Tyrosinase is an oxidase, the rate-limiting enzyme for controlling the production of melanin. The enzyme is involved in two distinct reactions of melanin synthesis. O-Quinone undergoes several reactions to form melanin. Tyrosinase is a copper-containing enzyme present in plant and animal tissues that catalyzes the production of melanin and other pigments from tyrosine by oxidation, as in the blackening of a peeled or sliced potato exposed to air, it is found inside melanosomes. In humans, the tyrosinase enzyme is encoded by the TYR gene. A mutation in the tyrosinase gene resulting in impaired tyrosinase production leads to type I oculocutaneous albinism, a hereditary disorder that affects one in every 20,000 people. Tyrosinase activity is important. If uncontrolled during the synthesis of melanin, it results in increased melanin synthesis. Decreasing tyrosinase activity has been targeted for the betterment or prevention of conditions related to the hyperpigmentation of the skin, such as melasma and age spots.
Several polyphenols, including flavonoids or stilbenoid, substrate analogues, free radical scavengers, copper chelators, have been known to inhibit tyrosinase. Henceforth, the medical and cosmetic industries are focusing research on tyrosinase inhibitors to treat skin disorders. In food industry, tyrosinase inhibition is desired as tyrosinase catalyzes the oxidation of phenolic compounds found in fruits and vegetables into quinones, which gives an undesirable taste and color and decreases the availability of certain essential amino acids as well as the digestibility of the products; as such effective tyrosinase inhibitors are needed in agriculture and the food industry. Well known tyrosinase inhibitors include kojic acid, coumarins, vanillic acid and vanillic alcohol. Tyrosinase has a wide range of functions in insects, including wound healing, melanin synthesis and parasite encapsulation; as a result, it is an important enzyme. Some insecticides are aimed to inhibit tyrosinase. Tyrosinase dopamine using dioxygen.
In the presence of catechol, benzoquinone is formed. Hydrogens removed from catechol combine with oxygen to form water; the substrate specificity becomes restricted in mammalian tyrosinase which uses only L-form of tyrosine or DOPA as substrates, has restricted requirement for L-DOPA as cofactor. Tyrosinases have been isolated and studied from a wide variety of plant and fungal species. Tyrosinases from different species are diverse in terms of their structural properties, tissue distribution, cellular location. No common tyrosinase protein structure occurring across all species has been found; the enzymes found in plant and fungal tissue differ with respect to their primary structure, glycosylation pattern, activation characteristics. However, all tyrosinases have in type 3 copper centre within their active sites. Here, two copper atoms are each coordinated with three histidine residues. Human tyrosinase is a single membrane-spanning transmembrane protein. In humans, tyrosinase is sorted into melanosomes and the catalytically active domain of the protein resides within melanosomes.
Only a small, enzymatically inessential part of the protein extends into the cytoplasm of the melanocyte. As opposed to fungal tyrosinase, human tyrosinase is a membrane-bound glycoprotein and has 13% carbohydrate content; the derived TYR allele is associated with lighter skin pigmentation in human populations. It is most common in Europe, but is found at lower, moderate frequencies in Central Asia, the Middle East, North Africa, among the San and Mbuti Pygmies; the two copper atoms within the active site of tyrosinase enzymes interact with dioxygen to form a reactive chemical intermediate that oxidizes the substrate. The activity of tyrosinase is similar to a related class of copper oxidase. Tyrosinases and catechol oxidases are collectively termed polyphenol oxidases; the gene for tyrosinase is regulated by the microphthalmia-associated transcription factor. GeneReviews/NCBI/NIH/UW entry on Oculocutaneous Albinism Type 1 Tyrosinase at the US National Library of Medicine Medical Subject Headings
The Jmol applet, among other abilities, offers an alternative to the Chime plug-in, no longer under active development. While Jmol has many features that Chime lacks, it does not claim to reproduce all Chime functions, most notably, the Sculpt mode. Chime requires plug-in installation and Internet Explorer 6.0 or Firefox 2.0 on Microsoft Windows, or Netscape Communicator 4.8 on Mac OS 9. Jmol operates on a wide variety of platforms. For example, Jmol is functional in Mozilla Firefox, Internet Explorer, Google Chrome, Safari. Chemistry Development Kit Comparison of software for molecular mechanics modeling Jmol extension for MediaWiki List of molecular graphics systems Molecular graphics Molecule editor Proteopedia PyMOL SAMSON Official website Wiki with listings of websites and moodles Willighagen, Egon. "Fast and Scriptable Molecular Graphics in Web Browsers without Java3D". Doi:10.1038/npre.2007.50.1
Simplified molecular-input line-entry system
The simplified molecular-input line-entry system is a specification in the 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 been extended. In 2007, an open standard called. Other linear notations include the Wiswesser line notation, ROSDAL, SYBYL Line Notation; the original SMILES specification was initiated by David Weininger at the USEPA Mid-Continent Ecology Division Laboratory in Duluth in the 1980s. Acknowledged for their parts in the early development were "Gilman Veith and Rose Russo and Albert Leo and Corwin Hansch for supporting the work, Arthur Weininger and Jeremy Scofield for assistance in programming the system." The Environmental Protection Agency funded the initial project to develop SMILES. It has since been modified and extended by others, most notably by Daylight Chemical Information Systems.
In 2007, an open 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 considered to have the advantage of being more human-readable than InChI; the term SMILES refers to a line notation for encoding molecular structures and specific instances should be called SMILES strings. However, the term SMILES is commonly used to refer to both a single SMILES string and a number of SMILES strings; the terms "canonical" and "isomeric" can lead to some confusion when applied to SMILES. The terms are not mutually exclusive. A number of 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; this SMILES is unique for each structure, although dependent on the canonicalization algorithm used to generate it, is termed the canonical SMILES.
These algorithms first convert the SMILES to an internal representation of the molecular structure. Various algorithms for generating canonical SMILES have been developed and include those by Daylight Chemical Information Systems, OpenEye Scientific Software, MEDIT, Chemical Computing Group, MolSoft LLC, the Chemistry Development Kit. A common application of canonical SMILES is indexing and ensuring uniqueness of molecules in a database; the original paper that described the CANGEN algorithm claimed to generate unique SMILES strings for graphs representing molecules, but the algorithm fails for a number of simple cases and cannot be considered a correct method for representing a graph canonically. There is 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, double bond geometry; these are structural features that cannot be specified by connectivity alone and SMILES which encode this information are termed isomeric SMILES.
A notable feature of these rules is. The term isomeric SMILES is applied to SMILES in which isotopes are specified. In terms of a graph-based computational procedure, SMILES is a string obtained by printing the symbol nodes encountered in a depth-first tree traversal of a chemical graph; the chemical graph is first trimmed to remove hydrogen atoms and cycles are broken to turn it into a spanning tree. Where cycles have been broken, numeric suffix labels are included to indicate the connected nodes. Parentheses are used to indicate points of branching on the tree; the resultant SMILES form depends on the choices: of the bonds chosen to break cycles, of the starting atom used for the depth-first traversal, of the order in which branches are listed when encountered. Atoms are represented by the standard abbreviation of the chemical elements, in square brackets, such as for gold. Brackets may be omitted in the common case of atoms which: are in the "organic subset" of B, C, N, O, P, S, F, Cl, Br, or I, have no formal charge, have the number of hydrogens attached implied by the SMILES valence model, are the normal isotopes, are not chiral centers.
All other elements must be enclosed in brackets, have charges and hydrogens shown explicitly. For instance, the SMILES for water may be written as either O or. Hydrogen may be written as a separate atom; when brackets are used, the symbol H is added if the atom in brackets is bonded to one or more hydrogen, followed by the number of hydrogen atoms if greater than 1 by the sign + for a positive charge or by - for a negative charge. For example, for ammonium. If there is more than one charge, it is written as digit.
5-hydroxytryptamine receptors or 5-HT receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both inhibitory neurotransmission; the serotonin receptors are activated by the neurotransmitter serotonin, which acts as their natural ligand. The serotonin receptors modulate the release of many neurotransmitters, including glutamate, GABA, epinephrine / norepinephrine, acetylcholine, as well as many hormones, including oxytocin, vasopressin, cortisol and substance P, among others; the serotonin receptors influence various biological and neurological processes such as aggression, appetite, learning, mood, nausea and thermoregulation. The serotonin receptors are the target of a variety of pharmaceutical and recreational drugs, including many antidepressants, anorectics, gastroprokinetic agents, antimigraine agents and entactogens. Serotonin receptors are found in all animals and are known to regulate longevity and behavioral aging in the primitive nematode, Caenorhabditis elegans.
5-hydroxytryptamine receptors or 5-HT receptors, or serotonin receptors are found in the central and peripheral nervous systems. They can be divided into 7 families of G protein-coupled receptors except for the 5-HT3 receptor, a ligand-gated ion channel, which activate an intracellular second messenger cascade to produce an excitatory or inhibitory response. In 2014, a novel 5-HT receptor was isolated from the small white butterfly, Pieris rapae, named pr5-HT8, it does not occur in mammals and shares low similarity to the known 5-HT receptor classes. The 7 general serotonin receptor classes include a total of 14 known serotonin receptors; the specific types have been characterized as follows: Note that there is no 5-HT1C receptor since, after the receptor was cloned and further characterized, it was found to have more in common with the 5-HT2 family of receptors and was redesignated as the 5-HT2C receptor. Nonselective agonists of 5-HT receptor subtypes include ergotamine, which activates 5-HT1A, 5-HT1D, 5-HT1B, D2 and norepinephrine receptors.
LSD is a 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5, 5-HT6 agonist. The genes coding for serotonin receptors are expressed across the mammalian brain. Genes coding for different receptors types follow different developmental curves. There is a developmental increase of HTR5A expression in several subregions of the human cortex, paralleled by a decreased expression of HTR1A from the embryonic period to the post-natal one. A number of receptors were classed as "5-HT1-like" - by 1998 it was being argued that, since these receptors were "a heterogeneous population of 5-HT1B, 5-HT1D and 5-HT7" receptors the classification was redundant. Serotonin+Receptors at the US National Library of Medicine Medical Subject Headings "5-Hydroxytryptamine Receptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Rubenstein LA, Lanzara RG. "Activation of G protein-coupled receptors entails cysteine modulation of agonist binding". Cogprints. Retrieved 2008-04-11. Paterson LM, Kornum BR, Nutt DJ, Pike VW, Knudsen GM.
"5-HT radioligands for human brain imaging with PET and SPECT". Med Res Rev. 33: 54–111. Doi:10.1002/med.20245. PMC 4188513. PMID 21674551
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are proteins, but in non-protein coding genes such as transfer RNA or small nuclear RNA genes, the product is a functional RNA; the process of gene expression is used by all known life—eukaryotes and utilized by viruses—to generate the macromolecular machinery for life. Several steps in the gene expression process may be modulated, including the transcription, RNA splicing and post-translational modification of a protein. Gene regulation gives the cell control over structure and function, is the basis for cellular differentiation and the versatility and adaptability of any organism. Gene regulation may serve as a substrate for evolutionary change, since control of the timing and amount of gene expression can have a profound effect on the functions of the gene in a cell or in a multicellular organism. In genetics, gene expression is the most fundamental level at which the genotype gives rise to the phenotype, i.e. observable trait.
The genetic code stored in DNA is "interpreted" by gene expression, the properties of the expression give rise to the organism's phenotype. Such phenotypes are expressed by the synthesis of proteins that control the organism's shape, or that act as enzymes catalysing specific metabolic pathways characterising the organism. Regulation of gene expression is thus critical to an organism's development. A gene is a stretch of DNA. Genomic DNA consists of two antiparallel and reverse complementary strands, each having 5' and 3' ends. With respect to a gene, the two strands may be labeled the "template strand," which serves as a blueprint for the production of an RNA transcript, the "coding strand," which includes the DNA version of the transcript sequence.. The production of the RNA copy of the DNA is called transcription, is performed in the nucleus by RNA polymerase, which adds one RNA nucleotide at a time to a growing RNA strand as per the complementarity law of the bases; this RNA is complementary to the template 3' → 5' DNA strand, itself complementary to the coding 5' → 3' DNA strand.
Therefore, the resulting 5' → 3' RNA strand is identical to the coding DNA strand with the exception that Thymines are replaced with uracils in the RNA. A coding DNA strand reading "ATG" is indirectly transcribed through the “TAC” in the non-coding template strand as "AUG" in the mRNA. In prokaryotes, transcription is carried out by a single type of RNA polymerase, which needs a DNA sequence called a Pribnow box as well as a sigma factor to start transcription. In eukaryotes, transcription is performed by three types of RNA polymerases, each of which needs a special DNA sequence called the promoter and a set of DNA-binding proteins—transcription factors—to initiate the process. RNA polymerase. RNA polymerase II transcribes all protein-coding genes but some non-coding RNAs. Pol II includes a C-terminal domain, rich in serine residues; when these residues are phosphorylated, the CTD binds to various protein factors that promote transcript maturation and modification. RNA polymerase III transcribes 5S rRNA, transfer RNA genes, some small non-coding RNAs.
Transcription ends. While transcription of prokaryotic protein-coding genes creates messenger RNA, ready for translation into protein, transcription of eukaryotic genes leaves a primary transcript of RNA, which first has to undergo a series of modifications to become a mature mRNA; these include 5' capping, set of enzymatic reactions that add 7-methylguanosine to the 5' end of pre-mRNA and thus protect the RNA from degradation by exonucleases. The m7G cap is bound by cap binding complex heterodimer, which aids in mRNA export to cytoplasm and protect the RNA from decapping. Another modification is 3' polyadenylation, they occur if polyadenylation signal sequence is present in pre-mRNA, between protein-coding sequence and terminator. The pre-mRNA is first cleaved and a series of ~200 adenines are added to form poly tail, which protects the RNA from degradation. Poly tail is bound by multiple poly-binding proteins necessary for mRNA export and translation re-initiation. A important modification of eukaryotic pre-mRNA is RNA splicing.
The majority of eukaryotic pre-mRNAs consist of alternating segments called introns. During the process of splicing, an RNA-protein catalytical complex known as spliceosome catalyzes two transesterification reactions, which remove an intron and release it in form of lariat structure, splice neighbouring exons together. In certain cases, some introns or exons can be either removed or retained in mature mRNA; this so-called alternative splicing creates series of different transcripts originating from a single gene. Because these transcripts can be translated into different proteins, splicing extends the complexity of eukaryotic gene expression. Extensive RNA processing may be an evolutionary advantage made possible by the nucleus of eukaryotes. In prokaryotes and translation happen together, whilst in eukaryotes, the nuclear membrane separates the two processes, giving time for RNA processing to
An enzyme inhibitor is a molecule that binds to an enzyme and decreases its activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors, they are used in pesticides. Not all molecules; the binding of an inhibitor can stop a substrate from entering the enzyme's active site and/or hinder the enzyme from catalyzing its reaction. Inhibitor binding is either irreversible. Irreversible inhibitors react with the enzyme and change it chemically; these inhibitors modify key amino acid residues needed for enzymatic activity. In contrast, reversible inhibitors bind non-covalently and different types of inhibition are produced depending on whether these inhibitors bind to the enzyme, the enzyme-substrate complex, or both. Many drug molecules are enzyme inhibitors, so their discovery and improvement is an active area of research in biochemistry and pharmacology. A medicinal enzyme inhibitor is judged by its specificity and its potency. A high specificity and potency ensure.
Enzyme inhibitors occur and are involved in the regulation of metabolism. For example, enzymes in a metabolic pathway can be inhibited by downstream products; this type of negative feedback slows the production line when products begin to build up and is an important way to maintain homeostasis in a cell. Other cellular enzyme inhibitors are proteins that bind to and inhibit an enzyme target; this can help control enzymes that may be damaging like proteases or nucleases. A well-characterised example of this is the ribonuclease inhibitor, which binds to ribonucleases in one of the tightest known protein–protein interactions. Natural enzyme inhibitors can be poisons and are used as defences against predators or as ways of killing prey. Reversible inhibitors attach to enzymes with non-covalent interactions such as hydrogen bonds, hydrophobic interactions and ionic bonds. Multiple weak bonds between the inhibitor and the active site combine to produce strong and specific binding. In contrast to substrates and irreversible inhibitors, reversible inhibitors do not undergo chemical reactions when bound to the enzyme and can be removed by dilution or dialysis.
There are four kinds of reversible enzyme inhibitors. They are classified according to the effect of varying the concentration of the enzyme's substrate on the inhibitor. In competitive inhibition, the substrate and inhibitor cannot bind to the enzyme at the same time, as shown in the figure on the right; this results from the inhibitor having an affinity for the active site of an enzyme where the substrate binds. This type of inhibition can be overcome by sufficiently high concentrations of substrate, i.e. by out-competing the inhibitor. However, the apparent Km will increase as it takes a higher concentration of the substrate to reach the Km point, or half the Vmax. Competitive inhibitors are similar in structure to the real substrate. In uncompetitive inhibition, the inhibitor binds only to the substrate-enzyme complex; this type of inhibition causes Vmax to Km to decrease. In non-competitive inhibition, the binding of the inhibitor to the enzyme reduces its activity but does not affect the binding of substrate.
As a result, the extent of inhibition depends only on the concentration of the inhibitor. Vmax will decrease due to the inability for the reaction to proceed as efficiently, but Km will remain the same as the actual binding of the substrate, by definition, will still function properly. In mixed inhibition, the inhibitor can bind to the enzyme at the same time as the enzyme's substrate. However, the binding of the inhibitor affects the binding of the substrate, vice versa; this type of inhibition can be reduced, but not overcome by increasing concentrations of substrate. Although it is possible for mixed-type inhibitors to bind in the active site, this type of inhibition results from an allosteric effect where the inhibitor binds to a different site on an enzyme. Inhibitor binding to this allosteric site changes the conformation of the enzyme so that the affinity of the substrate for the active site is reduced. Reversible inhibition can be described quantitatively in terms of the inhibitor's binding to the enzyme and to the enzyme-substrate complex, its effects on the kinetic constants of the enzyme.
In the classic Michaelis-Menten scheme below, an enzyme binds to its substrate to form the enzyme–substrate complex ES. Upon catalysis, this complex breaks down to release free enzyme; the inhibitor can bind to ES with the dissociation constants Ki or Ki', respectively. When an enzyme has multiple substrates, inhibitors can show different types of inhibition depending on which substrate is considered; this results from the active site containing two different binding sites within the active site, one for each substrate. For example, an inhibitor might compete with
In vitro studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology and its subdisciplines are traditionally done in labware such as test tubes, Petri dishes, microtiter plates. Studies conducted using components of an organism that have been isolated from their usual biological surroundings permit a more detailed or more convenient analysis than can be done with whole organisms. In contrast to in vitro experiments, in vivo studies are those conducted in animals, including humans, whole plants. In vitro studies are conducted using components of an organism that have been isolated from their usual biological surroundings, such as microorganisms, cells, or biological molecules. For example, microorganisms or cells can be studied in artificial culture media, proteins can be examined in solutions. Colloquially called "test-tube experiments", these studies in biology and their subdisciplines are traditionally done in test tubes, Petri dishes, etc.
They now involve the full range such as the omics. In contrast, studies conducted in living beings are called in vivo. Examples of in vitro studies include: the isolation and identification of cells derived from multicellular organisms in. Viruses, which only replicate in living cells, are studied in the laboratory in cell or tissue culture, many animal virologists refer to such work as being in vitro to distinguish it from in vivo work in whole animals. Polymerase chain reaction is a method for selective replication of specific DNA and RNA sequences in the test tube. Protein purification involves the isolation of a specific protein of interest from a complex mixture of proteins obtained from homogenized cells or tissues. In vitro fertilization is used to allow spermatozoa to fertilize eggs in a culture dish before implanting the resulting embryo or embryos into the uterus of the prospective mother. In vitro diagnostics refers to a wide range of medical and veterinary laboratory tests that are used to diagnose diseases and monitor the clinical status of patients using samples of blood, cells, or other tissues obtained from a patient.
In vitro testing has been used to characterize specific adsorption, distribution and excretion processes of drugs or general chemicals inside a living organism. These ADME process parameters can be integrated into so called "physiologically based pharmacokinetic models" or PBPK. In vitro studies permit a species-specific, more convenient, more detailed analysis than can be done with the whole organism. Just as studies in whole animals more and more replace human trials, so are in vitro studies replacing studies in whole animals. Living organisms are complex functional systems that are made up of, at a minimum, many tens of thousands of genes, protein molecules, RNA molecules, small organic compounds, inorganic ions, complexes in an environment, spatially organized by membranes, in the case of multicellular organisms, organ systems; these myriad components interact with each other and with their environment in a way that processes food, removes waste, moves components to the correct location, is responsive to signalling molecules, other organisms, sound, taste and balance.
This complexity makes it difficult to identify the interactions between individual components and to explore their basic biological functions. In vitro work simplifies the system under study, so the investigator can focus on a small number of components. For example, the identity of proteins of the immune system, the mechanism by which they recognize and bind to foreign antigens would remain obscure if not for the extensive use of in vitro work to isolate the proteins, identify the cells and genes that produce them, study the physical properties of their interaction with antigens, identify how those interactions lead to cellular signals that activate other components of the immune system. Another advantage of in vitro methods is that human cells can be studied without "extrapolation" from an experimental animal's cellular response. In vitro methods can be miniaturized and automated, yielding high-throughput screening methods for testing molecules in pharmacology or toxicology The primary disadvantage of in vitro experimental studies is that it may be challenging to extrapolate from the results of in vitro work back to the biology of the intact organism.
Investigators doing in vitro work must be careful to avoid over-interpretation of their results, which can lead to erroneous conclusions about organismal and systems biology. For example, scientists developing a new viral drug to treat an infection with a pathogenic virus may find that a candidate drug functions to prevent viral repl