Tyrosine or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group; the word "tyrosine" is from the Greek tyros, meaning cheese, as it was first discovered in 1846 by German chemist Justus von Liebig in the protein casein from cheese. It is called tyrosyl when referred to as a functional side chain. While tyrosine is classified as a hydrophobic amino acid, it is more hydrophilic than phenylalanine, it is encoded by the codons UAC and UAU in messenger RNA. Aside from being a proteinogenic amino acid, tyrosine has a special role by virtue of the phenol functionality, it occurs in proteins. It functions as a receiver of phosphate groups. Phosphorylation of the hydroxyl group can change the activity of the target protein, or may form part of a signaling cascade via SH2 domain binding. A tyrosine residue plays an important role in photosynthesis. In chloroplasts, it acts as an electron donor in the reduction of oxidized chlorophyll.
In this process, it loses the hydrogen atom of its phenolic OH-group. This radical is subsequently reduced in the photosystem II by the four core manganese clusters; the Dietary Reference Intake for phenylalanine and tyrosine is 33 mg per kilogram of body weight, or 15 mg per pound. For a 70 kg person, this is 2310 mg. Tyrosine, which can be synthesized in the body from phenylalanine, is found in many high-protein food products such as chicken, fish, yogurt, cottage cheese, peanuts, pumpkin seeds, sesame seeds, soy products, lima beans and bananas. For example, the white of an egg has about 250 mg per egg, while lean beef/lamb/pork/salmon/chicken/turkey contains about 1000 mg per 3 ounces portion. In plants and most microorganisms, tyr is produced via prephenate, an intermediate on the shikimate pathway. Prephenate is oxidatively decarboxylated with retention of the hydroxyl group to give p-hydroxyphenylpyruvate, transaminated using glutamate as the nitrogen source to give tyrosine and α-ketoglutarate.
Mammals synthesize tyrosine from the essential amino acid phenylalanine, derived from food. The conversion of phe to tyr is catalyzed by a monooxygenase; this enzyme catalyzes the reaction causing the addition of a hydroxyl group to the end of the 6-carbon aromatic ring of phenylalanine, such that it becomes tyrosine. Some of the tyrosine residues can be tagged with a phosphate group by protein kinases. In its phosphorylated form, tyrosine is called phosphotyrosine. Tyrosine phosphorylation is considered to be one of the key steps in signal transduction and regulation of enzymatic activity. Phosphotyrosine can be detected through specific antibodies. Tyrosine residues may be modified by the addition of a sulfate group, a process known as tyrosine sulfation. Tyrosine sulfation is catalyzed by tyrosylprotein sulfotransferase. Like the phosphotyrosine antibodies mentioned above, antibodies have been described that detect sulfotyrosine. In dopaminergic cells in the brain, tyrosine is converted to L-DOPA by the enzyme tyrosine hydroxylase.
TH is the rate-limiting enzyme involved in the synthesis of the neurotransmitter dopamine. Dopamine can be converted into other catecholamines, such as norepinephrine and epinephrine; the thyroid hormones triiodothyronine and thyroxine in the colloid of the thyroid are derived from tyrosine. The latex of Papaver somniferum, the opium poppy, has been shown to convert tyrosine into the alkaloid morphine and the bio-synthetic pathway has been established from tyrosine to morphine by using Carbon-14 radio-labelled tyrosine to trace the in-vivo synthetic route. Tyrosine ammonia lyase is an enzyme in the natural phenols biosynthesis pathway, it transforms L-tyrosine into p-coumaric acid. Tyrosine is the precursor to the pigment melanin. Tyrosine is needed to synthesize the benzoquinone structure which forms part of coenzyme Q10; the decomposition of L-tyrosine begins with an α-ketoglutarate dependent transamination through the tyrosine transaminase to para-hydroxyphenylpyruvate. The positional description para, abbreviated p, mean that the hydroxyl group and side chain on the phenyl ring are across from each other.
The next oxidation step catalyzes by p-hydroxyphenylpyruvate dioxygenase and splitting off CO2 homogentisate. In order to split the aromatic ring of homogentisate, a further dioxygenase, homogentisate 1,2-dioxygenase is required. Thereby, through the incorporation of a further O2 molecule, maleylacetoacetate is created. Fumarylacetoacetate is created by maleylacetoacetate cis-trans-isomerase through rotation of the carboxyl group created from the hydroxyl group via oxidation; this cis-trans-isomerase contains glutathione as a coenzyme. Fumarylacetoacetate is split by the enzyme fumarylacetoacetate hydrolase through the addition of a water molecule. Thereby fumarate and acetoacetate are liberated. Acetoacetate is a ketone body, activated with succinyl-CoA, thereafter it can be converted into acetyl-CoA, which in turn can be oxidized by the citric acid cycle or be used for fatty acid synthesis. Phloretic acid is a urinary metabolite of tyrosine in rats. Three structural isomers of L-tyrosine are known.
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Phenylalanine is an essential α-amino acid with the formula C9H11NO2. It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine; this essential amino acid is classified as neutral, nonpolar because of the inert and hydrophobic nature of the benzyl side chain. The L-isomer is used to biochemically form proteins, coded for by DNA. Phenylalanine is a precursor for tyrosine, the monoamine neurotransmitters dopamine and epinephrine, the skin pigment melanin, it is encoded by the codons UUU and UUC. Phenylalanine is found in the breast milk of mammals, it is used in the manufacture of food and drink products and sold as a nutritional supplement for its reputed analgesic and antidepressant effects. It is a direct precursor to the neuromodulator phenethylamine, a used dietary supplement; as an essential amino acid, phenylalanine is not synthesized de novo in humans and other animals, who must ingest phenylalanine or phenylalanine-containing proteins.
The first description of phenylalanine was made in 1879, when Schulze and Barbieri identified a compound with the empirical formula, C9H11NO2, in yellow lupine seedlings. In 1882, Erlenmeyer and Lipp first synthesized phenylalanine from phenylacetaldehyde, hydrogen cyanide, ammonia; the genetic codon for phenylalanine was first discovered by J. Heinrich Matthaei and Marshall W. Nirenberg in 1961, they showed that by using mRNA to insert multiple uracil repeats into the genome of the bacterium E. coli, they could cause the bacterium to produce a polypeptide consisting of repeated phenylalanine amino acids. This discovery helped to establish the nature of the coding relationship that links information stored in genomic nucleic acid with protein expression in the living cell. Good sources of phenylalanine are eggs, liver, beef and soybeans; the Food and Nutrition Board of the U. S. Institute of Medicine set Recommended Dietary Allowances for essential amino acids in 2002. For phenylalanine plus tyrosine, for adults 19 years and older, 33 mg/kg body weight/day.
L-Phenylalanine is biologically converted into L-tyrosine, another one of the DNA-encoded amino acids. L-tyrosine in turn is converted into L-DOPA, further converted into dopamine and epinephrine; the latter three are known as the catecholamines. Phenylalanine uses the same active transport channel as tryptophan to cross the blood–brain barrier. In excessive quantities, supplementation can interfere with the production of serotonin and other aromatic amino acids as well as nitric oxide due to the overuse of the associated cofactors, iron or tetrahydrobiopterin; the corresponding enzymes in for those compounds are the aromatic amino acid hydroxylase family and nitric oxide synthase. Phenylalanine is the starting compound used in the synthesis of flavonoids. Lignan is derived from tyrosine. Phenylalanine is converted to cinnamic acid by the enzyme phenylalanine ammonia-lyase; the genetic disorder phenylketonuria is the inability to metabolize phenylalanine because of a lack of the enzyme phenylalanine hydroxylase.
Individuals with this disorder are known as "phenylketonurics" and must regulate their intake of phenylalanine. Phenylketonurics use blood tests to monitor the amount of phenylalanine in their blood. Lab results may report phenylalanine levels using either mg/dL and μmol/L. One mg/dL of phenylalanine is equivalent to 60 μmol/L. A "variant form" of phenylketonuria called hyperphenylalaninemia is caused by the inability to synthesize a cofactor called tetrahydrobiopterin, which can be supplemented. Pregnant women with hyperphenylalaninemia may show similar symptoms of the disorder, but these indicators will disappear at the end of gestation. Pregnant women with PKU must control their blood phenylalanine levels if the fetus is heterozygous for the defective gene because the fetus could be adversely affected due to hepatic immaturity. A non-food source of phenylalanine is the artificial sweetener aspartame; this compound is metabolized by the body into several chemical byproducts including phenylalanine.
The breakdown problems phenylketonurics have with the buildup of phenylalanine in the body occurs with the ingestion of aspartame, although to a lesser degree. Accordingly, all products in Australia, the U. S. and Canada that contain aspartame must be labeled: "Phenylketonurics: Contains phenylalanine." In the UK, foods containing aspartame must carry ingredient panels that refer to the presence of "aspartame or E951" and they must be labeled with a warning "Contains a source of phenylalanine." In Brazil, the label "Contém Fenilalanina" is mandatory in products which contain it. These warnings are placed to help individuals avoid such foods. Geneticists sequenced the genome of macaques in 2007, their investigations found "some instances where the normal form of the macaque protein looked like the diseased human protein" including markers for PKU. The stereoisomer D-phenylalanine can be produced by conventional organic synthesis, either as a single enantiomer or as a component of the racemic mixture.
It does not participate in protein biosynthesis although it is found in proteins in small amounts - aged proteins and food proteins that have been processed. The biological functions of D-amino acids remain unclear, although D-phenylalanine has pharmacological activity at niacin receptor 2. DL-Phenylalanine is marketed as a nutritional supplement for its purported analgesic and antidepressant activ
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
Dopamine is an organic chemical of the catecholamine and phenethylamine families. It functions both as a hormone and a neurotransmitter, plays several important roles in the brain and body, it is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical L-DOPA, synthesized in the brain and kidneys. Dopamine is synthesized in plants and most animals. In the brain, dopamine functions as a neurotransmitter—a chemical released by neurons to send signals to other nerve cells; the brain includes several distinct dopamine pathways, one of which plays a major role in the motivational component of reward-motivated behavior. The anticipation of most types of rewards increases the level of dopamine in the brain, many addictive drugs increase dopamine release or block its reuptake into neurons following release. Other brain dopamine pathways are involved in motor control and in controlling the release of various hormones; these pathways and cell groups form a dopamine system, neuromodulatory.
In popular culture and media, dopamine is seen as the main chemical of pleasure, but the current opinion in pharmacology is that dopamine instead confers motivational salience. Outside the central nervous system, dopamine functions as a local paracrine messenger. In blood vessels, it acts as a vasodilator. With the exception of the blood vessels, dopamine in each of these peripheral systems is synthesized locally and exerts its effects near the cells that release it. Several important diseases of the nervous system are associated with dysfunctions of the dopamine system, some of the key medications used to treat them work by altering the effects of dopamine. Parkinson's disease, a degenerative condition causing tremor and motor impairment, is caused by a loss of dopamine-secreting neurons in an area of the midbrain called the substantia nigra, its metabolic precursor L-DOPA can be manufactured. There is evidence that schizophrenia involves altered levels of dopamine activity, most antipsychotic drugs used to treat this are dopamine antagonists which reduce dopamine activity.
Similar dopamine antagonist drugs are some of the most effective anti-nausea agents. Restless legs syndrome and attention deficit hyperactivity disorder are associated with decreased dopamine activity. Dopaminergic stimulants can be addictive in high doses, but some are used at lower doses to treat ADHD. Dopamine itself is available as a manufactured medication for intravenous injection: although it cannot reach the brain from the bloodstream, its peripheral effects make it useful in the treatment of heart failure or shock in newborn babies. A dopamine molecule consists of a catechol structure with one amine group attached via an ethyl chain; as such, dopamine is the simplest possible catecholamine, a family that includes the neurotransmitters norepinephrine and epinephrine. The presence of a benzene ring with this amine attachment makes it a substituted phenethylamine, a family that includes numerous psychoactive drugs. Like most amines, dopamine is an organic base; as a base, it is protonated in acidic environments.
The protonated form is water-soluble and stable, but can become oxidized if exposed to oxygen or other oxidants. In basic environments, dopamine is not protonated. In this free base form, it is less water-soluble and more reactive; because of the increased stability and water-solubility of the protonated form, dopamine is supplied for chemical or pharmaceutical use as dopamine hydrochloride—that is, the hydrochloride salt, created when dopamine is combined with hydrochloric acid. In dry form, dopamine hydrochloride is a fine colorless powder. Dopamine is synthesized in a restricted set of cell types neurons and cells in the medulla of the adrenal glands; the primary and minor metabolic pathways are: Primary: L-Phenylalanine → L-Tyrosine → L-DOPA → Dopamine Minor: L-Phenylalanine → L-Tyrosine → p-Tyramine → Dopamine Minor: L-Phenylalanine → m-Tyrosine → m-Tyramine → DopamineThe direct precursor of dopamine, L-DOPA, can be synthesized indirectly from the essential amino acid phenylalanine or directly from the non-essential amino acid tyrosine.
These amino acids are found in nearly every protein and so are available in food, with tyrosine being the most common. Although dopamine is found in many types of food, it is incapable of crossing the blood–brain barrier that surrounds and protects the brain, it must therefore be synthesized inside the brain to perform its neuronal activity. L-Phenylalanine is converted into L-tyrosine by the enzyme phenylalanine hydroxylase, with molecular oxygen and tetrahydrobiopterin as cofactors. L-Tyrosine is converted into L-DOPA by the enzyme tyrosine hydroxylase, with tetrahydrobiopterin, O2, iron as cofactors. L-DOPA is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase, with pyridoxal phosphate as the cofactor. Dopamine itself is used as precursor in the synthesis o
A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. They are sometimes called blockers. In pharmacology, antagonists have affinity but no efficacy for their cognate receptors, binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at receptors. Antagonists mediate their effects by binding to the active site or to the allosteric site on a receptor, or they may interact at unique binding sites not involved in the biological regulation of the receptor's activity. Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex, which, in turn, depends on the nature of antagonist–receptor binding; the majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally defined binding sites on receptors. The English word antagonist in pharmaceutical terms comes from the Greek ἀνταγωνιστής – antagonistēs, "opponent, villain, rival", derived from anti- and agonizesthai.
Biochemical receptors are large protein molecules that can be activated by the binding of a ligand such as a hormone or a drug. Receptors can be membrane-bound, as cell surface receptors, or inside the cell as intracellular receptors, such as nuclear receptors including those of the mitochondrion. Binding occurs as a result of non-covalent interactions between the receptor and its ligand, at locations called the binding site on the receptor. A receptor may contain one or more binding sites for different ligands. Binding to the active site on the receptor regulates receptor activation directly; the activity of receptors can be regulated by the binding of a ligand to other sites on the receptor, as in allosteric binding sites. Antagonists mediate their effects through receptor interactions by preventing agonist-induced responses; this may be accomplished by binding to the allosteric site. In addition, antagonists may interact at unique binding sites not involved in the biological regulation of the receptor's activity to exert their effects.
The term antagonist was coined to describe different profiles of drug effects. The biochemical definition of a receptor antagonist was introduced by Ariens and Stephenson in the 1950s; the current accepted definition of receptor antagonist is based on the receptor occupancy model. It narrows the definition of antagonism to consider only those compounds with opposing activities at a single receptor. Agonists were thought to turn "on" a single cellular response by binding to the receptor, thus initiating a biochemical mechanism for change within a cell. Antagonists were thought to turn "off" that response by'blocking' the receptor from the agonist; this definition remains in use for physiological antagonists, substances that have opposing physiological actions, but act at different receptors. For example, histamine lowers arterial pressure through vasodilation at the histamine H1 receptor, while adrenaline raises arterial pressure through vasoconstriction mediated by alpha-adrenergic receptor activation.
Our understanding of the mechanism of drug-induced receptor activation and receptor theory and the biochemical definition of a receptor antagonist continues to evolve. The two-state model of receptor activation has given way to multistate models with intermediate conformational states; the discovery of functional selectivity and that ligand-specific receptor conformations occur and can affect interaction of receptors with different second messenger systems may mean that drugs can be designed to activate some of the downstream functions of a receptor but not others. This means efficacy may depend on where that receptor is expressed, altering the view that efficacy at a receptor is receptor-independent property of a drug. By definition, antagonists display no efficacy to activate the receptors they bind. Antagonists do not maintain the ability to activate a receptor. Once bound, antagonists inhibit the function of agonists, inverse agonists, partial agonists. In functional antagonist assays, a dose-response curve measures the effect of the ability of a range of concentrations of antagonists to reverse the activity of an agonist.
The potency of an antagonist is defined by its half maximal inhibitory concentration. This can be calculated for a given antagonist by determining the concentration of antagonist needed to elicit half inhibition of the maximum biological response of an agonist. Elucidating an IC50 value is useful for comparing the potency of drugs with similar efficacies, however the dose-response curves produced by both drug antagonists must be similar; the lower the IC50 the greater the potency of the antagonist, the lower the concentration of drug, required to inhibit the maximum biological response. Lower concentrations of drugs may be associated with fewer side-effects; the affinity of an antagonist for its binding site, i.e. its ability to bind to a receptor, will determine the duration of inhibition of agonist activity. The affinity of an antagonist can be determined experimentally using Schild regression or for competitive antagonists in radioligand binding studies using the Cheng-Prusoff equation. Schild regression can be used to determine the nature of antagonism as beginning either competitive or non-competitive and Ki determination is independent of the affinity, efficacy or concentration of the agonist used.
However, it is important. The effects of receptor desensitization on reaching equilibrium must als