Allosteric enzyme

Allosteric enzymes are enzymes that change their conformational ensemble upon binding of an effector (allosteric modulator) which results in an apparent change in binding affinity at a different ligand binding site. This "action at a distance" through binding of one ligand affecting the binding of another at a distinctly different site, is the essence of the allosteric concept. Allostery plays a crucial role in many fundamental biological processes, including but not limited to cell signaling and the regulation of metabolism. Allosteric enzymes need not be oligomers as previously thought, and in fact many systems have demonstrated allostery within single enzymes.
In biochemistry, allosteric regulation (or allosteric control) is the regulation of a protein by binding an effector molecule at a site other than the enzyme's active site.
The site to which the effector binds is termed the "allosteric site". Allosteric sites allow effectors to bind to the protein, often resulting in a conformational change involving protein dynamics. Effectors that enhance the protein's activity are referred to as "allosteric activators", whereas those that decrease the protein's activity are called "allosteric inhibitors".
Allosteric regulations are a natural example of control loops, such as feedback from downstream products or feedforward from upstream substrates. Long-range allostery is especially important in cell signaling. Allosteric regulation is also particularly important in the cell's ability to adjust enzyme activity.
The term "allostery" comes from the Greek "allos" (ἄλλος), "other," and "stereos" (στερεὀς), "solid (object)." This is in reference to the fact that the regulatory site of an allosteric protein is physically distinct from its active site.
The protein catalyst (enzyme) may be part of a
multi-subunit complex, and/or may transiently
or permanently associate with a Cofactor
(e.g. adenosine triphosphate). Catalysis of biochemical reactions is vital due to the very low reaction rates of the uncatalysed
reactions. A key driver of protein evolution is the optimization of such catalytic
activities via protein dynamics.
Whereas enzymes without coupled domains/subunits display normal Michaelis-Menten kinetics, most allosteric enzymes have multiple coupled domains/subunits and show cooperative binding. Generally speaking, such cooperativity results in allosteric enzymes displaying a sigmoidal dependence on the concentration of their substrates in positively cooperative systems. This allows most allosteric enzymes to greatly vary catalytic output in response to small changes in effector concentration. Effector molecules, which may be the substrate itself (homotropic effectors) or some other small molecule (heterotropic effector), may cause the enzyme to become more active or less active by redistributing the ensemble between the higher affinity and lower affinity states. The binding sites for heterotropic effectors, called allosteric sites, are usually separate from the active site yet thermodynamically coupled. Allosteric Database (ASD, http://mdl.shsmu.edu.cn/ASD) provides a central resource for the display, search and analysis of the structure, function and related annotation for allosteric molecules, including allosteric enzymes and their modulators. Each enzyme is annotated with detailed description of allostery, biological process and related diseases, and each modulator with binding affinity, physicochemical properties and therapeutic area.
Kinetic properties.
Hemoglobin, though not an enzyme, is the canonical example of an allosteric protein molecule - and one of the earliest to have its crystal structure solved (by Max Perutz). More recently, the "E. coli" enzyme aspartate carbamoyltransferase (ATCase) has become another good example of allosteric regulation.
The kinetic properties of allosteric enzymes are often explained in terms of a conformational change between a low-activity, low-affinity "tense" or T state and a high-activity, high-affinity "relaxed" or R state. These structurally distinct enzyme forms have been shown to exist in several known allosteric enzymes.
However the molecular basis for conversion between the two states is not well understood. Two main models have been proposed to describe this mechanism: the "concerted model" of Monod, Wyman, and Changeux, and the "sequential model" of Koshland, Nemethy, and Filmer.
In the concerted model, the protein is thought to have two “all-or-none” global states. This model is supported by positive cooperativity where binding of one ligand increases the ability of the enzyme to bind to more ligands. The model is not supported by negative cooperativity where losing one ligand makes it easier for the enzyme to lose more.
In the sequential model there are many different global conformational/energy states. Binding of one ligand changes the enzyme so it can bind more ligands more easily, i.e. every time it binds a ligand it wants to bind another one.
Neither model fully explains allosteric binding, however. The recent combined use of physical techniques (for example, x-ray crystallography and solution small angle x-ray scattering or SAXS) and genetic techniques (site-directed mutagenesis or SDM) may improve our understanding of allostery.


4-aminobutyrate aminotransferase

4-aminobutyrate aminotransferase may refer to:


2-Ethyl-4,5-dimethylphenol

2-Ethyl-4,5-dimethylphenol is a phenol found in the essential oil of rosemary ("Rosmarinus officinalis"). It is also found in female elephant urine samples.


Hsp20

The heat shock protein Hsp20 family, also known as small heat shock proteins (sHSPs), is a family of heat shock proteins.
Prokaryotic and eukaryotic organisms respond to heat shock or other environmental stress by inducing the synthesis of proteins collectively known as heat-shock proteins (hsp). Amongst them is a family of proteins with an average molecular weight of 20 kDa, known as the hsp20 proteins. These seem to act as protein chaperones that can protect other proteins against heat-induced denaturation and aggregation. Hsp20 proteins seem to form large heterooligomeric aggregates. Structurally, this family is characterised by the presence of a conserved C-terminal domain, alpha-crystallin domain, of about 100 residues. Recently, small heat shock proteins (sHSPs) were found in marine viruses (cyanophages).
Function and regulation.
Hsp20, like all heat shock proteins, is in abundance when cells are under stressed conditions. Hsp20 is known to be expressed in many human tissues, including the brain and heart. Hsp20 has been studied extensively in cardiac myocytes and is known to act as a chaperon protein, binding to protein kinase 1 (PDK1) and allowing its nuclear transport. In addition, the phosphorylation of hsp20 has been shown to effect the structure of cells cytoskeletons. Due to hsp20 commonly forming dimers with itself when heated, its function of chaperoning can be greatly affected.


3-Ethylphenol

3-Ethylphenol is a phenol found in urine samples of female elephants.
It is used as a photographic chemical intermediate and an intermediate for the cyan coupler of photographic paper.
It's a tsetse fly attractant. Therefore, it's a kairomone.


Synergin gamma

Synergin gamma also known as AP1 subunit gamma-binding protein 1 (AP1GBP1) is a protein that in humans is encoded by the "SYNRG" gene.
Function.
This gene encodes a protein that interacts with the gamma subunit of AP1 clathrin-adaptor complex. The AP1 complex is located at the trans-Golgi network and associates specific proteins with clathrin-coated vesicles. This encoded protein may act to connect the AP1 complex to other proteins. Alternatively spliced transcript variants that encode different isoforms have been described for this gene.
Interactions.
AP1GBP1 has been shown to interact with AP1G1 and SCAMP1.


ATPase assay

The ATPase assay is a membrane assay that indirectly measures the activity of efflux transporters. ATP Binding Cassette or efflux transporters mediate the transport of substrates across cell membranes against a concentration gradient. ATP cleavage is tightly linked to substrate translocation, as the energy for the substrate translocation is derived from ATP hydrolysis. ATP hydrolysis yields inorganic phosphate (Pi), which can be measured by a simple colorimetric reaction. The amount of Pi liberated is directly proportional to the activity of the transporter.
Use of ATPase Assay.
The ATPase assay is designed to indicate the nature of the interaction between the compound and the transporter. The ATPase assays are used in two different modes: ATPase activation and ATPase inhibition. Transported substrates increase baseline ATPase activity, while inhibitors or slowly transported compounds inhibit baseline ATPase activity and/or the ATPase activity measured in the presence of a stimulating agent. The ATPase assays can therefore have the potential for determining whether a compound acts as a transporter substrate and/or inhibitor.
Mutations in the ATPase domain result in loss of transport function. The activity of the multidrug transporter in drug-resistant cells is associated with rapid cellular ATP depletion when ATP synthesis is inhibited.


Ergosterol peroxide

Ergosterol peroxide (5α,8α-epidioxy-22"E"-ergosta-6,22-dien-3β-ol) is a steroid derivative. It has been isolated from a variety of fungi, yeast, lichens and sponges, and has been reported to exhibit immunosuppressive, anti-inflammatory, antiviral, trypanocidal and antitumor activities "in vitro".


Ribulose 5-phosphate

Ribulose 5-phosphate is one of the end-products of the pentose phosphate pathway. It is also an intermediate in the Calvin cycle.
It is formed by phosphogluconate dehydrogenase, and it can be acted upon by phosphopentose isomerase and phosphopentose epimerase.
In plants, Ribulose 5-phosphate produced from the pentose-phosphate pathway is converted into Ribulose-1-5-bisphosphate by the enzyme phosphoribokinase.


Fumarate reductase (NADH)

In enzymology, a fumarate reductase (NADH) () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are succinate and NAD+, whereas its three products are fumarate, NADH, and H+.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-CH group of donor with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is succinate:NAD+ oxidoreductase. Other names in common use include NADH-fumarate reductase, NADH-dependent fumarate reductase, and fumarate reductase (NADH).


HSPA6

Heat shock 70 kDa protein 6 is a protein that in humans is encoded by the "HSPA6" gene.


Cadherin cytoplasmic region

In molecular biology, the cadherin cytoplasmic region is a conserved region found at the C-terminus of cadherin proteins. A key determinant to the strength of the binding that it is mediated by cadherins is the juxtamembrane region (the part of the cytoplasmic region which is adjacent to the transmembrane domain) of the cadherin. This region induces clustering and also binds to the protein catenin (p120ctn). The cytoplasmic region is highly conserved in sequence and has been shown experimentally to regulate the cell-cell binding function of the extracellular domain of E-cadherin, possibly through interaction with the cytoskeleton.


Puerarin

Puerarin, one of several known isoflavones, is found in a number of plants and herbs, such as the root of "Pueraria" ("Radix puerariae") notably of the kudzu plant.
Puerarin is the 8-"C"-glucoside of daidzein.


SLC6A20

Solute carrier family 6, member 20 also known as SLC6A20 is a protein which in humans is encoded by the "SLC6A20" gene.
Function.
Transport of small hydrophilic substances across cell membranes is mediated by substrate-specific transporter proteins which have been classified into several families of related genes. The protein encoded by this gene is a member of the subgroup of transporter with unidentified substrates within the Na+ and Cl− coupled transporter family. This gene is expressed in kidney, and its alternative splicing generates 2 transcript variants.
Clinical significance.
Mutation in the SLC6A20 gene are associated with iminoglycinuria.
One of a cluster of 6 genes "(SLC6A20", "LZTFL1", "CCR9", "FYCO1", "CXCR6" and "XCR1") on chromosome 3 at location 3p21.31 associated with a genetic susceptibility to COVID-19 respiratory failure.


PERK inhibitors

A PERK inhibitor is a small molecule compound that unlike any existing drug inhibits the expression of protein kinase RNA–like endoplasmic reticulum kinase. The (first such) inhibitor demonstrated the ability to halt brain cell death in mice with prion disease. It represents a major new pathway for drug research on brain illness, including Alzheimer's disease and Parkinson's disease. The compound works by blocking a faulty signal in brains afflicted by neurodegenerative diseases that shuts down the production of essential proteins, leaving brain cells unprotected and soon dead.
The compound can be administered orally and is able to cross the blood–brain barrier. The compound produced significant side effects, including weight loss and mild diabetes, caused by damage to the pancreas.
PERK.
The PERK enzyme plays a key role in activating the brain's defence mechanism. In mice with prion disease, inhibiting PERK restored translation of proteins that protect brain cells, renewed normal behaviours and prevented memory loss. Unfortunately, the treatment was not shown to extend survival in prion-infected treated mice.


Biotin attachment domain

Biotin/lipoyl attachment domain has a conserved lysine residue that binds biotin or lipoic acid. Biotin plays a catalytic role in some carboxyl transfer reactions and is covalently attached, via an amide bond, to a lysine residue in enzymes requiring this coenzyme. Lipoamide acyltransferases have an essential cofactor, lipoic acid, which is covalently bound via an amide linkage to a lysine group. The lipoic acid cofactor is found in a variety of proteins.
Human proteins containing this domain.
ACACA; ACACB; DBT; DLAT; DLST; DLSTP; MCCC1; PC;
PCCA; PDHX;


Procollagen-proline dioxygenase

Procollagen-proline dioxygenase, commonly known as prolyl hydroxylase, is a member of the class of enzymes known as alpha-ketoglutarate-dependent hydroxylases. These enzymes catalyze the incorporation of oxygen into organic substrates through a mechanism that requires alpha-Ketoglutaric acid, Fe2+, and ascorbate. This particular enzyme catalyzes the formation of (2"S", 4"R")-4-hydroxyproline, a compound that represents the most prevalent post-translational modification in the human proteome.
Enzyme mechanism.
Procollagen-proline dioxygenase catalyzes the following reaction:
L-proline + alpha-ketoglutaric acid + O2 → (2"S", 4"R")-4-hydroxyproline + succinate + CO2
The mechanism for the reaction is similar to that of other dioxygenases, and occurs in two distinct stages: In the first, a highly reactive Fe(IV)=O species is produced. Molecular oxygen is bound end-on in an axial position, producing a dioxygen unit. Nucleophilic attack on C2 generates a tetrahedral intermediate, with loss of the double bond in the dioxygen unit and bonds to iron and the alpha carbon of 2-oxoglutarate. Subsequent elimination of CO2 coincides with the formation of the Fe(IV)=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 reaction mechanism, one molecule of 2-oxoglutarate is decarboxylated, forming succinate. This succinate is hydrolyzed and replaced with another 2-oxoglutarate after each reaction, and it has been concluded that in the presence of 2-oxoglutarate, enzyme-bound Fe2+ is rapidly converted to Fe3+, leading to inactivation of the enzyme. Ascorbate is utilized as a cofactor to reduce Fe3+ back to Fe2+.
Enzyme structure.
Prolyl hydroxylase is a tetramer with 2 unique subunits. The α subunit is 59 kDa and is responsible for both peptide binding and for catalytic activity. The peptide binding domain spans residues 140-215 of the α subunit, and consists of a concave surface lined with multiple tyrosine residues which interact favorably with the proline-rich substrate. 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 enzyme’s localization to and retention in the endoplasmic reticulum. This subunit is identical to the enzyme known as protein disulfide isomerase.
Biological function.
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. Specifically, hydroxylation increases the melting temperature (Tm) of helical collagen by 16 °C, as compared to unhydroxylated collagen, a difference that allows the protein to be stable at body temperature.
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, and conotoxins, among others.
Disease relevance.
As prolyl hydroxylase requires ascorbate as a cofactor to function, its absence compromises the enzyme’s activity. The resulting decreased hydroxylation leads to the disease condition known as scurvy. Since stability of collagen is compromised in scurvy patients, symptoms include weakening of blood vessels causing purpura, petechiae, and gingival bleeding.
Hypoxia-inducible factor (HIF) 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; hydroxylation of HIF allows the protein to be targeted for degradation. HIF prolyl-hydroxylase has been targeted by a variety of inhibitors that aim to treat stroke, kidney disease, ischemia, anemia, and other important diseases.


TEX35

TEX35 is a protein that in humans is encoded by the "TEX35" gene.


Ribulose

Ribulose is a ketopentose — a monosaccharide containing five carbon atoms, and including a ketone functional group. It has chemical formula 5105. Two enantiomers are possible, -ribulose (-erythro-pentulose) and -ribulose (-erythro-pentulose). -Ribulose is the diastereomer of -xylulose.
Ribulose sugars are composed in the pentose phosphate pathway from arabinose. They are important in the formation of many bioactive substances. For example, -ribulose is an intermediate in the fungal pathway for -arabitol production. Also, as the 1,5-bisphosphate, -ribulose combines with carbon dioxide at the start of the photosynthesis process in green plants (carbon dioxide trap).
Ribulose has the same stereochemistry at carbons 3 and 4 as the five-carbon aldoses ribose and arabinose.


Tipredane

Tipredane (developmental code name SQ-27239) is a synthetic glucocorticoid corticosteroid which was never marketed.


IgA protease

IgA protease may refer to:


2-methylacyl-CoA dehydrogenase

In enzymology, a 2-methylacyl-CoA dehydrogenase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are 2-methylbutanoyl-CoA and acceptor, whereas its two products are 2-methylbut-2-enoyl-CoA and reduced acceptor.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-CH group of donor with other acceptors. The systematic name of this enzyme class is 2-methylbutanoyl-CoA:acceptor oxidoreductase. Other names in common use include branched-chain acyl-CoA dehydrogenase, 2-methyl branched chain acyl-CoA dehydrogenase, and 2-methylbutanoyl-CoA:(acceptor) oxidoreductase. This enzyme participates in valine, leucine and isoleucine degradation.


ST turn

The ST turn is a structural feature in proteins and polypeptides. Each consists of three amino acid residues (labeled "i", "i" + 1 and "i" + 2) in which residue "i" is a serine (S) or threonine (T) that forms a hydrogen bond from its sidechain oxygen group to the mainchain NH group of residue "i" + 2.
Similar motifs occur with aspartate or asparagine as residue "i", called asx turn. Four types of asx turn and ST turn can be distinguished: types I, I’, II and II’. These categories correspond (via sidechain-mainchain mimicry of residue i) to those of the more abundant hydrogen-bonded beta turns, which have four residues and a hydrogen bond between the CO of residue "i" and the NH of residue "i" + 3. Regarding their occurrence in proteins, they differ in that type I is the commonest of the four beta turns while type II’ is the commonest of the ST and asx turns.
Asx and ST turns both occur frequently at the N-termini of α-helices, as part of asx motifs or ST motifs, with the asx, serine or threonine as the N cap residue. They are thus often regarded as helix capping features.
Evidence for a functionally relevant ST turn is provided in the CDR3 region of the T-cell receptor (B chain, V domain)
A proportion of ST turns are accompanied by a mainchain-mainchain hydrogen bond that qualifies them as ST motifs.


6-Hydroxyflavone

6-Hydroxyflavone is a flavone, a type of chemical compound. It is one of the noncompetitive inhibitors of cytochrome P450 2C9. It is reported in leaves of "Barleria prionitis" Linn. (a common Acanthaceae from India).
6-Hydroxyflavone may have a potential as a therapeutic drug capable for the treatment of anxiety-like disorders.


ST motif

The ST motif is a commonly occurring feature in proteins and polypeptides. It consists of four or five amino acid residues with either serine or threonine as the first residue (residue "i"). It is defined by two internal hydrogen bonds. One is between the side chain oxygen of residue "i" and the main chain NH of residue "i" + 2 or "i" + 3; the other is between the main chain oxygen of residue "i" and the main chain NH of residue "i" + 3 or "i" + 4. Two websites are available for finding and examining ST motifs in proteins, Motivated Proteins: and PDBeMotif.

When one of the hydrogen bonds is between the main chain oxygen of residue "i" and the side chain NH of residue "i" + 3 the motif incorporates a beta turn. When one of the hydrogen bonds is between the side chain oxygen of residue "i" and the main chain NH of residue "i" + 2 the motif incorporates an ST turn.
As with ST turns, a significant proportion of ST motifs occur at the N-terminus of an alpha helix with the serine or threonine as the N cap residue. They have thus often been described as helix capping features.
A related motif is the asx motif which has aspartate or asparagine as the first residue.
Two well conserved threonines at α-helical N-termini occur as ST motifs and form part of the characteristic nucleotide binding sites of SF1 and SF2 type DNA and RNA helicases.
It has been suggested that the sequences SPXX or STXX are frequently found at DNA-binding sites and also that they are recognized as substrates by some protein kinases. Structural studies of polypeptides indicate that such tetrapeptides can adopt the hydrogen bonding pattern of the ST motif.


Fucosidase

Tissue alpha-L-fucosidase is an enzyme that in humans is encoded by the "FUCA1" gene.
Alpha-Fucosidase is an enzyme that breaks down fucose.
Fucosidosis is an autosomal recessive lysosomal storage disease caused by defective alpha-L-fucosidase with accumulation of fucose in the tissues. Different phenotypes include clinical features such as neurologic deterioration, growth retardation, visceromegaly, and seizures in a severe early form; coarse facial features, angiokeratoma corporis diffusum, spasticity and delayed psychomotor development in a longer surviving form; and an unusual spondylometaphyseoepiphyseal dysplasia in yet another form.[supplied by OMIM]


Vasa gene

Vasa is an RNA binding protein with an ATP-dependent RNA helicase that is a member of the DEAD box family of proteins. The vasa gene, is essential for germ cell development and was first identified in "Drosophila melanogaster", but has since been found to be conserved in a variety of vertebrates and invertebrates including humans. The Vasa protein is found primarily in germ cells in embryos and adults, where it is involved in germ cell determination and function, as well as in multipotent stem cells, where its exact function is unknown.
Gene.
The Vasa gene is a member of the DEAD box family of RNA helicases in "Drosophila melanogaster." Its human ortholog, Ddx4, is located on human chromosome 5q. It is syntenic to mouse chromosome 13, where the mouse vasa gene, is located. The gene is conserved in many invertebrates and vertebrate species such as "C. elegans", "Xenopus", Zebrafish, flatworms, echinderms, molluscs, nematodes, mice and rats as an important part of germ line maintenance and function.
All vertebrate species and "Drosophila" have only one vasa ortholog. However, C. elegans has four Vasa genes, of which only one (GLH-1) is essential.
All DEAD box genes, including Vasa, have 9 conserved sequence motifs. The Vasa gene family evolved from a duplication event followed by acquiring certain domains. Early in the evolution of multicellular animals, the duplication of PL10 related DEAD-box gene occurred. This resulted in animals having both Vasa and PL10 genes, but plants and fungi only have PL10 genes and no Vasa. After the duplication event, the N-terminal region acquired Zn-knuckle domains which are now conserved in invertebrates. Vertebrates and insects both have lost the Zn-knuckle domains. The number of these domains vary between different species Vasa genes. An important property of Zn-knuckles, which can be categorized as classical zinc fingers, is that they are able to bind to single and double stranded DNA or RNA. The presence of Zn-knuckles in invertebrates and absence in vertebrates may be an indication of differences in target binding sites. Their presence may be important to functions outside germ line development. An exception to this theory is the presence of Zn-knuckles in all four C. elegans Vasa genes, which are restricted to functions in the germ line.
Protein.
The protein product in humans has 724 amino acids, a molecular mass of 79 kDa and 8 conserved domains in all DEAD-box proteins that is involved in RNA helicase activity. Domain V contains the DEAD motif. As with other Vasa related proteins, human Vasa has a N terminus rich in glycine and RGG motif repeats that function in RNA binding.
Vasa is regulated at the transcript and protein level. Developing embryos and adults regulate Vasa expression to cell and tissue specific locations. In Drosophila, zygotic transcription of Vasa occurs at pole cells, and stays germ-line specific throughout the life of the organism.
The Vasa promoter is regulated through methylation. In cells were Vasa is transcribed successfully, the promoter is hypomethylated and in all other cells it is methylated. When Vasa is hypermethylated in testes, spermatogenesis defects may occur.
Post-transcriptionally Vasa has several splice forms in different animals. In P. hawaiensis, Vasa transcript is uniformly distributed in the embryo and is localized depending on the stabilization of the 3’UTR (Untranslated Region to the germ line cells. Translation can be inhibited by cis regulatory elements in the transcript's 5' and 3' UTRs. They may inhibit translation by forming secondary RNA structures or binding trans-acting factors. Vasa expression localization is directed by repressing these translation inhibitory pathways.
Post-translationally, in "Drosophila", Vasa protein is localized to the pole plasm during embryonic development. Many other proteins in "Drosophila" are also localized to the poles. For example, Oskar protein was found to localize to pole plasm and may be involved in anchoring Vasa to polar granules in the posterior pole of the oocyte. Another enzyme, fat facets, may further stabilize Vasa in the pole plasm. Other post-translational modification includes phosphorylation of the Vasa ortholog in "C. elegans", and arginine methylation in a conserved region of mice, "Xenopus" and "Drosophila" Vasa genes.
Function.
One of main function of Vasa protein is in germ cell determination and function. It uses ATP dependent RNA helicase catalytic activity to regulate the translation of multiple mRNAs. Vasa unwinds the duplex RNA by binding and bending short stretches of the duplex in a non-processive manner. The conserved domain may act as chaperones by unwinding RNA secondary structures and refolding properly. pre-mRNA splicing, ribosome biogenesis, nuclear export, translational regulation and degradation.
Vasa was found to bind RNA in a sequence specific manner. In the Drosophila embryos, Vasa binds the Uracil rich motif of the mei-P26 UTR. A mutation in Vasa reduced the interaction of between Mei-P26 and initiation factor elF58 which in turn significantly reduced translation of the gene.
Recent evidence in invertebrates have found that Vasa has a role in multipotent stem cells, but the exact the function is unknown.
Mutations.
"Drosophila".
A null mutation causes female sterility due to severe defects in oogenesis but males are fertile.
Homozygous mutations for partial loss of function allows eggs to be fertilized but embryos lack germ cells.
"Mus musculus".
Mutations in Vasa homolog, "Mvh", cause defects in spermatogenesis but females are fertile. Male sterility may be due to deficiencies in germ cell proliferation and differentiation (the mouse homolog of Droso.). Female fertility may be due to functional redundancy by other DEAD-box family members. Null mutation still allows primordial germ cells to form but have severe defects.
"Homo sapiens".
Although there are no studies done on Vasa mutations in humans, it is likely that it would cause sterility.
These sex-specific phenotypes in mice and "Drosophila" mutants suggest that Vasa either regulated differently or has different target functions in the two germ line types.
Tissue, and subcellular distribution.
Vasa expression is restricted to tissue specific cells. Until recently it was thought that Vasa protein can only be found in gametes and is undetectable in somatic cells. Within germ cells, Vasa is expressed in the cytoplasm. During embryogenesis, Vasa is expressed in migratory primordial germ cells (PGCs) at the gonadal ridge in both males and females.This specificity allows Vasa to be used as a highly specific marker for germ cells. In a patient with Sertoli cell syndrome, no Vasa signal was detected from testicular biopsy. However, recent studies show that Vasa functions in other cells as well.
A study on "Macrostomum lignano" found Vasa expression in multipotent neoblast stem cells in addition to germ cells. However, RNAi knockdown revealed that either Vasa is non-essential in this organism or is made functionally redundant by other Vasa-like genes. Similar results were found on studies of the colonial ascidian "Botryllus primigenus", oysters, teleosts, "clawed frog", the parasitic wasp, and the crustacean "Parhyale hawaiensis".
Vasa expression has been observed in epithelial ovarian cancer cells. It was found to deter the DNA damage-induced G2 checkpoint by downregulating the expression of another gene. Vasa is also present in chicken embryonic stem cells where it induces expression of germ line genes. This function still supports the most important role of Vasa in germ line development. In Cnidarians, Vasa has a role in nerve cells and gland cells. Other examples include Vasa in multipotent stem cell cluster of "Polyascus polygenea" buds and stolon, Vasa in auxiliary cells of oyster ovaries, Vasa in non-germ-line lineages in the snail "Ilyanassa", Vasa in progenitor mesodermal posterior growth zone of the polychaete annelid "Platynereis dumerilii", and Vasa present in non-genetical segments during Oligochaete development. But no reports of vasa expressed outside of germ line cells in vertebrates or insects.
Expression.
In "Drosophila", "vasa" expression is seen in germ cells, specifically the germline stem cells (GSC's) of female ovaries and in the early stages of spermatogensis in the male testis.
Staining.
Due to the localization of "vasa", immunohistochemistry staining can be done with vasa antibodies. For example, "vasa" antibody staining is specific for germline stem cells in the "D. melanogaster" germarium.
This protein is localized to the cytoplasm of fetal germ cells and to the cytoplasm of developing oocytes in the mammals.


Oatfield Eclairs


Neuroprostanes

The neuroprostanes are prostaglandin-like compounds formed "in vivo" from the free radical-catalyzed peroxidation
of essential fatty acids (primarily docosahexaenoic acid) without the direct action of cyclooxygenase (COX) enzymes. The result is the formation of isoprostane-like compounds F4-, D4-, E4-, A4-, and J4-neuroprostanes which have been shown to be produced in vivo. These oxygenated essential fatty acids possess potent biological activity as anti-inflammatory mediators inhibiting the response of human macrophages that augment the perception of pain.


Acylglycerone-phosphate reductase

In enzymology, an acylglycerone-phosphate reductase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are 1-palmitoylglycerol 3-phosphate and NADP+, whereas its 3 products are palmitoylglycerone phosphate, NADPH, and H+.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-OH group of donor with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is 1-palmitoylglycerol-3-phosphate:NADP+ oxidoreductase. Other names in common use include palmitoyldihydroxyacetone-phosphate reductase, palmitoyl dihydroxyacetone phosphate reductase, palmitoyl-dihydroxyacetone-phosphate reductase, acyldihydroxyacetone phosphate reductase, and palmitoyl dihydroxyacetone phosphate reductase. This enzyme participates in glycerophospholipid and ether lipid metabolism.


3-hydroxy-4-oxoquinoline 2,4-dioxygenase

In enzymology, a 3-hydroxy-4-oxoquinoline 2,4-dioxygenase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are 3-hydroxy-1H-quinolin-4-one and O2, whereas its two products are N-formylanthranilate and CO.
This enzyme belongs to the family of oxidoreductases, specifically those acting on single donors with O2 as oxidant and incorporation of two atoms of oxygen into the substrate (oxygenases). The oxygen incorporated need not be derived from O2. The systematic name of this enzyme class is 3-hydroxy-1H-quinolin-4-one 2,4-dioxygenase (CO-forming). Other names in common use include (1H)-3-hydroxy-4-oxoquinoline 2,4-dioxygenase, 3-hydroxy-4-oxo-1,4-dihydroquinoline 2,4-dioxygenase, 3-hydroxy-4(1H)-one, 2,4-dioxygenase, and quinoline-3,4-diol 2,4-dioxygenase.


KIFAP3

Kinesin-associated protein 3 is a protein that in humans is encoded by the "KIFAP3" (also known as "KAP3") gene. It is a non-motor, accessory subunit which co-oligomerizes with the motor subunits KIF3A and KIF3B or KIF3C, to form heterotrimeric kinesin-2 motor proteins. Kinesin-2 KAP subunits were initially characterized in echinoderms and mice.
Function.
The small G protein GDP dissociation stimulator (smg GDS) is a regulator protein having two activities on a group of small G proteins including the Rho and Rap1 family members and Ki-Ras; one is to stimulate their GDP/GTP exchange reactions, and the other is to inhibit their interactions with membranes. The protein encoded by this gene contains 9 Armadillo repeats and interacts with the smg GDS protein through these repeats. This protein, which is highly concentrated around the endoplasmic reticulum, is phosphorylated by v-src, and this phosphorylation reduces the affinity of the protein for smg GDS. It is thought that this protein serves as a linker between human chromosome-associated polypeptide (HCAP) and KIF3A/B, a kinesin superfamily protein in the nucleus, and that it plays a role in the interaction of chromosomes with an ATPase motor protein.
Interactions.
KIFAP3 has been shown to interact with APC, SMC3 and RAP1GDS1.


Ulobetasol

Ulobetasol (INN) or halobetasol (USAN) is a corticosteroid used to treat psoriasis. It is a class I corticosteroid under the US classification and a group III corticosteroid under international classification, the most potent group of such drugs.
Ulobetasol propionate is usually supplied as a 0.05% topical cream. Ulobetasol is the strongest topical steroid available. It is also sold with tazarotene with 0.01% halobetasol and 0.045% tazarotene as a lotion branded as Duobrii (Bausch Health).
It is available as a generic medication.


HBcAg

HBcAg (core antigen) is a hepatitis B viral protein. It is an indicator of active viral replication; this means the person infected with Hepatitis B can likely transmit the virus on to another person (i.e. the person is infectious).
Structure and Function.
HBcAg is an antigen that can be found on the surface of the nucleocapsid core (the inner most layer of the hepatitis B virus). While both HBcAg and HBeAg are made from the same open reading frame, HBcAg is not secreted. HBcAg is considered "particulate" and it does not circulate in the blood but recent study show it can be detected in serum by Radioimmunoassay. However, it is readily detected in hepatocytes after biopsy. The presence of both HBcAg and HBeAg proteins together act as a marker of viral replication, and antibodies to these antigens are a marker of declining replication.
Interactions.
Tapasin can interact with HBcAg18-27 and enhance cytotoxic T-lymphocyte response against HBV.


Cutinase

A cutinase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are cutin and H2O, whereas its product is cutin monomer.
This enzyme belongs to the family of hydrolases, specifically those acting on carboxylic ester bonds. The systematic name of this enzyme class is cutin hydrolase.
Aerial plant organs are protected by a cuticle composed of an insoluble polymeric structural compound, cutin, which is a polyester composed of hydroxy and hydroxyepoxy fatty acids. Plant pathogenic fungi produce extracellular degradative enzymes that play an important role in pathogenesis. They include cutinase, which hydrolyses cutin, facilitating fungus penetration through the cuticle. Inhibition of the enzyme can prevent fungal infection through intact cuticles. Cutin monomers released from the cuticle by small amounts of cutinase on fungal spore surfaces can greatly increase the amount of cutinase secreted by the spore, the mechanism for which is as yet unknown.
Cutinase is a serine esterase containing the classical Ser, His, Asp triad of serine hydrolases. The
protein belongs to the alpha-beta class, with a central beta-sheet of 5 parallel strands covered by 5 helices on either side of the sheet. The active site cleft is partly covered by 2
thin bridges formed by amino acid side chains, by contrast with the hydrophobic lid possessed by other lipases. The protein also contains 2 disulfide bridges, which are essential for activity, their cleavage resulting in complete loss of enzymatic activity. Two cutinase-like proteins (MtCY39.35 and MtCY339.08c) have been found in the genome of the bacteria "Mycobacterium tuberculosis".


Beta sheet

The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet. A β-strand is a stretch of polypeptide chain typically 3 to 10 amino acids long with backbone in an extended conformation. The supramolecular association of β-sheets has been implicated in the formation of the fibrils and protein aggregates observed in amyloidosis, notably Alzheimer's disease.
History.
The first β-sheet structure was proposed by William Astbury in the 1930s. He proposed the idea of hydrogen bonding between the peptide bonds of parallel or antiparallel extended β-strands. However, Astbury did not have the necessary data on the bond geometry of the amino acids in order to build accurate models, especially since he did not then know that the peptide bond was planar. A refined version was proposed by Linus Pauling and Robert Corey in 1951. Their model incorporated the planarity of the peptide bond which they previously explained as resulting from keto-enol tautomerization.
Structure and orientation.
Geometry.
The majority of β-strands are arranged adjacent to other strands and form an extensive hydrogen bond network with their neighbors in which the N−H groups in the backbone of one strand establish hydrogen bonds with the C=O groups in the backbone of the adjacent strands. In the fully extended β-strand, successive side chains point straight up, then straight down, then straight up, etc. Adjacent β-strands in a β-sheet are aligned so that their Cα atoms are adjacent and their side chains point in the same direction. The "pleated" appearance of β-strands arises from tetrahedral chemical bonding at the Cα atom; for example, if a side chain points straight up, then the bonds to the C′ must point slightly downwards, since its bond angle is approximately 109.5°. The pleating causes the distance between C and C to be approximately , rather than the expected from two fully extended "trans" peptides. The "sideways" distance between adjacent Cα atoms in hydrogen-bonded β-strands is roughly .
However, β-strands are rarely perfectly extended; rather, they exhibit a twist. The energetically preferred dihedral angles near ("φ", "ψ") = (–135°, 135°) (broadly, the upper left region of the Ramachandran plot) diverge significantly from the fully extended conformation ("φ", "ψ") = (–180°, 180°). The twist is often associated with alternating fluctuations in the dihedral angles to prevent the individual β-strands in a larger sheet from splaying apart. A good example of a strongly twisted β-hairpin can be seen in the protein BPTI.
The side chains point outwards from the folds of the pleats, roughly perpendicularly to the plane of the sheet; successive amino acid residues point outwards on alternating faces of the sheet.
Hydrogen bonding patterns.
Because peptide chains have a directionality conferred by their N-terminus and C-terminus, β-strands too can be said to be directional. They are usually represented in protein topology diagrams by an arrow pointing toward the C-terminus. Adjacent β-strands can form hydrogen bonds in antiparallel, parallel, or mixed arrangements.
In an antiparallel arrangement, the successive β-strands alternate directions so that the N-terminus of one strand is adjacent to the C-terminus of the next. This is the arrangement that produces the strongest inter-strand stability because it allows the inter-strand hydrogen bonds between carbonyls and amines to be planar, which is their preferred orientation. The peptide backbone dihedral angles ("φ", "ψ") are about (–140°, 135°) in antiparallel sheets. In this case, if two atoms C and C are adjacent in two hydrogen-bonded β-strands, then they form two mutual backbone hydrogen bonds to each other's flanking peptide groups; this is known as a close pair of hydrogen bonds.
In a parallel arrangement, all of the N-termini of successive strands are oriented in the same direction; this orientation may be slightly less stable because it introduces nonplanarity in the inter-strand hydrogen bonding pattern. The dihedral angles ("φ", "ψ") are about (–120°, 115°) in parallel sheets. It is rare to find less than five interacting parallel strands in a motif, suggesting that a smaller number of strands may be unstable, however it is also fundamentally more difficult for parallel β-sheets to form because strands with N and C termini aligned necessarily must be very distant in sequence . There is also evidence that parallel β-sheet may be more stable since small amyloidogenic sequences appear to generally aggregate into β-sheet fibrils composed of primarily parallel β-sheet strands, where one would expect anti-parallel fibrils if anti-parallel were more stable.
In parallel β-sheet structure, if two atoms C and C are adjacent in two hydrogen-bonded β-strands, then they do "not" hydrogen bond to each other; rather, one residue forms hydrogen bonds to the residues that flank the other (but not vice versa). For example, residue "i" may form hydrogen bonds to residues "j" − 1 and "j" + 1; this is known as a wide pair of hydrogen bonds. By contrast, residue "j" may hydrogen-bond to different residues altogether, or to none at all.
The hydrogen bond arrangement in parallel beta sheet resembles that in an amide ring motif with 11 atoms.
Finally, an individual strand may exhibit a mixed bonding pattern, with a parallel strand on one side and an antiparallel strand on the other. Such arrangements are less common than a random distribution of orientations would suggest, suggesting that this pattern is less stable than the anti-parallel arrangement, however bioinformatic analysis always struggles with extracting structural thermodynamics since there are always numerous other structural features present in whole proteins. Also proteins are inherently constrained by folding kinetics as well as folding thermodynamics, so one must always be careful in concluding stability from bioinformatic analysis.
The hydrogen bonding of β-strands need not be perfect, but can exhibit localized disruptions known as β-bulges.
The hydrogen bonds lie roughly in the plane of the sheet, with the peptide carbonyl groups pointing in alternating directions with successive residues; for comparison, successive carbonyls point in the "same" direction in the alpha helix.
Amino acid propensities.
Large aromatic residues (tyrosine, phenylalanine, tryptophan) and β-branched amino acids (threonine, valine, isoleucine) are favored to be found in β-strands in the "middle" of β-sheets. Different types of residues (such as proline) are likely to be found in the "edge" strands in β-sheets, presumably to avoid the "edge-to-edge" association between proteins that might lead to aggregation and amyloid formation.
Common structural motifs.
A very simple structural motif involving β-sheets is the β-hairpin, in which two antiparallel strands are linked by a short loop of two to five residues, of which one is frequently a glycine or a proline, both of which can assume the dihedral-angle conformations required for a tight turn or a β-bulge loop. Individual strands can also be linked in more elaborate ways with longer loops that may contain α-helices.
Greek key motif.
The Greek key motif consists of four adjacent antiparallel strands and their linking loops. It consists of three antiparallel strands connected by hairpins, while the fourth is adjacent to the first and linked to the third by a longer loop. This type of structure forms easily during the protein folding process. It was named after a pattern common to Greek ornamental artwork (see meander).
β-α-β motif.
Due to the chirality of their component amino acids, all strands exhibit right-handed twist evident in most higher-order β-sheet structures. In particular, the linking loop between two parallel strands almost always has a right-handed crossover chirality, which is strongly favored by the inherent twist of the sheet. This linking loop frequently contains a helical region, in which case it is called a β-α-β motif. A closely related motif called a β-α-β-α motif forms the basic component of the most commonly observed protein tertiary structure, the TIM barrel.
β-meander motif.
A simple supersecondary protein topology composed of 2 or more consecutive antiparallel β-strands linked together by hairpin loops. This motif is common in β-sheets and can be found in several structural architectures including β-barrels and β-propellers.
Psi-loop motif.
The psi-loop (Ψ-loop) motif consists of two antiparallel strands with one strand in between that is connected to both by hydrogen bonds. There are four possible strand topologies for single Ψ-loops. This motif is rare as the process resulting in its formation seems unlikely to occur during protein folding. The Ψ-loop was first identified in the aspartic protease family.
Structural architectures of proteins with β-sheets.
β-sheets are present in all-β, α+β and α/β domains, and in many peptides or small proteins with poorly defined overall architecture. All-β domains may form β-barrels, β-sandwiches, β-prisms, β-propellers, and β-helices.
Structural topology.
The topology of a β-sheet describes the order of hydrogen-bonded β-strands along the backbone. For example, the flavodoxin fold has a five-stranded, parallel β-sheet with topology 21345; thus, the edge strands are β-strand 2 and β-strand 5 along the backbone. Spelled out explicitly, β-strand 2 is H-bonded to β-strand 1, which is H-bonded to β-strand 3, which is H-bonded to β-strand 4, which is H-bonded to β-strand 5, the other edge strand. In the same system, the Greek key motif described above has a 4123 topology. The secondary structure of a β-sheet can be described roughly by giving the number of strands, their topology, and whether their hydrogen bonds are parallel or antiparallel.
β-sheets can be "open", meaning that they have two edge strands (as in the flavodoxin fold or the immunoglobulin fold) or they can be "closed β-barrels" (such as the TIM barrel). β-Barrels are often described by their "stagger" or "shear". Some open β-sheets are very curved and fold over on themselves (as in the SH3 domain) or form horseshoe shapes (as in the ribonuclease inhibitor). Open β-sheets can assemble face-to-face (such as the β-propeller domain or immunoglobulin fold) or edge-to-edge, forming one big β-sheet.
Dynamic features.
β-pleated sheet structures are made from extended β-strand polypeptide chains, with strands linked to their neighbours by hydrogen bonds. Due to this extended backbone conformation, β-sheets resist stretching. β-sheets in proteins may carry out low-frequency accordion-like motion as observed by the Raman spectroscopy and analyzed with the quasi-continuum model.
Parallel β-helices.
A β-helix is formed from repeating structural units consisting of two or three short β-strands linked by short loops. These units "stack" atop one another in a helical fashion so that successive repetitions of the same strand hydrogen-bond with each other in a parallel orientation. See the β-helix article for further information.
In lefthanded β-helices, the strands themselves are quite straight and untwisted; the resulting helical surfaces are nearly flat, forming a regular triangular prism shape, as shown for the 1QRE archaeal carbonic anhydrase at right. Other examples are the lipid A synthesis enzyme LpxA and insect antifreeze proteins with a regular array of Thr sidechains on one face that mimic the structure of ice.
Righthanded β-helices, typified by the pectate lyase enzyme shown at left or P22 phage tailspike protein, have a less regular cross-section, longer and indented on one of the sides; of the three linker loops, one is consistently just two residues long and the others are variable, often elaborated to form a binding or active site. <br>
A two-sided β-helix (right-handed) is found in some bacterial metalloproteases; its two loops are each six residues long and bind stabilizing calcium ions to maintain the integrity of the structure, using the backbone and the Asp side chain oxygens of a GGXGXD sequence motif. This fold is called a β-roll in the SCOP classification.
In pathology.
Some proteins that are disordered or helical as monomers, such as amyloid β (see amyloid plaque) can form β-sheet-rich oligomeric structures associated with pathological states. The amyloid β protein's oligomeric form is implicated as a cause of Alzheimer's. Its structure has yet to be determined in full, but recent data suggest that it may resemble an unusual two-strand β-helix.
The side chains from the amino acid residues found in a β-sheet structure may also be arranged such that many of the adjacent sidechains on one side of the sheet are hydrophobic, while many of those adjacent to each other on the alternate side of the sheet are polar or charged (hydrophilic), which can be useful if the sheet is to form a boundary between polar/watery and nonpolar/greasy environments.


Tylactone synthase

Tylactone synthase or TYLS is a Type 1 polyketide synthase. TYLS is found in strains of "Streptomyces fradiae" and responsible for the synthesis of the macrolide ring, tylactone, the precursor of an antibiotic, tylosin. TYLS is composed of five large multi-functional proteins, TylGI-V. Each protein contains either one or two modules. Each module consists of a minimum of a Ketosynthase (KS), an Acyltransferase (AT), and an Acyl carrier protein (ACP) but may also contain a Ketoreductase (KR), Dehydrotase (DH), and Enoyl Reductase (ER) for additional reduction reactions. The domains of TYLS have similar activity domains to those found in other Type I polyketide synthase such as 6-Deoxyerythronolide B synthase (DEBS). The TYLS system also contains a loading module consisting of a ketosynthase‐like decarboxylase domain, an acyltransferase, and acyl carrier protein. The terminal Thioesterase terminates tylactone synthesis by cyclizing the macrolide ring. After the TYLS completes tylactone synthesis, the tylactone molecule is modified by oxidation at C-20 and C-23 and glycosylation of mycaminose, mycinose, and mycarose to produce tylosin.
Structure and function.
TylGI.
TylGI initiates synthesis via the loading module. The loading module contains a ketosynthase‐like decarboxylase domain (KSQ) that decarboxylates the methylmalonyl-CoA loaded onto the ACP via the AT. This results in a propionate molecule, which the ACP passes to the KS of module 1. Module 1 extends the propionate by loading methylmalonate onto the ACP and catalyzing a Claisen condensation with the propionate bound to the KS. The diketide product is then reduced by the KR on module 1 and the substrate is transferred via the ACP on module 1 to the KS of module 2. Module 2 loads the ACP with methylmalonate via the module 2 AT followed by a Claisen condensation with the diketide bound to the KS and a KR-mediated reduction, a reaction sequence similar to that of module 1. The DH then catalyzes dehydration resulting in an ACP bound triketide. The triketide is then passed via the ACP of module 2 to the KS of module 3 on TylGII via docking domains. Docking domains are large proteins with relatively weak affinities (Kd ≈ 20–100 μM) that are fused to the complementary C and N terminii of interacting polyketide synthase polypeptides.
TylGII.
The AT of module 3 loads malonyl-CoA onto the ACP, followed by a Claisen condensation with the bound triketide, a KR-mediated reduction and dehydration catalyzed by the DH. The tetraketide is then passed to module 4 on TylGIII paired docking domains.
TylGIII.
The AT of module 4 loads methylmalonyl-CoA onto the module 4 ACP and catalyzes a Claisen condensation with the bound tetraketide. However, since module 4 contains an inactive KR domain, the β-ketone condensation product is maintained. The AT on module 5 selects for ethylmalonyl-CoA and catalyzes a Claisen condensation followed by reduction via the KR and dehydration via the DH resulting in an alkene. The ER then saturates the alkene product. The hexaketide product of TylGIII is passed to the KS on module 6 on TylGIV via docking domain interactions.
TylGIV.
Module 6 loads methylmalonyl CoA onto the ACP and catalyzes a Claisen condensation followed by a β-keto reduction by the KR domain. The heptaketide product is then passed to the KS on module 7 on TylGV via paired docking domains on TylGIV.
TylGV.
Module 7 adds two carbon atoms via malonyl-CoA loaded onto the ACP, followed by the same series of reactions as those catalyzed by module 2. The linear octaketide is then cyclized via the Thioesterase domain to form the 16- membered ring of tylactone.
Engineering applications.
Because polyketide synthases catalyze stereospecific reactions, there is interest in engineering new molecules via PKS engineering. Efforts to engineer a hybrid PKS have met with some success. A team from Lilly Research Laboratories designed a hybrid tylactone/platenolide synthase that was able to accept the propionate substrate from the TYLS loading module instead of acetate, the natural precursor in the platenolide synthase system. This led to the production of a novel hybrid macrolactone. Other efforts have engineered systems by expressing a chalcomycin synthase genes along with the TYLS system. This points to the potential of coexpressing homologous PKS systems for the production of new products, however the high specificity of protein-protein interactions limits chimeric PKS engineering.
Biosynthesis reactions that interchange the KR domain from TYLS with the KR domain from DEBS lead to products with different stereochemistry. Other studies have elucidated the stereospecificity of the DEBS DH domain by co-incubating the DEBS DH domain with the TYLS KR from module 1 and comparing the product to that produced by the DEBS system.


3H domain

In molecular biology, the 3H domain is a protein domain named after its three highly conserved histidine residues. The 3H domain appears to be a smarr molecure-binding domain, based on its occurrence with other domains. Several proteins carrying this domain are transcriptional regulators from the biotin repressor family. The transcription regulator TM1602 from "Thermotoga maritima" is a DNA-binding protein thought to belong to a family of de novo NAD synthesis pathway regulators. TM1602 has an N-terminal DNA-binding domain and a C-terminal 3H regulatory domain. The N-terminal domain appears to bind to the NAD promoter region and repress the "de novo" NAD biosynthesis operon, while the C-terminal 3H domain may bind to nicotinamide, nicotinic acid, or other substrate/products. The 3H domain has a 2-layer alpha/beta sandwich fold.


Toloxatone

Toloxatone (Humoryl) is an antidepressant launched in 1984 in France for the treatment of depression. It acts as a selective reversible inhibitor of MAO-A (RIMA).


Melezitose

Melezitose, also spelled melicitose, is a nonreducing trisaccharide sugar that is produced by many plant sap eating insects, including aphids such as "Cinara pilicornis", by an enzyme reaction. This is beneficial to the insects, as it reduces the stress of osmosis by reducing their own water potential. The melezitose is part of the honeydew which acts as an attractant for ants and also as a food for bees. This is useful to the aphids as they have a symbiotic relationship with ants. Melezitose can be partially hydrolyzed to glucose and turanose the latter of which is an isomer of sucrose.


3beta(or 20alpha)-hydroxysteroid dehydrogenase

In enzymology, a 3-β(or 20-α)-hydroxysteroid dehydrogenase () is an enzyme that catalyzes the chemical reaction
This enzyme possesses the combined activities of the 3-β-hydroxysteroid dehydrogenase/Δ-5-4 isomerase and 20-α-hydroxysteroid dehydrogenase enzymes.


Spinasterol

α-Spinasterol is a stigmastane-type phytosterol found in a variety of plant sources such as spinach, from which it gets its name.
The chemical was recently found in "Gordonia ceylanica", the first time that this chemical was found in the "Gordonia" species.


Gap gene

A gap gene is a type of gene involved in the development of the segmented embryos of some arthropods. Gap genes are defined by the effect of a mutation in that gene, which causes the loss of contiguous body segments, resembling a gap in the normal body plan. Each gap gene, therefore, is necessary for the development of a section of the organism.
Gap genes were first described by Christiane Nüsslein-Volhard and Eric Wieschaus in 1980. They used a genetic screen to identify genes required for embryonic development in the fruit fly "Drosophila melanogaster". They found three genes – "knirps, Krüppel and hunchback" – where mutations caused deletion of particular stretches of segments. Later work identified more gap genes in the "Drosophila" early embryo – "giant", "huckebein" and "tailless". Further gap genes including orthodenticle and buttonhead are required for the development of the "Drosophila" head.
Once the gap genes had been identified at the molecular level it was found that each gap gene is expressed in a band in the early embryo generally correlated with the region that is absent in the mutant. In "Drosophila" the gap genes encode transcription factors, and they directly control the expression of another set of genes involved in segmentation, the pair-rule genes. The gap genes themselves are expressed under the control of maternal effect genes such as "bicoid" and "nanos", and regulate each other to achieve their precise expression patterns.
Gene activation.
Expression of tailless is activated by torso protein in the poles of the embryo. Tailless is also regulated in a complex manner by the maternal-effect gene bicoid.
Both embryonically-transcribed hunchback and maternally-transcribed hunchback are activated by bicoid protein in the anterior and is inhibited in the posterior by nanos protein. Embryonically-transcribed hunchback protein is able to exhibit the same effects on Krüppel and knirps as maternally-transcribed hunchback.
The Krüppel gene is activated when the bicoid protein gradient declines steeply, at the central part of the embryo. Krüppel is regulated by five regulatory proteins: bicoid, hunchback, tailless, knirps and giant. Krüppel is inhibited by high levels of hunchback, high levels of giant, and tailless, which establishes the anterior boundary of Krüppel expression. Krüppel is also inhibited by knirps and activated by low levels of bicoid and low levels of hunchback, which establishes the posterior boundary of Krüppel expression.
The knirps gene appears to be spontaneously activated. It is repressed by hunchback. Hunchback repression thus defines the anterior boundary of the knirps gene. Due to more efficient inhibition of the knirps gene by hunchback, knirps is expressed more posterially in the embryo compared to Krüppel. Tailless protein inhibits knirps gene expression in the posterior part of the embryo, allowing the knirps protein to be expressed only in the central part of the embryo (but more posterior compared to Krüppel). This is due to the ability of both hunchback and tailless to bind to the enhancer regions of knirps.
Mechanism of action.
The gap genes code for transcription factors that regulate the expression of pair-rule genes and homeotic genes by competing for binding to their enhancer regions.
It has been demonstrated that gap gene expression in the "Drosophila" blastoderm exhibit a property called as canalization, a property of developing organisms to produce a consistent phenotype despite variations in genotype or environment. It has been proposed that canalization is a manifestation of cross regulation of gap genes expression and can be understood as arising from the actions of attractors in the gap gene dynamical system.


Delta8-fatty-acid desaturase

Delta8-fatty-acid desaturase (, "Delta8-sphingolipid desaturase", "EFD1", "BoDES8", "SLD", "Delta8 fatty acid desaturase", "Delta8-desaturase") is an enzyme with systematic name "phytosphinganine,hydrogen donor:oxygen Delta8-oxidoreductase". This enzyme catalyses the following chemical reaction
This enzyme, which has been found mainly in plants, introduces a double bond at Delta8 of C18 and C20 fatty acids.


Nidogen-2

Nidogen-2, also known as osteonidogen, is a basal lamina protein of the nidogen family. It was the second nidogen to be described after nidogen-1 (entactin). Both play key roles during late embryonic development. In humans it is encoded by the "NID2" gene.


Beta bulge loop

Beta bulge loops are commonly occurring motifs in proteins and polypeptides consisting of five to six amino acids. There are two types: type 1, which is a pentapeptide; and type 2, with six amino acids. They are regarded as a type of beta bulge, and have the alternative name of type G1 beta bulge. Compared to other beta bulges, beta bulge loops give rise to chain reversal such that they often occur at the loop ends of beta hairpins; hairpins of this sort can be described as 3:5 (for a type 1 β bulge loop) or 4:6 (for type 2). Two websites are available for finding and examining β bulge loops in proteins, Motivated Proteins: and PDBeMotif: .
Type I beta bulge loops have two characteristic inter-main-chain hydrogen bonds. One is between the CO of residue i and the NH of residue i+3 (a β-turn); the other is between the CO of residue i+4 and the NH of residue i.
Type 2 beta bulge loops have two characteristic inter-main-chain hydrogen bonds. One is between the CO of residue i and the NH of residue i+4 (an α-turn); the other is between the CO of residue i+5 and the NH of residue i.
Beta bulge loops often have an aspartate, asparagine, serine or threonine at residue i, together with a nest (protein structural motif) at residues i+2 to i+4 (type 1) or residues i+3 to i+5 (type 2), with the side chain oxygen binding to the main chain NH groups of the nest. Site-directed mutagenesis of asx residues within a protein's β bulge loops has been described, showing that the side chain of an asx residue at various alternative positions within a β bulge loop binds to the nest and thereby helps stabilize the loop.


3-mercaptopyruvate sulfurtransferase

In enzymology, a 3-mercaptopyruvate sulfurtransferase () is an enzyme that catalyzes the chemical reactions of 3-mercaptopyruvate. This enzyme belongs to the family of transferases, specifically the sulfurtransferases. This enzyme participates in cysteine metabolism. It is encoded by the "MPST" gene.
The enzyme is of interest because it provides a pathway for detoxification of cyanide, especially since it occurs widely in the cytosol and distributed broadly.
Nomenclature.
The systematic name of this enzyme class is 3-mercaptopyruvate:cyanide sulfurtransferase. This enzyme is also called beta-mercaptopyruvate sulfurtransferase and in the older literature, human liver rhodanese.
Structure.
Gene.
The "MPST" gene lies on the chromosome location of 22q12.3 and consists of 6 exons. Alternatively spliced transcript variants encoding the same protein have been identified.
Protein.
The encoded cytoplasmic protein is a member of the rhodanese family but is not rhodanese itself, which is found only in mitochondria. MPST protein consists of 317 amino acid residues and weighs 35250Da. MPST contains two rhodanese domains with similar secondary structures suggesting a common evolutionary origin. The catalytic cysteine residue only exists in the C-terminal rhodanese domain. The protein can function as a monomer or as a disulfide-linked homodimer.
Function and mechanism.
The biological function of MPST remains unclear. It may be involved in cyanide detoxification, biosynthesis of thiosulfate, production of the signalling molecule hydrogen sulfide, or the degradation of cysteine.
MPST reacts with 3-MP to convert a cysteinyl residue to the persulfide-containing intermediate:
The persulfide group is labile, and can transfer S to other groups, such as cyanide. It is also susceptible to reduction to release hydrogen sulfide.
H2S is produced from l-cysteine by cystathionine-γ-lyase (CSE) and MPST. l-cysteine-dependent production of H2S by MPST is a two-step reaction. In the first step, cysteine transaminase converts l-cysteine along with α-ketoglutarate into 3-mercaptopyruvate (3-MP). Subsequently, MPST converts 3-MP into H2S. MPST catalyzes the transfer of a sulfur atom from mercaptopyruvate to sulfur acceptors like cyanides or thiol compounds. Thus it is also considered to participate in cysteine degradation. MPST generates H2S in coronary artery, mediating its effects through direct modulation of NO, namely vasodilation. This has important implications for H2S-based therapy in healthy and diseased coronary arteries.
Biological significance.
MPST is expressed in a number of tissues, including kidney, liver, lung, heart, muscle, spleen, and brain.
3-Mercaptopyruvate (3-MP), along with α-ketoglutarate, is derived from cysteine by the action of an aminotransferase. Thus MPST may participate in cysteine degradation.
Biomedical.
Hydrogen sulfide production.
H2S is produced from MPST (as well as by cystathionine-γ-lyase). MPST generates H2S in coronary artery, mediating its effects through direct modulation of NO, namely vasodilation. This has important implications for H2S-based therapy in healthy and diseased coronary arteries.
Mercaptolactate-cysteine disulfiduria.
Deficiency in MPST has been found related to mercaptolactate-cysteine disulfiduria, a rare inheritable disorder associated with oversecretion of mercaptolactate-cysteine disulfide in urine. Immunoreactivity for MPST was detected in malignant uroepithelium and muscular layer of bladder cancer samples. Protein levels and catalytic activities of MPST increased with the increase of malignant degrees in human bladder tissues and human urothelial cell carcinoma of bladder (UCB) cell lines and this may promote the application of MPST novel enzymes to UCB diagnosis or treatment.


Adenosine-tetraphosphatase

In enzymology, an adenosine-tetraphosphatase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are adenosine 5'-tetraphosphate and H2O, whereas its two products are ATP and phosphate.
This enzyme belongs to the family of hydrolases, specifically those acting on acid anhydrides in phosphorus-containing anhydrides. The systematic name of this enzyme class is adenosine-tetraphosphate phosphohydrolase. This enzyme participates in purine metabolism.
Structural studies.
As of late 2007, only one structure has been solved for this class of enzymes, with the PDB accession code .


Isofraxidin-7-glucoside

Isofraxidin-7-glucoside (calycanthoside) is a constituent of "Eleutherococcus senticosus" that is classified as a coumarin. It is a glucoside of isofraxidin.


Pyruvate carboxylase

Pyruvate carboxylase (PC) encoded by the gene PC is an enzyme of the ligase class that catalyzes (depending on the species) the physiologically irreversible carboxylation of pyruvate to form oxaloacetate (OAA).
The reaction it catalyzes is:
It is an important anaplerotic reaction that creates oxaloacetate from pyruvate. The enzyme is a mitochondrial protein containing a biotin prosthetic group, requiring magnesium or manganese and acetyl CoA.
Pyruvate carboxylase was first discovered in 1959 at Case Western Reserve University by M. F. Utter and D. B. Keech. Since then it has been found in a wide variety of prokaryotes and eukaryotes including fungi, bacteria, plants, and animals. In mammals, PC plays a crucial role in gluconeogenesis and lipogenesis, in the biosynthesis of neurotransmitters, and in glucose-induced insulin secretion by pancreatic islets. Oxaloacetate produced by PC is an important intermediate, which is used in these biosynthetic pathways. In mammals, PC is expressed in a tissue-specific manner, with its activity found to be highest in the liver and kidney (gluconeogenic tissues), in adipose tissue and lactating mammary gland (lipogenic tissues), and in pancreatic islets. Activity is moderate in brain, heart and adrenal gland, and least in white blood cells and skin fibroblasts.
Structure.
Structural studies of PC have been conducted by electron microscopy, by limited proteolysis, and by cloning and gasa sequencing of genes and cDNA encoding the enzyme. Most well characterized forms of active PC consist of four identical subunits arranged in a tetrahedron-like structure. Each subunit contains a single biotin moiety acting as a swinging arm to transport carbon dioxide to the catalytic site that is formed at the interface between adjacent monomers. Each subunit of the functional tetramer contains four domains: the biotin carboxylation (BC) domain, the transcarboxylation (CT) domain, the biotin carboxyl carrier (BCCP) domain and the recently termed PC tetramerization (PT) domain. From the two most complete crystal structures available, an asymmetric and symmetric form of the protein have been visualized. The "Staphylococcus aureus" tetramer in complex with the activator coenzyme A is highly symmetric, possessing 222 symmetry, and has been confirmed by cryo-EM studies. In contrast the "Rhizobium etli", tetramer in complex with ethyl-CoA, a non-hydrolyzable analog of acetyl-CoA, possesses only one line of symmetry.
Pyruvate carboxylase uses a covalently attached biotin cofactor which is used to catalyze the ATP– dependent carboxylation of pyruvate to oxaloacetate in two steps. Biotin is initially carboxylated at the BC active site by ATP and bicarbonate. The carboxyl group is subsequently transferred by carboxybiotin to a second active site in the CT domain, where pyruvate is carboxylated to generate oxaloacetate. The BCCP domain transfers the tethered cofactor between the two remote active sites. The allosteric binding site in PC offers a target for modifiers of activity that may be useful in the treatment of obesity or type II diabetes, and the mechanistic insights gained from the complete structural description of RePC (R. etli) permit detailed investigations into the individual catalytic and regulatory sites of the enzyme.
Reaction mechanism.
The reaction mechanism can be subdivided into two partial reactions (see figure to the right). In the first reaction, ATP is carboxylated to produce carbonic phosphoric anhydride [−O(−O)P(=O)O–C(=O)O−] which in turn carboxylates a biotin cofactor that is covalently attached to a lysine residue of the BCCP domain. Carbonic phosphoric anhydride decomposes into carbon dioxide and phosphate prior to attack by the enzyme linked biotin molecule. In most species, this reaction requires acetyl-CoA as an allosteric activator binding to the PT domain. In the second reaction, occurring in the CT domain of an adjacent monomer, carbon dioxide is transferred to the acceptor molecule, pyruvate, to form oxaloacetate. The reaction proceeds via the removal of a proton from pyruvate, by an as yet unidentified active site residue, to generate an enolate intermediate. The enolate intermediate then attacks CO2 transiently released from the enzyme linked biotin molecule. The resultant oxaloacetate is released. The biotin molecule is protonated by the aforementioned active site residue and released from the active site of the CT domain to be recarboxylated. The major regulator of enzyme activity, acetyl-CoA, stimulates the cleavage of ATP in the first partial reaction and also it has been shown to induce a conformational change in the tetrameric structure of the enzyme.
Function.
During gluconeogenesis, pyruvate carboxylase is involved in the synthesis of phosphoenolpyruvate (PEP) from pyruvate. Pyruvate is first converted by pyruvate carboxylase to oxaloacetate (OAA) in the mitochondrion requiring hydrolysis of one molecule of ATP. The OAA is then decarboxylated and simultaneously phosphorylated, which is catalyzed by one of two isoforms of phosphoenolpyruvate carboxykinase (PEPCK) either in the cytosol or in the mitochondria to produce PEP. Under ordinary gluconeogenic conditions, OAA is converted into PEP by mitochondrial PEPCK; the resultant PEP is then transported out of the mitochondrial matrix by an anion transporter carrier system, and converted into glucose by cytosolic gluconeogenic enzymes. However, during starvation when cytosolic NADH concentration is low and mitochrondrial NADH levels are high oxaloacetate can be used as a shuttle of reducing equivalents. As such OAA is converted into malate by mitochondrial malate dehydrogenase (MDH). After export into the cytosol, malate is converted back into OAA, with concomitant reduction of NAD+; OAA is subsequently converted to PEP which is available for gluconeogenesis in the cytosol along with the transported reducing equivalent NADH.
Very high levels of PC activity, together with high activities of other gluconeogenic enzymes including PEPCK, fructose-1,6-bisphosphatase and glucose-6-phosphatase in liver and kidney cortex, suggest that a primary role of PC is to participate in gluconeogenesis in these organs. During fasting or starvation when endogenous glucose is required for certain tissues (brain, white blood cells and kidney medulla), expression of PC and other gluconeogenic enzymes is elevated. In rats and mice, alteration of nutrition status has been shown to affect hepatic PC activity. Fasting promotes hepatic glucose production sustained by an increased pyruvate flux, and increases in PC activity and protein concentration; diabetes similarly increases gluconeogenesis through enhanced uptake of substrate and increased flux through liver PC in mice and rats. Similarly to other gluconeogenic enzymes, PC is positively regulated by glucagon and glucocorticoids while negatively regulated by insulin. Further supporting the key role of PC in gluconeogenesis, in dairy cattle, which have hexose absorption ability at adequate nutrition levels, PC and the associated gluconeogenic enzyme PEPCK are markedly elevated during the transition to lactation in proposed support of lactose synthesis for milk production.
Aside from the role of PC in gluconeogenesis, PC serves an anaplerotic role (an enzyme catalyzed reaction that can replenish the supply of intermediates in the citric acid cycle) for the tricarboxylic acid cycle (essential to provide oxaloacetate), when intermediates are removed for different biosynthetic purposes.
Clinical significance.
As a crossroad between carbohydrate and lipid metabolism, pyruvate carboxylase expression in gluconeogenic tissues, adipose tissues and pancreatic islets must be coordinated. In conditions of over nutrition, PC levels are increased in pancreatic β-cells to increase pyruvate cycling in response to chronically elevated levels of glucose. In contrast, PC enzyme levels in the liver are decreased by insulin; during periods of overnutrition adipocyte tissue is expanded with extreme expression of PC and other lipogenic enzymes. Hepatic control of glucose levels is still regulated in an over nutrition situation, but in obesity induced type 2 diabetes the regulation of peripheral glucose levels is no longer under regulation of insulin.
In type 2 diabetic rats, chronic exposure of β-cells to glucose due to peripheral insulin resistance results in decreased PC enzyme activity and decreased pyruvate cycling The continued overproduction of glucose by hepatocytes causes dramatic alteration of gene expression in β-cells with large increases in normally suppressed genes, and equivalent decreases in expression of mRNA for insulin, ion pumps necessary for insulin secretion, and metabolic enzymes related to insulin secretion, including pyruvate carboxylase Concurrently adipose tissue develops insulin resistance causing accumulation of triaglycerols and non-esterified fatty acids in circulation; these not only further impairing β-cell function, but also further decreasing PC expression. These changes result in the decline of the β-cell phenotype in decompensated diabetes.
A deficiency of pyruvate carboxylase can cause lactic acidosis as a result of lactate build up. Normally, excess pyruvate is shunted into gluconeogenesis via conversion of pyruvate into oxaloacetate, but because of the enzyme deficiency, excess pyruvate is converted into lactate instead. As a key role of gluconeogenesis is in the maintenance of blood sugar, deficiency of pyruvate carboxylase can also lead to hypoglycemia.


Cyclic nucleotide-binding domain

Proteins that bind cyclic nucleotides (cAMP or cGMP) share a structural domain of about 120 residues. The best studied of these proteins is the prokaryotic catabolite gene activator (also known as the cAMP receptor protein) (gene crp) where such a domain is known to be composed of three alpha-helices and a distinctive eight-stranded, antiparallel beta-barrel structure. There are six invariant amino acids in this domain, three of which are glycine residues that are thought to be essential for maintenance of the structural integrity of the beta-barrel. cAMP- and cGMP-dependent protein kinases (cAPK and cGPK) contain two tandem copies of the cyclic nucleotide-binding domain. The cAPK's are composed of two different subunits, a catalytic chain and a regulatory chain, which contains both copies of the domain. The cGPK's are single chain enzymes that include the two copies of the domain in their N-terminal section. Vertebrate cyclic nucleotide-gated ion-channels also contain this domain. Two such cations channels have been fully characterized, one is found in rod cells where it plays a role in visual signal
transduction.
Human proteins containing this domain.
CNBD1; CNGA1; CNGA2; CNGA3; CNGB1; CNGB3; HCN1;
HCN2; HCN3; HCN4; KCNH1; KCNH2; KCNH3; KCNH4; KCNH5;
KCNH6; KCNH7; KCNH8; PNPLA6; PNPLA7; PRKAR1A; PRKAR1B; PRKAR2A;
PRKAR2B; PRKG1; PRKG2; RAPGEF2; RAPGEF3; RAPGEF4; RAPGEF6; RCNC2;
SLC9A10; SLC9A11;


Neural cell adhesion molecule

Neural cell adhesion molecule (NCAM), also called CD56, is a homophilic binding glycoprotein expressed on the surface of neurons, glia and skeletal muscle. Although CD56 is often considered a marker of neural lineage commitment due to its discovery site, CD56 expression is also found in, among others, the hematopoietic system. Here, the expression of CD56 is mostly associated with, but not limited to, natural killer cells. CD56 has been detected on other lymphoid cells, including gamma delta (γδ) Τ cells and activated CD8+ T cells, as well as on dendritic cells. NCAM has been implicated as having a role in cell–cell adhesion, neurite outgrowth, synaptic plasticity, and learning and memory.
Forms, domains and homophilic binding.
NCAM is a glycoprotein of Immunoglobulin (Ig) superfamily.
At least 27 alternatively spliced NCAM mRNAs are produced, giving a wide diversity of NCAM isoforms. The three main isoforms of NCAM vary only in their cytoplasmic domain:
The extracellular domain of NCAM consists of five immunoglobulin-like (Ig) domains followed by two fibronectin type III (FNIII) domains. The different domains of NCAM have been shown to have different roles, with the Ig domains being involved in homophilic binding to NCAM, and the FNIII domains being involved signalling leading to neurite outgrowth.
Homophilic binding occurs between NCAM molecules on opposing surfaces ("trans-") and NCAM molecules on the same surface ("cis-")1. There is much controversy as to how exactly NCAM homophilic binding is arranged both in trans- and "cis-". Current models suggest "trans-" homophilic binding occurs between two NCAM molecules binding antiparallel between all five Ig domains or just IgI and IgII. "cis-" homophilic binding is thought to occur by interactions between both IgI and IgII, and IgI and IgIII, forming a higher order NCAM multimer. Both "cis-" and "trans-" NCAM homophilic binding have been shown to be important in NCAM “activation” leading to neurite outgrowth.
Minor exons.
Another layer of complexity is created by the insertion of other "minor" exons in the NCAM transcript. The two most notable are:
Posttranslational modification.
NCAM exhibits glycoforms as it can be posttranslationally modified by the addition of polysialic acid (PSA) to the fifth Ig domain, which is thought to abrogate its homophilic binding properties and can lead to reduced cell adhesion important in cell migration and invasion. PSA has been shown to be critical in learning and memory. Removal of PSA from NCAM by the enzyme endoneuraminidase (EndoN) has been shown to abolish long-term potentiation (LTP) and long-term depression (LTD).
Expression in normal cells.
The neural cell adhesion molecule NCAM1 appears on early embryonic cells and is important in the formation of cell collectives and their boundaries at sites of morphogenesis.
Later in development, NCAM1 (CD56) expression is found on various differentiated tissues and is a major CAM mediating adhesion among neurons and between neurons and muscle.
Function.
NCAM is thought to signal to induce neurite outgrowth via the fibroblast growth factor receptor (FGFR) and act upon the p59Fyn signaling pathway.
In nerves, NCAM1 regulates homophilic (like-like) interactions between neurons and between neurons and muscle; it associates with fibroblast growth factor receptor (FGFR) and stimulates tyrosine kinase activity of receptor to induce neurite outgrowth. When neural crest cells stop making N-CAM and N-cadherin, and start displaying integrin receptors, cells separate and migrate.
During hematopoiesis, CD56 is the prototypic marker of NK cells, also present on subset of CD4+ T cells and CD8+ T cells.
In cell adhesion, CD56 contributes to cell-cell adhesion or cell-matrix adhesion during embryonic development.
Pathology.
In anatomic pathology, pathologists make use of CD56 immunohistochemistry to recognize certain tumors.
Cancer.
A member of the NCAM superfamily, NCAM2 gene has been observed progressively downregulated in human papillomavirus-positive neoplastic keratinocytes derived from uterine cervical preneoplastic lesions at different levels of malignancy. For this reason, NCAM2 is likely to be associated with tumorigenesis and may be a potential prognostic marker for uterine cervical preneoplastic lesions progression.
Alzheimer's disease.
NCAM2 is found in lower levels in hippocampal synapses of Alzheimer's disease sufferers and is found to be broken down by beta-amyloid.
Anti-NCAM therapy.
NCAM has been used as a target molecule for experimental antibody-based immunotherapy. Successful radio-immunolocalisation of metastases was demonstrated after giving injections of NCAM-binding 123J-UJ13a or 131J-UJ13a radio-immunoconjugates to children with neuroblastoma. Patients with small cell lung cancer were treated with the anti-NCAM immunotoxine huN901-DM1 in two different clinical studies, revealing acceptable toxicity and signs of clinical response.


Estrin (compound)

Estrin (American English), or oestrin (British English), also known as estra-1,3,5(10)-triene, is an estrane steroid. It is dehydrogenated estrane with double bonds specifically at the C1, C3, and C5(10) positions. Estrin is a parent structure of the estrogen steroid hormones estradiol, estrone, and estriol, which have also been known as dihydroxyestrin, ketohydroxyestrin, and trihydroxyestrin, respectively.
Unlike its estrogen derivatives, estrin itself possesses minimal estrogenic activity, as hydroxyl and/or keto substitutions at the C3 and C17 positions are critical for high binding affinity to the estrogen receptors. Estrin has been found to be on the order of 1,000-fold less potent than estradiol in inducing estrogenic responses "in vitro". In addition to estrin, estratrien-17β-ol, which lacks the 3-hydroxyl group of estradiol, and 3-hydroxyestratriene, which lacks the 17β-hydroxyl group of estradiol, both have measurable affinity for the estrogen receptor and are able to activate the receptor and induce progesterone receptor expression.
The term "estrin" is also a synonym for "estrogen". It was coined by Sir Alan S. Parkes and C. W. Bellerby in 1926 to describe the hormone secreted from the ovaries that induces estrus in animals (i.e., estrogen).


E. coli nitroreductase

"E. coli" nitroreductase is a flavoprotein found in the bacteria "Escherichia coli". It catalyses the reduction of nitro groups in a wide range of substrates to produce the corresponding hydroxylamine. Although its role "in vivo" is unclear, it has been identified as useful in the metabolism of a number of prodrugs in anti-cancer gene therapy.


Factor V

Factor V (pronounced factor five) is a protein of the coagulation system, rarely referred to as proaccelerin or labile factor. In contrast to most other coagulation factors, it is not enzymatically active but functions as a cofactor. Deficiency leads to predisposition for hemorrhage, while some mutations (most notably factor V Leiden) predispose for thrombosis.
Genetics.
The gene for factor V is located on the first chromosome (1q24). It is genomically related to the family of multicopper oxidases, and is homologous to coagulation factor VIII. The gene spans 70 kb, consists of 25 exons, and the resulting protein has a relative molecular mass of approximately 330kDa.
Structure.
Factor V protein consists of six domains: A1-A2-B-A3-C1-C2.
The A domains are homologous to the A domains of the copper-binding protein ceruloplasmin, and form a triangular as in that protein. A copper ion is bound in the A1-A3 interface, and A3 interacts with the plasma.
The C domains belong to the phospholipid-binding discoidin domain family (unrelated to C2 domain), and the C2 domain mediates membrane binding. The B domain C-terminus acts as a cofactor for the anticoagulant protein C activation by protein S.
Activation of factor V to factor Va is done by cleavage and release of the B domain, after which the protein no longer assists in activating protein C. The protein is now divided to a heavy chain, consisting of the A1-A2 domains, and a light chain, consisting of the A3-C1-C2 domains. Both form non-covalently a complex in a calcium-dependent manner. This complex is the pro-coagulant factor Va.
Physiology.
Factor V synthesis occurs in the liver, principally. The molecule circulates in plasma as a single-chain molecule with a plasma half-life of 12–36 hours.
Factor V is able to bind to activated platelets and is activated by thrombin. On activation, factor V is spliced in two chains (heavy and light chain with molecular masses of 110000 and 73000, respectively) which are noncovalently bound to each other by calcium. The thereby activated factor V (now called FVa) is a cofactor of the prothrombinase complex: The activated factor X (FXa) enzyme requires calcium and activated factor V (FVa) to convert prothrombin to thrombin on the cell surface membrane.
Factor Va is degraded by activated protein C, one of the principal physiological inhibitors of coagulation. In the presence of thrombomodulin, thrombin acts to decrease clotting by activating protein C; therefore, the concentration and action of protein C are important determinants in the negative feedback loop through which thrombin limits its own activation.
Role in disease.
Various hereditary disorders of factor V are known. Deficiency is associated with a rare mild form of hemophilia (termed parahemophilia or Owren parahemophilia), the incidence of which is about 1:1,000,000. It inherits in an autosomal recessive fashion.
Other mutations of factor V are associated with venous thrombosis. They are the most common hereditary causes for thrombophilia (a tendency to form blood clots). The most common one of these, factor V Leiden, is due to the replacement of an arginine residue with glutamine at amino acid position 506 (R506Q). All prothrombotic factor V mutations (factor V Leiden, factor V Cambridge, factor V Hong Kong) make it resistant to cleavage by activated protein C ("APC resistance"). It therefore remains active and increases the rate of thrombin generation.
History.
Until the discovery of factor V, coagulation was regarded as a product of four factors: calcium (IV) and thrombokinase (III) together acting on prothrombin (II) to produce fibrinogen (I); this model had been outlined by Paul Morawitz in 1905.
The suggestion that an additional factor might exist was made by Dr Paul Owren (1905–1990), a Norwegian physician, during his investigations into the bleeding tendency of a lady called Mary (1914–2002). She had suffered from nosebleeds and menorrhagia (excessive menstrual blood loss) for most her life, and was found to have a prolonged prothrombin time, suggesting either vitamin K deficiency or chronic liver disease leading to prothrombin deficiency. However, neither were the case, and Owren demonstrated this by correcting the abnormality with plasma from which prothrombin had been removed. Using Mary's serum as index, he found that the "missing" factor, which he labeled V (I–IV having been used in Morawitz' model), had particular characteristics. Most investigations were performed during the Second World War, and while Owren published his results in Norway in 1944, he could not publish them internationally until the war was over. They appeared finally in "The Lancet" in 1947.
The possibility of an extra coagulation factor was initially resisted on methodological grounds by Drs Armand Quick and Walter Seegers, both world authorities in coagulation. Confirmatory studies from other groups led to their final approval several years later.
Owren initially felt that factor V (labile factor or proaccelerin) activated another factor, which he named VI. VI was the factor that accelerated the conversion from prothrombin to thrombin. It was later discovered that factor V was "converted" (activated) by thrombin itself, and later still that factor VI was simply the activated form of factor V.
The complete amino acid sequence of the protein was published in 1987. In 1994 factor V Leiden, resistant to inactivation by protein C, was described; this abnormality is the most common genetic cause for thrombosis.
Interactions.
Factor V has been shown to interact with Protein S.