Bromodomain

A bromodomain is an approximately 110 amino acid protein domain that recognizes acetylated lysine residues, such as those on the "N"-terminal tails of histones. Bromodomains, as the "readers" of lysine acetylation, are responsible in transducing the signal carried by acetylated lysine residues and translating it into various normal or abnormal phenotypes. Their affinity is higher for regions where multiple acetylation sites exist in proximity. This recognition is often a prerequisite for protein-histone association and chromatin remodeling. The domain itself adopts an all-α protein fold, a bundle of four alpha helices each separated by loop regions of variable lengths that form a hydrophobic pocket that recognizes the acetyl lysine.
Discovery.
The bromodomain was identified as a novel structural motif by John W. Tamkun and colleagues studying the drosophila gene "Brahma"/"brm", and showed sequence similarity to genes involved in transcriptional activation. The name "bromodomain" is derived from the relationship of this domain with "Brahma" and is unrelated to the chemical element bromine.
Bromodomain-containing proteins.
Bromodomain-containing proteins can have a wide variety of functions, ranging from histone acetyltransferase activity and chromatin remodeling to transcriptional mediation and co-activation. Of the 43 known in 2015, 11 had two bromodomains, and one protein had 6 bromodomains. Preparation, biochemical analysis, and structure determination of the bromodomain containing proteins have been described in details.
Bromo- and Extra-Terminal domain (BET) family.
A well-known example of a bromodomain family is the BET (Bromodomain and extraterminal domain) family. Members of this family include BRD2, BRD3, BRD4 and BRDT.
Other.
However proteins such as ASH1L also contain a bromodomain. Dysfunction of BRD proteins has been linked to diseases such as human squamous cell carcinoma and other forms of cancer. Histone acetyltransferases, including EP300 and PCAF, have bromodomains in addition to acetyl-transferase domains.
Not considered part of the BET family (yet containing a bromodomain) are BRD7, and BRD9.
Role in human disease.
The role of bromodomains in translating a deregulated cell acetylome into disease phenotypes was recently unveiled by the development of small molecule bromodomain inhibitors. This breakthrough discovery highlighted bromodomain-containing proteins as key players in cancer biology, as well as inflammation and remyelination in multiple sclerosis.
Members of the BET family have been implicated as targets in both human cancer and multiple sclerosis. BET inhibitors have shown therapeutic effects in multiple preclinical models of cancer and are currently in clinical trials in the United States. Their application in multiple sclerosis is still in the preclinical stage.
Small molecule inhibitors of non-BET bromodomain proteins BRD7 and BRD9 have also been developed.


4-hydroxybenzoyl-CoA thioesterase

In enzymology, a 4-hydroxybenzoyl-CoA thioesterase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are 4-hydroxybenzoyl-CoA and H2O, whereas its two products are 4-hydroxybenzoate and CoA.
This enzyme belongs to the family of hydrolases, specifically those acting on thioester bonds. The systematic name of this enzyme class is 4-hydroxybenzoyl-CoA hydrolase. This enzyme participates in 2,4-dichlorobenzoate degradation.
Structural studies.
As of late 2007, 7 structures have been solved for this class of enzymes, with PDB accession codes , , , , , , and .


Barrier-to-autointegration factor

In molecular biology, barrier-to-autointegration factor (BAF) is a family of essential proteins that is highly conserved in metazoan evolution, and which may act as DNA-bridging proteins. BAF binds directly to double-stranded DNA, to transcription activators, and to inner nuclear membrane proteins, including lamin A filaments that anchor nuclear pore complexes in place, and nuclear LEM-domain proteins that bind to laminin filaments and chromatin. New findings suggest that BAF has structural roles in nuclear assembly and chromatin organization, represses gene expression and might interlink chromatin structure, nuclear architecture and gene regulation in metazoans.
BAF can be exploited by retroviruses to act as a host component of pre-integration complexes, which promote the integration of the retroviral DNA into the host chromosome by preventing autointegration (integration into itself). BAF might contribute to the assembly or activity of retroviral pre-integration complexes through direct binding to the retroviral proteins p55 Gag and matrix, as well as to DNA.


(acyl-carrier-protein) phosphodiesterase

In enzymology, a [acyl-carrier-protein] phosphodiesterase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are holo-[acyl-carrier-protein] and HO, whereas its two products are 4'-phosphopantetheine and apo-[acyl-carrier-protein].
This enzyme belongs to the family of hydrolases, specifically those acting on phosphoric diester bonds. The systematic name of this enzyme class is holo-[acyl-carrier-protein] 4'-pantetheine-phosphohydrolase. Other names in common use include ACP hydrolyase, ACP phosphodiesterase, AcpH, and [acyl-carrier-protein] 4'-pantetheine-phosphohydrolase. This enzyme participates in pantothenate and coa biosynthesis.
Structural studies.
As of late 2007, two structures have been solved for this class of enzymes, with PDB accession codes and .


Nuclear cap-binding protein complex

Nuclear cap-binding protein complex is a RNA-binding protein which binds to the 5' cap of pre-mRNA. The cap and nuclear cap-binding protein have many functions in mRNA biogenesis including splicing, 3'-end formation by stabilizing the interaction of the 3'-end processing machinery, nuclear export and protection of the transcripts from nuclease degradation. When RNA is exported to the cytoplasm the nuclear cap-binding protein complex is replaced by cytoplasmic cap binding complex. The nuclear cap-binding complex is a functional heterodimer and composed of Cbc1/Cbc2 in yeast and CBC20/CBC80 in multicellular eukaryotes. Human nuclear cap-binding protein complex shows the large subunit, CBC80 consists of 757 amino acid residues. Its secondary structure contains approximately sixty percent of helical and one percent of beta sheet in the strand. The small subunit, CBC20 has 98 amino acid residues. Its secondary structure contains approximately twenty percent of helical and twenty-four percent of beta sheet in the strand. Human nuclear cap-binding protein complex plays important role in the maturation of pre-mRNA and in uracil-rich small nuclear RNA.


24,25-Dihydroxycholecalciferol

24,25-Dihydroxycholecalciferol, also known as 24,25-dihydroxyvitamin D3 and (24"")-hydroxycalcidiol (abbreviated as 24(R),25-(OH)2D3), is a compound which is closely related to 1,25-dihydroxyvitamin D3, the active form of vitamin D3. Like vitamin D3 itself and calcifediol (25-hydroxyvitamin D3), it is inactive as a hormone both "in vitro" and "in vivo". It was first identified in 1972 in the laboratory of Hector DeLuca and Michael F. Holick.
Formation and significance.
24,25-dihydroxyvitamin D3 is formed from 25-hydroxyvitamin D3 by the action of CYP24A1 (25-hydroxyvitamin D3-24-hydroxylase). CYP24A1 appears to be "a multicatalytic enzyme catalyzing most, if not all, of the reactions in the C-24/C-23 pathway of 25-OH-D3 metabolism."
It has been proposed that 24,25-dihydroxyvitamin D3 is a metabolite of 25-hydroxyvitamin D3 which is destined for excretion.
It is not known whether the compound might also have some physiologically significant activity. Some evidence of a possible receptor has been obtained.


Glycoside hydrolase family 3

Hello Kevin. In molecular biology, glycoside hydrolase family 3 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 over 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 3 CAZY GH_3 comprises enzymes with a number of known activities; beta-glucosidase (EC 3.2.1.21); beta-xylosidase (); N-acetyl beta-glucosaminidase (EC 3.2.1.52); glucan beta-1,3-glucosidase (); cellodextrinase (); exo-1,3-1,4-glucanase (). These enzymes are two-domain globular proteins that are N-glycosylated at three sites.


2-dehydro-3-deoxy-D-pentonate aldolase

In enzymology, a 2-dehydro-3-deoxy-D-pentonate aldolase () is an enzyme that catalyzes the chemical reaction
Hence, this enzyme has one substrate, 2-dehydro-3-deoxy-D-pentonate, and two products, pyruvate and glycolaldehyde.
This enzyme belongs to the family of lyases, specifically the aldehyde-lyases, which cleave carbon-carbon bonds. The systematic name of this enzyme class is 2-dehydro-3-deoxy-D-pentonate glycolaldehyde-lyase (pyruvate-forming). Other names in common use include 2-keto-3-deoxy-D-pentonate aldolase, 3-deoxy-D-pentulosonic acid aldolase, and 2-dehydro-3-deoxy-D-pentonate glycolaldehyde-lyase. This enzyme participates in pentose and glucuronate interconversions.


Clofenamide

Clofenamide (or diumide) is a low-ceiling sulfonamide diuretic.


Virus-like particle

Virus-like particles (VLPs) are molecules that closely resemble viruses, but are non-infectious because they contain no viral genetic material. They can be naturally occurring or synthesized through the individual expression of viral structural proteins, which can then self assemble into the virus-like structure. Combinations of structural capsid proteins from different viruses can be used to create recombinant VLPs. VLPs derived from the Hepatitis B virus (HBV) and composed of the small HBV derived surface antigen (HBsAg) were described in 1968 from patient sera. VLPs have been produced from components of a wide variety of virus families including Parvoviridae (e.g. adeno-associated virus), Retroviridae (e.g. HIV), Flaviviridae (e.g. Hepatitis C virus), Paramyxoviridae (e.g. Nipah) and bacteriophages (e.g. Qβ, AP205). VLPs can be produced in multiple cell culture systems including bacteria, mammalian cell lines, insect cell lines, yeast and plant cells.
VLPs can also refer to structures produced by some LTR retrotransposons (under Ortervirales) in nature. These are defective, immature virions, sometimes containing genetic material, that are generally non-infective due to the lack of a functional viral envelope. In addition, wasps produce polydnavirus vectors with pathogenic genes (but not core viral genes) or gene-less VLPs to help control their host.
Applications.
Therapeutic and imaging agents.
VLPs are a candidate delivery system for genes or other therapeutics. These drug delivery agents have been shown to effectively target cancer cells "in vitro". It is hypothesized that VLPs may accumulate in tumor sites due to the enhanced permeability and retention effect, which could be useful for drug delivery or tumor imaging.
Vaccines.
VLPs are useful as vaccines. VLPs contain repetitive, high density displays of viral surface proteins that present conformational viral epitopes that can elicit strong T cell and B cell immune responses.; the particles' small radius of roughly 20-200 nm allows for sufficient draining into lymph nodes. Since VLPs cannot replicate, they provide a safer alternative to attenuated viruses. VLPs were used to develop FDA-approved vaccines for Hepatitis B and human papillomavirus, which are commercially available.
There are currently a selection of vaccines against human papilloma virus (HPV) such as Cervarix by GlaxoSmithKline along with Gardasil and Gardasil-9, produced by Merck & Co. Gardasil consists of recombinant VLPs assembled from the L1 proteins of HPV types 6, 11, 16, and 18 expressed in yeast and is adjuvanted with aluminum hydroxyphosphate sulfate. Gardasil-9 consists of L1 epitopes of 31, 33, 45, 52 and 58 in addition to the listed L1 epitopes found in Gardasil. Cervarix consists of recombinant VLPs assembled from the L1 proteins of HPV types 16 and 18, expressed in insect cells, and is adjuvanted with 3-O-Desacyl-4-monophosphoryl lipid (MPL) A and aluminum hydroxide.
The first VLP vaccine that addresses malaria, Mosquirix, (RTS,S) has been approved by regulators in the EU. It was expressed in yeast. RTS,S is a portion of the Plasmodium falciparum circumsporozoite protein fused to the Hepatitis B surface antigen (RTS), combined with Hepatitis B surface antigen (S), and adjuvanted with AS01 (consisting of (MPL)A and saponin).
Research suggests that VLP vaccines against influenza virus could provide stronger and longer-lasting protection against flu viruses than conventional vaccines. Production can begin as soon as the virus strain is sequenced and can take as little as 12 weeks, compared to 9 months for traditional vaccines. In early clinical trials, VLP vaccines for influenza appeared to provide complete protection against both the Influenza A virus subtype H5N1 and the 1918 flu pandemic. Novavax and Medicago Inc. have run clinical trials of their VLP flu vaccines.
VLPs have also been used to develop a pre-clinical vaccine candidate against chikungunya virus.
Lipoparticle technology.
The VLP lipoparticle was developed to aid the study of integral membrane proteins. Lipoparticles are stable, highly purified, homogeneous VLPs that are engineered to contain high concentrations of a conformationally intact membrane protein of interest. Integral Membrane proteins are involved in diverse biological functions and are targeted by nearly 50% of existing therapeutic drugs. However, because of their hydrophobic domains, membrane proteins are difficult to manipulate outside of living cells. Lipoparticles can incorporate a wide variety of structurally intact membrane proteins, including G protein-coupled receptors (GPCR)s, ion channels and viral Envelopes. Lipoparticles provide a platform for numerous applications including antibody screening, production of immunogens and ligand binding assays.
Assembly.
The understanding of self-assembly of VLPs was once based on viral assembly. This is rational as long as the VLP assembly takes place inside the host cell ("in vivo"), though the self-assembly event was found "in vitro" from the very beginning of the study about viral assembly. Study also reveals that "in vitro" assembly of VLPs competes with aggregation and certain mechanisms exist inside the cell to prevent the formation of aggregates while assembly is ongoing.
Linking targeting groups to VLP surfaces.
Attaching proteins, nucleic acids, or small molecules to the VLP surface, such as for targeting a specific cell type or for raising an immune response is useful. In some cases a protein of interest can be genetically fused to the viral coat protein. However, this approach sometimes leads to impaired VLP assembly and has limited utility if the targeting agent is not protein-based. An alternative is to assemble the VLP and then use chemical crosslinkers, reactive unnatural amino acids or SpyTag/SpyCatcher reaction in order to covalently attach the molecule of interest. This method is effective at directing the immune response against the attached molecule, thereby inducing high levels of neutralizing antibody and even being able to break tolerance to self-proteins displayed on VLPs.


Piericidin A

Piericidin A is an antibiotic agent. It was discovered from Streptomyces mobaraensis. Being an inhibitor of NADH dehydrogenase, it inhibits electron transfer; its structure resembles that of the ubiquinone, therefore it competes with QB for binding sites in NADH dehydrogenase as well as Photosystem II.


Isomaltulose

Isomaltulose is a disaccharide carbohydrate composed of glucose and fructose. The glucose and fructose are linked by an alpha-1,6-glycosidic bond (chemical name: 6-"0"-α--glucopyranosyl--fructose). Isomaltulose is present in honey and sugarcane extracts. It tastes similar to sucrose (table sugar) with half the sweetness. Isomaltulose, also known by the trade name Palatinose, is manufactured by enzymatic rearrangement (isomerization) of sucrose from beet sugar. The enzyme and its source were discovered in Germany in 1950, and since then its physiological role and physical properties have been studied extensively. Isomaltulose has been used as an alternative to sugar in foods in Japan since 1985, in the EU since 2005, in the US since 2006, and in Australia and New Zealand since 2007, besides other countries worldwide. Analytical methods for characterization and assay of commercial isomaltulose are laid down, for example, in the Food Chemicals Codex. Its physical properties closely resemble those of sucrose, making it easy to use in existing recipes and processes.
Isomaltulose is hydrogenated to produce isomalt, a minimally digestible carbohydrate that is used as a sugar replacer, for example in sugar-free candies and confectionery.
Like sucrose, isomaltulose can be digested to glucose and fructose. However, while in sucrose the glucose is linked to the anomeric carbon of the fructose (an α-1,2 linkage), in isomaltulose the linkage is to the 6 carbon (α-1,6), making isomaltulose a reducing sugar, unlike sucrose. The fructose in isomaltulose exists in a ring structure that readily opens to exhibit a carbonyl group as in ketones and aldehydes, which explains why isomaltulose is a reducing sugar. In comparison with sucrose and most other carbohydrates, isomaltulose is not a significant substrate for oral bacteria. Consequently, acid production from isomaltulose in the mouth is too slow to promote tooth decay.
Function.
In nutrition, isomaltulose is a source of food energy, providing the same amount of energy as sucrose. Like sucrose, isomaltulose provides sweetness to foods, but isomaltulose is only about half as sweet as sucrose. In food preparation and processing, both isomaltulose and sucrose have similar characteristics allowing recipes that use sucrose able to use isomaltulose instead or together.
Available carbohydrate.
Isomaltulose is an available carbohydrate like sucrose and most other sugars or maltodextrins, in the sense that it is fully metabolised in the small intestine, and does not enter the large intestine or get excreted in urine.
When eaten by humans, isomaltulose is digested completely and absorbed. Its intestinal digestion involves the enzyme isomaltase, which is located at the surface of the brush border lining the inner wall of the small intestine. This enzyme is otherwise involved in the digestion of α-1,6 linkages present in starch. The products of isomaltulose digestion are glucose and fructose, which are absorbed and enter the bloodstream. Once absorbed, the glucose and fructose follow the same metabolic pathways through the body as if they were derived from sucrose. While fructose is mostly converted to glucose or glycogen stores in the liver, glucose from the small intestine and liver is distributed via the circulatory system to different parts of the body where it serves cellular metabolism as an energy source directly or indirectly after storage as glycogen in the tissues of the body, especially in skeletal muscle.
Source of energy.
As an available carbohydrate, the food energy value of isomaltulose is identical to that of sucrose. For both, it is 4 kcal/g (17 kJ/g), a value that is used in food labelling or dietary planning.
Slow and sustained release of carbohydrate and energy.
Isomaltulose is slow to be digested and absorbed, and is therefore gradually released as glucose and fructose into the bloodstream. After ingestion, the enzymatic digestion of sucrose and isomaltulose occur on the same sucrase-isomaltase enzyme complex, which is located in the small intestine. Several studies show that this complex breaks down isomaltulose more slowly than sucrose. The maximum rate at which isomaltase can process isomaltulose (Vmax) is 4.5 times lower than that of sucrase for sucrose.
As a result of its slow digestion, isomaltulose travels further through the human small intestine than does sucrose, as evidenced by the difference in incretin responses they elicit. The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is secreted from the earlier (proximal) part of the small intestine in lower amounts after ingestion of isomaltulose than sucrose, whereas the incretin hormone glucagon-like peptide-1 (GLP-1) is secreted from a later (distal) part of the small intestine in higher amounts with isomaltulose than with sucrose.
Compared with sucrose, the absorption of energy as carbohydrate from isomaltulose is prolonged. The resulting sustained energy supply to the body from isomaltulose is reflected in the prolonged shape of the blood glucose concentration response curve.
Lower blood glucose and insulin response.
The blood glucose and insulin concentrations after ingestion of isomaltulose are lower than those due to sucrose or glucose, giving isomaltulose a glycemic index (GI) of 32 as recorded in the Sydney University GI database, compared to 67 for sucrose and 100 for glucose, making isomaltulose a particularly low-GI carbohydrate (GI<55).
Confirmation of a low glycaemic response to isomaltulose is provided in numerous studies for different population groups including healthy people, overweight or obese persons, prediabetic persons, and type 1 or type 2 diabetes patients. Among these studies, all show the lower blood glucose response of isomaltulose and where tested also show the associated reduction in the blood insulin response. A significant role for the incretin hormone GLP-1 has been established, which is secreted in response to distal carbohydrate absorption and limits the rise in blood glucose concentration after a meal.
A claim corresponding to the low glycemic response of isomaltulose and its potential to lower the blood glucose response to foods when replacing other sugars has been approved in EU legislation following the publication of a positive opinion from the European Food Safety Authority.<ref name="EFSA 2011/2076"></ref>
In the long term, when eating a diet including carbohydrate, avoiding undesirably high concentrations of glucose in blood and the associated demand for insulin, is supportive of the prevention and management of diabetes mellitus, cardiovascular disease, and possibly overweight and obesity—as indicated by the International Carbohydrate Quality Consortium consensus of expert nutrition scientists. Continuous monitoring of 24-h blood glucose concentration following diets including isomaltulose instead of sucrose lowers the blood glucose profile over the day, as a result of a lower blood glucose response to individual meals.
A lower glycemic diet can be achieved by choosing foods with low or reduced glycemic properties, more specifically by choosing lower GI foods from within each food group (fruit, vegetable, whole grains, etc.). The use of Isomaltulose in place of sucrose and other carbohydrates allows for the production of foods with reduced GI. Several studies provide evidence of improvements in both blood glucose control and lipid metabolism in both diabetic and non-diabetic persons upon regular consumption of isomaltulose when compared with other carbohydrates such as sucrose, maltodextrin, or glucose.
Effect on fat oxidation.
Compared to other carbohydrates, isomaltulose ingestion is associated with higher rates of fat oxidation and lower rates of fat storage. First, isomaltulose "dives" under entsymatic radar surpassin GIP producing upper part of the small intestine. It finds the degrading entsyme deep down in the GLP part of the intestine. GLP/GIP balance favors late insulin secretion, and shuts down glucagon secretion. Thus the release or new production of liver glucose is slowed down. Mechanistically this involves a lower blood glucose concentration with reduced insulin secretion, which in turn allows more fatty acids to be released from adipose tissue for oxidation as an energy source. The lower insulin concentration also decreases carbohydrate oxidation, allowing more fatty acids to be oxidized. A lower insulin concentration also lowers the rate of liver free fatty acid recycling via plasma VLDL triglycerides and reduces the storage of triglycerides in adipose tissue. Practical implications include higher rates of fat oxidation after ingestion of isomaltulose than higher glycaemic carbohydrates. This has been shown in many studies with different areas of focus:
Weight management and body composition.
Studies have looked at the effects on fat oxidation and other metabolic responses when replacing sugars with isomaltulose in meals (or drinks) taken by healthy or overweight to obese adults, with or without impaired glucose tolerance, while largely sedentary. These studies have shown isomaltulose to have a role in reducing adiposity, at least central obesity. Abdominal fat decreases when consuming isomaltulose instead of sucrose (sugar replacement) or instead of breakfast calories (largely carbohydrate replacement). This is brought about at least in part by a lower GIP and higher GLP-1 response when carbohydrate is slow to digest and is absorbed slowly in the lower (distal) small intestine.
Physical activity and sports nutrition.
Others studies have examined the potential benefits of slow and sustained release of carbohydrate during physical activity. Using isomaltulose in place of other ingested carbohydrates, higher rates of fat oxidation also occur during endurance activities, where preserving glycogen is important.
In addition, trials using a recovery protein drink have shown that incorporating isomaltulose and a nutritional supplement (β-hydroxy- β-methylbutyrate ) may help recovery from resistance exercise—so reducing of muscle damage and improving athletic performance.
Type 1 diabetes patients engaging in physical activity.
In people with type 1 diabetes, taking isomaltulose instead of glucose during moderate carbohydrate loading before exercise improves blood glucose control and protects against hypoglycemia while maintaining running performance. The reduced risk of exercise-induced hypoglycemia arises in part from a lower requirement for insulin by injection (50% lower) when using isomaltulose and in part from the higher contribution of fat oxidation to energy metabolism, which preserves glycogen stores, further reducing the risk of hypoglycemia.
Cognitive performance (mood and memory).
The rate of glucose supply from dietary carbohydrates can affect cognitive performance, with effects on mood and memory having been shown in several studies that compared isomaltulose with higher glycaemic carbohydrates taken at breakfast, showing improvements in mood and memory in healthy children, middle-aged adults, and aged adults.
Oral health.
Isomaltulose is ‘kind to teeth’. Fermentation of carbohydrates by bacteria in the mouth (especially on the teeth) is responsible for the formation of dental plaque and oral acids. The acid initiates tooth demineralisation and tooth decay (dental caries). Isomaltulose largely resists fermentation by oral bacteria and is the first carbohydrate of its kind with negligible acid production on teeth, as shown by pH telemetry. The evidence is strong and provides the basis for ‘kind to teeth’ claims approved by both the Food and Drug Administration in the USA and European authorities following a positive opinion from the European Food Safety Authority.
Use.
Isomaltulose is used in foods, drinks and health products owing to several of its properties. It is used in foods and beverages, where it provides a natural sucrose-like sweetness profile with a sweetening power about half that of sucrose, and no aftertaste. It has very low moisture absorption (hygroscopy), giving it free-flowing properties in instant powders, which because of their low risk of lumping can easily be used in drinks and other instant products. It is highly stable during processing, including acidic conditions and environments where bacteria might grow. In sports beverages, for instance, isotonicity (osmotic pressure equal to that of fluids in the body) can be maintained during storage over the beverage's shelf-life.
Isomaltulose finds application in baked goods, pastry glazings and icings, breakfast cereals, cereal bars, dairy produce, sugar confectionery (e.g. chocolates, jellies, chewy confections and chewing or bubble gum), frozen desserts, fruit-juice beverages, malt beverages, sports beverages, energy drinks, instant drinks, and special and clinical nutrition feeds.
Isomaltulose in permitted for use in foods and drinks in many regions worldwide. For example, it is generally recognized as safe (GRAS) by the U.S. Food and Drug Administration, is approved as a novel food by the European Commission, and in Japan has the status FOSHU (food for specific health use).


Monocarboxylate transporter

The monocarboxylate transporters, or MCTs, are a family of proton-linked
plasma membrane transporters that carry molecules having one carboxylate group (monocarboxylates), such as lactate and pyruvate, across biological membranes. MCTs are expressed in nearly every kind of cell.
Lactate and the Cori cycle.
Lactate has long been considered a byproduct resulting from glucose breakdown through glycolysis during anaerobic metabolism. Glycolysis requires the coenzyme NAD+, and reduces it to NADH. As a means of regenerating NAD+ to allow glycolysis to continue, lactate dehydrogenase catalyzes the conversion of pyruvate to lactate in the cytosol, oxidizing NADH to NAD+. Lactate is then transported from the peripheral tissues to the liver. There it is reformed into pyruvate and ultimately to glucose, which can travel back to the peripheral tissues, completing the Cori cycle.
Thus, lactate has traditionally been considered a toxic metabolic byproduct that could give rise to fatigue and muscle pain during anaerobic respiration. Lactate can be thought of essentially as payment for "oxygen debt", defined by Hill and Lupton as the "total amount of oxygen used, after cessation of exercise in recovery there from".
Clinical significance.
Highly malignant tumors rely heavily on aerobic glycolysis (metabolism of glucose to lactic acid even under presence of oxygen; Warburg effect) and thus need to efflux lactic acid via MCTs to the tumor micro-environment to maintain a robust glycolytic flux and to prevent the tumor from being "pickled to death". The MCTs have been successfully targeted in pre-clinical studies using RNAi and a small-molecule inhibitor alpha-cyano-4-hydroxycinnamic acid (ACCA; CHC) to show that inhibiting lactic acid efflux is a very effective therapeutic strategy against highly glycolytic malignant tumors.
See also.
Monocarboxylate transporters:


DNAJC3

DnaJ homolog subfamily C member 3 is a protein that in humans is encoded by the "DNAJC3" gene.
Function.
The protein encoded by this gene contains multiple tetratricopeptide repeat (TPR) motifs as well as the highly conserved J domain found in DNAJ chaperone family members. It is a member of the tetratricopeptide repeat family of proteins and acts as an inhibitor of the interferon-induced, dsRNA-activated protein kinase (PKR).
Clinical significance.
The DNAJC3 protein is an important apoptotic constituent. During a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response. It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.
Moreover, an important role for DNAJC3 has been attributed to diabetes mellitus as well as multi system neurodegeneration. Diabetes mellitus and neurodegeneration are common diseases for which shared genetic factors are still only partly known. It was shown that loss of the BiP (immunoglobulin heavy-chain binding protein) co-chaperone DNAJC3 leads to diabetes mellitus and widespread neurodegeneration. Accordingly, three siblings were investigated with juvenile-onset diabetes and central and peripheral neurodegeneration, including ataxia, upper-motor-neuron damage, peripheral neuropathy, hearing loss, and cerebral atrophy. Subsequently, exome sequencing identified a homozygous stop mutation in DNAJC3. Further screening of a diabetes database with 226,194 individuals yielded eight phenotypically similar individuals and one family carrying a homozygous DNAJC3 deletion. DNAJC3 was absent in fibroblasts from all affected subjects in both families. To delineate the phenotypic and mutational spectrum and the genetic variability of DNAJC3, 8,603 exomes were further analyzed, including 506 from families affected by diabetes, ataxia, upper-motor-neuron damage, peripheral neuropathy, or hearing loss. This analysis revealed only one further loss-of-function allele in DNAJC3 and no further associations in subjects with only a subset of the features of the main phenotype. Notably, the DNAJC3 protein is also considered as an important marker for stress in the endoplasmatic reticulum.
Interactions.
DNAJC3 has been shown to interact with:


Keratin 8

Keratin, type II cytoskeletal 8 also known as cytokeratin-8 (CK-8) or keratin-8 (K8) is a keratin protein that is encoded in humans by the "KRT8" gene. It is often paired with keratin 18.
Utility as an immunohistochemical stain.
Antibodies to CK8 (e.g. CAM 5.2) can be used to differentiate lobular carcinoma of the breast from ductal carcinoma of the breast. CAM 5.2, an antibody that reacts with an epitope found on both CK8 and CK18, is used in immunohistochemistry to demonstrate certain forms of cancer. In normal tissue, it reacts mainly with secretory epithelia, but not with squamous epithelium, such as that found in the skin, cervix, and esophagus. However, it also reacts with a range of malignant cells, including those derived from secretory epithelia, but also some squamous carcinomata, such as spindle cell carcinoma. It is considered useful in identifying microscopic metastases of breast carcinoma in lymph nodes, and in distinguishing Paget's disease from malignant melanoma. It also reacts with neuroendocrine tumors.
Keratin 8 is often used together with keratin 18 and keratin 19 to differentiate cells of epithelial origin from hematopoietic cells in tests that enumerate circulating tumor cells in blood.
Interactions.
Keratin 8 has been shown to interact with MAPK14, Pinin and PPL.


HR (gene)

Protein hairless is a protein that in humans is encoded by the "HR" gene.
This gene encodes a protein whose function has been linked to hair growth. A similar protein in rat functions as a transcriptional corepressor for thyroid hormone and interacts with histone deacetylases.
Human Genetics.
Variations in this gene are involved in low levels of hair (baldness / alopecia / hypotrichosis) Mutations in this gene in humans have been documented in cases of autosomal recessive congenital alopecia and atrichia with papular lesions.
The protein contains a Zinc finger domain.


Tribenoside

Tribenoside (Glyvenol) is a vasoprotective drug used to treat hemorrhoids. It has mild anti-inflammatory, analgesic, and wound healing properties. Tribenoside stimulates laminin α5 production and laminin-332 deposition to help repair the basement membrane during the wound healing process. It is a mixture of the α- and β-anomers.
Tribenoside has been shown to induce drug hypersensitivity syndrome in association with CMV reactivation.


Prorenoic acid

Prorenoic acid, or prorenoate, is a synthetic steroidal antimineralocorticoid which was never marketed.


Convallarin

Convallarin is a crystalline glucoside extracted from the Lily of the Valley plant ("Convallaria majalis").
It may be obtained from the alcoholic extract of the residue from which the convallamarin has been removed with water. The alcoholic solution is treated with lead acetate, the filtrate freed from lead by hydrogen sulfide, and crystallised by concentration. An aqueous solution froths like soap and water when shaken. By long boiling with diluted acids it is split up into glucose and convallaretin.
It is probably a mixture.
Action and uses.
Convallarin causes nausea and diarrhea.


TRIM33

Tripartite motif-containing 33 (TRIM33) also known as transcriptional intermediary factor 1 gamma (TIF1-γ), is a human gene.
The protein encoded by this gene is thought to be a transcriptional corepressor. However unlike the related TIF1-α and TIF1-β proteins, few transcription factors such as Smad4 that interact with TIF1-γ have been identified.
Structure.
The protein is a member of the tripartite motif family. This motif includes three zinc-binding domains:
and a coiled-coil region.
Three alternatively spliced transcript variants for this gene have been described, however, the full-length nature of one variant has not been determined.
Interactions.
TRIM33 has been shown to interact with TRIM24.
Role in cancer.
TRIM33 acts as a tumor suppressor gene preventing the development chronic myelomonocytic leukemia.
TRIM33 regulates also the TGF-β1 receptor and promotes physiological aging of hematopoietic stem cells.
TRIM33 acts as an oncogene by preventing apoptosis in B-cell leukemias.


Epoxide hydrase

Epoxide hydrase may refer to:


Ethanolamide

Ethanolamides are chemical compounds which are amides formed from carboxylic acids and ethanolamine. Some ethanolamides are naturally occurring, such as anandamide, palmitoylethanolamide and prostamides, which play physiological roles as lipid neurotransmitters and autacoids.
The crystal structure of the membrane enzyme NAPE-PLD has revealed how these endogenous ethanolamides are generated from cell membranes, and that bile acids play a role in their production.
Ethanolamides can be prepared synthetically by heating esters with ethanolamine.


4-hydroxyacetophenone monooxygenase

In enzymology, a 4-hydroxyacetophenone monooxygenase () is an enzyme that catalyzes the chemical reaction:
The 4 substrates of this enzyme are (4-hydroxyphenyl)ethan-1-one, NADPH, H+, and O2, whereas its 3 products are 4-hydroxyphenyl acetate, NADP+, and H2O.
This enzyme belongs to the family of oxidoreductases, specifically those acting on paired donors, with O2 as oxidant and incorporation or reduction of oxygen. The oxygen incorporated need not be derived from O2 with NADH or NADPH as one donor, and incorporation of one atom o oxygen into the other donor. The systematic name of this enzyme class is (4-hydroxyphenyl)ethan-1-one,NADPH:oxygen oxidoreductase (ester-forming). This enzyme is also called HAPMO. This enzyme participates in bisphenol a degradation.


Glycerophosphohydrolase

Glycerophosphohydrolase may refer to:


Rusticyanin

Rusticyanin (RCN) is a copper protein with a type I copper center that plays an integral role in electron transfer. It can be extracted from the periplasm of the gram-negative bacterium Thiobacillus ferrooxidans (T. ferrooxidans), also known as Acidithiobacillus ferrooxidans (At. ferrooxidans). Rusticyanin is also found in the membrane-bound form in the surface of T. ferrooxidans. It is a part of an electron transfer chain for Fe(II) oxidation.
Function.
As T. ferrooxidans can grow aerobically at pH values of 1.6 to 3.5, it obtains its energy for chemolithotrophic growth on soluble ferrous ions. Rusticyanin is involved in the respiratory oxidation of ferrous ions to ferric ions, producing three protons for every ferrous ion oxidized. The mechanism of electron transfer in the respiratory oxidation pathway of Fe2+ in T. ferrooxidans is still unclear despite decades of research in this area. However, the involvement of rusticyanin in shuttling electrons from a cytochrome c2 to another cytochrome c4 during the oxidation of ferrous to ferric ions is experimentally shown. Rusticyanin is thought to shuttle electrons from high molecular weight cytochrome via cytochrome c552 to cytochrome oxidase. Predicted functional partners include coxD (cytochrome c oxidase, aa3-type, subunit IV, 64 amino acids), coxC (cytochrome c oxidase, aa3-type, subunit III, 184 amino acids), ctaB (protoheme IX farnesyltransferase), (cytochrome c, 485 amino acids), AFE_3142 (major facilitator family transporter, 397 amino acids), coxA (cytochrome c oxidase, aa3-type, subunit I, 627 amino acids), Cyc1 (cytochrome c552, 230 amino acids), and AFE_3141 (rrf2 family protein, 146 amino acids).
Reactions.
Fe(II) redox of cytochrome c552 and rusticyanin occurs with the following:
Fe2+[membrane] + an oxidized rusticyanin[membrane] → Fe3+[membrane] + a reduced rusticyanin[membrane];
a reduced rusticyanin[membrane] + an oxidized cytochrome c552[membrane] → an oxidized rusticyanin[membrane] + a reduced cytochrome c552[membrane];
a reduced rusticyanin[outside cell] + an oxidized CycA1 cytochrome[outside cell] → a reduced CycA1 cytochrome[outside cell] + an oxidized rusticyanin[outside cell]


Monacolin J

Monacolin J is a statin made by red yeast rice. Monacolin J is a precursor to simvastatin and has potential neuroprotective activities.


HSPA4

Heat shock 70 kDa protein 4 is a protein that in humans is encoded by the "HSPA4" gene.
The protein encoded by this gene was originally suggested to be a member of the heat shock protein 70 family. However it is now known that human HSPA4 is an equivalent to mouse the Apg-2 protein and is a member of the Hsp110 family.
Interactions.
HSPA4 has been shown to interact with:


Type I keratin

Type I keratins (or Type I cytokeratins) are cytokeratins that constitute the Type I intermediate filaments (IFs) of the intracytoplasmatic cytoskeleton, which is present in all mammalian epithelial cells. Most of the type I keratins consist of acidic, low molecular weight proteins which in vivo are arranged in pairs of heterotypic Type I and Type II keratin chains, coexpressed during differentiation of simple and stratified epithelial tissues.
Type I keratins are encoded on chromosome 17q and encompasses: K9, K10, K11, K12, K13, K14, K15, K16, K17, K18, K19 and K20. Their molecular weight ranges from 40 kDa (K19) to 64 kDa (K9).


3-oxoacyl-(acyl-carrier-protein) reductase (NADH)

In enzymology, a 3-oxoacyl-[acyl-carrier-protein] reductase (NADH) () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are (3R)-3-hydroxyacyl-[acyl-carrier-protein] and NAD+, whereas its 3 products are 3-oxoacyl-[acyl-carrier-protein], NADH, 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 (3R)-3-hydroxyacyl-[acyl-carrier-protein]:NAD+ oxidoreductase. Other names in common use include 3-oxoacyl-[acyl carrier protein] (reduced nicotinamide adenine, dinucleotide) reductase, and 3-oxoacyl-[acyl-carrier-protein] reductase (NADH).


NS-398

NS-398 is a COX-2 inhibitor used in the study of the function of cyclooxygenases.


Chitinase A N-terminal domain

In molecular biology, the chitinase A N-terminal domain is found at the N-terminus of a number of bacterial chitinases and similar viral proteins. It is organised into a fibronectin III module domain-like fold, comprising only beta strands. Its function is not known, but it may be involved in interaction with the enzyme substrate, chitin. It is separated by a hinge region from the catalytic domain; this hinge region is probably mobile, allowing the N-terminal domain to have different relative positions in solution.


Anitrazafen

Anitrazifen is a drug displaying COX-2 inhibitor activity.


COX5B

Cytochrome "c" oxidase subunit 5B, mitochondrial is an enzyme in humans that is a subunit of the cytochrome c oxidase complex, also known as Complex IV, the last enzyme in the mitochondrial electron transport chain. In humans, cytochrome c oxidase subunit 5B is encoded by the COX5B gene.
Structure.
The enzyme weighs 14 kDa and is composed of 129 amino acids. The protein is a subunit of Complex IV, which consists of 13 mitochondrial- and nuclear-encoded subunits. The sequence of subunit Vb is well conserved and includes three conserved cysteines that coordinate the zinc ion. Two of these cysteines are clustered in the C-terminal section of the subunit.
Gene.
The COX5B gene, located on the q arm of chromosome 2 in position 11.2, is made up of 4 exons and is 2,137 base pairs in length.
Function.
Cytochrome "c" oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain. It is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome "c" to oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane to drive ATP synthesis via protonmotive force. The mitochondrially-encoded subunits perform the electron transfer of proton pumping activities. The functions of the nuclear-encoded subunits are unknown but they may play a role in the regulation and assembly of the complex.
Summary reaction:
Clinical significance.
COX5A and COX5B are involved in the regulation of cancer cell metabolism by Bcl-2.
The "Trans"-activator of transcription protein (Tat) of human immunodeficiency virus (HIV) inhibits cytochrome "c" oxidase (COX) activity in permeabilized mitochondria isolated from both mouse and human liver, heart, and brain samples.
Interactions.
COX5B has been shown to interact with Androgen receptor.


Glycoside hydrolase family 97

In molecular biology, glycoside hydrolase family 97 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 97 (GH97) is a bacterial family. The central part of the GH97 family protein sequences represents a typical and complete (beta/alpha)8-barrel or catalytic TIM-barrel type domain. The N- and C-terminal parts of the sequences, mainly consisting of beta-strands, most probably form two additional non-catalytic domains with as yet unknown functions. The non-catalytic domains of glycosidases from the alpha-galactosidase and alpha-glucosidase superfamilies are also predominantly composed of beta-strands, and at least some of these domains are involved in oligomerisation and carbohydrate binding. In all known glycosidases with the (beta-alpha)8-barrel fold, the amino acid residues at the active site are located on the C-termini of the beta-strands.


Fructose 2,6-bisphosphate

Fructose 2,6-bisphosphate, abbreviated Fru-2,6-"P"2, is a metabolite that allosterically affects the activity of the enzymes phosphofructokinase 1 (PFK-1) and fructose 1,6-bisphosphatase (FBPase-1) to regulate glycolysis and gluconeogenesis. Fru-2,6-"P"2 itself is synthesized and broken down by the bifunctional enzyme phosphofructokinase 2/fructose-2,6-bisphosphatase (PFK-2/FBPase-2).
The synthesis of Fru-2,6-"P"2 is performed through a bifunctional enzyme containing both PFK-2 and FBPase-2, which is dephosphorylated, allowing the PFK-2 portion to phosphorylate fructose 6-phosphate using ATP. The breakdown of Fru-2,6-"P"2 is catalyzed by the phosphorylation of the bifunctional enzyme, which allows FBPase-2 to dephosphorylate fructose 2,6-bisphosphate to produce fructose 6-phosphate and Pi.
Effects on glucose metabolism.
Fru-2,6-"P"2 strongly activates glucose breakdown in glycolysis through allosteric modulation (activation) of phosphofructokinase 1 (PFK-1). Elevated expression of Fru-2,6-"P"2 levels in the liver allosterically activates phosphofructokinase 1 by increasing the enzyme’s affinity for fructose 6-phosphate, while decreasing its affinity for inhibitory ATP and citrate. At physiological concentration, PFK-1 is almost completely inactive, but interaction with Fru-2,6-"P"2 activates the enzyme to stimulate glycolysis and enhance breakdown of glucose.
Cellular stress as a result of oncogenesis or DNA damage among others, activates certain genes by the tumor suppressor p53. One such gene is for the expression of TP53-induced glycolysis and apoptosis regulator (TIGAR); an enzyme that inhibits glycolysis, monitors the cellular levels of reactive oxygen species, and protects cells from apoptosis. The structure of TIGAR is shown to be nearly identical to FBPase-2 on the bifunctional enzyme. TIGAR removes the allosteric effector, Fru-2,6-"P"2., therefore the activator does not enhance the affinity of the enzyme (PFK1) for its substrate (fructose 6-phosphate). Furthermore, TIGAR also removes the glycolytic intermediate fructose 1,6-bisphosphate, the product of the PFK catalyzed third reaction of glycolysis and the substrate for the following aldolase fourth reaction of glycolysis.
Production regulation.
The concentration of Fru-2,6-"P"2 in cells is controlled through regulation of the synthesis and breakdown by PFK-2/FBPase-2. The primary regulators of this are the hormones insulin, glucagon, and epinephrine which affect the enzyme through phosphorylation/dephosphorylation reactions. Release of the hormone glucagon triggers production of cyclic adenosine monophosphate (cAMP), which activates a cAMP-dependent protein kinase. This kinase phosphorylates the PFK-2/FBPase-2 enzyme at an NH2-terminal Ser residue with ATP to activate the FBPase-2 activity and inhibit the PFK-2 activity of the enzyme, thus reducing levels of Fru-2,6-"P"2 in the cell. With decreasing amounts of Fru-2,6-"P"2, glycolysis becomes inhibited while gluconeogenesis is activated. Insulin triggers the opposite response. As a phosphoprotein phosphatase, insulin dephosphorylates the enzyme, thus activating the PFK-2 and inhibiting the FBPase-2 activities. With additional Fru-2,6-"P"2 present, activation of PFK-1 occurs to stimulate glycolysis while inhibiting gluconeogenesis.
Regulation of sucrose production.
Fru-2,6-"P"2 plays an important role in the regulation of triose phosphates, the end products of the Calvin Cycle. In the Calvin Cycle, 5/6th of triose phosphates are recycled to make ribulose 1,5-bisphosphate. The remaining 1/6 of triose phosphate can be converted into sucrose or stored as starch. Fru-2,6-"P"2 inhibits production of fructose 6-phosphate, a necessary element for sucrose synthesis. When the rate of photosynthesis in the light reactions is high, triose phosphates are constantly produced and the production of Fru-2,6-"P"2 is inhibited, thus producing sucrose. Fru-2,6-"P"2 production is activated when plants are in the dark and photosynthesis and triose phosphates are not produced.


Chondroitinsulfatase

Chondroitinsulfatase may refer to:


E3 binding protein

E3 binding protein also known as pyruvate dehydrogenase protein X component, mitochondrial is a protein that in humans is encoded by the "PDHX" gene. The E3 binding protein is a component of the pyruvate dehydrogenase complex found only in eukaryotes. Defects in this gene are a cause of pyruvate dehydrogenase deficiency which results in neurological dysfunction and lactic acidosis in infancy and early childhood. This protein is also a minor antigen for antimitochondrial antibodies. These autoantibodies are present in nearly 95% of patients with primary biliary cholangitis, an autoimmune disease of the liver. In primary biliary cholangitis, activated T lymphocytes attack and destroy epithelial cells in the bile duct where this protein is abnormally distributed and overexpressed. Primary biliary cholangitis eventually leads to liver failure.
Structure.
The mRNA encoded by the human PDHX gene is approximately 2.5 kb in length, and expressed primarily in human skeletal and cardiac muscle tissues. The gene has been localized in humans to the 11th chromosome, with the specific location being 11p1.3.
The protein encoded by the human PDHX gene, also known as E3 binding protein (E3BP), is part of the pyruvate dehydrogenase complex, a required complex for cellular respiration that catalyzes the dehydration of pyruvate to Acetyl-CoA. The entire complex is 9.5 MDa in size, and has been described as 60-meric, meaning there are over 60 components that are assembled to make the entire complex. These subunits are conserved across many species, as the function of this complex is essential for the generation of ATP for all eukaryotes. The E3 binding protein directly interacts with the dihydrolipoamide transacetylase (E2) core, anchoring it to the complex. E3BP binds the I domain of E2 by its C-terminal I' domain. The composition of E2.E3BP was thought to be 60 E2 plus approximately 12 E3BP, however, equilibrium sedimentation and small angle x-ray scattering studies showed that the E3BP/E2 binding complex has a lower mass than the E2 subunit alone. Additionally, these studies showed that E3 binds to E2.E3BP outside the central dodecahedron of the PDH complex, and that this interaction creates a lower binding affinity for the E1 subunit. Together, these data support a substitution model, in which the smaller E3BP subunits replace the E2 subunits rather than adding to the 60-mer entire complex. The specific model illustrates 12 I domains of E2 being substituted by 12 I' domains of E3BP, thereby forming 6 dimer edges that are symmetrically located in the dodecahedron structure.
E3BP similarly binds to E3, having linker regions that connect an E3-binding domain and a lipoyl domain.
Crystallography of the complex has shown that, E3BD also binds to E3, though no significant conformational changes occur. In this binding, two E3 subunits come together to form the binding site. This has also shown that E3BP has residues that come into contact with the E3 component across its two-fold axis; this means that there is one binding site for this reaction on the E3 homodimer. Changing the central residues at the E3BD/E3 interface affect binding much more drastically than does changing peripheral residues. This data corroborates the theory of the existence of a “hot spot”. Specifically, there are three hydrophobic residues within the binding domain of E3BP - Pro133, Pro154, and Ile157 – that interact with the surface of both E3 polypeptide chains. This interaction is significantly stabilized by many ionic and hydrogen bonds that take place between the residues of three interacting polypeptide chains adjacent to the central hydrophobic patch. This specificity is most likely due to the lack of conformational flexibility of the binding fragment of E3BP and the complementary amino acid match with the E3 interface.
Function.
The pyruvate dehydrogenase (PDH) complex is located in the mitochondrial matrix and catalyzes the conversion of pyruvate to acetyl coenzyme A. The PDH complex thereby links glycolysis to the citric acid cycle. The PDH complex contains three catalytic subunits, E1, E2, and E3, two regulatory subunits, E1 kinase and E1 phosphatase, and a non-catalytic subunit, E3 binding protein (E3BP). This gene encodes the E3 binding protein subunit; also known as component X of the pyruvate dehydrogenase complex. This protein tethers E3 dimers to the E2 core of the PDH complex.
Clinical significance.
Mutations in the PDHX gene have been known to cause one form of pyruvate dehydrogenase deficiency. Pyruvate dehydrogenase deficiency is characterized by the buildup of a chemical called lactic acid in the body and a variety of neurological problems. Signs and symptoms of this condition usually first appear shortly after birth, and they can vary widely among affected individuals. The most common feature is a potentially life-threatening buildup of lactic acid (lactic acidosis), which can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat. People with pyruvate dehydrogenase deficiency usually have neurological problems as well. Most have delayed development of mental abilities and motor skills such as sitting and walking. Other neurological problems can include intellectual disability, seizures, weak muscle tone (hypotonia), poor coordination, and difficulty walking. Some affected individuals have abnormal brain structures, such as underdevelopment of the tissue connecting the left and right halves of the brain (corpus callosum), wasting away (atrophy) of the exterior part of the brain known as the cerebral cortex, or patches of damaged tissue (lesions) on some parts of the brain. Because of the severe health effects, many individuals with pyruvate dehydrogenase deficiency do not survive past childhood, although some may live into adolescence or adulthood.
While this deficiency primarily results in mutations in the E1 alpha subunit of the PDH complex, a few mutations have been identified in the PDX1 gene. Specific investigations of this gene have identified 78del85 and 965del59 mutations in a homozygous state, while some mutations could not be identified due to no PDHX mRNA being expressed in the individuals. In other cases, it has been reported that an entire exon, exon 10, was removed due to a gross deletion mutation; the mechanism for this has been theorized to be a mispairing, because there is an exact direct repeat, CCACTG, within the gene. Other large deletions (over 3900 bp) have been reported. E3BP, in coordination with the E2 subunit, has also been shown to be a secondary antigen for antimitochondrial antibodies and immune responses. The autoantibodies for this protein are present in the vast majority of patients with primary biliary cirrhosis, a chronic, progressive cholestatic liver disease that usually affects middle-aged women and eventually leads to liver failure.


Death effector domain

The death-effector domain (DED) is a protein interaction domain found only in eukaryotes that regulates a variety of cellular signalling pathways. The DED domain is found in inactive procaspases (cysteine proteases) and proteins that regulate caspase activation in the apoptosis cascade such as FAS-associating death domain-containing protein (FADD). FADD recruits procaspase 8 and procaspase 10 into a death induced signaling complex (DISC). This recruitment is mediated by a homotypic interaction between the procaspase DED and a second DED that is death effector domain in an adaptor protein that is directly associated with activated TNF receptors. Complex formation allows proteolytic activation of procaspase into the active caspase form which results in the initiation of apoptosis (cell death). Structurally the DED domain are a subclass of protein motif known as the death fold and contains 6 alpha helices, that closely resemble the structure of the Death domain (DD).
Structure.
DED is a subfamily of the DD superfamily (other recognizable domains in this superfamily are: caspase-recruitment domain (CARD), pyrin domain (PYD) and death domain (DD)). The subfamilies resemble structurally one another, all of them (and DED in particular) are composed of a bundle of 6 alpha-helices, but they diverge in the surface features.
The complete primary structure of this proteic domain has not been consensually defined. Some studies described residues 2-184, but C-terminus and N-terminus residues are not identified yet. The presence of amino acids that determine the solubility and aggregation to DED allowed to identify DED's in different proteins, such as caspase-8 and MC159. The secondary structure of the domain, as said, is built by 6 alpha-helices.
The tertiary structure of the domain has been described from the crystallization of caspase 8 in the human. The method used to describe the structure was X-RAY diffraction and the resolution obtained is 2.2 Å. DEDs in this protein show an asymmetric unit dimer, with its interface contains two hydrogen bonding networks, that appear as a filamentous structure.
DED's function is determined by its structure. As far as it is known, the homotypic interactions that activate caspase and trigger apoptosis are mediated by asymmetrical surface contacts between partners (like DED1 and DED2 in the caspase-8 case). The residues that form the surfaces are typically charged amino acids, but a short hydrophobic patch can also be observed on the interactive surface of the domain.
Function.
DED domain is best known for its role in apoptosis. However, DED-containing proteins are also involved in other cellular processes so that they control both life and death cell decisions.
Extrinsic apoptosis.
 Apoptosis is a controlled and programmed cell death that confers advantages during an organism lifecycle. The extrinsic pathway is directed by a family of proteases which become active in response to death stimuli. To know the role of DEDs in this process is important to observe the formation of the multiprotein death-including signalling complex (DISC).
DR4, TRAIL-R2 and CD95 are death receptors (members of TNF receptor superfamily) which interact together using their intracellular death domains (DDs). The DD of FADD, a protein containing a DED, can then interact with these DDs described. Here the function of FADD DED is to create a stabilized structure by self-associating FADD.
 These interactions are defined by helices α1/α4 and α2/α3: residues Ser1, Val6, His9, Leu43, Asp44 and Glu51 from α1/α4 are in contact with Thr21, Phe25, Lys33, Arg34, Glu37 and Glu51 from α2/α3 of the second molecule. Each interaction involves an area of 1062 Å2 and contributions from hydrophobic side chains, hydrogen bonding and salt bridges. The final homodimer has a structure oriented so that each subunit has the 2 interaction sites.
Procaspase-8, also a DED-containing protein, has affinity for the FADD DED. It's for that reason that they are recruited to FADD as monomers via their DEDs. These interaction is defined by α1/α4 of procapase-8 DED-A and FADD DED α2/α3 or α1/α4 of FADD DED and α2/α5 of procapase-8 DED-B. Procaspase-8 DED-B interacts with FADD and DED-A mediates capase-8 chain formation, or vice versa.
However, in both cases the interaction leads to create a dimer between procaspases, which generates a conformational change. This dimerization is essential to create the active site; a p12 subunit is liberated and it is subsequently processed to the small p10 subunit. The two molecules of procapase-8 are associated with these p10 subunits creating an active protease-8 cell death.
Necroptosis.
 During the creation of the DISC procaspase-8 can also heterodimerise with another DED-containing protein known as FLIPL. FLIPL’s pseudo-caspase has two tandem DEDs that are very similar to the N-terminus of capase-8, but in which there is an important mutation in the active site (cysteine to tyrosine).
This heterodimeration done between their DEDs prevents from the normal homodimeration so that the pseudo-caspase is unable to activate the apoptotic cascade. FLIPL ’s pseudo-caspase is more efficient at inducing the conformational change. However, FLIPL hasn’t enough enzymatic activity so that cleavage between the DEDs and p18 it’s not possible. In consequence it’s impossible to create the active protease cell death.
Procaspase-8 can also heterodimerise with FLIPS, also a DED containing protein. In this case heterodimerisation directly fails to activate procaspase-8 as the initial conformational change cannot take place in procaspase-8’s caspase domain.
This is how DED can also inhibit the apoptosis cascade, and the consequence is necroptosis.
The DED protein family.
DED-containing proteins.
Caspase-8 and caspase-10.
 Caspases are cysteine proteases responsible for dismantling off the cell during apoptosis.
These proteins are zymogens and become active after their cleavage at specific sites within the molecule.
Structure:
There are two groups of proteases:
The two tandem DEDs in the pro-domain of caspase induce the protein-protein interactions with other proteins like the FADD.
Studying caspases is important since they don’t only control apoptosis but also inhibit it, depending on the necessity of the cell. Scientists find that they are a mechanism that can regulate cell life and is important for cancer therapies.
FLICE-like inhibitory proteins (FLIPs).
FLICE-like inhibitory proteins (FLIPs) are cell inhibitors capable of stopping the death receptors’ signal, which cause cell apoptosis.
The first FLIPs that were identified were expressed by γ-herpes viruses so they were called v-FLIPs. These v-FLIPs were able to associate with the receptor in the death-inducing signaling complex (DISC), blocking that way the CD95-mediated apoptosis.
vFLIPs predominantly contain two sequential DEDs, which are highly homologous to the N-terminus of caspase-8.
 The cellular homologues of v-FLIPs are generally expressed in two forms:
 Both forms of c-FLIP are draft to the CD95 DISC, where they heterodimerize with caspase-8. c-FLIP has been involved in signaling alternative pathways, connecting the CD95 receptor to the NF-κB, JNK and MAPK pathways.
PEA-15/PED.
PEA-15 (Phosphoprotein Enriched in Astrocytes-15 kDa) also known as PED (Phosphoprotein Enriched in Diabetes) is a DED-containing protein with pleiotropic effects.
PED is a small, non-catalytic, protein consisting of an N-terminal death-effector domain (DED) and a C-terminal tail with irregular structure. PED/PEA-15 interacts with various types of proteins with and without DEDs, and its specificity of joining these proteins is mediated by the phosphorylation on two serine residues on the C-terminal tail:
 PEA-15 works as an antiapoptotic DED protein in several signaling cascades. In TNF α-, CD95- and TRAIL-mediated pathways, PEA-15 acts binding and disrupting FADD and caspase-8 interactions.
 Besides apoptosis, PEA-15 inhibits the insulin-mediated glucose transport in muscle cells, so a high level expression of PEA-15's mRNA has been associated to diabetes mellitus type II.
DEDD/DEDD2.
Death effector domain containing DNA binding (DEDD). Shows DNA binding capacity, localized in the nucleoli in overexpression where it associates with a molecule called DEDAF (DED-associated factor) that potentiates apoptosis. In addition it blocks RNA polymerase I transcription by binding to the DNA.
DEDD2 (FLAME-3) is a DEDD homologue that shares a 48.5% of the amino acidic sequence. It is noted to interact with c-FLIP and DEDD and to have an important role in polymerase II-dependent transcription repression.
Proteins with a DED-related domain.
HIP-1 and HIPPI.
Huntingtin interacting protein-1 (HIP-1) is a protein that interacts with huntingtin (Htt), another protein that when is mutated (with expanded polyglutamine repeats) forms protein aggregates in the brain of patients with Huntington's disease (HD).
 HIP-1 contains a pseudo death effector domain (pDED), that's why the overexpression of HIP-1 induces apoptosis in several cells as DED proteins do. This type of apoptosis depends on the pDED of the HIP-1, and it consists in the activation of caspase-3, an enzyme that is reduced when wild-type Htt is expressed, that fact suggests that HIP-1 cooperates with Htt in the pathomechanism of Huntington's disease.
 By yeast two-hybrid screening, HIP-1 has shown to interact with a protein of 419 amino acids called HIPPI (HIP-1 protein interactor). Succeeding experiments have revealed that the presence of HIPPI determines the HIP-1-induced apoptosis.
FLASH.
FLICE-associated huge protein. Contains a similar domain to DED, but the homology is very weak and its function is still unclear.
Therapeutically exploiting DED.
 DED complexes have been shown to function at crucial steps controlling life and death cell processes. This knowledge is particularly useful in therapy because there are so many pathologies related with an abnormal control of the cell life.
The absence of apoptosis is feature of cancer. In some cases the gene encoding procaspase-8 is silenced by methylation, so it is necessary to activate the gene using epigenetic treatments to have active protease.
In other cases there is an overexpression of FLIP, the anti-apoptotic molecule that prevents from the formation of the active caspase. In this case there are some anti-cancer agents that downregulate FLIP expression.
However, the abnormal apoptosis it is not exclusive from cancer, there are other pathologies such as inflammation and neurodegenerative diseases than can also be treated with these kind of therapeutics.


Alpha-fucosidase

Alpha-fucosidase may refer to one of two enzymes:


2-hydroxyisoflavanone dehydratase

In enzymology, a 2-hydroxyisoflavanone dehydratase () is an enzyme that catalyzes the chemical reaction
Hence, this enzyme has one substrate, 2,7,4'-trihydroxyisoflavanone, and two products, daidzein 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 2,7,4'-trihydroxyisoflavanone hydro-lyase (daidzein-forming). This enzyme is also called 2,7,4'-trihydroxyisoflavanone hydro-lyase. This enzyme participates in isoflavonoid biosynthesis.


Anthranilate 3-hydroxylase

Anthranilate 3-hydroxylase may refer to:


Sorbitan monooleate

Sorbitan monooleate is a food additive with the E number E494.


Uridine diphosphate glucose

Uridine diphosphate glucose (uracil-diphosphate glucose, UDP-glucose) is a nucleotide sugar. It is involved in glycosyltransferase reactions in metabolism.
Functions.
UDP-glucose is used in nucleotide sugar metabolism as an activated form of glucose, a substrate for enzymes called glucosyltransferases.
UDP-glucose is a precursor of glycogen and can be converted into UDP-galactose and UDP-glucuronic acid, which can then be used as substrates by the enzymes that make polysaccharides containing galactose and glucuronic acid.
UDP-glucose can also be used as a precursor of sucrose, lipopolysaccharides and glycosphingolipids.
Components.
UDP-glucose consists of the pyrophosphate group, the pentose sugar ribose, glucose, and the nucleobase uracil.


BsuBI/PstI restriction endonuclease

In molecular biology, the BsuBI/PstI restriction endonuclease family is a family of type II restriction endonucleases. It includes BsuBI and PstI. The enzymes of the BsuBI restriction/modification (R/M) system recognise the target sequence 5'CTGCAG and are functionally identical with those of the PstI R/M system.


Mitochondrial trifunctional protein deficiency

Mitochondrial trifunctional protein deficiency (MTP deficiency or MTPD) is an autosomal recessive fatty acid oxidation disorder that prevents the body from converting certain fats to energy, particularly during periods without food. People with this disorder have inadequate levels of an enzyme that breaks down a certain group of fats called long-chain fatty acids.
Signs and symptoms.
The presentation of mitochondrial trifunctional protein deficiency may begin during infancy, features that occur are: low blood sugar, weak muscle tone, and liver problems. Infants with this disorder are at risk for heart problems, breathing difficulties, and pigmentary retinopathy. Signs and symptoms of mitochondrial trifunctional protein deficiency that may begin "after" infancy include hypotonia, muscle pain, a breakdown of muscle tissue, and a loss of sensation in the extremities called peripheral neuropathy. Some who have MTP deficiency show a progressive course associated with myopathy, and recurrent rhabdomyolysis.
Genetics.
The genetics of mitochondrial trifunctional protein deficiency is based on mutations in the HADHA and HADHB genes which cause this disorder. These genes each provide instructions for making part of an enzyme complex called mitochondrial trifunctional protein. This enzyme complex functions in mitochondria, the energy-producing centers within cells: mitochondrial trifunctional protein contains three enzymes that each perform a different function. This enzyme complex is required to metabolize a group of fats called long-chain fatty acids. These fatty acids are stored in the body's fat tissues and are a major source of energy for the heart and muscles. During periods of fasting, fatty acids are also an important energy source for the liver and other tissues.
Mutations in the HADHA or HADHB genes that cause mitochondrial trifunctional protein deficiency disrupt all functions of this enzyme complex. Without enough of this enzyme complex, long-chain fatty acids cannot be metabolized. As a result, these fatty acids are not converted to energy, which can lead to some features of this disorder. Long-chain fatty acids may also build up and damage the liver, heart, and muscles. This abnormal buildup causes other symptoms of mitochondrial trifunctional protein deficiency.
The "mechanism" of this condition indicates that the mitochondrial trifunction protein catalyzes 3 steps in mitochondrial beta-oxidation of fatty acids: long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain enoyl-CoA hydratase, and long-chain thiolase activities. Trifunctional protein deficiency is characterized by decreased activity of all 3 enzymes. Clinically, trifunctional protein deficiency usually results in sudden unexplained infant death, cardiomyopathy, or skeletal myopathy.
Diagnosis.
Diagnosis of mitochondrial trifunctional protein deficiency is often confirmed using tandem mass spectrometry. Genetic counseling is available for this condition. Additionally the following exams are available:
Treatment.
Management for mitochondrial trifunctional protein deficiency entails the following:


Spirolactone

Spirolactones are a class of functional group in organic chemistry featuring a cyclic ester attached spiro to another ring system. The name is also used to refer to a class of synthetic steroids, called steroid-17α-spirolactones, 17α-spirolactosteroids, or simply 17α-spirolactones, which feature their spirolactone group at the C17α position. They are antimineralocorticoids, or antagonists of the mineralocorticoid receptor (which is activated predominantly by the mineralocorticoid steroid hormone aldosterone), and have been employed clinically as potassium-sparing diuretics. Some also possess progestogenic and/or antiandrogen properties, which have both contributed to side effects and been utilized for medical indications (e.g., spironolactone as an antiandrogen, and drospirenone as a progestin). The spirolactones were developed by G. D. Searle & Company in the 1950s and thereafter and were denoted as "SC" compounds (e.g., SC-9420 for spironolactone).
The spirolactones include the marketed drugs spironolactone (SC-9420; Aldactone), canrenone (SC-9376; Cantaren, Luvion), potassium canrenoate (SC-14266; Venactone, Soldactone), eplerenone (SC-66110, CGP-30083; Inspra), and drospirenone (ZK-30595; Yasmin). Spirolactones that were not ever marketed include SC-5233, SC-8109, SC-11927 (Catatoxic Steroid 1; CS-1), spiroxasone, prorenone (SC-23133), prorenoate potassium (SC-23992), 7α-thiospironolactone (SC-24813), mexrenone (SC-25152, ZK-32055), dicirenone (SC-26304), 7α-thiomethylspironolactone (SC-26519), mexrenoate potassium (SC-26714), spirorenone (ZK-35973), ZK-91587 (15β,16β-methylenemexrenone), mespirenone (ZK-94679), and ZK-97894 (7α-thiomethylmespirenone). Oxprenoate potassium (RU-28318) is not a spirolactone by definition but is a closely related antimineralocorticoid that was never marketed.
SC-5233 (6,7-dihydrocanrenone), the C17α propanoic acid lactone of testosterone (androst-4-en-17β-ol-3-one), is the unsubstituted parent or prototype compound of the spirolactones, and is one of a few of the simplest members of the series along with SC-8109 (the 19-demethyl analogue of SC-5233) and canrenone (the 1,2-didehydro analogue of SC-5233). Spironolactone is a derivative of SC-5233 with a 7α-acetylthio group (that is, SC-5233 is 7α-desthioacetylspironolactone).


Aspein

Aspein is an unusually acidic bivalve shell matrix protein, which may have important roles in calcium carbonate biomineralization. The Aspein gene ("aspein", Uniprot: Q76K52) encodes a sequence of 413 amino acids, including a high proportion of Asp (60.4%), Gly (16.0%), and Ser (13.2%), and the predicted isoelectric point is 1.78. This is the most acidic of all the molluscan shell matrix proteins sequenced so far, or probably even of all known proteins on earth. The main body of aspein is occupied by (Asp)2–10 sequences punctuated with Ser–Gly dipeptides. RT-PCR demonstrated that the transcript of aspein is expressed at the outer edge of the mantle, corresponding to the calcitic prismatic layer, but not at the inner part of the mantle, corresponding to the aragonitic nacreous layer. Aspein is likely responsible for directed formation of calcite in the shell of the pearl oyster "Pinctada fucata".


TECTB

Beta-tectorin is a protein that in humans is encoded by the "TECTB" gene.
Function.
The genes for alpha-tectorin and beta-tectorin (this protein) encode the major noncollagenous proteins of the tectorial membrane of the cochlea.


E-64

E-64 is an epoxide which can irreversibly inhibit a wide range of cysteine peptidases.
The compound was first isolated and identified from "Aspergillus japonicus" in 1978. It has since been shown to inhibit many cysteine peptidases such as papain, cathepsin B, cathepsin L, calpain and staphopain.
The low toxic effects of the inhibitor, in addition to its effective mechanism of action, makes E-64 a potential template for drugs to treat diseases where high levels of a cysteine proteases are the primary cause.
Structure and mechanism of inhibition.
E-64 possesses a "trans"-epoxysuccinic acid group coupled to a modified dipeptide. The covalent attachment of E-64 to the active site cysteine occurs via nucleophillic attack from the thiol group of the cysteine on C2 of the epoxide. Early studies suggested that the amino-4-guanidinobutane bound in the S3' subsite and the leucyl group in the S2' subsite, however published crystal structures of E-64 complexed with papain indicated that E-64 binds via the S subsites.


Glucose-regulated protein

Glucose-regulated protein is a protein in the endoplasmic reticulum in the cell.
It comes in several different molecular masses, including:


(S)-6-hydroxynicotine oxidase

In enzymology, a (S)-6-hydroxynicotine oxidase () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are (S)-6-hydroxynicotine, HO, and O, whereas its two products are 1-(6-hydroxypyridin-3-yl)-4-(methylamino)butan-1-one and HO.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-NH group of donors with oxygen as acceptor. The systematic name of this enzyme class is (S)-6-hydroxynicotine:oxygen oxidoreductase. Other names in common use include L-6-hydroxynicotine oxidase, 6-hydroxy-L-nicotine oxidase, and 6-hydroxy-L-nicotine:oxygen oxidoreductase. It employs one cofactor, FAD.


3-hydroxyacyl-coenzyme A dehydrogenase deficiency

3-hydroxyacyl-coenzyme A dehydrogenase deficiency is a rare condition that prevents the body from converting certain fats to energy, particularly during fasting. Normally, through a process called fatty acid oxidation, several enzymes work in a step-wise fashion to metabolize fats and convert them to energy. People with 3-hydroxyacyl-coenzyme A dehydrogenase deficiency have inadequate levels of an enzyme required for a step that metabolizes groups of fats called medium chain fatty acids and short chain fatty acids; for this reason this disorder is sometimes called medium- and short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (M/SCHAD) deficiency.
Signs and symptoms.
Typically, initial signs and symptoms of this disorder occur during infancy or early childhood and can include poor appetite, vomiting, diarrhea, lethargy, hypoglycemia, hypotonia, liver problems, and hyperinsulinism (high levels of insulin). Insulin controls the amount of sugar that moves from the blood into cells for conversion to energy. Individuals with 3-hydroxyacyl-coenzyme A dehydrogenase deficiency are also at risk for complications such as seizures, life-threatening heart and breathing problems, coma, and sudden unexpected death.
Problems related to 3-hydroxyacyl-coenzyme A dehydrogenase deficiency can be triggered by periods of fasting or by illnesses such as viral infections. This disorder is sometimes mistaken for Reye syndrome, a severe disorder that may develop in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections.
Genetics.
Mutations in the "HADH" gene lead to inadequate levels of an enzyme called 3-hydroxyacyl-coenzyme A dehydrogenase. Medium-chain and short-chain fatty acids cannot be metabolized and processed properly without sufficient levels of this enzyme. As a result, these fatty acids are not converted to energy, which can lead to characteristic features of this disorder, such as lethargy and hypoglycemia. Medium-chain and short-chain fatty acids or partially metabolized fatty acids may build up in tissues and damage the liver, heart, and muscles, causing more serious complications.
This condition is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder each carry one copy of the altered gene but do not show signs and symptoms of the disorder.


3-aci-nitropropanoate oxidase

In enzymology, a 3-aci-nitropropanoate oxidase () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are 3-aci-nitropropanoate, O2, and H2O, whereas its 3 products are 3-oxopropanoate, nitrite, and H2O2.
This enzyme belongs to the family of oxidoreductases, specifically those acting on other nitrogenous compounds as donors with oxygen as acceptor. The systematic name of this enzyme class is 3-aci-nitropropanoate:oxygen oxidoreductase. This enzyme is also called propionate-3-nitronate oxidase. It employs one cofactor, FMN.


Diacetyl reductase ((S)-acetoin forming)

Diacetyl reductase ((S)-acetoin forming) (, "(S)-acetoin dehydrogenase") is an enzyme with systematic name "(S)-acetoin:NAD+ oxidoreductase". This enzyme catalyses the following chemical reaction
The reaction is catalysed in the reverse direction. This activity is usually associated with butanediol dehydrogenase activity (EC 1.1.1.4 or EC 1.1.1.76). While the butanediol dehydrogenase activity is reversible, diacetyl reductase activity is irreversible. This enzyme has been reported in the bacteria "Geobacillus stearothermophilus", "Enterobacter aerogenes" and "Klebsiella pneumoniae". Different from EC 1.1.1.303, diacetyl reductase ((R)-acetoin forming).


Fibrillin

Fibrillin is a glycoprotein, which is essential for the formation of elastic fibers found in connective tissue.
Fibrillin is secreted into the extracellular matrix by fibroblasts and becomes incorporated into the insoluble microfibrils, which appear to provide a scaffold
for deposition of elastin.
Clinical aspects.
Marfan syndrome is a genetic disorder of the connective tissue caused by defected FBN1 gene. Mutations in FBN1 and FBN2 are also sometimes associated with adolescent idiopathic scoliosis.
Types.
Fibrillin-1.
Fibrillin-1 is a major component of the microfibrils that form a sheath surrounding the amorphous elastin. It is believed that the microfibrils are composed of end-to-end polymers of fibrillin. To date, 3 forms of fibrillin have been described. The fibrillin-1 protein was isolated by Engvall in 1986, and mutations in the FBN1 gene cause Marfan syndrome.
This protein is found in humans, and its gene is found on chromosome 15. At present more than 1500 different mutations have been described.
Structure.
There is no complete, high-resolution structure of fibrillin-1. Instead, short fragments have been produced recombinantly and their structures solved by X-ray crystallography or using NMR spectroscopy. A recent example is the structure of the fibrillin-1 hybrid2 domain, in context of its flanking calcium binding epidermal growth factor domains, which was determined using X-ray crystallography to a resolution of 1.8 Å. The microfibrils that are made up of fibrillin protein are responsible for different cell-matrix interactions in the human body.
Fibrillin-2.
Fibrillin-2 was isolated in 1994 by Zhang and is thought to play a role in early elastogenesis. Mutations in the fibrillin-2 gene have been linked to Beal's Syndrome.
Fibrillin-3.
More recently, fibrillin-3 was described and is believed to be located mainly in the brain. Along with the brain, fibrillin-3 has been localized in the gonads and ovaries of field mice.
Fibrillin-4.
Fibrillin-4 was first discovered in zebrafish, and has a sequence similar to fibrillin-2.


Aminoacylase

In enzymology, an aminoacylase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are N-acyl-L-amino acid and H2O, whereas its two products are carboxylate and L-amino acid.
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 "N-acyl-L-amino acid amidohydrolase". Other names in common use include dehydropeptidase II, histozyme, hippuricase, benzamidase, acylase I, hippurase, amido acid deacylase, L-aminoacylase, acylase, aminoacylase I, L-amino-acid acylase, alpha-N-acylaminoacid hydrolase, long acyl amidoacylase, and short acyl amidoacylase. This enzyme participates in urea cycle and metabolism of amino groups.
Enzyme structure.
As of late 2007, two structures have been solved for this class of enzymes, with PDB accession codes and . These structures also correspond to two known primary amino acid sequences for aminoacylases. The associated papers identify two types of domains comprising aminoacylases: Zinc binding domains - which bind Zn2+ ions - and domains that facilitate dimerization of Zinc binding domains. It is this dimerization that allows catalysis to occur, since aminoacylase's active site lies between its two Zinc binding domains.
Bound Zinc facilitates the binding of the N-acyl-L-amino acid substrate, causing a conformational shift that brings the protein's subunits together around the substrate and allowing catalysis to occur. Aminoacylase 1 exists in a heterotetrameric structure, meaning 2 Zinc binding domains and 2 dimerization domains come together to make aminoacylase 1's quaternary structure.
Enzyme Mechanism.
Aminoacylase is a metallo-enzyme that needs Zinc (Zn2+) as a cofactor to function. The Zinc ions inside of aminoacylase are each coordinated to histidine, glutamate, aspartate, and water. The Zinc ion polarizes the water, facilitating its deprotonation by a nearby basic residue. The negatively charged hydroxide ion is nucleophilic and attacks the electrophilic carbonyl carbon of the substrate's acyl group. The exact mechanism after this point is unknown, with one possibility being that the carbonyl then reforms, breaks the amide bond, and forms the two products. At some point in the mechanism, another water molecule enters and coordinates with Zinc, returning the enzyme to its original state.
The nucleophilic attack by water is the rate-limiting step of aminoacylase's catalytic mechanism. This nucleophilic attack is reversible while the subsequent steps are fast and irreversible. This reaction sequence is an example of Michaelis–Menten kinetics, allowing one to determine KM, Kcat, Vmax, turnover number, and substrate specificity through classic Michaelis-Menten enzyme experiments. The second and third forward steps cause the formation and release of the reaction's products.
Biological function.
Aminoacylases are expressed in the kidney, where they recycle N-acyl-L-amino acids as L-amino acids and aid in urea cycle regulation.
N-acyl-L-amino acids are formed when L-amino acids have their N-terminus covalently bonded to an acyl group. The acyl group provides stability for the amino acid, making it more resistant to degradation. Additionally, N-acyl-L-amino acids cannot be used directly as building blocks for proteins and must first be converted to L-amino acids by aminoacylase. Again, the L-amino acid products can be used for biosynthesis or catabolized energy.
Aminoacylase is involved in the regulation of the urea cycle. N-acetyl-L-glutamate is an allosteric activator of carbamoyl phosphate synthetase, a crucial enzyme that commits NH4+ molecules to the urea cycle. The urea cycle gets rid of excess ammonia (NH4+) in the body, a process that must be up-regulated during times of increased protein catabolism, as amino acid breakdown produces large amounts of NH4+. When amino acid catabolism increases, N-Acetylglutamate synthase is up-regulated, producing more N-acetyl-L-glutamate, which up-regulates carbamoyl phosphate synthetase and allows it to dispose of the excess NH4+ from catabolism.
Aminoacylase is up-regulated during times of nutrient deficit or starvation, causing N-acetyl-L-glutamate breakdown, which down-regulates carbamoyl phosphate synthetase and the rest of the urea cycle. This response is evolutionarily advantageous, since a nutrient deficit means there isn't as much NH4+ that needs to be disposed of and since the body wants to salvage as many amino acids as it can.
Disease relevance.
Aminoacylase 1 deficiency (A1D) is a rare disease caused by an autosomal recessive mutation in the aminoacylase 1 gene (ACY1) on chromosome 3p21. The lack of functional aminoacylase 1 caused by A1D results in a dysfunctional urea cycle, causing an array of neurological disorders including seizures, muscular hypotonia, mental retardation, and impaired psychomotor development. A1D has also been associated with autism . Patients with A1D often start expressing symptoms shortly after birth but seem to recover fully in the next few years.
Aminoacylase 2 deficiency - also known as Canavan's disease - is another rare disease caused by a mutation in the ASPA gene (on chromosome 17) that leads to a deficiency in the enzyme aminoacylase 2. Aminoacylase 2 is known for the fact that it can hydrolyze N-acetylaspartate while aminoacylase 1 cannot.
Industrial relevance.
Aminoacylases have been used for the production of L-amino acids in industrial settings since the late 1950s. Since aminoacylases are substrate specific for N-acyl-L-amino acids and not N-acyl-D-amino acids, aminoacylases can be used to reliably take a mixture of these two reactants and only convert the L enantiomers into products - which can then be isolated by solubility from the unreacted N-acyl-D-amino acids. While this process was done in a batch reactor for many years, a faster and less wasteful process was developed in the late 1970s that placed aminoacylases in a column that N-acyl-amino acids were then continuously washed through. This process is still used in industrial settings today to convert N-acyl-amino acids to amino acids in an enantiomerically specific way.
Evolution.
Many scientific studies throughout the past half century have used porcine aminoacylase as their model aminoacylase enzyme. The amino acid sequence and primary structure of porcine aminoacylase have been determined. Porcine aminoacylase 1 is composed of two identical heterodimeric subunits each consisting of 406 amino acids, with acetylalanine at the N-terminus of each. Porcine aminoacylase differs from human aminoacylase in structure but replicates its function. It can be inferred from this data that these two enzymes evolved from a common ancestral protein, retaining function but diverging in structure over time.


Coenzyme Q reductase

Coenzyme Q reductase may refer to:


2-phosphosulfolactate phosphatase

In enzymology, a 2-phosphosulfolactate phosphatase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are (2R)-2-phospho-3-sulfolactate and H2O, whereas its two products are (2R)-3-sulfolactate and phosphate.
This enzyme belongs to the family of hydrolases, specifically those acting on phosphoric monoester bonds. The systematic name of this enzyme class is (R)-2-phospho-3-sulfolactate phosphohydrolase. Other names in common use include (2R)-phosphosulfolactate phosphohydrolase, and ComB phosphatase.
Structural studies.
As of late 2007, only one structure has been solved for this class of enzymes, with the PDB accession code .