Factor X

Factor X, also known by the eponym Stuart–Prower factor, is an enzyme () of the coagulation cascade. It is a serine endopeptidase (protease group S1, PA clan). Factor X is synthesized in the liver and requires vitamin K for its synthesis.
Factor X is activated, by hydrolysis, into factor Xa by both factor IX (with its cofactor, factor VIII in a complex known as "intrinsic Tenase") and factor VII with its cofactor, tissue factor (a complex known as "extrinsic Tenase "). It is therefore the first member of the "final common pathway" or "thrombin pathway".
It acts by cleaving prothrombin in two places (an arg-thr and then an arg-ile bond), which yields the active thrombin. This process is optimized when factor Xa is complexed with activated co-factor V in the prothrombinase complex.
Factor Xa is inactivated by protein Z-dependent protease inhibitor (ZPI), a serine protease inhibitor (serpin). The affinity of this protein for factor Xa is increased 1000-fold by the presence of protein Z, while it does not require protein Z for inactivation of factor XI. Defects in protein Z lead to increased factor Xa activity and a propensity for thrombosis.
The half life of factor X is 40–45 hours.
Structure.
The first crystal structure of human factor Xa was deposited in May 1993. To date, 191 crystal structures of factor Xa with various inhibitors have been deposited in the protein data bank. The active site of factor Xa is divided into four subpockets as S1, S2, S3 and S4. The S1 subpocket determines the major component of selectivity and binding. The S2 sub-pocket is small, shallow and not well defined. It merges with the S4 subpocket. The S3 sub-pocket is located on the rim of the S1 pocket and is quite exposed to solvent. The S4 sub-pocket has three ligand binding domains: the "hydrophobic box", the "cationic hole" and the water site. Factor Xa inhibitors generally bind in an L-shaped conformation, where one group of the ligand occupies the anionic S1 pocket lined by residues Asp189, Ser195, and Tyr228, and another group of the ligand occupies the aromatic S4 pocket lined by residues Tyr99, Phe174, and Trp215. Typically, a fairly rigid linker group bridges these two interaction sites.
Genetics.
The human factor X gene is located on chromosome 13 (13q34).
Role in disease.
Inborn deficiency of factor X is very rare (1:1,000,000), and may present with epistaxis (nosebleeds), hemarthrosis (bleeding into joints) and gastrointestinal blood loss. Apart from congenital deficiency, low factor X levels may occur occasionally in a number of disease states. For example, factor X deficiency may be seen in amyloidosis, where factor X is adsorbed to the amyloid fibrils in the vasculature.
Deficiency of vitamin K or antagonism by warfarin (or similar medication) leads to the production of an inactive factor X. In warfarin therapy, this is desirable to prevent thrombosis. As of late 2007, four out of five emerging anti-coagulation therapeutics targeted this enzyme.
Inhibiting Factor Xa would offer an alternate method for anticoagulation. Direct Xa inhibitors are popular anticoagulants.
Polymorphisms in Factor X have been associated with an increased prevalence in bacterial infections, suggesting a possible role directly regulating the immune response to bacterial pathogens.
Therapeutic use.
Factor X is part of fresh frozen plasma and the prothrombinase complex. There are two commercially available Factor X concentrates: "Factor X P Behring" manufactured by CSL Behring, and high purity Factor X Coagadex produced by Bio Products Laboratory and approved for use in the United States by the FDA in October 2015, and in the EU in March 2016, after earlier acceptance by CHMP and COMP.
Kcentra, manufactured by CSL Behring, is a concentrate containing coagulation Factors II, VII, IX and X, and antithrombotic Proteins C and S.
Use in biochemistry.
The factor Xa protease can be used in biochemistry to cleave off protein tags that improve expression or purification of a protein of interest. Its preferred cleavage site (after the arginine in the sequence Ile-Glu/Asp-Gly-Arg, IEGR or IDGR) can easily be engineered between a tag sequence and the protein of interest. After expression and purification, the tag is then proteolytically removed by factor Xa.
Factor Xa.
Factor Xa is the activated form of the coagulation factor X, known eponymously as Stuart-Prower factor. Factor X is an enzyme, a serine endopeptidase, which plays a key role at several stages of the coagulation system. Factor X is synthesized in the liver. The most commonly used anticoagulants in clinical practice, warfarin and the heparin series of anticoagulants and fondaparinux, act to inhibit the action of Factor Xa in various degrees.
Traditional models of coagulation developed in the 1960s envisaged two separate cascades, the extrinsic (tissue factor (TF)) pathway and the intrinsic pathway. These pathways converge to a common point, the formation of the Factor Xa/Va complex which together with calcium and bound on a phospholipids surface, generate thrombin (Factor IIa) from prothrombin (Factor II).
A new model, the cell-based model of anticoagulation appears to explain more fully the steps in coagulation. This model has three stages: 1) initiation of coagulation on TF-bearing cells, 2) amplification of the procoagulant signal by thrombin generated on the TF-bearing cell and 3) propagation of thrombin generation on the platelet surface. Factor Xa plays a key role in all three of these stages.
In stage 1, Factor VII binds to the transmembrane protein TF on the surface of cells and is converted to Factor VIIa. The result is a Factor VIIa/TF complex, which catalyzes the activation of Factor X and Factor IX. Factor Xa formed on the surface of the TF-bearing cell interacts with Factor Va to form the prothrombinase complex which generates small amounts of thrombin on the surface of TF-bearing cells.
In stage 2, the amplification stage, if enough thrombin has been generated, then activation of platelets and platelet-associated cofactors occurs.
In stage 3, thrombin generation, Factor XIa activates free Factor IX on the surface of activated platelets. The activated Factor IXa with Factor VIIIa forms the "tenase" complex. This "tenase" complex activates more Factor X, which in turn forms new prothrombinase complexes with Factor Va. Factor Xa is the prime component of the prothrombinase complex which converts large amounts of prothrombin—the "thrombin burst". Each molecule of Factor Xa can generate 1000 molecules of thrombin. This large burst of thrombin is responsible for fibrin polymerization to form a thrombus.
Factor Xa also plays a role in other biological processes that are not directly related to coagulation, like wound healing, tissue remodelling, inflammation, angiogenesis and atherosclerosis.
Inhibition of the synthesis or activity of Factor X is the mechanism of action for many anticoagulants in use today. Warfarin, a synthetic derivative of coumarin, is the most widely used oral anticoagulant in the US. In some European countries, other coumarin derivatives (phenprocoumon and acenocoumarol) are used. These agents known as vitamin K antagonists (VKA), inhibit the vitamin K-dependent carboxylation of Factors II (prothrombin), VII, IX, X in the hepatocyte. This carboxylation after the translation is essential for the physiological activity.
Heparin (unfractionated heparin) and its derivatives low molecular weight heparin (LMWH) bind to a plasma cofactor, antithrombin (AT) to inactivate several coagulation factors IIa, Xa, XIa and XIIa. The affinity of unfractionated heparin and the various LMWHs for Factor Xa varies considerably. The efficacy of heparin-based anticoagulants increases as selectivity for Factor Xa increases. LMWH shows increased inactivation of Factor Xa compared to unfractionated heparin, and fondaparinux, an agent based on the critical pentasacharide sequence of heparin, shows more selectivity than LMWH. This inactivation of Factor Xa by heparins is termed "indirect" since it relies on the presence of AT and not a direct interaction with Factor Xa.
Recently a new series of specific, direct acting inhibitors of Factor Xa has been developed. These include the drugs rivaroxaban, apixaban, betrixaban, LY517717, darexaban (YM150), edoxaban and 813893. These agents have several theoretical advantages over current therapy. They may be given orally. They have rapid onset of action. And they may be more effective against Factor Xa in that they inhibit both free Factor Xa and Factor Xa in the prothrombinase complex.
History.
American and British scientists described deficiency of factor X independently in 1953 and 1956, respectively. As with some other coagulation factors, the factor was initially named after these patients, a Mr Rufus Stuart (1921) and a Miss Audrey Prower (1934).
Interactions.
Factor X has been shown to interact with Tissue factor pathway inhibitor.


2-haloalkanoic acid dehalogenase

2-haloalkanoic acid dehalogenase may refer to:


Galactoside

A galactoside is a glycoside containing galactose. The H of the OH group on carbon-1 of galactose is replaced by an organic moiety.
Depending on whether the glycosidic bond lies "above" or "below" the plane of the galactose molecule, galactosides are classified as α-galactosides or β-galactosides.
A β-galactoside is a type of galactoside in which the glycosidic bond lies above the plane of the galactose residue. The most commonly recognized and used β-galactoside in biochemistry is lactose. However, other chemicals, such as ONPG, are known, but these are typically synthesized for biochemical assays. Enzymes that break the β-galactoside glycosidic bond are called β-galactosidases.


Antifungal protein family

The antifungal protein family is a protein family, with members sharing a structure consisting of five antiparallel beta strands which are highly twisted creating a beta barrel stabilised by four internal disulphide bridges. A cationic site adjacent to a hydrophobic stretch on the protein surface may constitute a phospholipid binding site.
Human epithelium produce antifungal proteins. The proteins kill fungi by inducing apoptosis and/or forming pores on the cell membrane.


Large neutral amino acids transporter small subunit 3

Large neutral amino acids transporter small subunit 3 is a protein that in humans is encoded by the "SLC43A1" gene.


Peptide transporter carbon starvation family

The Peptide Transporter Carbon Starvation (CstA) Family (TC# 2.A.114) is a member of the APC superfamily and consists of proteins from bacteria and archaea. These proteins are of various sizes and topologies. For example, CstA of "E. coli" has 701 aas with 18 putative TMSs. It has a long N-terminal CstA domain and a short C-terminal DUF4161 domain. This protein is encoded by a carbon starvation inducible gene, "cstA", that is under cyclic AMP-CRP control. Circumstantial evidence suggested that it may be a peptide transporter. A "Campylobacter jejuni" homologue has been shown to transport di- and tripeptides (see TC# 2.A.114.1.5). Proteins currently known to belong to the CstA family are listed in the Transporter Classification Database. As of early 2016, there is no crystal structural data available for members of the CstA family on RCSB.


Sodium cellulose phosphate

Sodium cellulose phosphate is a drug used to treat hypercalcemia and hypercalciuria. It has been used to prevent kidney stones.
This compound is an ion-exchange resin that can not be absorbed by the body. However, it can be used to restore the normal intestinal calcium absorption. When it is taken orally, it binds strongly to calcium and inhibits its absorption into the blood. From there, inhibition is caused due to the lower intraluminal calcium levels, which is typically available for absorption.
The mechanism of action of the drug compound can cause a couple of internal effects. Due to the binding activity of the compound with calcium, it will also bind with magnesium and cause a depletion in the body. Working off of this effect, sodium cellulose phosphate will bind with divalent intestinal cations. Because of this binding, more oxalate is available in the blood. This high level of oxalate within the intestine can also be a source of renal stones.
Studies.
In the late 1970s and early 1980s, physiological action studies took place to show how intestinal calcium was absorbed and how it affects other functions within the body. By a study done at the University of Texas, it was found that sodium cellulose phosphate inhibited calcium absorption through three separate techniques.
Through these studies, major conclusions were made regarding the drug compound. Sodium cellulose phosphate reduces the renal excretion of magnesium and calcium. Phosphate and oxalate were both increased in the urine, one due to intestinal hydrolysis and the other to a reduced oxalate complex. Overall, it was noted that the drug could be used to correct the increased calcium absorption that occurs in absorptive hypercalciuria.
Calcibind.
The major US dosage form of sodium cellulose phosphate is Calcibind, which was developed and brought to market by Mission Pharma. Calcibind is a powder dosage form, which comes in small, 2.5 gram doses, individually packaged. The patent for this product was approved on December 28, 1982. The product was eventually removed from the market for reasons that have not been found at this time.
Hypercalcemia.
This condition occurs when there is a raised level of calcium in the blood, compared to the normal range of 2.2–2.6 mmol/L. Typical symptoms of this condition include renal stones, bone pain, abdominal discomfort, and nausea/vomiting. More severe symptoms are associated with psychiatric overtones which are consumed with anxiety, depression, and insomnia.
Hypercalciuria.
Hypercalciuria occurs when there is an elevated level of calcium in the urine. This condition is due to severe calcium reabsorption within the intestines.


Aldohexose


AADAT

Kynurenine/alpha-aminoadipate aminotransferase, mitochondrial, also known as alpha-aminoadipate aminotransferase and kynurenine aminotransferase 2, is a mitochondrial enzyme that in humans is encoded by the "AADAT" gene. It converts alpha-aminoadipate to alpha-ketoadipate. It is also one of the Kynurenine—oxoglutarate transaminases.


Galangin

Galangin is a flavonol, a type of flavonoid.
Occurrence.
Galangin is found in high concentrations in "Alpinia officinarum" (lesser galangal) and "Helichrysum aureonitens". It is also found in the rhizome of "Alpinia galanga" and in propolis.
Biological activities.
Galangin has been shown to have "in vitro" antibacterial and antiviral activity. It also inhibits the growth of breast tumor cells "in vitro".


AP endonuclease

Apurinic/apyrimidinic (AP) endonuclease is an enzyme that is involved in the DNA base excision repair pathway (BER). Its main role in the repair of damaged or mismatched nucleotides in DNA is to create a nick in the phosphodiester backbone of the AP site created when DNA glycosylase removes the damaged base.
There are four types of AP endonucleases that have been classified according to their mechanism and site of incision. Class I AP endonucleases () cleave 3′ to AP sites by a β-lyase mechanism, leaving an unsaturated aldehyde, termed a 3′-(4-hydroxy-5-phospho-2-pentenal) residue, and a 5′-phosphate. Class II AP endonucleases incise DNA 5′ to AP sites by a hydrolytic mechanism, leaving a 3′-hydroxyl and a 5′-deoxyribose phosphate residue. Class III and class IV AP endonucleases also cleave DNA at the phosphate groups 3′ and 5′ to the baseless site, but they generate a 3′-phosphate and a 5′-OH.
Humans have two AP endonucleases, APE1 and APE2. APE1 exhibits robust AP-endonuclease activity, which accounts for >95% of the total cellular activity, and APE1 is considered to be the major AP endonuclease in human cells. Human AP endonuclease (APE1), like most AP endonucleases, is of class II and requires an Mg2+ in its active site in order to carry out its role in base excision repair. The yeast homolog of this enzyme is APN1.
Human AP Endonuclease 2 (APE2), like most AP endonucleases, is also of class II. The exonuclease activity of APE2 is strongly dependent upon metal ions. However, APE2 was more than 5-fold more active in the presence of manganese than of magnesium ions. The conserved domains involved in catalytic activity are located at the N-terminal part of both APE1 and APE2. In addition, the APE2 protein has a C-terminal extension, which is not present in APE1, but can also be found in homologs of human APE2 such as APN2 proteins of "S. cerevisiae" and "S. pombe".
Structure of APE1.
APE1 contains several amino acid residues that enable it to react selectively with AP sites. Three APE1 residues (Arg73, Ala74, and Lys78) contact three consecutive DNA phosphates on the strand opposite the one containing the AP site while Tyr128 and Gly127 span and widen the minor groove, anchoring the DNA for the extreme kinking caused by the interaction between positive residues found in four loops and one α-helix and the negative phosphate groups found in the phosphodiester backbone of DNA.
This extreme kinking forces the baseless portion of DNA into APE1's active site. This active site is bordered by Phe266, Trp280, and Leu282, which pack tightly with the hydrophobic side of the AP site, discriminating against sites that do have bases. The AP site is then further stabilized through hydrogen bonding of the phosphate group 5´ to the AP site with Asn174, Asn212, His309, and the Mg2+ ion while its orphan base partner is stabilized through hydrogen bonding with Met270. The phosphate group 3' to the AP site is stabilized through hydrogen bonding to Arg177. Meanwhile, an Asp210 in the active site, which is made more reactive due to the increase in its pKa (or the negative log of acid dissociation constant) caused through its stabilization through its hydrogen bonding between Asn68 and Asn212, activates the nucleophile that attacks and cleaves the phosphodiester backbone and probably results in the observed maximal APE1 activity at a pH of 7.5.
Mechanism.
The APE1 enzyme creates a nick in the phosphodiester backbone at an abasic (baseless) site through a simple acyl substitution mechanism. First, the Asp210 residue in the active site deprotonates a water molecule, which can then perform a nucleophilic attack on the phosphate group located 5´ to the AP site. Next, electrons from one of the oxygen atom in the phosphate group moves down, kicking off one of the other oxygen to create a free 5´ phosphate group on the AP site and a free 3´-OH on the normal nucleotide, both of which are stabilized by the Mg2+ ion.
Inhibition of APE1.
Known inhibitors of APE1 include 7-nitroindole-2-carboxylic acid (NCA) and lucanthone. Both of these structures possess rings attached to short chains, which appear similar to the deoxyribose sugar ring without a base attached and phosphodiester bond in DNA. Further, both contain many H-bond acceptors which may interact with the H-bond donors in the active site of APE1, causing these inhibitors to stick in the active site and preventing the enzyme from catalyzing other reactions.
APE1 as chemopreventive target.
Because APE1 performs an essential function in DNA base-excision repair pathway, it has become a target for researchers looking for means to prevent cancer cells from surviving chemotherapy. Not only is APE1 needed in and of itself to create the nick in the DNA backbone so that the enzymes involved later in the BER pathway can recognize the AP-site, it also has a redox function that helps activate other enzymes involved in DNA repair. As such, knocking down APE1 could lead to tumor cell sensitivity, thus preventing cancer cells from persisting after chemotherapy.
APE2 enzyme activity.
APE2 has much weaker AP endonuclease activity than APE1, but its 3'-5' exonuclease activity is strong compared with APE1 and it has a fairly strong 3'-phosphodiesterase activity.
The APE2 3' –5' exonuclease activity has the ability to hydrolyze blunt-ended duplex DNA, partial DNA duplexes with a recessed 3' -terminus or a single nucleotide gap containing heteroduplex DNA. The APE2 3'-phosphodiesterase activity can remove modified 3'-termini, such as 3'-phosphoglycolate as well as mismatched nucleotides from the 3' primer end of DNA.
APE2 is required for ATR-Chk1 DNA damage response following oxidative stress.
References.
Molecular graphics images were produced using the UCSF Chimera package from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIH P41 RR-01081).


2,5-dioxopiperazine hydrolase

In enzymology, a 2,5-dioxopiperazine hydrolase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are 2,5-dioxopiperazine and H2O, whereas its product is glycylglycine.
This enzyme belongs to the family of hydrolases, those acting on carbon-nitrogen bonds other than peptide bonds, specifically in cyclic amides. The systematic name of this enzyme class is 2,5-dioxopiperazine amidohydrolase. Other names in common use include cyclo(Gly-Gly) hydrolase, and cyclo(glycylglycine) hydrolase.


Hypophosphatasia

Hypophosphatasia (also called deficiency of alkaline phosphatase or phosphoethanolaminuria and sometimes abbreviated as HPP) is a rare, and sometimes fatal, metabolic bone disease. Clinical symptoms are heterogeneous, ranging from the rapidly fatal, perinatal variant, with profound skeletal hypomineralization, respiratory compromise or vitamin B6 dependent seizures to a milder, progressive osteomalacia later in life. Tissue non-specific alkaline phosphatase (TNSALP) deficiency in osteoblasts and chondrocytes impairs bone mineralization, leading to rickets or osteomalacia. The pathognomonic finding is subnormal serum activity of the TNSALP enzyme, which is caused by one of 388 genetic mutations identified to date, in the gene encoding TNSALP. Genetic inheritance is autosomal recessive for the perinatal and infantile forms but either autosomal recessive or autosomal dominant in the milder forms.
The prevalence of hypophosphatasia is not known; one study estimated the live birth incidence of severe forms to be 1:100,000. and some studies report a higher prevalence of milder disease.
Symptoms and signs.
There is a remarkable variety of symptoms that depends, largely, on the age of the patient at initial presentation, ranging from death "in utero" to relatively mild bone problems with or without dentition symptoms in adult life although neurological and extra-skeletal symptoms are also reported. Although several clinical sub-types of the disease have been characterized, based on the age at which skeletal lesions are discovered, the disease is best understood as a single continuous spectrum of severity.
As the presentation of adult disease is highly variable, incorrect or missed diagnosis may occur. In one study, 19% of patients diagnosed with fibromyalgia had laboratory findings suggestive of possible hypophosphatasia.
One case report details a 35-year old female with low serum ALP and mild pains but no history of rickets, fractures or dental problems. Subsequent evaluation showed osteopenia and renal microcalcifications and an elevation of PEA. The genetic mutations found in this case were previously reported in perinatal, infantile and childhood hypophosphatasia, but not adult hypophosphatasia.
Perinatal hypophosphatasia.
Perinatal hypophosphatasia is the most lethal form. Profound hypomineralization results in caput membranaceum (a soft calvarium), deformed or shortened limbs during gestation and at birth, and rapid death due to respiratory failure. Stillbirth is not uncommon and long-term survival is rare. Neonates who manage to survive suffer increasing respiratory compromise due to softening of the bones (osteomalacia) and underdeveloped lungs (hypoplastic). Ultimately, this leads to respiratory failure. Epilepsy (seizures) can occur and can prove lethal. Regions of developing, unmineralized bone (osteoid) may expand and encroach on the marrow space, resulting in myelophthisic anemia.
In radiographic examinations, perinatal hypophosphatasia can be distinguished from even the most severe forms of osteogenesis imperfecta and congenital dwarfism. Some stillborn skeletons show almost no mineralization; others have marked undermineralization and severe osteomalacia. Occasionally, there can be a complete absence of ossification in one or more vertebrae. In the skull, individual bones may calcify only at their centers. Another unusual radiographic feature is bony spurs that protrude laterally from the shafts of the ulnae and fibulae. Despite the considerable patient-to-patient variability and the diversity of radiographic findings, the X-ray can be considered diagnostic.
Infantile hypophosphatasia.
Infantile hypophosphatasia presents in the first 6 months of life, with the onset of poor feeding and inadequate weight gain. Clinical manifestations of rickets often appear at this time. Although cranial sutures appear to be wide, this reflects hypomineralization of the skull, and there is often “functional” craniosynostosis. If the patient survives infancy, these sutures can permanently fuse. Defects in the chest, such as flail chest resulting from rib fractures, lead to respiratory compromise and pneumonia. Elevated calcium in the blood (hypercalcemia) and urine (hypercalcenuria) are also common, and may explain the renal problems and recurrent vomiting seen is this disease.
Radiographic features in infants are generally less severe than those seen in perinatal hypophosphatasia. In the long bones, there is an abrupt change from a normal appearance in the shaft (diaphysis) to uncalcified regions near the ends (metaphysis), which suggests the occurrence of an abrupt metabolic change. In addition, serial radiography studies suggest that defects in skeletal mineralization (i.e. rickets) persist and become more generalized. Mortality is estimated to be 50% in the first year of life.
Childhood hypophosphatasia.
Hypophosphatasia in childhood has variable clinical expression. As a result of defects in the development of the dental cementum, the deciduous teeth (baby teeth) are often lost before the age of 5. Frequently, the incisors are lost first; occasionally all of the teeth are lost prematurely. Dental radiographs can show the enlarged pulp chambers and root canals that are characteristic of rickets.
Patients may experience delayed walking, a characteristic waddling gait, stiffness and pain, and muscle weakness (especially in the thighs) consistent with nonprogressive myopathy. Typically, radiographs show defects in calcification and characteristic bony defects near the ends of major long bones. Growth retardation, frequent fractures, and low bone density (osteopenia) are common. In severely-affected infants and young children, cranial bones can fuse prematurely, despite the appearance of open fontanels on radiographic studies. The illusion of open fontanels results from hypomineralization of large areas of the calvarium. Premature bony fusion of the cranial sutures may elevate intracranial pressure.
Adult hypophosphatasia.
Adult hypophosphatasia can be associated with rickets, premature loss of deciduous teeth, or early loss of adult dentation followed by relatively good health. Osteomalacia results in painful feet due to poor healing of metatarsal stress fractures. Discomfort in the thighs or hips due to femoral pseudofractures can be distinguished from other types of osteomalacia by their location in the lateral cortices of the femora.
Some patients suffer from calcium pyrophosphate dihydrate crystal depositions with occasional attacks of arthritis (pseudogout), which appears to be the result of elevated endogenous inorganic pyrophosphate (PPi) levels. These patients may also suffer articular cartilage degeneration and pyrophosphate arthropathy. Radiographs reveal pseudofractures in the lateral cortices of the proximal femora and stress fractures, and patients may experience osteopenia, chondrocalcinosis, features of pyrophosphate arthropathy, and calcific periarthritis.
Odontohypophosphatasia.
Odontohypophosphatasia is present when dental disease is the only clinical abnormality, and radiographic and/or histologic studies reveal no evidence of rickets or osteomalacia. Although hereditary leukocyte abnormalities and other disorders usually account for this condition, odontohypophosphatasia may explain some “early-onset periodontitis” cases.
Causes.
Hypophosphatasia is associated with a molecular defect in the gene encoding tissue non-specific alkaline phosphatase (TNSALP). TNSALP is an enzyme that is tethered to the outer surface of osteoblasts and chondrocytes. TNSALP hydrolyzes several substances, including inorganic pyrophosphate (PPi) and pyridoxal 5’-phosphate (PLP), a major form of vitamin B6.
When TSNALP is low, inorganic pyrophosphate (PPi) accumulates outside of cells, and inhibits formation of hydroxyapatite, one of the main components of bone, causing rickets in infants and children and osteomalacia (soft bones) in adults. PLP is the principal form of vitamin B6 and must be dephosphorylated by TNSALP before it can cross the cell membrane. Vitamin B6 deficiency in the brain impairs synthesis of neurotransmitters, which can cause seizures. In some cases, a build-up of calcium pyrophosphate dihydrate (CPPD) crystals in the joint can cause pseudogout.
Genetics.
Perinatal and infantile hypophosphatasia are inherited as autosomal recessive traits with homozygosity or compound heterozygosity for two defective TNSALP alleles. The mode of inheritance for childhood, adult, and odonto forms of hypophosphatasia can be either autosomal dominant or recessive. Autosomal transmission accounts for the fact that the disease affects males and females with equal frequency. Genetic counseling is complicated by the disease’s variable inheritance pattern, and by incomplete penetration of the trait.
Hypophosphatasia is a rare disease that has been reported worldwide and appears to affect individuals of all ethnicities. The prevalence of severe hypophosphatasia is estimated to be 1:100,000 in a population of largely Anglo-Saxon origin. The frequency of mild hypophosphatasia is more challenging to assess because the symptoms may escape notice or be misdiagnosed. The highest incidence of hypophosphatasia has been reported in the Mennonite population in Manitoba, Canada where one in every 25 individuals are considered carriers and one in every 2,500 newborns exhibits severe disease. Hypophosphatasia is considered particularly rare in people of African ancestry in the U.S.
Diagnosis.
Dental findings.
Hypophosphatasia is often discovered because of an early loss of deciduous (baby or primary) teeth with the root intact. Researchers have recently documented a positive correlation between dental abnormalities and clinical phenotype. Poor dentition is also noted in adults.
Laboratory testing.
The symptom that best characterizes hypophosphatasia is low serum activity of alkaline phosphatase enzyme (ALP). In general, lower levels of enzyme activity correlate with more severe symptoms. The decrease in ALP activity leads to an increase in pyridoxal 5’-phosphate (PLP), which is the major form of Vitamin B6, in the blood, although tissue levels of Vitamin B6 may be unremarkable and correlates with disease severity. Urinary inorganic pyrophosphate (PPi) levels are elevated in most hypophosphatasia patients and, although it remains only a research technique, this increase has been reported to accurately detect carriers of the disease. In addition, most patients have an increased level of urinary phosphoethanolamine (PEA) although some may not. PLP screening is preferred over PEA due to cost and sensitivity.
Tests for serum tissue-non-specific ALP (sometimes referred to as TNSALP) levels are part of the standard comprehensive metabolic panel (CMP) that is used in routine exams, although bone-specific ALP testing may be indicative of disease severity.
Radiography.
Despite patient-to-patient variability and the diversity of radiographic findings, the X-ray is diagnostic in infantile hypophosphatasia. Skeletal defects are found in nearly all patients and include hypomineralization, rachitic changes, incomplete vertebrate ossification and, occasionally, lateral bony spurs on the ulnae and fibulae.
In newborns, X-rays readily distinguish hypophosphatasia from osteogenesis imperfecta and congenital dwarfism. Some stillborn skeletons show almost no mineralization; others have marked undermineralization and severe rachitic changes. Occasionally there can be peculiar complete or partial absence of ossification in one or more vertebrae. In the skull, individual membranous bones may calcify only at their centers, making it appear that areas of the unossified calvarium have cranial sutures that are widely separated when, in fact, they are functionally closed. Small protrusions (or "tongues") of radiolucency often extend from the metaphyses into the bone shaft.
In infants, radiographic features of hypophosphatasia are striking, though generally less severe than those found in perinatal hypophosphatasia. In some newly diagnosed patients, there is an abrupt transition from relatively normal-appearing diaphyses to uncalcified metaphases, suggesting an abrupt metabolic change has occurred. Serial radiography studies can reveal the persistence of impaired skeletal mineralization (i.e. rickets), instances of sclerosis, and gradual generalized demineralization.
In adults, X-rays may reveal bilateral femoral pseudofractures in the lateral diaphysis. These pseudofractures may remain for years, but they may not heal until they break completely or the patient receives intramedullary fixation. These patients may also experience recurrent metatarsal fractures. DXA may show abnormal bone mineral density which may correlate with disease severity, although bone mineral density in HPP patients may not be systemically reduced.
Genetic analysis.
All clinical sub-types of hypophosphatasia have been traced to genetic mutations in the gene encoding TNSALP, which is localized on chromosome 1p36.1-34 in humans (ALPL; OMIM#171760). Approximately 388 distinct mutations have been described in the TNSALP gene. An up-to-date list of mutations is available online at The Tissue Nonspecific Alkaline Phosphatase Gene Mutations Database. About 80% of the mutations are missense mutations. The number and diversity of mutations results in highly variable phenotypic expression, and there appears to be a correlation between genotype and phenotype in hypophosphatasia”. Mutation analysis is possible and available in 3 laboratories.
Treatment.
As of October 2015, asfotase alfa (Strensiq) has been approved by the FDA for the treatment of hypophosphatasia.
Some evidence exists to support the use of teraparatide in adult-HPP.
Current management consists of palliating symptoms, maintaining calcium balance and applying physical, occupational, dental and orthopedic interventions, as necessary.
History.
It was discovered initially in 1936 but was fully named and documented by a Canadian Pediatrician, John Campbell Rathbun (1915-1972) while examining and treating a baby boy with very low levels of alkaline phosphatase in 1948. The genetic basis of the disease was mapped out only some 40 years later. This condition is sometimes called "Rathbun's Syndrome" after its principal documenter.


Dockerin

Dockerin is a protein domain found in the cellulosome cellular structure of anaerobic bacteria. It is found on many endoglucanase enzymes. The dockerin's binding partner is the cohesin domain, located on the scaffoldin protein. This interaction between the dockerin domains of the enzyme constituents of the cellulosome and the cohesin domains of the scaffoldin protein is essential to the construction of the cellulosome complex. The Dockerin domain has two in-tandem repeats of a non-EF hand calcium binding motif. Each motif is characterized by a loop-helix structure. The three-dimensional structure of dockerin has been determined in solution, as well as in complex with Cohesin.
There are three types of Dockerin domains: I, II and III which bind to Cohesin Type I, Cohesin Type II and Cohesin Type III respectively. A type I dockerin domain is 65-70 residues long. The binding specificity of Type I interaction was well studied by structural and mutagenesis studies. Type II interaction is less well characterized.
External links.
Protein Structure:
Specificity Characterization:


DHR2 domain

DHR2 (DOCK homology region 2), also known as CZH2 or Docker2, is a protein domain of approximately 450-550 amino acids that is present in the DOCK family of proteins. This domain functions as a guanine nucleotide exchange factor (GEF) domain for small G proteins of the Rho family. DHR2 domains bear no significant similarity to the well described DH domain (Dbl homologous domain) present in other RhoGEFs such as Vav, P-Rex and TRIO. Indeed, the most divergent mammalian DHR2 domains share only 16-17% sequence similarity.


Arylsulfotransferase

Arylsulfotransferase may refer to:


2,2-dialkylglycine decarboxylase (pyruvate)

In enzymology, a 2,2-dialkylglycine decarboxylase (pyruvate) () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are 2,2-dialkylglycine and pyruvate, whereas its 3 products are dialkyl ketone, CO2, and L-alanine.
This enzyme belongs to the family of lyases, specifically the carboxy-lyases, which cleave carbon-carbon bonds. The systematic name of this enzyme class is 2,2-dialkylglycine carboxy-lyase (amino-transferring L-alanine-forming). Other names in common use include dialkyl amino acid (pyruvate) decarboxylase, alpha-dialkyl amino acid transaminase, 2,2-dialkyl-2-amino acid-pyruvate aminotransferase, L-alanine-alpha-ketobutyrate aminotransferase, dialkylamino-acid decarboxylase (pyruvate), and 2,2-dialkylglycine carboxy-lyase (amino-transferring). It employs one cofactor, pyridoxal phosphate.
Structural studies.
As of late 2007, 16 structures have been solved for this class of enzymes, with PDB accession codes , , , , , , , , , , , , , , , and .


2-(hydroxymethyl)-3-(acetamidomethylene)succinate hydrolase

In enzymology, a 2-(hydroxymethyl)-3-(acetamidomethylene)succinate hydrolase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are 2-(hydroxymethyl)-3-(acetamidomethylene)succinate and H2O, whereas its 4 products are acetate, 2-(hydroxymethyl)-4-oxobutanoate, NH3, and CO2.
This enzyme belongs to the family of hydrolases, those acting on carbon-nitrogen bonds other than peptide bonds, specifically in linear amides. The systematic name of this enzyme class is 2-(hydroxymethyl)-3-(acetamidomethylene)succinate amidohydrolase (deaminating, decarboxylating). Other names in common use include compound B hydrolase, alpha-hydroxymethyl-alpha'-(N-acetylaminomethylene)succinic acid, and hydrolase. This enzyme participates in vitamin B6 metabolism.


Mannosamine

D-Mannosamine (2-amino-2-deoxymannose) is a hexosamine derivative of mannose.


Insulin-like growth factor-binding protein

The insulin-like growth factor-binding protein (IGFBP) serves as a transport protein for insulin-like growth factor 1 (IGF-1).
Function.
Approximately 98% of IGF-1 is always bound to one of six binding proteins (IGF-BP). IGFBP-3, the most abundant protein, accounts for 80% of all IGF binding. IGF-1 binds to IGFBP-3 in a 1:1 molar ratio. IGF-BP also binds to IGF-1 inside the liver, allowing growth hormone to continuously act upon the liver to produce more IGF-1.
IGF binding proteins (IGFBPs) are proteins of 24 to 45 kDa. All six IGFBPs share 50% homology with each other and have binding affinities for IGF-I and IGF-II at the same order of magnitude as the ligands have for the IGF-IR.
The IGFBPs help to lengthen the half-life of circulating IGFs in all tissues, including the prostate. Individual IGFBPs may act to enhance or attenuate IGF signaling depending on their physiological context (i.e. cell type). Even with these similarities, some characteristics are different: chromosomal location, heparin binding domains, RGD recognition site, preference for binding IGF-I or IGF-II, and glycosylation and phosphorylation differences. These structural differences can have a tremendous impact on how the IGFBPs interact with cellular basement membranes.
Family members.
In humans, IGFBPs are transcribed from the following seven genes:


Diethyl 2-methyl-3-oxosuccinate reductase

In enzymology, a diethyl 2-methyl-3-oxosuccinate reductase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are diethyl (2R,3R)-2-methyl-3-hydroxysuccinate and NADP+, whereas its 3 products are diethyl 2-methyl-3-oxosuccinate, 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 diethyl-(2R,3R)-2-methyl-3-hydroxysuccinate:NADP+ 3-oxidoreductase.


Dipeptidyl-dipeptidase

Dipeptidyl-dipeptidase (, "dipeptidyl tetrapeptide hydrolase", "dipeptidyl ligase", "tetrapeptide dipeptidase") is an enzyme. This enzyme catalyses the following chemical reaction
This thiol-activated peptidase is isolated from cabbage ("Brassica oleracea").


Gummy bear

Gummy bears (German: "Gummibär") are small, fruit gum candies, similar to a jelly baby in some English-speaking countries. The candy is roughly long and shaped in the form of a bear. The gummy bear is one of many gummies, popular gelatin-based candies sold in a variety of shapes and colors.
History.
The gummy bear originated in Germany, where it is popular under the name (gum or gummy bear), or in the endearing form ([little] gum or gummy bear). Gum arabic was the original base ingredient used to produce the gummy bears, hence the name "gum" or "gummy". Hans Riegel Sr., a confectioner from Bonn, started the Haribo company in 1920. In 1922, inspired by the trained bears seen at street festivities and markets in Europe through to the 19th century, he invented the Dancing Bear ("Tanzbär"), a small, affordable, fruit-flavored gum candy treat for children and adults alike, which was much larger in form than its later successor, the Gold-Bear ("Goldbär"). Even during Weimar Germany's hyperinflation period that wreaked havoc on the country, Haribo's fruit-gum Dancing Bear treats remained affordably priced for a mere 1 Pfennig, in pairs, at kiosks. The success of the Dancing Bear's successor would later become Haribo's world-famous Gold-Bears candy product in 1967.
Variations and flavors.
The success of gummi bears has spawned the production of many other gummy candies that look like animals and other objects: rings, worms, frogs, snakes, hamburgers, cherries, sharks, penguins, hippos, lobsters, octopuses, apples, peaches, oranges, and even "Ampelmännchen", Smurfs, and spiders. Manufacturers offer sizes from the standard candy size, and smaller, to bears that weigh several kilograms.
In the United States, Haribo gummy bears are sold in five flavors: raspberry (red); orange (orange); strawberry (green); pineapple (colorless); and lemon (yellow). Trolli's bears are similarly most often sold in five flavors in the United States, and in the same colors; however, Trolli's red bear is strawberry-flavored, while the green is lime and the colorless is grape. Many companies emulate either Haribo or Trolli flavor-color combinations. Health-oriented brands, which often use all-natural flavors, sometimes opt for more and different flavors. For example, the boxed bulk gummis sold by Sunflower/Newflower Markets include grape, pineapple-coconut, and peach, among others.
Ingredients and production.
The traditional gummy bear is made from a mixture of sugar, glucose syrup, starch, flavoring, food coloring, citric acid, and gelatin. However, recipes vary, such as organic candy, those suitable for vegetarians, or those following religious dietary laws.
Production uses a specialized machine called a starch mogul. The image of the gummy bear is stamped into a tray filled with powdered starch. The hot, liquid mixture is poured into the indentations in the starch and allowed to cool overnight. Once the mixture has set, the candies can be removed from the mold and packaged. The molds are open on top, so only the bear's front is formed while the back remains flat. The original design for each type of candy is carved into plaster by an artist, then duplicated by a machine and used to create the starch molds for the production line.
Gummy bears made with bovine, porcine or piscine gelatin are not suitable for vegetarians and vegans. Those with porcine gelatin or from animals not slaughtered in either of the two contradictory ritualistic fashions do not conform to kashrut or halal dietary laws. In its factory in Turkey, Haribo produces halal bears and other sweets which are made with bovine gelatin. Also, some gummy bears are made with pectin or starch instead of gelatin, making them suitable for vegetarians.
Large sour gummy bears are larger and flatter than regular ones, have a softer texture, and include fumaric acid or other acid ingredients to produce a sour flavor. Some manufacturers produce sour bears with a different texture, based on starch instead of gelatin. Typically, starch produces a shorter (cleaner bite, less chewy) texture than gelatin.
Health issues.
Gummy bears ordinarily contain mostly empty calories, but recently gummy bears containing vitamin C, produced by manufacturers such as Sconza or Bear Essentials, are being marketed to parents of young children. Multivitamins have also been produced in the form of gummi bears to motivate consumption by young, picky eaters.
Gummy bears, and other gummi candy, stick to teeth and may cause tooth decay. However, gummi bears containing the cavity-fighting additive xylitol (wood sugar) are now being tested. Trolli has developed a line of gummi candy which is claimed to help the immune system and teeth: the acti-line.
There has been concern that gelatin in most gummy bears may harbor prions, particularly those that cause bovine spongiform encephalopathy (BSE) in cattle and new-variant Creutzfeldt–Jakob disease in humans. Based on studies, the United States FDA and other national organizations and countries consider the risk of BSE transmission through gelatin to be minuscule as long as precautions are followed during manufacturing.


Stigmasterol

Stigmasterol – a plant sterol ("phytosterol") – is among the most abundant of plant sterols, having a major function to maintain the structure and physiology of cell membranes. In the European Union, it is a food additive listed with E number E499, and may be used in food manufacturing to increase the phytosterol content, potentially lowering the levels of LDL cholesterol.
Discovery.
Once called "Wulzen factor" in the mid-20th century, stigmasterol was discovered by the University of California physiologist Rosalind Wulzen (born 1886).
Natural occurrences.
Stigmasterol is an unsaturated phytosterol occurring in the plant fats or oils of numerous plants, such as soybean, calabar bean, and rape seed, and in herbs used in herbalism practices, including the Chinese herbs "Ophiopogon japonicus" (Mai men dong), in "Mirabilis jalapa".
Stigmasterol is a constituent of various vegetables, legumes, nuts, seeds, and unpasteurized milk. Pasteurization will inactivate stigmasterol. Edible oils contains higher amount than vegetables.
Uses.
Stigmasterol is a food additive in manufactured food products in the United Kingdom and European Union. It was introduced as a precursor by Percy Lavon Julian for industrial large-scale manufacture of semisynthetic progesterone, a valuable human hormone that plays an important physiological role in the regulatory and tissue rebuilding mechanisms related to estrogen effects, as well as acting as an intermediate in the biosynthesis of androgens, estrogens, and corticoids. It is also used as the precursor of vitamin D3.
The Upjohn company used stigmasterol as the starting raw material for commercial synthesis of cortisone in 1959.
Research.
As one of the major phytosterols, stigmasterol is included among sterol compounds in the diet having potential to reduce the risk of cardiovascular diseases. Consumption of 2 grams per day of plant sterols is associated with a reduction in blood LDL cholesterol of 8-10%, possibly lowering cardiovascular disease risk. As a factor in cellular processes of plants, stigmasterol may have roles in plant stress responses, metabolism, and enzymes involved in biosynthesis of plant cell membranes. Stigmasterol has also been shown to exert anti-angiogenic and anti-cancer effects via the downregulation of TNF-alpha and VEGFR-2.
Potential precursor of boldenone.
Being a steroid, stigmasterol is precursor of anabolic steroid boldenone. Boldenone undecylenate is commonly used in veterinary medicine to induce growth in cattle, but it is also one of the most commonly abused anabolic steroids in sports. This led to suspicion that some athletes testing positive for boldenone didn't consume the steroid itself, but rather consumed foods rich in stigmasterol; this turned out not to be the case.


Ranunculin

Ranunculin is an unstable glucoside found in plants of the buttercup family (Ranunculaceae). On maceration, for example when the plant is wounded, it is enzymatically broken down into glucose and the toxin protoanemonin.


Aspergillusol A

Aspergillusol A is an alpha-glucosidase inhibitor isolated from marine "Aspergillus". Structurally, it consists of an erythritol group in the center, with two hydroxyimino-phenylpropanoyl groups attached to it from either side. It was synthesized in 2010 by researchers from King Fahd University of Petroleum and Minerals, starting with 4-hydroxybenzaldehyde.


Resocortol

Resocortol is a synthetic glucocorticoid corticosteroid which was never marketed.


Celloxylanase

Celloxylanase is the name of enzyme which degrade the glycans and the xylans.


Glycoside hydrolase family 45

In molecular biology, glycoside hydrolase family 45 is a family of glycoside hydrolases.
Glycoside hydrolases are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycoside hydrolases, based on sequence similarity, has led to the definition of >100 different families. This classification is available on the CAZy web site, and also discussed at CAZypedia, an online encyclopedia of carbohydrate active enzymes.
Glycoside hydrolase family 45 CAZY GH_45 comprises enzymes with only one known activity; endoglucanase (). This family is also known as cellulase family K. The best conserved region in these enzymes is located in the N-terminal section. It contains an aspartic acid residue which has been shown to act as a nucleophile in the catalytic mechanism. This also has several cysteines that are involved in forming disulphide bridges.


Cortistatins

The cortistatins are a group of steroidal alkaloids first isolated in 2006 from the marine sponge "Corticium simplex". The cortistatins were first discovered in a search for naturally occurring compounds that inhibit proliferation of human umbilical vein endothelial cells (HUVECs), with cortistatin A being the most potent compound in the class.
The Shair group at Harvard along with collaborators have shown that cortistatin A is a highly potent and selective inhibitor of CDK8 and CDK19, the kinases that associate with Mediator complex. Out of 386 kinases evaluated, cortistatin A only inhibited CDK8 and CDK19, revealing that it is among the most selective kinase inhibitors. It was also shown that cortistatin A potently inhibits growth of acute myeloid leukemia cells and AML in two in vivo mouse models. Identification of dominant drug-resistant alleles of CDK8 and CDK19 demonstrate that these kinases mediate the activity of cortistatin A in AML cells. Thus, inhibition of CDK8 and CDK19 is a new therapeutic approach to AML. Cortistatin A caused selective and disproportionate up-regulation of super-enhancer-associated genes in AML cells which contributed to its anti-leukemic activity. This work indicated that CDK8 and CDK19 are negative regulators of super-enhancer-associated genes in AML.
Di-dehydrocortistatin A suppresses viral replication in cells infected with HIV via binding to the Tat protein.
Cortistatin A was synthesized by the Shair, Myers, Baran and Nicolaou labs.


Saringosterol

Saringosterol is an isolate of "Lessonia nigrescens" that has activity against "Mycobacterium tuberculosis".


CRM domain

In molecular biology, the CRM domain is an approximately 100-amino acid RNA-binding domain. The name CRM (chloroplast RNA splicing and ribosome maturation) has been suggested to reflect the functions established for four characterised members of the family: "Zea mays" (Maize) CRS1, CAF1 and CAF2 proteins and the "Escherichia coli" protein YhbY. Proteins containing the CRM domain are found in eubacteria, archaea, and plants. The CRM domain is represented as a stand-alone protein in archaea and bacteria, and in single- and multi-domain proteins in plants. It has been suggested that prokaryotic CRM proteins existed as ribosome-associated proteins prior to the divergence of archaea and bacteria, and that they were co-opted in the plant lineage as RNA binding modules by incorporation into diverse protein contexts. Plant CRM domains are predicted to reside not only in the chloroplast, but also in the mitochondrion and the nucleo/cytoplasmic compartment. The diversity of the CRM domain family in plants suggests a diverse set of RNA targets.
The CRM domain is a compact alpha/beta domain consisting of a four-stranded beta sheet and three alpha helices with an alpha-beta-alpha-beta-alpha-beta-beta topology. The beta sheet face is basic, consistent with a role in RNA binding. Proximal to the basic beta sheet face is another moiety that could contribute to nucleic acid recognition. Connecting strand beta1 and helix alpha2 is a loop with a six amino acid motif, GxxG flanked by large aliphatic residues, within which one 'x' is typically a basic residue.
"Escherichia coli" YhbY is associated with pre-50S ribosomal subunits, which implies a function in ribosome assembly. GFP fused to a single-domain CRM protein from maize localises to the nucleolus, suggesting that an analogous activity may have been retained in plants. A CRM domain containing protein in plant chloroplasts has been shown to function in group I and II intron splicing. "In vitro" experiments with an isolated maize CRM domain have shown it to have RNA binding activity. These and other results suggest that the CRM domain evolved in the context of ribosome function prior to the divergence of Archaea and Bacteria, that this function has been maintained in extant prokaryotes, and that the domain was recruited to serve as an RNA binding module during the evolution of plant genomes. YhbY has a fold similar to that of the C-terminal domain of translation initiation factor 3 (IF3C), which binds to 16S rRNA in the 30S ribosome.


Familial dysbetalipoproteinemia

Familial dysbetalipoproteinemia or type III hyperlipoproteinemia is a condition characterized by increased total cholesterol and triglyceride levels, and decreased HDL levels.
Signs and symptoms.
Signs of familial dysbetaproteinemia include xanthoma striatum palmare (orange or yellow discoloration of the palms) and tuberoeruptive xanthomas over the elbows and knees. The disease leads to premature atherosclerosis and therefore a possible early onset of coronary artery disease and peripheral vascular disease leading to a heart attack, i.e. myocardial infarction, chest pain on exercise, i.e. angina pectoris or stroke in young adults or middle aged patients.
Causes.
This condition is caused by a mutation in apolipoprotein E (ApoE), that serves as a ligand for the liver receptor for chylomicrons, IDL and VLDL, also known as very-low-density-lipoprotein receptor. The normal ApoE turns into the defective ApoE2 form due to a genetic mutation. This defect prevents the normal metabolism of chylomicrons, IDL and VLDL, otherwise known as remnants, and therefore leads to accumulation of cholesterol within scavenger cells (macrophages) to enhance development and acceleration of atherosclerosis.
Treatment.
First line of management are fibrates.


Mannose 6-phosphate

Mannose-6-phosphate (M6P) is a molecule bound by lectin in the immune system. M6P is converted to fructose 6-phosphate by mannose phosphate isomerase.
M6P is a key targeting signal for acid hydrolase precursor proteins that are destined for transport to lysosomes. The M6P tag is added to such proteins in the "cis"-Golgi apparatus. Specifically, in a reaction involving uridine diphosphate (UDP) and "N"-acetylglucosamine, the enzyme N-acetylglucosamine-1-phosphate transferase catalyzes the "N"-linked glycosylation of asparagine residues with M6P. Once appropriately marked with the M6P targeting signal, these proteins are moved to the "trans"-Golgi network. There, the M6P moiety is recognized and bound by mannose 6-phosphate receptor (MPR) proteins at pH 6.5–6.7.
The M6P-tagged lysosomal enzymes are shipped to the late endosomes via vesicular transport. Enzyme replacement therapy (ERT) for several lysosomal storage diseases relies on this pathway to efficiently direct synthetic enzymes to the lysosome where each can metabolize its particular substrate. The pH in the late endosome can reach 6.0, which causes dissociation of M6P from its receptor. Upon release, the enzymes are ferried to their final destination in the lysosomes. The MPRs are packed into vesicles that bud off the late endosome and return to the "trans"-Golgi network. In this way, the MPRs can be recycled.


Gulose

Gulose is an aldohexose sugar. It is a monosaccharide that is very rare in nature, but has been found in archaea, bacteria and eukaryotes. It also exists as a syrup with a sweet taste. It is soluble in water and slightly soluble in methanol. Neither the - and -forms are fermentable by yeast.
Gulose is a C-3 epimer of galactose.


Glycoside hydrolase family 73

In molecular biology, glycoside hydrolase family 73 is a family of glycoside hydrolases.
Glycoside hydrolases are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycoside hydrolases, based on sequence similarity, has led to the definition of >100 different families. This classification is available on the CAZy web site, and also discussed at CAZypedia, an online encyclopedia of carbohydrate active enzymes.
Glycoside hydrolase family 73 CAZY GH_73 includes peptidoglycan hydrolases with endo-β-N-acetylglucosaminidase specificity. Members of this family include mannosyl-glycoprotein endo-beta-N-acetylglucosamidase and flagellar protein J (flgJ), which has been shown to hydrolyse peptidoglycan.


Saccharide transporter

The bacterial phosphoenolpyruvate: sugar phosphotransferase system (PTS) is a multi-protein system involved in the regulation of a variety of metabolic and transcriptional processes. The PTS catalyzes the phosphorylation of incoming sugar substrates concomitant with their translocation across the cell membrane. The general mechanism of the PTS is the following: a phosphoryl group from phosphoenolpyruvate (PEP) is transferred to enzyme-I (EI) of PTS which in turn transfers it to a phosphoryl carrier protein (HPr). Phospho-HPr then transfers the phosphoryl group to a sugar-specific permease which consists of at least three structurally distinct domains (IIA, IIB, and IIC) which can either be fused together in a single polypeptide chain or exist as two or three interactive chains, formerly called enzymes II (EII) and III (EIII). The IIC domain catalyzes the transfer of a phosphoryl group from IIB to the sugar substrate.


Pseudopterosin A

Pseudopterosin A is a diterpene glycoside isolated from the gorgonian sea whip "Antillogorgia elisabethae", found in the Bahamas and Florida Keys. Pseudopterosins A-D, which differ in the degree of acetylation at the sugar ring, were first isolated and reported in 1986. There are at least 25 unique diterpenes isolated from this species of marine animal. Samples of "P. elisabethae" from the Bahamas are found to have higher concentrations of pseudopterosins than populations from the Florida Keys, which have a greater diversity in diterpene structures.
Uses.
Pseudopterosins have anti-inflammatory and analgesic activity, with a mechanism of action different from the common non-steroidal anti-inflammatory drugs, NSAIDs. Commercially, pseudopterosins are found in skin creams as topical anti-inflammatory agents.
Biosynthesis.
Elisabethatriene (2) has been identified as a key intermediate for the synthesis of the class of pseudopterosins and "seco"-pseudopterosins. A proposed mechanistic pathway for the synthesis of elisabethatriene from geranylgeranyl pyrophosphate (GGPP, 1), is described below. Elisabethatriene synthase, a diterpene cyclase enzyme, catalyzes the transformation of the diterpene GGPP to a 10-membered carbon skeleton followed by hydride migration towards the bicyclic ring system. This cyclase enzyme has been identified as a key enzyme in forming the carbon skeleton of pseudopterosins in one step. An alternative mechanism has been proposed in which a six-membered ring is formed first, then a second ring closing for the bicyclic system.
The biosynthesis of the pseudopterosins continues with an aromatization to erogorgiaene (3), two oxidations to a dihyroxyerogorgiaene (4, then 5), and another oxidation to an ortho-hydroxyquinone (6). Ring closure (7), re-aromatization to (8) and glycosylation yield Pseudopterosin A (9). This is a plausible biosynthetic pathway, and intermediates 2, 3, 6, 7, and 8 have been identified using radio labeling studies. An alternative mechanism has been proposed with no hydroxyquinone intermediate (6). Rather, molecule 3 undergoes two subsequent oxidations at C-6 and C-7 to a structure resembling 8, then glycosylation to pseudopterosin.
The branching point for the biosynthesis of the tricyclic pseudopterosins versus the bicyclic "seco"-pseudopterosins occurs at compound 11, the aromatized bicycle erogorgiaene. 11 is oxidized once then hydroxylated followed by glycolsylation to make the bicyclic "seco"-pseudopterosins.
The proposed synthesis of artificial anti-inflammatory metabolites is modeled after pseudopterosins and is based on the bicyclic "seco"-pseudopterosin structure 6.


Dichloroarcyriaflavin A synthase

Dichloroarcyriaflavin A synthase () is an enzyme with systematic name "dichlorochromopyrrolate,NADH:oxygen 2,5-oxidoreductase (dichloroarcyriaflavin A-forming)". This enzyme catalyses the following chemical reaction
RebP is an NAD-dependent cytochrome P450 oxygenase that performs an aryl-aryl bond formation


Glutarate-semialdehyde dehydrogenase

In enzymology, a glutarate-semialdehyde dehydrogenase () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are glutarate semialdehyde, NAD+, and H2O, whereas its 3 products are glutarate, NADH, and H+.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the aldehyde or oxo group of donor with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is glutarate-semialdehyde:NAD+ oxidoreductase. This enzyme is also called glutarate semialdehyde dehydrogenase. This enzyme participates in lysine degradation.


Sedoheptulose

Sedoheptulose or -"altro"-heptulose is a ketoheptose—a monosaccharide with seven carbon atoms and a ketone functional group. It is one of the few heptoses found in nature, and is found in various fruits and vegetables ranging from carrots and leeks to figs, mangos and avocados.
It is an intermediate in respiratory and photosynthetic pathways and plays a vital role in the non-oxidative branch of the pentose phosphate pathway.
Studies have shown that sedoheptulose is able to reduce pro-inflammatory markers "in vitro" such as interleukin-6 (IL-6) and C-reactive protein and thus might be able reduce low-level inflammation in humans.
Furthermore, the absence of dietary sedoheptulose and related heptoses can trigger the development of cystinosis when coupled with a rare genetic defect.
References.


Daisy Roulland-Dussoix

Daisy Roulland-Dussoix (9 September 1936 – 5 January 2014) was a Swiss molecular microbiologist. She was one of the discoverers of restriction enzymes during her doctoral studies. There is controversy over whether she should have received the 1978 Nobel prize in Physiology and Medicine, which was awarded to Hamilton O. Smith, Daniel Nathans, and Werner Arber.
Early life.
Daisy Roulland-Dussoix was born September 9, 1936 in Geneva, Switzerland. Daughter of Edmond Louis Dussoix and Elsa Margaetha (Sauerbrey) Dussoix.
Education.
Daisy Roulland-Dussoix (née Daisy Dussoix) gained her first degree in Chemistry and Biology from University of Geneva (1958), followed by her doctorate in Biophysics (1964).
Scientific career.
She worked for her PhD with Werner Arber and Eduard Kellenberger, Swiss microbial geneticists, at the time when the barriers to infection of bacterial cells by virus (bacteriophage) first became apparent, leading to the discovery of restriction and modification enzymes that have subsequently become essential molecular biology tools. These enzymes result in cleavage of DNA by enzymes at sites characterised by specific sequences unless these are protected by prior enzymatic modification to the DNA bases. This system protects bacterial cells from viral infection.
The research of Grete Kellenberger-Gujer had already demonstrated that phage DNA could be degraded by host bacterial cells. Daisy Dussoix and Werner Arber showed that this process required enzymes, resulting in two publications that paved the way for discovery and isolation of the restriction and modification enzymes involved.
 They had previously presented these results at the First International Biophysics Congress in Stockholm in 1961.
In 1964 Dussoix moved to Stanford University, USA, funded by a Jane Coffin Childs postdoctoral fellowship to work with Robert Lehman. She subsequently worked as Assistant Professor in Residence in the Department of Microbiology from 1968 at the University of California, San Francisco and continued to study DNA restriction and modification with Herbert W Boyer.
She later worked with the research group of Harold E. Varmus on understanding how avian src protoncogenes worked. She subsequently moved to the University of California, Berkeley.
In early 1980 Dussoix-Roulland returned to Europe and worked at the Institut Pasteur in Paris on detection of mycoplasmas using PCR-based molecular methods. She was appointed Group Head of the Mycoplasma Laboratory in 1987 in the Viral Oncology Unit of Luc Montagnier. Her publications from these years focused on mycobacterium and mycoplasmas, specifically genetic and molecular characterization and the development of detection methods.
Contributions, and controversy over recognition of Dussoix's contribution towards Werner Arber Nobel Prize.
Dussoix-Roulland was a member of the research groups of two future Nobel Prizewinners (Werner Arber (for discovery of restriction enzymes), and the group of Harold Varmus and J. Michael Bishop (for the cellular origin of retroviral oncogenes). Her contribution to these discoveries, and whether she should have had greater recognition, has been a topic of controversy.
Specifically, the work on host-controlled DNA modification and discovery of restriction endonucleases, which earned Arber the Nobel prize in Physiology or Medicine (along with Hamilton Smith and Daniel Nathans), was described in two 1962 articles where Dussoix and Arber were the sole authors.
In a letter to her brother and sister-in-law, written in 1978, shortly after the award of the Nobel prize to Arber, Dussoix-Rolland states that "I am very furious, because apparently he has not even mentioned my name, and I have done half of the work for which he received the Nobel Prize". In Arber's biographical sketch on the Nobel Prize site, it is stated that the findings "that restriction and modification were properties of the bacterial strains and acted not only on infecting bacteriophage DNA, but also on cellular DNA as manifested in conjugation experiments" were reported by himself and Daisy Dussoix for the first time to the scientific community during the First International Biophysics Congress held in Stockholm in the summer of 1961.
Dussoix was not thanked or credited individually as a collaborator directly involved in the work rewarded by the Nobel prize. The text of Arber's Nobel lecture states that together with Grete Kellenberger "Daisy Dussoix, a Ph. D. student, studied the breakdown of DNA from irradiated phage λ upon infection of normal host bacteria".
In a letter to her brother (December 7, 1978), Dussoix states: "I have worked with Werner from 1959 to 1963, at which time they (Edouard) forced me to change my PhD thesis project, reportedly because I could not use work done with Werner, but in reality because Werner, after returning from the USA, in order to be paid decently had to engage himself on research on radiation, for which at the time there was more money.
Since Werner was not at all interested in doing the research for which he was paid, somebody had to do it, and that somebody was me, this is why for more than a year before my departure to the USA I was not able to work on restriction, and that should not count for my thesis. In any event, I think that the Nobel Prize was awarded for the two papers published in 62".
Personal life.
In 1964 she married Daniel Roulland, chef at The Star in San Francisco. In 1996 she contracted malaria and as a consequence suffered from long-term neurological problems. Following the death of her husband, she returned to Geneva in 2006, where she died in 2014.


Incadronic acid

Incadronic acid (INN, trade name Bisphonal) is a bisphosphonate.


Hydroxypregnanedione

Hydroxypregnanedione may refer to:


Hyocholic acid

Hyocholic acid or 3α,6α,7α-trihydroxy-5β-cholan-24-oic acid is a bile acid found as one of the main forms in pig, and at low concentrations in other species including humans. Hyocholic acid differs from the primary bile acids found in humans by having a third hydroxyl group in the α-conformation at the 6-position, unlike cholic acid, which has a 12-hydroxyl, and chenodeoxycholic acid which has neither a 6- or 12-hydroxyl. It also differs from the muricholic acids found in rodents, as they are 6β-hydroxylated, and can have the 7-hydroxyl in either the α- or β- positions, forming α- or β-muricholic acids.
Hyocholic acid is conjugated in the liver before secretion with taurine or with glycine to give taurohyocholate or glycohyocholates. Bacterial 7α-dehydroxylation in the colon produces the secondary bile acid, hyodeoxycholic acid. Epimerization of the 7-hydroxyl to the β-position is found in ω-muricholic acid (also known as β-hyocholic acid).
The enzyme responsible for the 6-hydroxylation reaction of chendeoxycholic acid in the pig is the cytochrome P450 "CYP4A21".
Hyocholic acid can be found in humans with cholestasis and may be increased after sleeve gastrectomy for obesity.


D-sedoheptulose 7-phosphate isomerase

D-sedoheptulose 7-phosphate isomerase (, "sedoheptulose-7-phosphate isomerase", "phosphoheptose isomerase", "gmhA (gene)", "lpcA (gene)") is an enzyme with systematic name "D-glycero-D-manno-heptose 7-phosphate aldose-ketose-isomerase". This enzyme catalyses the following chemical reaction
In Gram-negative bacteria the enzyme is involved in biosynthesis of ADP-L-glycero-β-D-manno-heptose.


Tezacitabine

Tezacitabine is a ribonucleotide reductase inhibitor. It is a synthetic purine nucleoside analogue with potential antineoplastic activity. It is used in synthetic DNA.


DNA-3-methyladenine glycosylase I

DNA-3-methyladenine glycosylase I (, "deoxyribonucleate 3-methyladenine glycosidase I", "3-methyladenine DNA glycosylase I", "DNA-3-methyladenine glycosidase I") is an enzyme with systematic name "alkylated-DNA glycohydrolase (releasing methyladenine and methylguanine)". This enzyme catalyses the following chemical reaction
This enzyme is involved in the removal of alkylated bases from DNA in "Escherichia coli".


2-methylisocitrate dehydratase

In enzymology, a 2-methylisocitrate dehydratase () is an enzyme that catalyzes the chemical reaction
Hence, this enzyme has one substrate, (2S,3R)-3-hydroxybutane-1,2,3-tricarboxylate, and two products, (Z)-but-2-ene-1,2,3-tricarboxylate and H2O.
This enzyme belongs to the family of lyases, specifically the hydro-lyases, which cleave carbon-oxygen bonds. The systematic name of this enzyme class is (2S,3R)-3-hydroxybutane-1,2,3-tricarboxylate hydro-lyase [(Z)-but-2-ene-1,2,3-tricarboxylate-forming]. This enzyme is also called (2S,3R)-3-hydroxybutane-1,2,3-tricarboxylate hydro-lyase. This enzyme participates in propanoate metabolism.


Alginase II

Alginase II may refer to:


Oatfield Liquorice Toffee


BESS domain

In molecular biology, the BESS domain is a protein domain which has been named after the three proteins that originally defined the domain: BEAF (Boundary element associated factor 32), Suvar(3)7 and Stonewall ). The BESS domain is 40 amino acid residues long and is predicted to be composed of three alpha helices, as such it might be related to the myb/SANT HTH domain. The BESS domain directs a variety of protein-protein interactions, including interactions with itself, with Dorsal, and with a TBP-associated factor. It is found in a single copy in Drosophila proteins and is often associated with the MADF domain.
Proteins known to contain a BESS domain include:


4-Hydroxycinnamate decarboxylase

4-Hydroxycinnamate decarboxylase is an enzyme that uses "p"-coumaric acid to produce 4-ethylphenol.
"p"-Coumaric acid is the precursor of 4-ethylphenol produced by the yeast "Saccharomyces" and "Brettanomyces" in wine. The yeast converts this to 4-vinylphenol via the enzyme cinnamate decarboxylase.
4-Hydroxycinnamate decarboxylase can also be induced in bacteria species such as "Klebsiella oxytoca" and works also with p-coumaric acid analogs such as caffeic acid, ferulic acid and E-2,4-dihydroxycinnamic acid.


ACDC domain

The "A"P2-"C"oincident "D"omain mainly at the "C"arboxy-terminus, or ACDC domain, is a protein domain that occurs in proteins from apicomplexan parasites.
It is found exclusively in apicomplexan proteins that also contain AP2 (Apetala 2-integrase) DNA binding domains (ApiAP2 proteins). In 8 of 9 known examples in the malarial parasite "Plasmodium falciparum" it is near the carboxy terminus, with the remaining one being at the amino terminus. As yet, beyond its identification and the observation that it occurs only in ApiAP2 proteins, the function of the ACDC domain is unknown. Two proteins with the ACDC domain were found in the nucleus of "P. falciparum", as detected by a proteomic method, suggesting a role in nuclear biology.


Aldehyde dehydrogenase (FAD-independent)

In enzymology, an aldehyde dehydrogenase (FAD-independent) () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are aldehyde, H2O, and acceptor, whereas its two products are carboxylate and reduced acceptor.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the aldehyde or oxo group of donor with other acceptors. The systematic name of this enzyme class is aldehyde:acceptor oxidoreductase (FAD-independent). Other names in common use include aldehyde oxidase, aldehyde oxidoreductase, Mop, and AORDd.
Structural studies.
As of late 2007, only one structure has been solved for this class of enzymes, with the PDB accession code .


C8orf82

Chromosome 8 open reading frame 82 is a protein encoded in humans by the C8orf82 gene.
Gene.
C8orf82 is a gene located on the minus strand of chromosome 8 in the species "Homo sapiens" at locus 8q24. The gene is 3,400 bases long and contains 3 exons.
mRNA.
The mRNA produced by the C8orf82 gene is 1,979 base pairs long with coding sequence that starts at base 159 and ends at base 809. According to NCBI Gene there are no alternative transcripts or isoforms. AceView lists several alternative transcripts and isoforms, the existence of which is uncertain.
Homology.
C8orf82 is conserved among invertebrates, fish, reptiles, mammals, and protists. C8orf82 was not found to be conserved among bacteria, archaea, plants, fungi, or trichoplax. The domain of unknown function DUF4505 seems to be well conserved among most orthologs.
Orthologs.
Below is a table of orthologs obtained using Blast.
Evolutionary history.
C8orf82 does not belong to a specific gene family and has no other known alternative splice isoforms. This holds true for its most distant ancestor as well.
The above graph show's how the behavior of C8orf82's percent of amino acid changes over time is similar to that of fibrinogen and vastly different from cytochrome c indicating a very slow rate of change over time.
Below is a graph that depicts the percent identity change of the orthologs listed in the ortholog table based on the orthologs dates of divergence.
Protein.
The C8orf82 gene encodes for the protein termed "UPF0598 protein C8orf82" or just C8orf82.
General properties.
The protein is 216 amino acids long and contains a domain of unknown function DUF4505. This domain of unknown function is also known as pfam14956. The protein has a molecular weight of 23.8 kDa and an isoelectric point of 9.36.
Compositional features.
Isoleucine (0.5%) and lysine (1.4%) within C8orf82 were found to occur in lower frequencies compared to other normal human proteins, while proline(9.7%) and arginine (10.6%) had slightly higher occurrence frequencies.
Post-translational modifications.
Predicted post-translational modifications based on ExPASy tests include phosphorylation sites at several serines, threonines, and tyrosines. In addition tyrosine sulfation, sumoylation, O-linked glycosylation, O-ß-GlcNAc attachment sites and an NES motif was also detected.
Subcellular localization.
C8orf82 is predicted to be localized within the mitochondria using PSORT II analysis. The results of a "k"-NN prediction attributed 60.9% to mitochondrial localization and 26.1% to nuclear localization.
Interacting proteins.
ETFA has been shown to interact with C8orf82 using high-throughput affinity-purification mass spectrometry.
Expression.
Using antibody staining, most normal cells showed moderate cytoplasmic and nuclear immunoreactivity. Strong staining was observed in placental trophoblasts. Lymphoid tissues, glial cells and myocytes were weakly stained or negative. A staining analysis was also done on cancer cells and the results were as follows; a majority of malignant cells displayed weak to moderate positivity. Many cases of malignant carcinoids and lymphomas were negative. In all these tests, only a single antibody was used (CAB034331).
Microarray data has shown C8orf82 to be ubiquitously expressed.
An EST profile for C8orf82 also shows ubiquitous expression.


Clavaric acid

Clavaric acid is a triterpenoid produced by the mushroom "Hypholoma sublateritium". Clavaric acid was discovered by Merck Research Laboratories in a random screening of natural extracts. Clavaric acid is a reversible farnesyltransferase inhibitor with an IC50 of 1.3 μM.


5,8-linoleate diol synthase

5,8-linoleate diol synthase may refer to:


Geranylgeranyl-diphosphate diphosphohydrolase

Geranylgeranyl-diphosphate diphosphohydrolase may refer to:


Zhankuic acid

Zhankuic acids are sterols isolated from "Taiwanofungus camphoratus". Zhankuic acid C possesses anti-inflammatory properties owing to its role as a selective TLR4/MD-2 antagonist.


Tenomodulin

Tenomodulin, also referred to as tendin, myodulin, Tnmd, or TeM, is a protein encoded by the TNMD (Tnmd) gene and was discovered independently by Brandau and Shukunami in 2001 as a gene sharing high similarity with the already known chondromodulin-1 (Chm1). It is a tendon-specific gene marker known to be important for tendon maturation with key implications for the residing tendon stem/progenitor cells (TSPCs) as well as for the regulation of endothelial cell migration in chordae tendineae cordis in the heart and in experimental tumour models. It is highly expressed in tendons, explaining the rationale behind its name and the establishment as being marker gene for tendinous and ligamentous lineages.
Gene and protein structure.
TNMD belongs to the new family of type II transmembrane glycoproteins. The gene is localized on the X chromosome and accounts for an approximately 1.4 kb transcript and a predicted protein consisting of 317 amino acids. The gene is composed of seven exons. The second exon encodes the transmembrane domain (amino acid position 31-49) and no signal peptide. TNMD contains a putative protease recognition sequence (Arg-Xxx-Xxx-Arg) identified at the position 233-236. Unlike chondromodulin-1, TNMD does not have a processing signal for furin protease. The extracellular part, prior the putative cleavage site, contains a BRICHOS extracellular domain found also in several other unrelated proteins. This domain consists of a homologous sequence of approximately 100 amino acids containing a pair of conserved cysteine residues. It has been suggested that BRICHOS participates in the protein post-translational processing, however the exact function remains unclear. TNMD contains two N-glycosylation sites at position 94 and 180. Protein analyses in eye and periodontal ligament revealed full length TNMD protein as a double band of 40 and 45 kDa. It has been experimentally proven that the 45 kDa band corresponds to glycosylated TNMD, while 40 kDa band is non-glycosylated TNMD. The last exon of TNMD gene encodes the conserved C-terminal cysteine-rich domain, which makes up the part of the protein sharing highest resemblance to chondromodulin-I (77% similarity/66% identity). This domain contains C-terminal hydrophobic tail with eight Cys residues forming four disulphide-bridges, which are well conserved across vertebrate species. A smaller cyclic structure forming by single Cys280-Cys292 disulphide bridge in TNMD has been shown to exert an anti-angiogenic function, while the other three disulphide-bridges are speculated to hold this cyclic structure and C-terminal hydrophobic tail separated from each other to avoid the formation of intramolecular aggregates. In certain tendon tissues such as Achilles tendon and chordae tendineae cordis, 16 kDa cleaved C-terminal part of TNMD was detected in the collagenous extracellular matrix.
Expression pattern.
TNMD is highly expressed on messenger and protein levels in tendons and ligaments, but has also been found in other tissues.
- In tendon development first signals are detectable as early as E9.5, but upregulated from E14.5 onwards, marking the differentiated stage of tendon progenitors.
- Mouse periodontal ligaments demonstrated tenomodulin protein expression at 3 and 4 weeks postnatal, a time period corresponding to molar eruptive and post-eruptive phases when the teeth become functional.
- Other tendinous tissues known to express Tnmd are the diaphragm and chordae tendineae cordis.
- Masseter muscle is compartmentalized by a laminar structure, which was shown to elevate Tnmd mRNA in mouse embryos between E12.5 to E17.5, which further decreased after birth. The epimysium of skeletal muscle is also TNMD -positive.
- Tnmd mRNA was detected in eyes, more specifically in the sclerocornea, tendon of the extraocular muscle and the retinal ganglion cell layer, lens fibre cells, inner nuclear layer cells and pigment epithelium.
- Tnmd mRNA was detected in mouse skin at E15.5 and in human subcutaneous adipose tissue and adipocytes.
- In situ hybridization revealed Tnmd expression in various parts of the adult mouse brain such as the dentate gyrus, CA regions of the hippocampus, neurons in the cerebral nuclei, cerebellum, Purkinje cells and neuronal cells in the cerebellar nucleus.
- Rat mandibular condylar cartilage is positive for Tnmd mRNA at 1 week and is downregulated after 5 weeks.
Putative signalling pathway.
The putative signalling pathway of TNMD is largely unknown due to unidentified direct binding partners. Many knockout mouse models with tendon phenotypes have helped in understanding which upstream factors or pathways affect Tnmd expression. Similarly, the generation of Tnmd knockout mouse model allowed the suggestion of possible downstream effectors. It is important to emphasize that most of the below studies show correlations between Tnmd expression or function to other genes and not a direct link in a common signalling cascade.
Regarding upstream regulators of Tnmd expression the description of the scleraxis (Scx) knockout mouse line suggested that Scx can directly drive Tnmd transcription, because Scx deletion led to complete elimination of Tnmd expression. Overexpression of scleraxis in cultured tenocytes or in mesenchymal stem cells significantly upregulated Tnmd expression. The deletion of myostatin in mice resulted in a parallel decrease in Scx and Tnmd mRNA levels, while myostatin stimulation of fibroblasts led to their upregulation, suggesting myostatin as an upstream factor in the Tnmd pathway. Egr1/2 transcription factors can induce Scx and collagen I gene expression, hence it would be interesting to investigate if Egr1 or 2 also can affect Tnmd expression. The absence of the Mohawk (Mkx) gene led to significantly lower Tnmd expression as well as collagen I and fibromodulin. A significant loss of Tnmd was noticeable in Mkx knockouts at E16.5, while Scx expression was unchanged [22], suggesting that Mkx can also directly affect Tnmd expression. Activation of the Wnt/β-catenin signalling pathway in bone marrow-derived stem cells resulted in Tnmd upregulation. Scx and Mkx expression were unaffected, suggesting the Wnt/ β-catenin signalling works independent from these transcription factors.
Regarding downstream factors, the Tnmd knockout mouse model suggested correlation to collagen I based on the observed abnormal collagen fibrillogenesis resulting in pathologically thicker fibres. The lower cellular density and proliferation in the mutant tendons, as well as the reduced self-renewal and earlier senescence of Tnmd-deficient tendon stem/progenitor cells was coupled with downregulation of the proliferative marker Cyclin D1 and upregulation of the senescent marker p53. A study analysing ruptures of human chordae tendineae cordis revealed loss of Tnmd expression in the affected area coupled with upregulation of VEGF-A and MMP1, 2 and 13.
Function and correlation to disease.
In the last decade major breakthroughs in understanding the roles of TNMD in tendons and other tissues and cells have been made. The exact TNMD functions vary according to the type of cell and tissue, and in great extent they remain still not fully deciphered. Also how precisely TNMD contributes to pathophysiology of some correlated diseases is still unclear.
- In tendons it proves to have beneficial functions for the maintenance of the tissue because its loss results in premature tendon ageing characterized with dysregulated collagen fibrillogenesis and reduced cell density and proliferation. Tnmd exerts a positive effect on tendon-derived stem/progenitor cells by supporting self-renewal and preventing senescence, actions in which the C-terminal cysteine-rich domain alone is sufficient. The first studies on Tnmd expression during tendon healing suggested a time-dependent role, which needs to be further elucidated.
- In periodontal ligaments mediating the teeth connection to the jaw bones, Tnmd contributes to proper fibroblast adhesion.
- In tendinous structures chordae tendineae cordis, which connect papillary muscle to the atrioventricular valves in the heart, local absence of Tnmd leads to enhanced angiogenesis, VEGF-A production and MMPs activation. This is followed by cordis ruptures which can cause mitral regurgitation and cardiac valvular diseases.
- With respect to Tnmd anti-angiogenic function in vivo, no major abnormalities in vessel formation and density were detected during tendon and retina development in the knockout mouse model. The latter finding is open for discussion because a study with recombinant tenomodulin has shown an obliterating vessel effect in retina when injected in vivo in the vitreous body.
- In ectopic tumour in vivo models, induced expression of TNMD in mouse melanoma cells resulted in suppression of tumour growth due to reduced vessel density.
- TNMD transduction in human retinal and umbilical vein endothelial cells resulted in reduced cell proliferation or migration, correspondingly.
- Multiple research studies on cell phenotypisation after gene overexpression, stimulation with growth factors or mechanical stress, tissue engineering and biomaterial evaluation utilize Tnmd expression as marker for tendinous and ligamentous cell lineage.
- Research conducted on a genomic level by single nucleotide polymorphism has presented interesting correlations between Tnmd and a variety of diseases namely obesity, type 2 diabetes, metabolic syndrome, Alzheimer's disease and age-related macular degeneration. How exactly these SNPs affect Tnmd transcription, splicing or protein amino acid sequence remains still unknown.
- A strong correlation between Tnmd mRNA expression and the progression of several diseases such as obesity, metabolic syndrome and juvenile dermatomyositis has been shown. Generally, in all these cases higher tenomodulin levels corresponded to advanced disease state.


Esterase D

Esterase D may refer to:


CHASE domain

The CHASE domain is an extracellular protein domain, which is found in transmembrane receptor from bacteria, lower eukaryotes and plants. It has been named CHASE (Cyclases/Histidine kinases Associated Sensory Extracellular) because of its presence in diverse receptor-like proteins with histidine kinase and nucleotide cyclase domains. The CHASE domain is 200-230 amino acids long and always occurs N-terminally in extracellular or periplasmic locations, followed by an intracellular tail housing diverse enzymatic signalling domains such as histidine kinase, adenyl cyclase, GGDEF-type nucleotide cyclase and EAL-type phosphodiesterase domains, as well as non-enzymatic domains such PAS, GAF, phosphohistidine and response regulatory domains. The CHASE domain is predicted to bind diverse low molecular weight ligands, such as the cytokinin-like adenine derivatives or peptides, and mediate signal transduction through the respective receptors.
The CHASE domain has a predicted alpha+beta fold, with two extended alpha helices on both boundaries and two central alpha helices separated by beta sheets. The termini are less conserved compared with the central part of the domain, which shows strongly conserved motif.


Azobenzene reductase

Azobenzene reductase also known as azoreductase () is an enzyme that catalyzes the chemical reaction:
The 3 substrates of this enzyme are N,N-dimethyl-1,4-phenylenediamine, aniline, and nicotinamide adenine dinucleotide phosphate ion, whereas its 3 products are 4-(dimethylamino)azobenzene, nicotinamide adenine dinucleotide phosphate, and hydrogen ion.
This enzyme belongs to the family of oxidoreductases, specifically those acting on other nitrogenous compounds as donors with NAD+ or NADP+ as acceptor.
Mechanism.
The reaction catalyzed by this enzyme proceeds via a ping-pong mechanism by using 2 equivalents of NAD(P)H to reduce one equivalent of the azo compound substrate (for example methyl red where Ar = "p"-dimethylaniline and Ar' = "o"-benzoic acid) into two equivalents of aniline product:
Substrate specificity.
Most azoreductase isoenzymes can reduce methyl red, but are not able to reduce sulfonated azo dyes. The unique azoreductase isozyme from "Bacillus" sp. B29 has the ability to reduce sulfonated azo dyes however.
Nomenclature.
The systematic name of this enzyme class is N,N-dimethyl-1,4-phenylenediamine, aniline:NADP+ oxidoreductase. Other names in common use include:
Structural studies.
As of late 2007, 3 structures have been solved for this class of enzymes, with PDB accession codes , , and . Please check the last updated data on RCSB PDB site.


Pentose

In chemistry, a pentose is a monosaccharide (simple sugar) with five carbon atoms. The chemical formula of all pentoses is , and their molecular weight is 150.13 g/mol.
Pentoses are very important in biochemistry. Ribose is a constituent of RNA, and the related molecule, deoxyribose, is a constituent of DNA. Phosphorylated pentoses are important products of the pentose phosphate pathway, most importantly ribose 5-phosphate (R5P), which is used in the synthesis of nucleotides and nucleic acids, and erythrose 4-phosphate (E4P), which is used in the synthesis of aromatic amino acids.
Like some other monosaccharides, pentoses exist in two forms, open-chain (linear) or closed-chain (cyclic), that easily convert into each other in water solutions. The linear form of a pentose, which usually exists only in solutions, has an open-chain backbone of five carbons. Four of these carbons have one hydroxyl functional group (–OH) each, connected by a single bond, and one has an oxygen atom connected by a double bond (=O), forming a carbonyl group (C=O). The remaining bonds of the carbon atoms are satisfied by six hydrogen atoms. Thus the structure of the linear form is H–(CHOH)"x"–C(=O)–(CHOH)4-"x"–H, where "x" is 0, 1, or 2.
The term "pentose" sometimes is assumed to include deoxypentoses, such as deoxyribose: compounds with general formula that can be described as derived from pentoses by replacement of one or more hydroxyl groups with hydrogen atoms.
Classification.
The aldopentoses are a subclass of the pentoses which, in the linear form, have the carbonyl at carbon 1, forming an aldehyde derivative with structure H–C(=O)–(CHOH)4–H. The most important example is ribose. The ketopentoses have instead the carbonyl at positions 2 or 3, forming a ketone derivative with structure H–CHOH–C(=O)–(CHOH)3–H (2-ketopentose) or H–(CHOH)2–C(=O)–(CHOH)2–H (3-ketopentose). The latter is not known to occur in nature and are difficult to synthesize.
In the open form, there are 8 aldopentoses and 4 2-ketopentoses, stereoisomers that differ in the spatial position of the hydroxyl groups. These forms occur in pairs of optical isomers, generally labelled " or " by conventional rules (independently of their optical activity).
Aldopentoses.
The aldopentoses have three chiral centers; therefore, eight (23) different stereoisomers are possible.
Ribose is a constituent of RNA, and the related molecule, deoxyribose, is a constituent of DNA. Phosphorylated pentoses are important products of the pentose phosphate pathway, most importantly ribose 5-phosphate (R5P), which is used in the synthesis of nucleotides and nucleic acids, and erythrose 4-phosphate (E4P), which is used in the synthesis of aromatic amino acids.
Ketopentoses.
The 2-ketopentoses have two chiral centers; therefore, four (22) different stereoisomers are possible. The 3-ketopentoses are rare.
Cyclic form.
The closed or cyclic form of a pentose is created when the carbonyl group interacts with an hydroxyl in another carbon, turning the carbonyl into a hydroxyl and creating an ether bridge –O– between the two carbons. This intramolecular reaction yields a cyclic molecule, with a ring consisting of one oxygen atom and usually four carbon atoms; the cyclic compounds are then called furanoses, for having the same rings as the cyclic ether tetrahydrofuran.
The closure turns the carboxyl carbon into a chiral center, which may have any of two configurations, depending on the position of the new hydroxyl. Therefore, each linear form can produce two distinct closed forms, identified by prefixes "α" and "β".
Deoxy pentoses.
The one deoxypentose has two total steroisomers.
Properties.
In the cell, pentoses have a higher metabolic stability than hexoses.
A polymer composed of pentose sugars is called a pentosan.
Tests for pentoses.
The most important tests for pentoses rely on converting the pentose to furfural, which then reacts with a chromophore. In Tollens’ test for pentoses (not to be confused with Tollens' silver-mirror test for reducing sugars) the furfural ring reacts with phloroglucinol to produce a colored compound; in the aniline acetate test with aniline acetate; and in Bial's test, with orcinol. In each of these tests, pentoses react much more strongly and quickly than hexoses.


P3 protein

P3 protein is a protein that in humans is encoded by the "SLC10A3" gene.
This gene maps to a GC-rich region of the X chromosome and was identified by its proximity to a CpG island. It is thought to be a housekeeping gene.


Glycoside hydrolase family 20

In molecular biology, glycoside hydrolase family 20 is a family of glycoside hydrolases.
Glycoside hydrolases are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycoside hydrolases, based on sequence similarity, has led to the definition of >100 different families. This classification is available on the CAZy web site, and also discussed at CAZypedia, an online encyclopedia of carbohydrate active enzymes.
Glycoside hydrolase family 20 CAZY GH_20 comprises enzymes with several known activities; beta-hexosaminidase (); lacto-N-biosidase (). Carbonyl oxygen of the C-2 acetamido group of the substrate acts as the catalytic nucleophile/base in this family of enzymes.
In the brain and other tissues, beta-hexosaminidase A degrades GM2 gangliosides; specifically, the enzyme hydrolyses terminal non-reducing N-acetyl-D-hexosamine residues in N-acetyl-beta-D-hexosaminides. There are 3 forms of beta-hexosaminidase: hexosaminidase A is a trimer, with one alpha, one beta-A and one beta-B chain; hexosaminidase B is a tetramer of two beta-A and two beta-B chains; and hexosaminidase S is a homodimer of alpha chains. The two beta chains are derived from the cleavage of a precursor. Mutations in the beta-chain lead to Sandhoff disease, a lysosomal storage disorder characterised by accumulation of GM2 ganglioside.


Progesterone/Estradiol hemisuccinate