In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers; the word dimer has roots meaning "two parts", di- + -mer. A protein dimer is a type of protein quaternary structure. A protein homodimer is formed by two identical proteins. A protein heterodimer is formed by two different proteins. Most protein dimers in biochemistry are not connected by covalent bonds. An example of a non-covalent heterodimer is the enzyme reverse transcriptase, composed of two different amino acid chains. An exception is dimers that are linked by disulfide bridges such as the homodimeric protein NEMO; some proteins contain specialized domains to ensure specificity. Antibodies Receptor tyrosine kinases Transcription factors Leucine zipper motif proteins Nuclear receptors 14-3-3 proteins G protein-coupled receptors G protein βγ-subunit dimer Kinesin Triosephosphateisomerase Alcohol dehydrogenase Factor XI Factor XIII Toll-like receptor Fibrinogen Variable surface glycoproteins of the Trypanosoma parasite Tubulin Type II restriction enzymes Dimer Protein trimer Oligomer ProtCID
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
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
Histidine decarboxylase is an enzyme responsible for catalyzing the decarboxylation of histidine to form histamine. In mammals, histamine is an important biogenic amine with regulatory roles in neurotransmission, gastric acid secretion and immune response. Histidine decarboxylase is the sole member of the histamine synthesis pathway, producing histamine in a one-step reaction. Histamine cannot be generated by any other known enzyme. HDC is therefore the primary source of histamine in eukaryotes; the enzyme employs a pyridoxal 5'-phosphate cofactor, in similarity to many amino acid decarboxylases. Eukaryotes, as well as gram-negative bacteria share a common HDC, while gram-positive bacteria employ an evolutionarily unrelated pyruvoyl-dependent HDC. In humans, histidine decarboxylase is encoded by the HDC gene. Histidine decarboxylase is a group II pyridoxal-dependent decarboxylase, along with aromatic-L-amino-acid decarboxylase, tyrosine decarboxylase. HDC is expressed as a 74 kDa polypeptide, not enzymatically functional.
Only after post-translational processing does the enzyme become active. This processing consists of truncating much of the protein's C-terminal chain, reducing the peptide molecular weight to 54 kDa. Histidine decarboxylase exists as a homodimer, with several amino acids from the respective opposing chain stabilizing the HDC active site. In HDC's resting state, PLP is covalently bound in a Schiff base to lysine 305, stabilized by several hydrogen bonds to nearby amino acids aspartate 273, serine 151 and the opposing chain's serine 354. HDC contains several regions that are sequentially and structurally similar to those in a number of other pyridoxal-dependent decarboxylases; this is evident in the vicinity of the active site lysine 305. HDC decarboxylates histidine through the use of a PLP cofactor bound in a Schiff base to lysine 305. Histidine initiates the reaction by displacing lysine 305 and forming a aldimine with PLP. Histidine's carboxyl group leaves the substrate, forming carbon dioxide.
This is the rate-limiting step of the all process, requiring an activation energy of 17.6 kcal/mol and fitting the experimental turnover of 1.73 s − 1. After the decarboxylation takes place, the PLP intermediate is protonated by tyrosine 334 from the second subunit; the protonation is mediated by a water molecule and it is fast and very exergonic. PLP re-forms its original Schiff base at lysine 305, histamine is released; this mechanism is similar to those employed by other pyridoxal-dependent decarboxylases. In particular, the aldimine intermediate is a common feature of all known PLP-dependent decarboxylases. HDC is specific for its histidine substrate. Histidine decarboxylase is the primary biological source of histamine. Histamine is an important biogenic amine. There are four different histamine receptors, H1, H2, H3, H4, each of which carries a different biological significance. H1 modulates several functions of the central and peripheral nervous system, including circadian rhythm, body temperature and appetite.
H2 activation results in smooth muscle relaxation. H3 controls histamine turnover by feedback inhibition of histamine release. H4 plays roles in mast cell chemotaxis and cytokine production. In humans, HDC is expressed in mast cells and basophil granulocytes. Accordingly, these cells contain the body's highest concentrations of histamine granules. Non-mast cell histamine is found in the brain, where it is used as a neurotransmitter. HDC can be inhibited by histidine methyl ester. Antihistamines are a class of medications designed to reduce unwanted effects of histamine in the body. Typical antihistamines block specific histamine receptors, depending on what physiological purpose they serve. For example, diphenhydramine and inhibits the H1 histamine receptor to relieve symptoms of allergic reactions. Inhibitors of histidine decarboxylase can conceivably be used as atypical antihistamines. Tritoqualine, as well as various catechins, such as epigallocatechin-3-gallate, a major component of green tea, have been shown to target HDC and histamine-producing cells, reducing histamine levels and providing anti-inflammatory, anti-tumoral, anti-angiogenic effects.
Mutations in the gene for Histidine decarboxylase have been observed in one family with Tourette syndrome and are not thought to account for most cases of TS. Aromatic L-amino acid decarboxylase Tyrosine decarboxylase Decarboxylation Histamine Antihistamine Pyridoxal 5'-phosphate Mast cell Histidine+Decarboxylase at the US National Library of Medicine Medical Subject Headings This article incorporates text from the United States National Library of Medicine, in the public domain
Neurotransmitters are endogenous chemicals that enable neurotransmission. It is a type of chemical messenger which transmits signals across a chemical synapse, such as a neuromuscular junction, from one neuron to another "target" neuron, muscle cell, or gland cell. Neurotransmitters are released from synaptic vesicles in synapses into the synaptic cleft, where they are received by neurotransmitter receptors on the target cells. Many neurotransmitters are synthesized from simple and plentiful precursors such as amino acids, which are available from the diet and only require a small number of biosynthetic steps for conversion. Neurotransmitters play a major role in shaping everyday life and functions, their exact numbers are unknown, but more than 200 chemical messengers have been uniquely identified. Neurotransmitters are stored in synaptic vesicles, clustered close to the cell membrane at the axon terminal of the presynaptic neuron. Neurotransmitters are released into and diffuse across the synaptic cleft, where they bind to specific receptors on the membrane of the postsynaptic neuron.
Most neurotransmitters are about the size of a single amino acid. A released neurotransmitter is available in the synaptic cleft for a short time before it is metabolized by enzymes, pulled back into the presynaptic neuron through reuptake, or bound to a postsynaptic receptor. Short-term exposure of the receptor to a neurotransmitter is sufficient for causing a postsynaptic response by way of synaptic transmission. In response to a threshold action potential or graded electrical potential, a neurotransmitter is released at the presynaptic terminal. Low level "baseline" release occurs without electrical stimulation; the released neurotransmitter may move across the synapse to be detected by and bind with receptors in the postsynaptic neuron. Binding of neurotransmitters may influence the postsynaptic neuron in either an inhibitory or excitatory way; this neuron may be connected to many more neurons, if the total of excitatory influences are greater than those of inhibitory influences, the neuron will "fire".
It will create a new action potential at its axon hillock to release neurotransmitters and pass on the information to yet another neighboring neuron. Until the early 20th century, scientists assumed that the majority of synaptic communication in the brain was electrical. However, through the careful histological examinations by Ramón y Cajal, a 20 to 40 nm gap between neurons, known today as the synaptic cleft, was discovered; the presence of such a gap suggested communication via chemical messengers traversing the synaptic cleft, in 1921 German pharmacologist Otto Loewi confirmed that neurons can communicate by releasing chemicals. Through a series of experiments involving the vagus nerves of frogs, Loewi was able to manually slow the heart rate of frogs by controlling the amount of saline solution present around the vagus nerve. Upon completion of this experiment, Loewi asserted that sympathetic regulation of cardiac function can be mediated through changes in chemical concentrations. Furthermore, Otto Loewi is credited with discovering acetylcholine —the first known neurotransmitter.
Some neurons do, communicate via electrical synapses through the use of gap junctions, which allow specific ions to pass directly from one cell to another. There are four main criteria for identifying neurotransmitters: The chemical must be synthesized in the neuron or otherwise be present in it; when the neuron is active, the chemical must produce a response in some target. The same response must be obtained. A mechanism must exist for removing the chemical from its site of activation. However, given advances in pharmacology and chemical neuroanatomy, the term "neurotransmitter" can be applied to chemicals that: Carry messages between neurons via influence on the postsynaptic membrane. Have little or no effect on membrane voltage, but have a common carrying function such as changing the structure of the synapse. Communicate by sending reverse-direction messages that affect the release or reuptake of transmitters; the anatomical localization of neurotransmitters is determined using immunocytochemical techniques, which identify the location of either the transmitter substances themselves, or of the enzymes that are involved in their synthesis.
Immunocytochemical techniques have revealed that many transmitters the neuropeptides, are co-localized, that is, one neuron may release more than one transmitter from its synaptic terminal. Various techniques and experiments such as staining and collecting can be used to identify neurotransmitters throughout the central nervous system. There are many different ways. Dividing them into amino acids and monoamines is sufficient for some classification purposes. Major neurotransmitters: Amino acids: glutamate, aspartate, D-serine, γ-aminobutyric acid, glycine Gasotransmitters: nitric oxide, carbon monoxide, hydrogen sulfide Monoamines: dopamine, epinephrine, serotonin Trace amines: phenethylamine, N-methylphenethylamine, tyramine, 3-iodothyronamine, tryptamine, etc. Peptides: oxytocin, substance P, cocaine and amphetamine regulated transcript, opioid peptides Purines: adenosine triphosphate, adenosine Catecholamines: dopamine, epinephrine Others: acetylcholine, etc. In addition, over 50 neuroactive pepti
A cofactor is a non-protein chemical compound or metallic ion, required for an enzyme's activity. Cofactors can be considered "helper molecules"; the rates at which these happen are characterized by enzyme kinetics. Cofactors can be subclassified as either inorganic ions or complex organic molecules called coenzymes, the latter of, derived from vitamins and other organic essential nutrients in small amounts. A coenzyme, or covalently bound is termed a prosthetic group. Cosubstrates are transiently bound to the protein and will be released at some point get back in; the prosthetic groups, on the other hand, are bound permanently to the protein. Both of them have the same function, to facilitate the reaction of enzymes and protein. Additionally, some sources limit the use of the term "cofactor" to inorganic substances. An inactive enzyme without the cofactor is called an apoenzyme, while the complete enzyme with cofactor is called a holoenzyme; some enzymes or enzyme complexes require several cofactors.
For example, the multienzyme complex pyruvate dehydrogenase at the junction of glycolysis and the citric acid cycle requires five organic cofactors and one metal ion: loosely bound thiamine pyrophosphate, covalently bound lipoamide and flavin adenine dinucleotide, cosubstrates nicotinamide adenine dinucleotide and coenzyme A, a metal ion. Organic cofactors are vitamins or made from vitamins. Many contain the nucleotide adenosine monophosphate as part of their structures, such as ATP, coenzyme A, FAD, NAD+; 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 major groups: organic Cofactors, such as flavin or heme, inorganic cofactors, such as the metal ions Mg2+, Cu+, Mn2+, or iron-sulfur clusters. Organic cofactors are sometimes further divided into prosthetic groups.
The term coenzyme refers to enzymes and, as such, to the functional properties of a protein. On the other hand, "prosthetic group" emphasizes the nature of the binding of a cofactor to a protein and, refers to a structural property. Different sources give different definitions of coenzymes and prosthetic groups; some consider bound organic molecules as prosthetic groups and not as coenzymes, while others define all non-protein organic molecules needed for enzyme activity as coenzymes, classify those that are bound as coenzyme prosthetic groups. These terms are used loosely. A 1980 letter in Trends in Biochemistry Sciences noted the confusion in the literature and the arbitrary distinction made between prosthetic groups and coenzymes group and proposed the following scheme. Here, cofactors were defined as an additional substance apart from protein and substrate, required for enzyme activity and a prosthetic group as a substance that undergoes its whole catalytic cycle attached to a single enzyme molecule.
However, the author could not arrive at a single all-encompassing definition of a "coenzyme" and proposed that this term be dropped from use in the literature. Metal ions are common cofactors; 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 includes iron, manganese, copper and molybdenum. Although chromium deficiency causes impaired glucose tolerance, no human enzyme that uses this metal as a cofactor has been identified. Iodine is an essential trace element, but this element is used as part of the structure of thyroid hormones rather than as an enzyme cofactor. Calcium is another special case, in that it is required as a component of the human diet, it is needed for the full activity of many enzymes, such as nitric oxide synthase, protein phosphatases, adenylate kinase, but calcium activates these enzymes in allosteric regulation binding to these enzymes in a complex with calmodulin.
Calcium is, therefore, a cell signaling molecule, not considered a cofactor of the enzymes it regulates. Other organisms require additional metals as enzyme cofactors, such as vanadium in the nitrogenase of the nitrogen-fixing bacteria of the genus Azotobacter, tungsten in the aldehyde ferredoxin oxidoreductase of the thermophilic archaean Pyrococcus furiosus, cadmium in the carbonic anhydrase from the marine diatom Thalassiosira weissflogii. In many cases, the cofactor includes both an organic component. One diverse set of examples is the heme proteins, which consist of a porphyrin ring coordinated to iron. Iron-sulfur clusters are complexes of iron and sulfur atoms held within proteins by cysteinyl residues, they play both structural and functional roles, including electron transfer, redox sensing, as structural modules. Organic cofactors are small organic molecules that can be either loosely or bound to the enzyme and directly participate in the reaction. In the latter case, when it is difficult to remove without denaturing the enzyme, it can be called a prosthetic group.
It is important to emphasize that there is no sharp division between loosely and bound cofactors. Indeed, many such as NAD+ can be bound in some enzymes, while it is loosely bound in others. Another example is thiamine pyrophosphate, bound in transketolase or pyruvate decarboxylase, while it is less tightly