1.
BRENDA
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BRENDA is an information system representing one of the most comprehensive enzyme repositories. It is a resource that comprises molecular and biochemical information on enzymes that have been classified by the IUBMB. Every classified enzyme is characterized with respect to its catalyzed biochemical reaction, kinetic properties of the corresponding reactants are described in detail. BRENDA contains enzyme-specific data manually extracted from scientific literature and additional data derived from automatic information retrieval methods such as text mining. It provides a user interface that allows a convenient and sophisticated access to the data. BRENDA was founded in 1987 at the former German National Research Centre for Biotechnology in Braunschweig and was published as a series of books. Its name was originally an acronym for the Braunschweig Enzyme Database, from 1996 to 2007, BRENDA was located at the University of Cologne. There, BRENDA developed into a publicly accessible enzyme information system, in 2007, BRENDA returned to Braunschweig. Currently, BRENDA is maintained and further developed at the Department of Bioinformatics, a major update of the data in BRENDA is performed twice a year. Besides the upgrade of its content, improvements of the interface are also incorporated into the BRENDA database. The latest update was performed in January 2015, Database, The database contains more than 40 data fields with enzyme-specific information on more than 7000 EC numbers that are classified according to the IUBMB. Currently, BRENDA contains manually annotated data from over 140,000 different scientific articles, each enzyme entry is clearly linked to at least one literature reference, to its source organism, and, where available, to the protein sequence of the enzyme. An important part of BRENDA represent the more than 110,000 enzyme ligands, the term ligand is used in this context to all low molecular weight compounds which interact with enzymes. These include not only metabolites of primary metabolism, co-substrates or cofactors, the origin of these molecules ranges from naturally occurring antibiotics to synthetic compounds that have been synthesized for the development of drugs or pesticides. Furthermore, cross-references to external resources such as sequence and 3D-structure databases. Extensions, Since 2006, the data in BRENDA is supplemented with information extracted from the literature by a co-occurrence based text mining approach. For this purpose, four text-mining repositories FRENDA, AMENDA, DRENDA and KENDA were introduced and these text-mining results were derived from the titles and abstracts of all articles in the literature database PubMed. Data access, There are several tools to access to the data in BRENDA
2.
MetaCyc
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The MetaCyc database contains extensive information on metabolic pathways and enzymes from many organisms. MetaCyc is also used in engineering and metabolomics research. MetaCyc contains extensive data on individual enzymes, describing their subunit structure, cofactors, activators and inhibitors, substrate specificity, MetaCyc data on reactions includes predicted atom mappings that describe the correspondence between atoms in the reactant compounds and the product compounds. It also provides enzyme mini-reviews and literature references, MetaCyc data on metabolites includes chemical structures, predicted Gibbs free energies of formation, and links to external databases
3.
Protein Data Bank
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The Protein Data Bank is a crystallographic database for the three-dimensional structural data of large biological molecules, such as proteins and nucleic acids. The PDB is overseen by a called the Worldwide Protein Data Bank. The PDB is a key resource in areas of structural biology, most major scientific journals, and some funding agencies, now require scientists to submit their structure data to the PDB. Many other databases use protein structures deposited in the PDB, for example, SCOP and CATH classify protein structures, while PDBsum provides a graphic overview of PDB entries using information from other sources, such as Gene ontology. By 1971, one of Meyers programs, SEARCH, enabled researchers to access information from the database to study protein structures offline. SEARCH was instrumental in enabling networking, thus marking the beginning of the PDB. Upon Hamiltons death in 1973, Tom Koeztle took over direction of the PDB for the subsequent 20 years, in January 1994, Joel Sussman of Israels Weizmann Institute of Science was appointed head of the PDB. In October 1998, the PDB was transferred to the Research Collaboratory for Structural Bioinformatics, the new director was Helen M. Berman of Rutgers University. In 2003, with the formation of the wwPDB, the PDB became an international organization, the founding members are PDBe, RCSB, and PDBj. Each of the four members of wwPDB can act as deposition, data processing, the data processing refers to the fact that wwPDB staff review and annotate each submitted entry. The data are automatically checked for plausibility. The PDB database is updated weekly, likewise, the PDB holdings list is also updated weekly. As of 14 March 2017, the breakdown of current holdings is as follows,103,514 structures in the PDB have a structure factor file,9,057 structures have an NMR restraint file. 2,826 structures in the PDB have a chemical shifts file, therefore, the final conformation of the protein is obtained, in the latter case, by solving a distance geometry problem. A few proteins are determined by cryo-electron microscopy, the significance of the structure factor files, mentioned above, is that, for PDB structures determined by X-ray diffraction that have a structure file, the electron density map may be viewed. The data of such structures is stored on the electron density server, however, since 2007, the rate of accumulation of new protein structures appears to have plateaued. The file format used by the PDB was called the PDB file format. This original format was restricted by the width of computer punch cards to 80 characters per line, around 1996, the macromolecular Crystallographic Information file format, mmCIF, which is an extension of the CIF format started to be phased in
4.
PubMed
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PubMed is a free search engine accessing primarily the MEDLINE database of references and abstracts on life sciences and biomedical topics. The United States National Library of Medicine at the National Institutes of Health maintains the database as part of the Entrez system of information retrieval, from 1971 to 1997, MEDLINE online access to the MEDLARS Online computerized database primarily had been through institutional facilities, such as university libraries. PubMed, first released in January 1996, ushered in the era of private, free, home-, the PubMed system was offered free to the public in June 1997, when MEDLINE searches via the Web were demonstrated, in a ceremony, by Vice President Al Gore. Information about the journals indexed in MEDLINE, and available through PubMed, is found in the NLM Catalog. As of 5 January 2017, PubMed has more than 26.8 million records going back to 1966, selectively to the year 1865, and very selectively to 1809, about 500,000 new records are added each year. As of the date,13.1 million of PubMeds records are listed with their abstracts. In 2016, NLM changed the system so that publishers will be able to directly correct typos. Simple searches on PubMed can be carried out by entering key aspects of a subject into PubMeds search window, when a journal article is indexed, numerous article parameters are extracted and stored as structured information. Such parameters are, Article Type, Secondary identifiers, Language, publication type parameter enables many special features. As these clinical girish can generate small sets of robust studies with considerable precision, since July 2005, the MEDLINE article indexing process extracts important identifiers from the article abstract and puts those in a field called Secondary Identifier. The secondary identifier field is to store numbers to various databases of molecular sequence data, gene expression or chemical compounds. For clinical trials, PubMed extracts trial IDs for the two largest trial registries, ClinicalTrials. gov and the International Standard Randomized Controlled Trial Number Register, a reference which is judged particularly relevant can be marked and related articles can be identified. If relevant, several studies can be selected and related articles to all of them can be generated using the Find related data option, the related articles are then listed in order of relatedness. To create these lists of related articles, PubMed compares words from the title and abstract of each citation, as well as the MeSH headings assigned, using a powerful word-weighted algorithm. The related articles function has been judged to be so precise that some researchers suggest it can be used instead of a full search, a strong feature of PubMed is its ability to automatically link to MeSH terms and subheadings. Examples would be, bad breath links to halitosis, heart attack to myocardial infarction, where appropriate, these MeSH terms are automatically expanded, that is, include more specific terms. Terms like nursing are automatically linked to Nursing or Nursing and this important feature makes PubMed searches automatically more sensitive and avoids false-negative hits by compensating for the diversity of medical terminology. The My NCBI area can be accessed from any computer with web-access, an earlier version of My NCBI was called PubMed Cubby
5.
National Center for Biotechnology Information
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The National Center for Biotechnology Information is part of the United States National Library of Medicine, a branch of the National Institutes of Health. The NCBI is located in Bethesda, Maryland and was founded in 1988 through legislation sponsored by Senator Claude Pepper, the NCBI houses a series of databases relevant to biotechnology and biomedicine and is an important resource for bioinformatics tools and services. Major databases include GenBank for DNA sequences and PubMed, a database for the biomedical literature. Other databases include the NCBI Epigenomics database, all these databases are available online through the Entrez search engine. NCBI is directed by David Lipman, one of the authors of the BLAST sequence alignment program. He also leads a research program, including groups led by Stephen Altschul, David Landsman, Eugene Koonin, John Wilbur, Teresa Przytycka. NCBI is listed in the Registry of Research Data Repositories re3data. org, NCBI has had responsibility for making available the GenBank DNA sequence database since 1992. GenBank coordinates with individual laboratories and other databases such as those of the European Molecular Biology Laboratory. Since 1992, NCBI has grown to other databases in addition to GenBank. The NCBI assigns a unique identifier to each species of organism, the NCBI has software tools that are available by WWW browsing or by FTP. For example, BLAST is a sequence similarity searching program, BLAST can do sequence comparisons against the GenBank DNA database in less than 15 seconds. RAG2/IL2RG The NCBI Bookshelf is a collection of freely accessible, downloadable, some of the books are online versions of previously published books, while others, such as Coffee Break, are written and edited by NCBI staff. BLAST is a used for calculating sequence similarity between biological sequences such as nucleotide sequences of DNA and amino acid sequences of proteins. BLAST is a tool for finding sequences similar to the query sequence within the same organism or in different organisms. It searches the query sequence on NCBI databases and servers and post the results back to the browser in chosen format. Input sequences to the BLAST are mostly in FASTA or Genbank format while output could be delivered in variety of such as HTML, XML formatting. HTML is the output format for NCBIs web-page. Entrez is both indexing and retrieval system having data from sources for biomedical research
6.
Enzyme
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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 later 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
7.
Catalysis
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Catalysis is the increase in the rate of a chemical reaction due to the participation of an additional substance called a catalyst. In most cases, reactions occur faster with a catalyst because they require less activation energy, furthermore, since they are not consumed in the catalyzed reaction, catalysts can continue to act repeatedly. Often only tiny amounts are required in principle, in the presence of a catalyst, less free energy is required to reach the transition state, but the total free energy from reactants to products does not change. A catalyst may participate in multiple chemical transformations, the effect of a catalyst may vary due to the presence of other substances known as inhibitors or poisons or promoters. Catalyzed reactions have an activation energy than the corresponding uncatalyzed reaction, resulting in a higher reaction rate at the same temperature. However, the mechanics of catalysis is complex. Usually, the catalyst participates in this slowest step, and rates are limited by amount of catalyst, in heterogeneous catalysis, the diffusion of reagents to the surface and diffusion of products from the surface can be rate determining. A nanomaterial-based catalyst is an example of a heterogeneous catalyst, analogous events associated with substrate binding and product dissociation apply to homogeneous catalysts. Although catalysts are not consumed by the reaction itself, they may be inhibited, deactivated, in heterogeneous catalysis, typical secondary processes include coking where the catalyst becomes covered by polymeric side products. Additionally, heterogeneous catalysts can dissolve into the solution in a system or sublimate in a solid–gas system. The production of most industrially important chemicals involves catalysis, similarly, most biochemically significant processes are catalysed. Research into catalysis is a field in applied science and involves many areas of chemistry, notably organometallic chemistry. Catalysis is relevant to aspects of environmental science, e. g. the catalytic converter in automobiles. Many transition metals and transition metal complexes are used in catalysis as well, Catalysts called enzymes are important in biology. A catalyst works by providing a reaction pathway to the reaction product. The rate of the reaction is increased as this route has a lower activation energy than the reaction route not mediated by the catalyst. The disproportionation of hydrogen peroxide creates water and oxygen, as shown below,2 H2O2 →2 H2O + O2 This reaction is preferable in the sense that the reaction products are more stable than the starting material, though the uncatalysed reaction is slow. In fact, the decomposition of hydrogen peroxide is so slow that hydrogen peroxide solutions are commercially available and this reaction is strongly affected by catalysts such as manganese dioxide, or the enzyme peroxidase in organisms
8.
Chemical reaction
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A chemical reaction is a process that leads to the transformation of one set of chemical substances to another. Nuclear chemistry is a sub-discipline of chemistry that involves the reactions of unstable. The substance initially involved in a reaction are called reactants or reagents. Chemical reactions are characterized by a chemical change, and they yield one or more products. Reactions often consist of a sequence of individual sub-steps, the elementary reactions. Chemical reactions are described with chemical equations, which present the starting materials, end products. Chemical reactions happen at a characteristic reaction rate at a given temperature, typically, reaction rates increase with increasing temperature because there is more thermal energy available to reach the activation energy necessary for breaking bonds between atoms. Reactions may proceed in the forward or reverse direction until they go to completion or reach equilibrium, Reactions that proceed in the forward direction to approach equilibrium are often described as spontaneous, requiring no input of free energy to go forward. Non-spontaneous reactions require input of energy to go forward. Different chemical reactions are used in combinations during chemical synthesis in order to obtain a desired product, in biochemistry, a consecutive series of chemical reactions form metabolic pathways. These reactions are catalyzed by protein enzymes. Chemical reactions such as combustion in fire, fermentation and the reduction of ores to metals were known since antiquity, in the Middle Ages, chemical transformations were studied by Alchemists. They attempted, in particular, to lead into gold, for which purpose they used reactions of lead. The process involved heating of sulfate and nitrate minerals such as sulfate, alum. In the 17th century, Johann Rudolph Glauber produced hydrochloric acid and sodium sulfate by reacting sulfuric acid, further optimization of sulfuric acid technology resulted in the contact process in the 1880s, and the Haber process was developed in 1909–1910 for ammonia synthesis. From the 16th century, researchers including Jan Baptist van Helmont, Robert Boyle, the phlogiston theory was proposed in 1667 by Johann Joachim Becher. It postulated the existence of an element called phlogiston, which was contained within combustible bodies. This proved to be false in 1785 by Antoine Lavoisier who found the explanation of the combustion as reaction with oxygen from the air
9.
Limonene
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Limonene is a colorless liquid hydrocarbon classified as a cyclic terpene. The more common d-isomer possesses a strong smell of oranges and it is used in chemical synthesis as a precursor to carvone and as a renewables-based solvent in cleaning products. The less common l-isomer is found in mint oils and has a piney, limonene takes its name from the lemon, as the rind of the lemon, like other citrus fruits, contains considerable amounts of this compound, which contributes to their odor. Limonene is a molecule, and biological sources produce one enantiomer, the principal industrial source, citrus fruit, contains d-limonene. Racemic limonene is known as dipentene, d-Limonene is obtained commercially from citrus fruits through two primary methods, centrifugal separation or steam distillation. Limonene is a relatively stable terpene and can be distilled without decomposition and it oxidizes easily in moist air to produce carveol, carvone, and limonene oxide. With sulfur, it undergoes dehydrogenation to p-cymene, limonene occurs commonly as the d or -enantiomer, but racemizes to dipentene at 300 °C. When warmed with mineral acid, limonene isomerizes to the conjugated diene α-terpinene, evidence for this isomerization includes the formation of Diels-Alder adducts between α-terpinene adducts and maleic anhydride. It is possible to effect reaction at one of the double bonds selectively, anhydrous hydrogen chloride reacts preferentially at the disubstituted alkene, whereas epoxidation with mCPBA occurs at the trisubstituted alkene. In another synthetic method Markovnikov addition of trifluoroacetic acid followed by hydrolysis of the acetate gives terpineol, limonene is formed from geranyl pyrophosphate, via cyclization of a neryl carbocation or its equivalent as shown. The final step involves loss of a proton from the cation to form the alkene, the most widely practiced conversion of limonene is to carvone. The three step reaction begins with the addition of nitrosyl chloride across the trisubstituted double bond. This species is then converted to the oxime with base, d-Limonene applied to skin may cause irritation, but otherwise appears to be safe for human uses. Limonene is common in cosmetic products, as the main odor constituent of citrus, d-limonene is used in food manufacturing and some medicines, e. g. It is added to cleaning products such as hand cleansers to give a lemon-orange fragrance, in contrast, l-limonene has a piney, turpentine-like odor. In natural and alternative medicine, d-limonene is marketed to relieve gastroesophageal reflux disease, limonene is increasingly being used as a solvent for cleaning purposes, such as the removal of oil from machine parts, as it is produced from a renewable source. It is used as a paint stripper and is useful as a fragrant alternative to turpentine. Limonene is also used as a solvent in some model airplane glues, all-natural commercial air fresheners, with air propellants, containing limonene are used by philatelists to remove self-adhesive postage stamps from envelope paper
10.
Hydrogen ion
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A hydrogen ion is created when a hydrogen atom loses or gains an electron. A lone positively charged ion can readily combine with other particles. Due to its high charge density of approximately 2×1010 times that of a sodium ion. The hydrogen ion is recommended by IUPAC as a term for all ions of hydrogen. Depending on the charge of the ion, two different classes can be distinguished, positively charged ions and negatively charged ions, a hydrogen atom is made up of a nucleus with charge +1, and a single electron. Therefore, the positively charged ion possible has charge +1. In connection with acids, hydrogen ions typically refers to hydrons, Hydrogen atom contains a single proton and a single electron. Removal of the electron gives a cation, whereas addition of a gives a anion. The hydrogen anion, with its loosely held two-electron cloud, has a larger radius than the neutral atom, which in turn is much larger than the bare proton of the cation. Hydrogen forms the cation that has no electrons, but even cations that still retain one or more electrons are still smaller than the neutral atoms or molecules from which they are derived. This happens when hydrogen ions get pushed across the membrane creating a high concentration inside the thylakoid membrane, however, because of osmosis the H+ will force itself out of the membrane through ATP synthase. Utilizing their kinetic energy to escape, the protons will spin the ATP synthase which in turn will create ATP and this happens in cellular respiration as well though the concentrated membrane will instead be the inner membrane of the mitochondria. Hydrogen ions are also important in pH as they are responsible for if a compound is acidic or basic, water detaches to form H+ and hydroxides. This process is referred to as the self-ionization of water Acid Protonation Dihydrogen cation Trihydrogen cation Britannica Molecular Hydrogen Foundation
11.
Oxygen
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Oxygen is a chemical element with symbol O and atomic number 8. It is a member of the group on the periodic table and is a highly reactive nonmetal. By mass, oxygen is the third-most abundant element in the universe, after hydrogen, at standard temperature and pressure, two atoms of the element bind to form dioxygen, a colorless and odorless diatomic gas with the formula O2. This is an important part of the atmosphere and diatomic oxygen gas constitutes 20. 8% of the Earths atmosphere, additionally, as oxides the element makes up almost half of the Earths crust. Most of the mass of living organisms is oxygen as a component of water, conversely, oxygen is continuously replenished by photosynthesis, which uses the energy of sunlight to produce oxygen from water and carbon dioxide. Oxygen is too reactive to remain a free element in air without being continuously replenished by the photosynthetic action of living organisms. Another form of oxygen, ozone, strongly absorbs ultraviolet UVB radiation, but ozone is a pollutant near the surface where it is a by-product of smog. At low earth orbit altitudes, sufficient atomic oxygen is present to cause corrosion of spacecraft, the name oxygen was coined in 1777 by Antoine Lavoisier, whose experiments with oxygen helped to discredit the then-popular phlogiston theory of combustion and corrosion. One of the first known experiments on the relationship between combustion and air was conducted by the 2nd century BCE Greek writer on mechanics, Philo of Byzantium. In his work Pneumatica, Philo observed that inverting a vessel over a burning candle, Philo incorrectly surmised that parts of the air in the vessel were converted into the classical element fire and thus were able to escape through pores in the glass. Many centuries later Leonardo da Vinci built on Philos work by observing that a portion of air is consumed during combustion and respiration, Oxygen was discovered by the Polish alchemist Sendivogius, who considered it the philosophers stone. In the late 17th century, Robert Boyle proved that air is necessary for combustion, English chemist John Mayow refined this work by showing that fire requires only a part of air that he called spiritus nitroaereus. From this he surmised that nitroaereus is consumed in both respiration and combustion, Mayow observed that antimony increased in weight when heated, and inferred that the nitroaereus must have combined with it. Accounts of these and other experiments and ideas were published in 1668 in his work Tractatus duo in the tract De respiratione. Robert Hooke, Ole Borch, Mikhail Lomonosov, and Pierre Bayen all produced oxygen in experiments in the 17th and the 18th century but none of them recognized it as a chemical element. This may have been in part due to the prevalence of the philosophy of combustion and corrosion called the phlogiston theory, which was then the favored explanation of those processes. Established in 1667 by the German alchemist J. J. Becher, one part, called phlogiston, was given off when the substance containing it was burned, while the dephlogisticated part was thought to be its true form, or calx. The fact that a substance like wood gains overall weight in burning was hidden by the buoyancy of the combustion products
12.
Product (chemistry)
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Products are the species formed from chemical reactions. During a chemical reaction reactants are transformed into products after passing through an energy transition state. This process results in the consumption of the reactants, when represented in chemical equations products are by convention drawn on the right-hand side, even in the case of reversible reactions. The properties of such as their energies help determine several characteristics of a chemical reaction such as whether the reaction is exergonic or endergonic. Additionally the properties of a product can make it easier to extract and purify following a chemical reaction, reactants are molecular materials used to create chemical reactions. The atoms arent created or destroyed, the materials are reactive and reactants are rearranging during a chemical reaction. Here is an example of reactants, CH4 + O2, a non-example is CO2 + H2O or energy. Much of chemistry research is focused on the synthesis and characterization of beneficial products, as well as the detection, other fields include natural product chemists who isolate products created by living organisms and then characterize and study these products. The products of a chemical reaction influence several aspects of the reaction, if the products are lower in energy than the reactants, then the reaction will give off excess energy making it an exergonic reaction. Such reactions are thermodynamically favorable and tend to happen on their own, if the kinetics of the reaction are high enough, however, then the reaction may occur too slowly to be observed, or not even occur at all. If the products are higher in energy than the reactants then the reaction will require energy to be performed and is therefore an endergonic reaction. Additionally if the product is less stable than a reactant, then Lefflers assumption holds that the state will more closely resemble the product than the reactant. Ever since the mid nineteenth century chemists have been preoccupied with synthesizing chemical products. Much of synthetic chemistry is concerned with the synthesis of new chemicals as occurs in the design and creation of new drugs, in biochemistry, enzymes act as biological catalysts to convert substrate to product. For example, the products of the enzyme lactase are galactose and glucose, S + E → P + E Where S is substrate, P is product and E is enzyme. Some enzymes display a form of promiscuity where they convert a single substrate into multiple different products and it occurs when the reaction occurs via a high energy transition state that can be resolved into a variety of different chemical products. Some enzymes are inhibited by the product of their reaction binds to the enzyme and this can be important in the regulation of metabolism as a form of negative feedback controlling metabolic pathways. Product inhibition is also an important topic in biotechnology, as overcoming this effect can increase the yield of a product, Chemical reaction Substrate Reagent Precursor Catalyst Enzyme Product Derivative Chemical equilibrium Second law of thermodynamics
13.
Water
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Water is a transparent and nearly colorless chemical substance that is the main constituent of Earths streams, lakes, and oceans, and the fluids of most living organisms. Its chemical formula is H2O, meaning that its molecule contains one oxygen, Water strictly refers to the liquid state of that substance, that prevails at standard ambient temperature and pressure, but it often refers also to its solid state or its gaseous state. It also occurs in nature as snow, glaciers, ice packs and icebergs, clouds, fog, dew, aquifers, Water covers 71% of the Earths surface. It is vital for all forms of life. Only 2. 5% of this water is freshwater, and 98. 8% of that water is in ice and groundwater. Less than 0. 3% of all freshwater is in rivers, lakes, and the atmosphere, a greater quantity of water is found in the earths interior. Water on Earth moves continually through the cycle of evaporation and transpiration, condensation, precipitation. Evaporation and transpiration contribute to the precipitation over land, large amounts of water are also chemically combined or adsorbed in hydrated minerals. Safe drinking water is essential to humans and other even though it provides no calories or organic nutrients. There is a correlation between access to safe water and gross domestic product per capita. However, some observers have estimated that by 2025 more than half of the population will be facing water-based vulnerability. A report, issued in November 2009, suggests that by 2030, in developing regions of the world. Water plays an important role in the world economy, approximately 70% of the freshwater used by humans goes to agriculture. Fishing in salt and fresh water bodies is a source of food for many parts of the world. Much of long-distance trade of commodities and manufactured products is transported by boats through seas, rivers, lakes, large quantities of water, ice, and steam are used for cooling and heating, in industry and homes. Water is an excellent solvent for a variety of chemical substances, as such it is widely used in industrial processes. Water is also central to many sports and other forms of entertainment, such as swimming, pleasure boating, boat racing, surfing, sport fishing, Water is a liquid at the temperatures and pressures that are most adequate for life. Specifically, at atmospheric pressure of 1 bar, water is a liquid between the temperatures of 273.15 K and 373.15 K
14.
Cofactor (biochemistry)
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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 also 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, thus, 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, magnesium, manganese, cobalt, copper, zinc, and molybdenum. Although chromium deficiency causes impaired glucose tolerance, no human enzyme that uses this metal as a cofactor has been identified, iodine is also an essential trace element, but this element is used as part of the structure of thyroid hormones rather than as an enzyme cofactor
15.
Heme
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Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group, these are known as hemoproteins. Hemoproteins have diverse functions including the transportation of diatomic gases, chemical catalysis, diatomic gas detection. The heme iron serves as a source or sink of electrons during electron transfer or redox chemistry, in peroxidase reactions, the porphyrin molecule also serves as an electron source. In the transportation or detection of gases, the gas binds to the heme iron. During the detection of gases, the binding of the gas ligand to the heme iron induces conformational changes in the surrounding protein. Hemoproteins achieve their remarkable diversity by modifying the environment of the heme macrocycle within the protein matrix. For example, the ability of hemoglobin to effectively deliver oxygen to tissues is due to amino acid residues located near the heme molecule. Hemoglobin reversibly binds to oxygen in the lungs when the pH is high, when the situation is reversed, hemoglobin will release oxygen into the tissues. This phenomenon, which states that hemoglobins oxygen binding affinity is inversely proportional to both acidity and concentration of carbon dioxide, is known as the Bohr effect. There are several biologically important kinds of heme, The most common type is heme B, other important types include heme A, isolated hemes are commonly designated by capital letters while hemes bound to proteins are designated by lower case letters. Cytochrome a refers to the heme A in specific combination with membrane protein forming a portion of cytochrome c oxidase, the following carbon numbering system of porphyrins is an older numbering used by biochemists and not the 1–24 numbering system recommended by IUPAC which is shown in the table above. Heme l is the derivative of heme B which is attached to the protein of lactoperoxidase, eosinophil peroxidase. The addition of peroxide with the glutamyl-375 and aspartyl-225 of lactoperoxidase forms ester bonds between amino acid residues and the heme 1- and 5-methyl groups, respectively. Similar ester bonds with two methyl groups are thought to form in eosinophil and thyroid peroxidases. Heme l is one important characteristic of animal peroxidases, plant peroxidases incorporate heme B, lactoperoxidase and eosinophil peroxidase are protective enzymes responsible for the destruction of invading bacteria and virus. Thyroid peroxidase is the enzyme catalyzing the biosynthesis of the important thyroid hormones, because lactoperoxidase destroys invading organisms in the lungs and excrement, it is thought to be an important protective enzyme. Heme m is the derivative of heme B covalently bound at the site of myeloperoxidase. Heme m contains the two ester bonds at the heme 1- and 5-methyls as in heme l found in other mammalian peroxidases, myeloperoxidase is present in mammalian neutrophils and is responsible for the destruction of invading bacteria and viruse
16.
PubMed Identifier
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PubMed is a free search engine accessing primarily the MEDLINE database of references and abstracts on life sciences and biomedical topics. The United States National Library of Medicine at the National Institutes of Health maintains the database as part of the Entrez system of information retrieval, from 1971 to 1997, MEDLINE online access to the MEDLARS Online computerized database primarily had been through institutional facilities, such as university libraries. PubMed, first released in January 1996, ushered in the era of private, free, home-, the PubMed system was offered free to the public in June 1997, when MEDLINE searches via the Web were demonstrated, in a ceremony, by Vice President Al Gore. Information about the journals indexed in MEDLINE, and available through PubMed, is found in the NLM Catalog. As of 5 January 2017, PubMed has more than 26.8 million records going back to 1966, selectively to the year 1865, and very selectively to 1809, about 500,000 new records are added each year. As of the date,13.1 million of PubMeds records are listed with their abstracts. In 2016, NLM changed the system so that publishers will be able to directly correct typos. Simple searches on PubMed can be carried out by entering key aspects of a subject into PubMeds search window, when a journal article is indexed, numerous article parameters are extracted and stored as structured information. Such parameters are, Article Type, Secondary identifiers, Language, publication type parameter enables many special features. As these clinical girish can generate small sets of robust studies with considerable precision, since July 2005, the MEDLINE article indexing process extracts important identifiers from the article abstract and puts those in a field called Secondary Identifier. The secondary identifier field is to store numbers to various databases of molecular sequence data, gene expression or chemical compounds. For clinical trials, PubMed extracts trial IDs for the two largest trial registries, ClinicalTrials. gov and the International Standard Randomized Controlled Trial Number Register, a reference which is judged particularly relevant can be marked and related articles can be identified. If relevant, several studies can be selected and related articles to all of them can be generated using the Find related data option, the related articles are then listed in order of relatedness. To create these lists of related articles, PubMed compares words from the title and abstract of each citation, as well as the MeSH headings assigned, using a powerful word-weighted algorithm. The related articles function has been judged to be so precise that some researchers suggest it can be used instead of a full search, a strong feature of PubMed is its ability to automatically link to MeSH terms and subheadings. Examples would be, bad breath links to halitosis, heart attack to myocardial infarction, where appropriate, these MeSH terms are automatically expanded, that is, include more specific terms. Terms like nursing are automatically linked to Nursing or Nursing and this important feature makes PubMed searches automatically more sensitive and avoids false-negative hits by compensating for the diversity of medical terminology. The My NCBI area can be accessed from any computer with web-access, an earlier version of My NCBI was called PubMed Cubby
17.
Procollagen-proline dioxygenase
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Procollagen-proline dioxygenase, commonly known as prolyl hydroxylase, is a member of the class of enzymes known as 2-oxoglutarate-dependent dioxygenases. These enzymes catalyze the incorporation of oxygen into organic substrates through a mechanism that requires 2-oxoglutarate, Fe2+ and this particular enzyme catalyzes the formation of -4-hydroxyproline, a compound that represents the most prevalent post-translational modification in the human proteome. Molecular oxygen is bound end-on in a position, producing a dioxygen unit. Nucleophilic attack on C2 generates an intermediate, with loss of the double bond in the dioxygen unit and bonds to iron. Subsequent elimination of CO2 coincides with the formation of the Fe=O species, the second stage involves the abstraction of the pro-R hydrogen atom from C-4 of the proline substrate followed by radical combination, which yields hydroxyproline. As a consequence of the mechanism, one molecule of 2-oxoglutarate is decarboxylated. Ascorbate is utilized as a cofactor to reduce Fe3+ back to Fe2+, prolyl hydroxylase is a tetramer with 2 unique subunits. The α subunit is 59 kDa and is responsible for peptide binding and for catalytic activity. The peptide binding domain spans residues 140-215 of the α subunit, the active site consists of Fe2+ bound to two histidine residues and one aspartate residue, a characteristic shared by most 2-oxoglutarate-dependent dioxygenases. The 55 kDa β subunit is responsible for the localization to. Interestingly, this subunit is identical to the known as protein disulfide isomerase. Prolyl hydroxylase catalyzes the formation of hydroxyproline, which is the most abundant post-translational modification in human body, the modification has a significant impact on the stability of collagen, the major connective tissue of the human body. The enzyme acts specifically on proline contained within the X-Pro-Gly motif – where Pro is proline, because of this motif-specific behavior, the enzyme also acts on other proteins that contain this same sequence. Such proteins include C1q, elastins, PrP, Argonaute 2, as prolyl hydroxylase requires ascorbate as a cofactor to function, its absence compromises the enzyme’s activity. The resulting decreased hydroxylation leads to the condition known as scurvy. Since stability of collagen is compromised in scurvy patients, symptoms include weakening of blood vessels causing purpura, petechiae, hypoxia-inducible factor is an evolutionarily conserved transcription factor that allows the cell to respond physiologically to decreases in oxygen. A class of prolyl hydroxylases which act specifically on HIF has been identified, HIF prolyl-hydroxylase has been targeted by a variety of inhibitors that aim to treat stroke, kidney disease, ischemia, anemia, and other important diseases
18.
Nicotinamide adenine dinucleotide
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Nicotinamide adenine dinucleotide is a coenzyme found in all living cells. The compound is a dinucleotide, because it consists of two nucleotides joined through their phosphate groups, one nucleotide contains an adenine base and the other nicotinamide. Nicotinamide adenine dinucleotide exists in two forms, an oxidized and reduced form abbreviated as NAD+ and NADH respectively, in metabolism, nicotinamide adenine dinucleotide is involved in redox reactions, carrying electrons from one reaction to another. The coenzyme is, therefore, found in two forms in cells, NAD+ is an oxidizing agent – it accepts electrons from other molecules and becomes reduced and this reaction forms NADH, which can then be used as a reducing agent to donate electrons. These electron transfer reactions are the function of NAD. However, it is used in other cellular processes, the most notable one being a substrate of enzymes that add or remove chemical groups from proteins. Because of the importance of these functions, the involved in NAD metabolism are targets for drug discovery. In organisms, NAD can be synthesized from simple building-blocks from the amino acids tryptophan or aspartic acid, in an alternative fashion, more complex components of the coenzymes are taken up from food as the vitamin called niacin. Similar compounds are released by reactions that break down the structure of NAD and these preformed components then pass through a salvage pathway that recycles them back into the active form. Some NAD is also converted into nicotinamide adenine dinucleotide phosphate, the chemistry of this related coenzyme is similar to that of NAD, nicotinamide adenine dinucleotide, like all dinucleotides, consists of two nucleosides joined by a pair of bridging phosphate groups. The nucleosides each contain a ring, one with adenine attached to the first carbon atom. The nicotinamide moiety can be attached in two orientations to this carbon atom. Because of these two structures, the compound exists as two diastereomers. It is the diastereomer of NAD+ that is found in organisms. These nucleotides are joined together by a bridge of two groups through the 5 carbons. In metabolism, the compound accepts or donates electrons in redox reactions, such reactions involve the removal of two hydrogen atoms from the reactant, in the form of a hydride ion, and a proton. The proton is released into solution, while the reductant RH2 is oxidized, the midpoint potential of the NAD+/NADH redox pair is −0.32 volts, which makes NADH a strong reducing agent. The reaction is reversible, when NADH reduces another molecule and is re-oxidized to NAD+
19.
Flavin-containing monooxygenase
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The flavin-containing monooxygenase protein family specializes in the oxidation of xeno-substrates in order to facilitate the excretion of these compounds from living organisms. These enzymes can oxidize a wide array of heteroatoms, particularly soft nucleophiles, such as amines, sulfides and this reaction requires an oxygen, an NADPH cofactor, and an FAD prosthetic group. FMOs share several features, such as a NADPH binding domain, FAD binding domain. These monooxygenases are often misclassified because they share activity profiles similar to those of cytochrome P450, prior to the 1960s, the oxidation of xenotoxic materials was thought to be completely accomplished by CYP450. However, in the early 1970s, Dr and this flavoprotein named Zieglers enzyme exhibited unusual chemical and spectrometric properties. Upon further spectroscopic characterization and investigation of the pool of this enzyme. Once this was noticed, Dr. Zieglers enzyme was reclassified as a broadband flavin monooxygenase, in 1984, the first evidence for multiple forms of FMOs was elucidated by two different laboratories when two distinct FMOs were isolated from rabbit lungs. Since then, over 150 different FMO enzymes have been isolated from a wide variety of organisms. Up until 2002, only 5 FMO enzymes were isolated from mammals. However, a group of researchers found a sixth FMO gene located on human chromosome 1, the FMO family of genes is conserved across all phyla that have been studied so far, therefore some form of the FMO gene family can be found in all studied eukaryotes. FMO genes are characterized by structural and functional constraints, which led to the evolution of different types of FMOs in order to perform a variety of functions. Divergence between the types of FMOs occurred before the amphibians and mammals diverged into separate classes. FMO5 found in vertebrates appears to be older than other types of FMOs. Phylogenetic studies suggest that FMO1 and FMO3 are the most recent FMOs to evolve into enzymes with distinct functions, although FMO5 was the first distinct FMO, it is not clear what function it serves since it does not oxygenate the typical FMO substrates involved in first-pass metabolism. FMOs found in invertebrates are found to have originated polyphyletically, meaning that a similar gene evolved in invertebrates which was not inherited from a common ancestor. FMOs are found in fungi, yeast, plants, mammals, developmental and tissue specific expression has been studied in several mammalian species, including humans, mice, rats, and rabbits. However, because FMO expression is unique to animal species, it is difficult to make conclusions about human FMO regulation. It is likely that species-specific expression of FMOs contributes to differences in susceptibility to toxins, six functional forms of human FMO genes have been reported
20.
FMO2
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Dimethylaniline monooxygenase 2 is an enzyme that in humans is encoded by the FMO2 gene. The flavin-containing monooxygenases are NADPH-dependent enzymes that catalyze the oxidation of many drugs, in most mammals, there is a flavin-containing monooxygenase that catalyzes the N-oxidation of some primary alkylamines through an N-hydroxylamine intermediate. However, in humans, this enzyme is truncated and is rapidly degraded. The protein encoded by this gene represents the form and apparently has no catalytic activity. A functional allele found in African Americans has been reported, and this gene is found in a cluster with the FMO1, FMO3, and FMO4 genes on chromosome 1
21.
Nitric oxide synthase
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Nitric oxide synthases are a family of enzymes catalyzing the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule and it helps modulate vascular tone, insulin secretion, airway tone, and peristalsis, and is involved in angiogenesis and neural development. It may function as a retrograde neurotransmitter, nitric oxide is mediated in mammals by the calcium-calmodulin controlled isoenzymes eNOS and nNOS. It is the cause of septic shock and may function in autoimmune disease. As such, this stoichiometry is not generally observed, and reflects the three electrons supplied per NO by NADPH, nOSs are unusual in that they require five cofactors. Eukaryotic NOS isozymes are catalytically self-sufficient, the electron flow in the NO synthase reaction is, NADPH → FAD → FMN → heme → O2. Tetrahydrobiopterin provides an electron during the catalytic cycle which is replaced during turnover. NOS is the only enzyme that binds flavin adenine dinucleotide, flavin mononucleotide, heme. Arginine-derived NO synthesis has been identified in mammals, fish, birds, invertebrates, best studied are mammals, where three distinct genes encode NOS isozymes, neuronal, cytokine-inducible and endothelial. INOS and nNOS are soluble and found predominantly in the cytosol, evidence has been found for NO signaling in plants, but plant genomes are devoid of homologs to the superfamily which generates NO in other kingdoms. NO produced by eNOS has been shown to be an identical to the endothelium-derived relaxing factor produced in response to shear from increased blood flow in arteries. This dilates blood vessels by relaxing smooth muscle in their linings, ENOS is the primary controller of smooth muscle tone. ENOS plays a role in embryonic heart development and morphogenesis of coronary arteries. The neuronal isoform is involved in the development of nervous system and it functions as a retrograde neurotransmitter important in long term potentiation and hence is likely to be important in memory and learning. NNOS has many other functions, including regulation of cardiac function and peristalsis. The primary receiver for NO produced by eNOS and nNOS is soluble guanylate cyclase, s-nitrosylation appears to be an important mode of action. The inducible isoform iNOS produces large amounts of NO as a defense mechanism and it is synthesized by many cell types in response to cytokines and is an important factor in the response of the body to attack by parasites, bacterial infection, and tumor growth. It is also the cause of septic shock and may play a role in many diseases with an autoimmune etiology, NOS signaling is involved in development and in fertilization in vertebrates
22.
NOS1
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Nitric oxide synthase 1, also known as NOS1, is an enzyme that in humans is encoded by the NOS1 gene. Nitric oxide is a molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter and it is implicated in neurotoxicity associated with stroke and neurodegenerative diseases, neural regulation of smooth muscle, including peristalsis, and penile erection. NO is also responsible for endothelium-derived relaxing factor activity regulating blood pressure, in macrophages, NO mediates tumoricidal and bactericidal actions, as indicated by the fact that inhibitors of NO synthase block these effects. Neuronal NOS and macrophage NOS are distinct isoforms and it has been implicated in asthma, schizophrenia and restless leg syndrome. It has also investigated with respect to bipolar disorder and air pollution exposure. NOS1 has been shown to interact with DLG4 and NOS1AP, nitric oxide synthase This article incorporates text from the United States National Library of Medicine, which is in the public domain
23.
Nitric oxide synthase 2 (inducible)
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Nitric oxide synthase, inducible is an enzyme that in humans is encoded by the NOS2 gene. Nitric oxide is a free radical which acts as a biologic mediator in several processes, including neurotransmission. This gene encodes a nitric oxide synthase which is expressed in the liver and is inducible by a combination of lipopolysaccharide, three related pseudogenes are located within the Smith-Magenis syndrome region on chromosome 17. Alternative splicing of this results in two transcript variants encoding different isoforms. Nitric oxide synthase 2A has been shown to interact with Caveolin 1 and Rac2
24.
Endothelial NOS
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Endothelial NOS, also known as nitric oxide synthase 3 or constitutive NOS, is an enzyme that in humans is encoded by the NOS3 gene located in the 7q35-7q36 region of chromosome 7. This enzyme is one of three isoforms that synthesize nitric oxide, a small gaseous and lipophilic molecule that participates in several biological processes, NO produced by eNOS in the vascular endothelium plays crucial roles in regulating vascular tone, cellular proliferation, leukocyte adhesion, and platelet aggregation. Therefore, a functional eNOS is essential for a cardiovascular system. The reductase domain is linked to the domain by a calmodulin-binding sequence. The binding of the cofactor BH4 is essential for eNOS to efficiently generate NO, in the absence of this cofactor, eNOS shifts from a dimeric to a monomeric form, thus becoming uncoupled. In this conformation, instead of synthesizing NO, eNOS produces superoxide anion, ENOS has a protective function in the cardiovascular system, which is attributed to NO production. Regulation of the tone is one of the best known roles of NO in the cardiovascular system. CGMP, in turn, activates protein kinase G, which promotes multiple phosphorylation of cellular targets lowering cellular Ca2+ concentrations, NO also has antithrombotic effects that result of its diffusion across platelet membrane and sGC activation, resulting in inhibition of platelet aggregation. Moreover, NO affects leukocyte adhesion to the endothelium by inhibiting the nuclear factor kappa B. Furthermore, part of properties of NO is attributable to up-regulation of heme-oxygenase-I and ferritin expression. ENOS expression and activity are carefully controlled by multiple interconnected mechanisms of regulation present at the transcriptional, posttranscriptional, binding of transcription factors such as Sp1, Sp3, Ets-1, Elf-1, and YY1 to the NOS3 promoter and DNA methylation represents an important mechanism of transcriptional regulation. Posttranscriptionally, eNOS is regulated by modifications of the transcript, mRNA stability, subcellular localization. Posttranslational modifications of eNOS include fatty acid acylation, protein-protein interactions, substrate, and co-factor availability, importantly, eNOS is attached by myristoylation and palmitoylation to caveolae, a pocket-like invagination on the membrane rich in cholesterol and sphingolipids. With the binding of eNOS to caveolae, the enzyme is inactivated due to the strong, the binding of calcium-activated calmodulin to eNOS displaces caveolin-1 and activates eNOS. Moreover, eNOS activation is dynamically regulated by multiple phosphorylation sites at tyrosine, serine, impaired NO production is involved in the pathogenesis of several diseases such as hypertension, preeclampsia, diabetes mellitus, obesity, erectile dysfunction, and migraine. In this regard, a number of studies showed that polymorphisms in NOS3 gene affect the susceptibility to these diseases. The VNTR in intron 4 affects eNOS expression, and the susceptibility to hypertension, preeclampsia, obesity, growing evidence supports the association of diseases with NOS3 haplotypes. This approach may be more informative than the analysis of genetic polymorphisms one by one, statin treatment was more effective in increasing NO bioavailability in subjects carrying the CC genotype for the g. -786T>C polymorphism than in TT carriers
25.
Cholesterol 7 alpha-hydroxylase
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It is a cytochrome P450 enzyme, which belongs to the oxidoreductase class, and converts cholesterol to 7-alpha-hydroxycholesterol, the first and rate limiting step in bile acid synthesis. The inhibition of cholesterol 7-alpha-hydroxylase represses bile acid biosynthesis, the superfamily Cytochrome P450 was named in 1961, because of the 450-nm spectral peak pigment that cytochrome P450 has when reduced and bound to carbon monoxide. In the early 1960s, P450 was thought to be one enzyme, however, the membrane-associated and hydrophobic nature of the enzyme system impeded purification, and the number of proteins involved could not be accurately counted. Substrates identified to date include saturated and unsaturated fatty acids, eicosanoids, sterols and steroids, bile acids, vitamin D3 derivatives, retinoids, many cytochrome P450 enzymes can metabolise various exogenous compounds including drugs, environmental chemicals and pollutants, and natural plant products. The expression of many P450 enzymes is often induced by accumulation of a substrate, the ability of one P450 substrate to affect the concentrations of another in this manner is the basis for so-called drug-drug interactions, which complicate treatment. Cholesterol 7 alpha hydroxylase consists of 491 amino acids, which on folding forms 23 alpha helices and 26 beta sheets, cholesterol 7 alpha-hydroxylase is a cytochrome P450 heme enzyme that oxidizes cholesterol in the position 7 using molecular oxygen. CYP7A1 is located in the reticulum and is important for the synthesis of bile acid. Bile acids have powerful toxic properties like the membrane disruption and there are a range of mechanisms to restrict their accumulation in tissues. The discovery of farnesoid X receptor which is located in the liver, has opened new insights, bile acid activation of FXR represses the expression of CYP7A1 via, raising the expression of small heterodimer, a non-DNA binding protein. The increased abundance of SHP causes it to associate with liver receptor homolog -1, furthermore, there is an FXR/SHP-independent mechanism that also represses CYP7A1 expression. This FXR/SHP-independent pathway involves the interaction of bile acids with liver macrophages and these inflammatory cytokines, which include tumor necrosis factor alpha and interleukin-1beta, act upon the liver parenchymal cells causing a rapid repression of the CYP7A1 gene. Regulation of CYP7A1 occurs at several levels including synthesis, bile acids, steroid hormones, inflammatory cytokines, insulin, and growth factors inhibit CYP7A1 transcription through the 5′-upstream region of the promoter. The average life of this enzyme is between two and three hours, activity can be regulated by phosphorylation-dephosphorylation. CYP7A1 is upregulated by the nuclear receptor LXR when cholesterol levels are high, the effect of this upregulation is to increase the production of bile acids and reduce the level of cholesterol in hepatocytes. It is downregulated by Sterol regulatory element-binding proteins when plasma cholesterol levels are low, bile acids provide feedback inhibition of CYP7A1 by at least two different pathways, both involving the farnesoid X receptor, FXR. In the liver, bile acids bound to FXR induce Small heterodimer partner, SHP which binds to LRH-1, in the intestine, bile acids/FXR stimulate production of FGF15/19, which then acts as a hormone in the liver via FGFR4. One feature of enzymes is their high specificity and they are specific on a singular substrate, reaction or both together, that means, that the enzymes can catalyze all reactions wherein the substrate can experience. The enzyme cholesterol 7 alpha hydroxylase catalyzes the reaction that converts cholesterol into cholesterol 7 alpha hydroxylase reducing and oxidizing that molecule, click on genes, proteins and metabolites below to link to respective articles
26.
Methane monooxygenase
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Methane monooxygenase, or MMO, is an enzyme capable of oxidizing the C-H bond in methane as well as other alkanes. Methane monooxygenase belongs to the class of oxidoreductase enzymes, there are two well-studied forms of MMO, the soluble form and the particulate form. The active site in sMMO contains a di-iron center bridged by an atom, whereas the active site in pMMO utilizes copper. Structures of both proteins have been determined by X-ray crystallography, however, the location and mechanism of the site in pMMO is still poorly understood and is an area of active research. These enzymes have a relatively wide substrate specificity and can catalyse the oxidation of a range of substrates including ammonia, methane, halogenated hydrocarbons and these enzymes are composed of 3 subunits - A, B and C - and contain various metal centers, including copper. The A subunit from Methylococcus capsulatus resides primarily within the membrane and consists of 7 transmembrane helices and a beta-hairpin, a conserved glutamate residue is thought to contribute to a metal center. Methane monooxygenases are found in bacteria, a class of bacteria that exist at the interface of aerobic and anaerobic environments. One of the widely studied bacteria of this type is Methylococcus capsulatus. This bacterium was discovered in the hot springs of Bath, England, methanotrophic bacteria play an essential role of cycling carbon through anaerobic sediments. The chemistry behind the cycling takes a chemically inert hydrocarbon, methane, other hydrocarbons are oxidized by MMOs, so a new hydroxylation catalyst based on the understanding of MMO systems could possibly make a more efficient use of the world supply of natural gas. This is a monooxygenase reaction in which two reducing equivalents from NADH are utilized to split the O-O bond of O2. The best characterized forms of soluble MMO contains three components, hydroxylase, the β unit, and the reductase. Each of which is necessary for effective substrate hydroxylation and NADH oxidation, X-ray crystallography of the MMO shows that it is a dimer formed of three subunits, α2β2γ2. With 2.2 A resolution, the shows that MMO is a relatively flat molecule with the dimensions of 60 x 100 x 120 A. In addition, there is a wide canyon running along the interface with an opening in the center of the molecule. Most of the protomers involves helices from the α and β subunits with no participation from the γ subunit, also, the interactions with the protomers resembles ribonucleotide reductase R2 protein dimer interaction, resembling a heart. Each iron has a six coordinate octahedral environment, the dinuclear iron centers are positioned in the α subunit. The substrate must bind near the site in order for the reaction to take place
27.
CYP3A4
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Cytochrome P450 3A4, is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules, such as toxins or drugs, while many drugs are deactivated by CYP3A4, there are also some drugs which are activated by the enzyme. Some substances, such as juice and some drugs, interfere with the action of CYP3A4. These substances will therefore either amplify or weaken the action of drugs that are modified by CYP3A4. CYP3A4 is a member of the cytochrome P450 family of oxidizing enzymes, several other members of this family are also involved in drug metabolism, but CYP3A4 is the most common and the most versatile one. Like all members of family, it is a hemoprotein. In humans, the CYP3A4 protein is encoded by the CYP3A4 gene and this gene is part of a cluster of cytochrome P450 genes on chromosome 7q21.1. CYP3A4 is a member of the cytochrome P450 superfamily of enzymes, the cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, and other lipids components. The CYP3A4 protein localizes to the endoplasmic reticulum, and its expression is induced by glucocorticoids and this enzyme is involved in the metabolism of approximately half the drugs that are used today, including acetaminophen, codeine, ciclosporin, diazepam, and erythromycin. The enzyme also metabolizes some steroids and carcinogens, most drugs undergo deactivation by CYP3A4, either directly or by facilitated excretion from the body. Also, many substances are bioactivated by CYP3A4 to form their active compounds, CYP3A4 also possesses epoxygenase activity in that it metabolizes arachidonic acid to epoxyeicosatrienoic acids, i. e. -8, 9-, -11, 12-, and -14, 15-epoxyeicosatrienoic acids. The EETs have a range of activities including the promotion of certain types of cancers. 20-HETE has a range of activities that also include growth stimulation in breast. The CYP3A4 gene exhibits a more complicated upstream regulatory region in comparison with its paralogs. This increased complexity renders the CYP3A4 gene more sensitive to endogenous and exogenous PXR and CAR ligands and this change in consequence contributes to an increased human defense against cholestasis. Fetuses do not really express CYP3A4 in their liver tissue, but rather CYP3A7, CYP3A4 is absent in fetal liver but increases to approximately 40% of adult levels in the fourth month of life and 72% at 12 months. Although CYP3A4 is predominantly found in the liver, it is present in other organs and tissues of the body. CYP3A4 in the plays a important role in the metabolism of certain drugs
28.
Lanosterol 14 alpha-demethylase
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Lanosterol 14 α-demethylase is a cytochrome P450 enzyme that is involved in the conversion of lanosterol to 4, 4-dimethylcholesta-8,14, 24-trien-3β-ol. As a member of family, lanosterol 14 α-demethylase is responsible for an essential step in the biosynthesis of sterols. In particular, this protein catalyzes the removal of the C-14 α-methyl group from lanosterol and this demethylation step is regarded as the initial checkpoint in the transformation of lanosterol to other sterols that are widely used within the cell. In fungi, CYP51 catalyzes the demethylation of lanosterol to create an important precursor that is converted into ergosterol. This steroid then makes its way throughout the cell, where it alters the permeability and rigidity of plasma membranes much as cholesterol does in animals, the structural and functional properties of the cytochrome P450 superfamily have been subject to extensive diversification over the course of evolution. Recent estimates indicate that there are currently 10 classes and 267 families of CYP proteins, although CYP51s mode of action has been well conserved, the proteins sequence varies considerably between biological kingdoms. CYP51 sequence comparisons between kingdoms reveal only a 22-30% similarity in amino acid composition and these include residues in the B helix, B/C loop, C helix, I helix, K/β1-4 loop, and β-strand 1-4 that are responsible for forming the surface of the substrate binding cavity. Homology modeling reveals that substrates migrate from the surface of the protein to the enzymes buried active site through a channel that is formed in part by the A alpha helix and the β4 loop. Finally, the site contains a heme prosthetic group in which the iron is tethered to a thiolate ligand on a conserved cysteine residue. This group also binds diatomic oxygen at the sixth coordination site, the enzyme-catalyzed demethylation of lanosterol is believed to occur in three steps, each of which requires one molecule of diatomic oxygen and one molecule of NADPH. The aldehyde then departs as formic acid and a bond is simultaneously introduced to yield the demethylated product. The biological role of protein is also well-understood. The demethylated products of the CYP51 reaction are vital intermediates in pathways leading to the formation of cholesterol in humans, ergosterol in fungi, with the proliferation of immuno-suppressive diseases such as HIV/AIDS and cancer, patients have become increasingly vulnerable to opportunistic fungal infections. Azoles are currently the most popular class of antifungals used in agricultural and medical settings. These compounds bind as the ligand to the heme group in CYP51, thereby altering the structure of the active site. The effectiveness of imidazoles and triazoles as inhibitors of 14 α-demethylase have been confirmed through several experiments, some studies test for changes in the production of important downstream ergosterol intermediates in the presence of these compounds. Other studies employ spectrophotometry to quantify azole-CYP51 interactions, prolonged use of azoles as antifungals has resulted in the emergence of drug resistance among certain fungal strains. Mutations in the region of CYP51 genes, overexpression of CYP51
