond acceptors. Guanine has the C-6 carbonyl group that acts as the hydrogen acceptor, while a group at N-1. Guanine can be hydrolyzed with strong acid to glycine, ammonia, carbon dioxide, first, guanine gets deaminated to become xanthine. Guanine oxidizes more readily than adenine, the other purine-derivative base in DNA and its high melting point of 350 °C reflects the intermolecular hydrogen bonding between the oxo and amino groups in the molecules in the crystal. Because of this bonding, guanine is relatively insoluble in water. Between 1882 and 1906, Fischer determined the structure and also showed that uric acid can be converted to guanine, trace amounts of guanine form by the polymerization of ammonium cyanide. These results indicate guanine could arise in frozen regions of the primitive earth. In 1984, Yuasa reported a 0. 00017% yield of guanine after the discharge of NH3, CH4, C 2H6. However, it is whether the presence of guanine was not simply a resultant contaminant of the reaction. 10NH3 + 2CH4 + 4C2H6 + 2H2O → 2C5H8N5O + 25H2 A Fischer-Tropsch synthesis can also be used to form guanine, along with adenine, uracil, traubes synthesis involves heating 2,4, 5-triamino-1, 6-dihydro-6-oxypyrimidine with formic acid for several hours. The word guanine derives from the Spanish loanword guano, which itself is from the Quechua word wanu, as the Oxford English Dictionary notes, guanine is A white amorphous substance obtained abundantly from guano, forming a constituent of the excrement of birds. In 1656 in Paris, a Mr. Jaquin extracted from the scales of the fish Alburnus alburnus so-called pearl essence, in the cosmetics industry, crystalline guanine is used as an additive to various products, where it provides a pearly iridescent effect. It is also used in paints and simulated pearls and plastics
22.
IMP dehydrogenase
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IMP dehydrogenase is associated with cell proliferation and is a possible target for cancer chemotherapy. Mammalian and bacterial IMPDHs are tetramers of identical chains, there are two IMP dehydrogenase isozymes in humans. IMP dehydrogenase nearly always contains a long insertion that has two CBS domains within it, the structure of this enzyme is composed of a TIM barrel domain with two CBS domains inserted within a loop. It is inhibited by Mycophenolic acid, ribavirin, and 6TGMP, 6TGMP inhibition prevents purine interconversion and thus the synthesis of purine nucleotides. Humans express the following two IMP dehydrogenase isozymes, Purine metabolism This article incorporates text from the public domain Pfam and InterPro IPR001093
23.
B cell
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B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the immune system by secreting antibodies. Additionally, B cells present antigen and secrete cytokines, in mammals, B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the bursa of Fabricius, B cells, unlike the other two classes of lymphocytes, T cells and natural killer cells, express B cell receptors on their cell membrane. BCRs allow the B cell to bind a specific antigen, against which it will initiate an antibody response, B cells develop from hematopoietic stem cells that originate from bone marrow. HSCs first differentiate into multipotent progenitor cells, then common lymphoid progenitor cells, B cells undergo two types of selection while developing in the bone marrow to ensure proper development. Positive selection occurs through antigen-independent signaling involving both the pre-BCR and the BCR, if these receptors do not bind to their ligand, B cells do not receive the proper signals and cease to develop. This negative selection process leads to a state of central tolerance, to complete development, immature B cells migrate from the bone marrow to the spleen as well as pass through two transitional stages, T1 and T2. Throughout their migration to the spleen and after spleen entry, they are considered T1 B cells, within the spleen, T1 B cells transition to T2 B cells. T2 B cells differentiate into either follicular B cells or marginal zone B cells depending on signals received through the BCR, once differentiated, they are now considered mature B cells, or naive B cells. While immature and during the T1 phase, B cells express BCRCR of class IgH, B cell activation occurs in the secondary lymphoid organs, such as the spleen and lymph nodes. After B cells mature in the marrow, they migrate through the blood to SLOs. At the SLO, B cell activation begins when the B cell binds to an antigen via its BCR, antigen is presented to lymphocytes by APCs such as macrophages or dendritic cells, and include proteins, glycoproteins, polysaccharides, whole virus particles, and whole bacterial cells. Of the three B cell subsets, FO B cells preferentially undergo T cell-dependent activation while MZ B cells, B cell activation is enhanced through the activity of CD21, a surface receptor in complex with surface proteins CD19 and CD81. Antigens that activate B cells with the help of T-cell are known as T cell-dependent antigens and they are named as such because they are unable to induce a humoral response in organisms that lack T cells. B cell response to these antigens takes multiple days, though antibodies generated have an affinity and are more functionally versatile than those generated from T cell-independent activation. T helper cells, typically follicular T helper cells, that were activated with the same antigen recognize, following TCR-MHC-II-peptide binding, T cells express the surface protein CD40L as well as cytokines such as IL-4 and IL-21. T cell-derived cytokines bound by B cell cytokine receptors also promote B cell proliferation, immunoglobulin class switching, after B cells receive these signals, they are considered activated
24.
Adenine
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It also has functions in protein synthesis and as a chemical component of DNA and RNA. The shape of adenine is complementary to either thymine in DNA or uracil in RNA, the image on the right shows pure adenine, as an independent molecule. When connected into DNA, a covalent bond is formed between deoxyribose sugar and the bottom left nitrogen, so removing the hydrogen, the remaining structure is called an adenine residue, as part of a larger molecule. Adenosine is adenine reacted with ribose as used in RNA and ATP, deoxyadenosine adenine attached to deoxyribose, adenine forms several tautomers, compounds that can be rapidly interconverted and are often considered equivalent. However, in isolated conditions, i. e. in an inert gas matrix and in the gas phase, purine metabolism involves the formation of adenine and guanine. Adenine is one of the two purine nucleobases used in forming nucleotides of the nucleic acids, in DNA, adenine binds to thymine via two hydrogen bonds to assist in stabilizing the nucleic acid structures. In RNA, which is used for synthesis, adenine binds to uracil. Adenine forms adenosine, a nucleoside, when attached to ribose and it forms adenosine triphosphate, a nucleoside triphosphate, when three phosphate groups are added to adenosine. Adenosine triphosphate is used in cellular metabolism as one of the methods of transferring chemical energy between chemical reactions. In older literature, adenine was sometimes called Vitamin B4 and it is no longer considered a true vitamin or part of the Vitamin B complex. However, two B vitamins, niacin and riboflavin, bind with adenine to form the essential cofactors nicotinamide adenine dinucleotide and flavin adenine dinucleotide, hermann Emil Fischer was one of the early scientists to study adenine. It was named in 1885 by Albrecht Kossel, in reference to the pancreas from which Kossels sample had been extracted. On August 8,2011, a report, based on NASA studies with meteorites found on Earth, was published suggesting building blocks of DNA and RNA may have been formed extraterrestrially in outer space
25.
Adenosine
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Adenosine is a purine nucleoside composed of a molecule of adenine attached to a ribose sugar molecule moiety via a β-N9-glycosidic bond. It is also a neuromodulator, believed to play a role in promoting sleep, Adenosine also plays a role in regulation of blood flow to various organs through vasodilation. Common side effects include chest pain, feeling faint, shortness of breath along with tingling of the senses, serious side effects include a worsening dysrhythmia and low blood pressure. It appears to be safe in pregnancy, when it is administered intravenously, adenosine causes transient heart block in the atrioventricular node. It also causes endothelial-dependent relaxation of smooth muscle as is found inside the artery walls and this causes dilation of the normal segments of arteries, i. e. where the endothelium is not separated from the tunica media by atherosclerotic plaque. This feature allows physicians to use adenosine to test for blockages in the coronary arteries, the administration of adenosine also reduces blood flow to coronary arteries past the occlusion. Other coronary arteries dilate when adenosine is administered while the segment past the occlusion is already maximally dilated and this leads to less blood reaching the ischemic tissue, which in turn produces the characteristic chest pain. In individuals suspected of suffering from a supraventricular tachycardia, adenosine is used to identify the rhythm. Certain SVTs can be terminated with adenosine. This includes any re-entrant arrhythmias that require the AV node for the re-entry, e. g. AV reentrant tachycardia, in addition, atrial tachycardia can sometimes be terminated with adenosine. Fast rhythms of the heart that are confined to the atria or ventricles, however, the ventricular response rate is temporarily slowed with adenosine in such cases. Because of the effects of adenosine on AV node-dependent SVTs, adenosine is considered a class V antiarrhythmic agent, when adenosine is used to cardiovert an abnormal rhythm, it is normal for the heart to enter ventricular asystole for a few seconds. This can be disconcerting to a conscious patient, and is associated with angina-like sensations in the chest. Adenosine is used an adjunct to thallous chloride TI201 or Tc99m myocardial perfusion scintigraphy in patients unable to undergo adequate stress testing with exercise, due to adenosines extremely short half-life, the IV line is started as proximal to the heart as possible, such as the antecubital fossa. The IV push is often followed with a flush of 10-20 ccs of saline. If this has no effect, a dose of 12 mg can be given 1–2 minutes after the first dose, some clinicians may prefer to administer a higher dose, rather than repeat a dose that apparently had no effect. When given to dilate the arteries, such as in a stress test, the recommended dose may be increased in patients on theophylline, since methylxanthines prevent binding of adenosine at receptor sites. The dose is often decreased in patients on dipyridamole and diazepam because adenosine potentiates the effects of these drugs
26.
Uracil
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Uracil /ˈjʊərəsɪl/ is one of the four nucleobases in the nucleic acid of RNA that are represented by the letters A, G, C and U. The others are adenine, cytosine, and guanine, in RNA, uracil binds to adenine via two hydrogen bonds. In DNA, the uracil nucleobase is replaced by thymine, Uracil is a demethylated form of thymine. Uracil is a common and naturally occurring pyrimidine derivative, the name uracil was coined in 1885 by the German chemist Robert Behrend, who was attempting to synthesize derivatives of uric acid. Originally discovered in 1900 by Alberto Ascoli, it was isolated by hydrolysis of yeast nuclein, it was found in bovine thymus and spleen, herring sperm. It is a planar, unsaturated compound that has the ability to absorb light, based on 12C/13C isotopic ratios of organic compounds found in the Murchison meteorite, it is believed that uracil, xanthine and related molecules can also be formed extraterrestrially. In 2012, an analysis of data from the Cassini mission orbiting in the Saturn system showed that Titans surface composition may include uracil, in RNA, uracil base-pairs with adenine and replaces thymine during DNA transcription. In DNA, the substitution of thymine for uracil may have increased DNA stability. Uracil pairs with adenine through hydrogen bonding, when base pairing with adenine, uracil acts as both a hydrogen bond acceptor and a hydrogen bond donor. In RNA, uracil binds with a sugar to form the ribonucleoside uridine. When a phosphate attaches to uridine, uridine 5-monophosphate is produced, Uracil undergoes amide-imidic acid tautomeric shifts because any nuclear instability the molecule may have from the lack of formal aromaticity is compensated by the cyclic-amidic stability. The amide tautomer is referred to as the structure, while the imidic acid tautomer is referred to as the lactim structure. These tautomeric forms are predominant at pH7, the lactam structure is the most common form of uracil. Uracil also recycles itself to form nucleotides by undergoing a series of phosphoribosyltransferase reactions, degradation of uracil produces the substrates aspartate, carbon dioxide, and ammonia. C4H4N2O2 → H3NCH2CH2COO− + NH4+ + CO2 Oxidative degradation of uracil produces urea and maleic acid in the presence of H2O2 and Fe2+ or in the presence of diatomic oxygen, the first site of ionization of uracil is not known. The negative charge is placed on the anion and produces a pKa of less than or equal to 12. The basic pKa = -3.4, while the acidic pKa =9.389, in the gas phase, uracil has 4 sites that are more acidic than water. Uracil is rarely found in DNA, and this may have been a change to increase genetic stability
27.
Purine nucleoside phosphorylase
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Purine nucleoside phosphorylase also known as PNPase and inosine phosphorylase is an enzyme that in humans is encoded by the NP gene. This enzyme belongs to the family of glycosyltransferases, specifically the pentosyltransferases, the systematic name of this enzyme class is purine-nucleoside, phosphate ribosyltransferase. Other names in use include, This enzyme participates in 3 metabolic pathways, purine metabolism, pyrimidine metabolism. Purine nucleoside phosphorylase is an involved in purine metabolism. PNP metabolizes inosine into hypoxanthine and guanosine into guanine, in each case creating ribose phosphate, note, adenosine is first metabolized to inosine via the enzyme adenosine deaminase. Nucleoside phosphorylase is an enzyme which cleaves a nucleoside by phosphorylating the ribose to produce a nucleobase and ribose 1 phosphate and it is one enzyme of the nucleotide salvage pathways. These pathways allow the cell to produce nucleotide monophosphates when the de novo synthesis pathway has been interrupted or is non-existent, often the de novo pathway is interrupted as a result of chemotherapy drugs such as methotrexate or aminopterin. All salvage pathway enzymes require a high energy phosphate donor such as ATP or PRPP, thymidine can be phosphorylated by thymidine kinase. Uridine can be phosphorylated by uridine kinase, cytidine can be phosphorylated by cytidine kinase. Deoxycytidine can be phosphorylated by deoxycytidine kinase, adenosine uses the enzyme adenosine kinase, which is a very important enzyme in the cell. Attempts are being made to develop an inhibitor for the enzyme for use in cancer chemotherapy and this protein may use the morpheein model of allosteric regulation. PNPase, together with adenosine deaminase, serves a key role in purine catabolism, pNP-deficient patients will have an immunodeficiency problem. It affects only T-cells, B-cells are unaffected by the deficiency
28.
Peroxynitrite
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Peroxynitrite is an ion with the formula ONOO−. It is a structural isomer of nitrate, NO−3. Although its conjugate acid is reactive, peroxynitrite is stable in basic solutions. It is prepared by the reaction of peroxide with nitrite, H2O2 + NO−2 → ONOO− + H2O Peroxynitrite is an oxidant. Because of its properties, peroxynitrite can damage a wide array of molecules in cells, including DNA. In the laboratory, a solution of peroxynitrite can be prepared by treating acidified hydrogen peroxide with a solution of sodium nitrite and its concentration is indicated by the absorbance at 302 nm. ONOO− reacts nucleophilically with carbon dioxide, in vivo, the concentration of carbon dioxide is about 1 mM, and its reaction with ONOO− occurs quickly. Thus, under conditions, the reaction of ONOO− with carbon dioxide to form nitrosoperoxycarbonate is by far the predominant pathway for ONOO−. ONOOCO−2 homolyzes to form carbonate radical and nitrogen dioxide, again as a pair of caged radicals, approximately 66% of the time, these two radicals recombine to form carbon dioxide and nitrate. The other 33% of the time, these two radicals escape the solvent cage and become free radicals and it is these radicals that are believed to cause peroxynitrite-related cellular damage
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. PMID 12084941.