Carbohydrate-binding module

In molecular biology, a carbohydrate-binding module (CBM) is a protein domain found in carbohydrate-active enzymes (for example glycoside hydrolases). The majority of these domains have carbohydrate-binding activity. Some of these domains are found on cellulosomal scaffoldin proteins. CBMs were previously known as cellulose-binding domains. CBMs are classified into numerous families, based on amino acid sequence similarity. There are currently (June 2011) 64 families of CBM in the CAZy database.
CBMs of microbial glycoside hydrolases play a central role in the recycling of photosynthetically fixed carbon through their binding to specific plant structural polysaccharides. CBMs can recognise both crystalline and amorphous cellulose forms. CBMs are the most common non-catalytic modules associated with enzymes active in plant cell-wall hydrolysis. Many putative CBMs have been identified by amino acid sequence alignments but only a few representatives have been shown experimentally to have a carbohydrate-binding function.
CBM1.
Carbohydrate-binding module family 1 (CBM1) consists of 36 amino acids. This domain contains 4 conserved cysteine residues which are involved in the formation of two disulfide bonds.
CBM2.
Carbohydrate-binding module family 2 (CBM2) contains two conserved cysteines - one at each extremity of the domain - which have been shown to be involved in a disulfide bond. There are also four conserved tryptophans, two of which are involved in cellulose binding.
CBM3.
Carbohydrate-binding module family 3 (CBM3) is involved in cellulose binding and is found associated with a wide range of bacterial glycosyl hydrolases. The structure of this domain is known; it forms a beta sandwich.
CBM4.
Carbohydrate-binding module family 4 (CBM4) includes the two cellulose-binding domains, CBD(N1) and CBD(N2), arranged in tandem at the N terminus of the 1,4-beta-glucanase, CenC, from "Cellulomonas fimi". These homologous CBMs are distinct in their selectivity for binding amorphous and not crystalline cellulose. Multidimensional heteronuclear nuclear magnetic resonance (NMR) spectroscopy was used to determine the tertiary structure of the 152 amino acid N-terminal cellulose-binding domain from "C. fimi" 1,4-beta-glucanase CenC (CBDN1). The tertiary structure of CBDN1 is strikingly similar to that of the bacterial 1,3-1,4-beta-glucanases, as well as other sugar-binding proteins with jelly-roll folds. CBM4 and CBM9 are closely related.
CBM5.
Carbohydrate-binding module family 5 (CBM5) binds chitin. CBM5 and CBM12 are distantly related.
CBM6.
Carbohydrate-binding module family 6 (CBM6) is unusual in that it contains two substrate-binding sites, cleft A and cleft B. "Cellvibrio mixtus" endoglucanase 5A contains two CBM6 domains, the CBM6 domain at the C-terminus displays distinct ligand binding specificities in each of the substrate-binding clefts. Both cleft A and cleft B can bind cello-oligosaccharides, laminarin preferentially binds in cleft A, xylooligosaccharides only bind in cleft A and beta1,4,-beta1,3-mixed linked glucans only bind in cleft B.
CBM9.
Carbohydrate-binding module family 9 (CBM9) binds to crystalline cellulose. CBM4 and CBM9 are closely related.
CBM10.
Carbohydrate-binding module family 10 (CBM10) is found in two distinct sets of proteins with different functions. Those found in aerobic bacteria bind cellulose (or other carbohydrates); but in anaerobic fungi they are protein binding domains, referred to as dockerin domains. The dockerin domains are believed to be responsible for the assembly of a multiprotein cellulase/hemicellulase complex, similar to the cellulosome found in certain anaerobic bacteria.
In anaerobic bacteria that degrade plant cell walls, exemplified by "Clostridium thermocellum", the dockerin domains of the catalytic polypeptides can bind equally well to any cohesin from the same organism. More recently, anaerobic fungi, typified by "Piromyces equi", have been suggested to also synthesise a cellulosome complex, although the dockerin sequences of the bacterial and fungal enzymes are completely different. For example, the fungal enzymes contain one, two or three copies of the dockerin sequence in tandem within the catalytic polypeptide. In contrast, all the "C. thermocellum" cellulosome catalytic components contain a single dockerin domain. The anaerobic bacterial dockerins are homologous to EF hands (calcium-binding motifs) and require calcium for activity whereas the fungal dockerin does not require calcium. Finally, the interaction between cohesin and dockerin appears to be species specific in bacteria, there is almost no species specificity of binding within fungal species and no identified sites that distinguish different species.
The of dockerin from "P. equi" contains two helical stretches and four short beta-strands which form an antiparallel sheet structure adjacent to an additional short twisted parallel strand. The N- and C-termini are adjacent to each other.
CBM11.
Carbohydrate-binding module family 11 (CBM11) is found in a number of bacterial cellulases. One example is the CBM11 of Clostridium thermocellum Cel26A-Cel5E, this domain has been shown to bind both β-1,4-glucan and β-1,3-1,4-mixed linked glucans. CBM11 has beta-sandwich structure with a concave side forming a substrate-binding cleft.
CBM12.
Carbohydrate-binding module family 12 (CBM12) comprises two beta-sheets, consisting of two and three antiparallel beta strands respectively. It binds chitin via the aromatic rings of tryptophan residues. CBM5 and CBM12 are distantly related.
CBM14.
Carbohydrate-binding module family 14 (CBM14) is also known as the peritrophin-A domain. It is found in chitin binding proteins, particularly the peritrophic matrix proteins of insects and animal chitinases. Copies of the domain are also found in some baculoviruses. It is an extracellular domain that contains six conserved cysteines that probably form three disulfide bridges. Chitin binding has been demonstrated for a protein containing only two of these domains.
CBM15.
Carbohydrate-binding module family 15 (CBM15), found in bacterial enzymes, has been shown to bind to xylan and xylooligosaccharides. It has a beta-jelly roll fold, with a groove on the concave surface of one of the beta-sheets.
CBM17.
Carbohydrate-binding module family 17 (CBM17) appears to have a very shallow binding cleft that may be more accessible to cellulose chains in non-crystalline cellulose than the deeper binding clefts of family 4 CBMs. Sequence and structural conservation in families CBM17 and CBM28 suggests that they have evolved through gene duplication and subsequent divergence. CBM17 does not compete with CBM28 modules when binding to non-crystalline cellulose. Different CBMs have been shown to bind to different sirtes in amorphous cellulose, CBM17 and CBM28 recognise distinct non-overlapping sites in amorphous cellulose.
CBM18.
Carbohydrate-binding module family 18 (CBM18) (also known as chitin binding 1 or chitin recognition protein) is found in a number of plant and fungal proteins that bind N-acetylglucosamine (e.g. solanaceous lectins of tomato and potato, plant endochitinases, the wound-induced proteins: hevein, win1 and win2, and the "Kluyveromyces lactis" killer toxin alpha subunit). The domain may occur in one or more copies and is thought to be involved in recognition or binding of chitin subunits. In chitinases, as well as in the potato wound-induced proteins, this 43-residue domain directly follows the signal sequence and is therefore at the N terminus of the mature protein; in the killer toxin alpha subunit it is located in the central section of the protein.
CBM19.
Carbohydrate-binding module family 19 (CBM19), found in fungal chitinases, binds chitin.
CBM20.
Carbohydrate-binding module family 20 (CBM20) binds to starch.
CBM21.
Carbohydrate-binding module family 21 (CBM21), found in many eukaryotic proteins involved in glycogen metabolism, binds to glycogen.
CBM25.
Carbohydrate-binding module family 25 (CBM25) binds alpha-glucooligosaccharides, particularly those containing alpha-1,6 linkages, and granular starch.
CBM27.
Carbohydrate-binding module family 27 (CBM27) binds to beta-1,4-mannooligosaccharides, carob galactomannan, and konjac glucomannan, but not to cellulose (insoluble and soluble) or soluble birchwood xylan. CBM27 adopts a beta sandwich structure comprising 13 beta strands with a single, small alpha-helix and a single metal atom.
CBM28.
Carbohydrate-binding module family 28 (CBM28) does not compete with CBM17 modules when binding to non-crystalline cellulose. Different CBMs have been shown to bind to different sirtes in amorphous cellulose, CBM17 and CBM28 recognise distinct non-overlapping sites in amorphous cellulose. CBM28 has a "beta-jelly roll" topology, which is similar in structure to the CBM17 domains. Sequence and structural conservation in families CBM17 and CBM28 suggests that they have evolved through gene duplication and subsequent divergence.
CBM32.
Carbohydrate-binding module family 32 (CBM32) binds to diverse substrates, ranging from plant cell wall polysaccharides to complex glycans. The module has so far been found in microorganisms, including archea, eubacteria and fungi. CBM32 adopts a beta-sandwich fold and has a bound metal atom, most often observed to be calcium. CBM32 modules are associated with catalytic modules such as sialidases, B-N-acetylglucosaminidases, α-N-acetylglucosaminidases, mannanases and galactose oxidases.
CBM33.
Carbohydrate-binding module family 33 (CBM33) is a chitin-binding domain. It has a budded fibronectin type III fold consisting of two beta-sheets, arranged as a beta-sheet sandwich and a bud consisting of three short helices, located between beta-strands 1 and 2. It binds chitin via conserved polar amino acids. This domain is found in isolation in baculoviral spheroidin and spindolin proteins.
CBM48.
Carbohydrate-binding module family 48 (CBM48) is often found in enzymes containing glycosyl hydrolase family 13 catalytic domains. It is found in a range of enzymes that act on branched substrates i.e. isoamylase, pullulanase and branching enzyme. Isoamylase hydrolyses 1,6-alpha-D-glucosidic branch linkages in glycogen, amylopectin and dextrin; 1,4-alpha-glucan branching enzyme functions in the formation of 1,6-glucosidic linkages of glycogen; and pullulanase is a starch-debranching enzyme. CBM48 binds glycogen.
CBM49.
Carbohydrate-binding module family 49 (CBM49) is found at the C-terminal of cellulases and "in vitro" binding studies have shown it to binds to crystalline cellulose.


Glycol stearate

Glycol stearate (glycol monostearate or ethylene glycol monostearate) is an organic compound with the molecular formula C20H40O3. It is the ester of stearic acid and ethylene glycol. It is used as an ingredient in many types of personal care products and cosmetics including shampoos, hair conditioners, and skin lotions.


Ethylene-forming enzyme

Ethylene-forming enzyme may refer to:


CDP-glucose 4,6-dehydratase

In the field of enzymology, a CDP-glucose 4,6-dehydratase is an enzyme that catalyzes the chemical reaction
Hence, this enzyme has one substrate, CDP-glucose, and two products, CDP-4-dehydro-6-deoxy-D-glucose and H2O.
This enzyme belongs to the family of lyases, specifically the hydro-lyases, which cleave carbon-oxygen bonds. This enzyme participates in starch and sucrose metabolism. It employs one cofactor, NAD+.
Nomenclature.
The systematic name of this enzyme class is CDP-glucose 4,6-hydro-lyase (CDP-4-dehydro-6-deoxy-D-glucose-forming). Other names in common use include:
Structural studies.
As of late 2007, two structures have been solved for this class of enzymes, with PDB accession codes and .


Atizoram

Atizoram (CP-80633) is a phosphodiesterase 4 inhibitor.


Cholestenol

Cholestenol is a sterol that has been found in the skins of rats. It can be converted to cholesterol in mammals. Delta-7-cholestenol is also known as lathosterol.


Crp domain

In molecular biology, the CRP domain is a protein domain consisting of a helix-turn-helix (HTH) motif. It is found at the C-terminus of numerous bacterial transcription regulatory proteins. These proteins bind DNA via the CRP domain. These proteins are very diverse, but for convenience may be grouped into subfamilies on the basis of sequence similarity. This family groups together a range of proteins, including ANR, CRP, CLP, CysR, FixK, Flp, FNR, FnrN, HlyX and NtcA.


Benzthiazide

Benzthiazide (BAN/INN, also known as benzothiazide; trade names Aquatag, Dihydrex, Diucen, Edemax, Exna, Foven and others) is a thiazide diuretic used in the treatment of high blood pressure and edema. It is no longer available in the United States.
In the United Kingdom, it was also sold in combination with the potassium-sparing diuretic triamterene under the trade name Dytide. The same combination is still available in Switzerland as Dyrenium compositum.


Dipeptidyl-peptidase III

Dipeptidyl-peptidase III (, "dipeptidyl aminopeptidase III", "dipeptidyl arylamidase III", "enkephalinase B", "red cell angiotensinase") is an enzyme. This enzyme catalyses the following chemical reaction
This cytosolic peptidase that is active at neutral pH.


(S)-coclaurine-N-methyltransferase

In enzymology, a (S)-coclaurine-N-methyltransferase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are S-adenosyl methionine and (S)-coclaurine, whereas its two products are S-adenosylhomocysteine and (S)-N-methylcoclaurine.
This enzyme belongs to the family of transferases, specifically those transferring one-carbon group methyltransferases. The systematic name of this enzyme class is S-adenosyl-L-methionine:(S)-coclaurine-N-methyltransferase. This enzyme participates in alkaloid biosynthesis i.


Apolipoprotein

Apolipoproteins are proteins that bind lipids (oil-soluble substances such as fat and cholesterol) to form lipoproteins. They transport lipids (and fat soluble vitamins) in blood, cerebrospinal fluid and lymph.
The lipid components of lipoproteins are insoluble in water. However, because of their detergent-like (amphipathic) properties, apolipoproteins and other amphipathic molecules (such as phospholipids) can surround the lipids, creating a lipoprotein particle that is itself water-soluble, and can thus be carried through water-based circulation (i.e., blood, lymph).
In addition to stabilizing lipoprotein structure and solubilizing the lipid component, apolipoproteins interact with lipoprotein receptors and lipid transport proteins, thereby participating in lipoprotein uptake and clearance. They also serve as enzyme cofactors for specific enzymes involved in the metabolism of lipoproteins.
Apolipoproteins are also exploited by hepatitis C virus (HCV) to enable virus entry, assembly, and transmission. They play a role in viral pathogenesis and viral evasion from neutralizing antibodies.
Functions.
In lipid transport, apolipoproteins function as structural components of lipoprotein particles, ligands for cell-surface receptors and lipid transport proteins, and cofactors for enzymes (e.g. apolipoprotein C-II for lipoprotein lipase and apolipoprotein A-I (apoA1) for lecithin-cholesterol acyltransferase).
Different lipoproteins contain different classes of apolipoproteins, which influence their function. Apolipoprotein A-I (apoA1) is the major structural protein component of high-density lipoproteins (HDL), although it is present in other lipoproteins in smaller amounts. Apolipoprotein A-IV (apoA4) is present in chylomicrons, very-low-density lipoproteins (VLDL), and HDL. It is thought to act primarily in reverse cholesterol transport and intestinal lipid absorption via chylomicron assembly and secretion. ApoA-IV synthesized in hypothalamus is suggested to be a satiating factor which regulate the food intake of the rodent. Apolipoprotein B plays a particularly important role in lipoprotein transport being the primary organizing protein of many lipoproteins. Apolipoprotein C-III (apoC3) plays an important role in lipid metabolism specific in regulating the metabolism of triglyceride-rich lipoproteins (TRLs). Apolipoprotein D (apoD) is a soluble carrier protein of lipophilic molecules in neurons and glial cells within the central and peripheral nervous system and apoD can also modulate the stability and oxidation status of these molecules.
Apolipoprotein E (apoE) plays an important role in the transport and uptake of cholesterol by way of its high affinity interaction with lipoprotein receptors, including the low-density lipoprotein (LDL) receptor. ApoE is the major lipoprotein in the central nervous system. Recent findings with apoA1 and apoE suggest that the tertiary structures of these two members of the human exchangeable apolipoprotein gene family are related. The three-dimensional structure of the LDL receptor-binding domain of apoE indicates that the protein forms an unusually elongated four-helix bundle that may be stabilised by a tightly packed hydrophobic core that includes leucine zipper-type interactions and by numerous salt bridges on the mostly charged surface. Basic amino acids important for LDL receptor binding are clustered into a surface patch on one long helix.
Apolipoprotein F (apoF) is one of the minor apolipoprotein in blood plasma and it is a lipid transfer inhibit protein to inhibit cholesteryl ester transfer protein-mediated transfers of cholesteryl esters and triglycerides. Apolipoprotein M (apoM) participates in the lipid metabolism and exhibit anti‑atherosclerotic functions and it is presented in high-density lipoprotein (HDL), low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL).
Classes.
There are multiple classes of apolipoproteins and several sub-classes:
Exchangeable apolipoproteins (apoA, apoC, and apoE) have the same genomic structure and are members of a multi-gene family that probably evolved from a common ancestral gene. ApoA1 and ApoA4 are part of the APOA1/C3/A4/A5 gene cluster on chromosome 11.
Hundreds of genetic polymorphisms of the apolipoproteins have been described, and many of them alter their structure and function.
Synthesis and regulation.
Apolipoprotein synthesis in the intestine is regulated principally by the fat content of the diet.
Apolipoprotein synthesis in the liver is controlled by a host of factors, including dietary composition, hormones (insulin, glucagon, thyroxin, estrogens, androgens), alcohol intake, and various drugs (statins, niacin, and fibric acids). ApoB is an integral apoprotein whereas the others are peripheral apoproteins.
Apolipoprotein synthesis such as apoA4 in hypothalamus involves in the integration of signals for regulation of food intake which is regulated by vagal nerve and cholecystokinin.
Disease.
Apolipoprotein has been suggested to be implicated in several types of diseases and dysfunction.
Apolipoprotein C-I (apoC1) level increases in neuropathic pain and fibromyalgia patients which suggest it plays an important role in occurrence of these conditions.
Apolipoprotein C-III (apoC3) is a risk factor of cardiovascular disease. Accumulation of plasma TRLs caused by elevated apoC-III leading to hypertriglyceridaemia.
Apolipoprotein D (apoD) level increases in nervous system with a large number of neurologic disorders inclusive of Alzheimer's disease, schizophrenia, and stroke.
Apolipoprotein E (apoE) has been implicated in dementia and Alzheimer's disease.
Apolipoprtoein(a) (apo(a)) is a component of lipoprotein(a) (Lp(a)) and elevated plasma Lp(a) level is a heritable, independent, and possibly causal risk factor for Atherosclerotic Cardiovascular Disease (ASCVD). The cholesterol-rich apoB-containing lipoproteins are also participate in the pathogenesis of ASCVD.


Glyceraldehyde

Glyceraldehyde (glyceral) is a triose monosaccharide with chemical formula C3H6O3. It is the simplest of all common aldoses. It is a sweet, colorless, crystalline solid that is an intermediate compound in carbohydrate metabolism. The word comes from combining glycerol and aldehyde, as glyceraldehyde is glycerol with one alcohol group oxidized to an aldehyde.
Structure.
Glyceraldehyde has one chiral center and therefore exists as two different enantiomers with opposite optical rotation:
While the optical rotation of glyceraldehyde is (+) for "R" and (−) for "S", this is not true for all monosaccharides. The stereochemical configuration can only be determined from the chemical structure, whereas the optical rotation can only be determined empirically (by experiment).
It was by a lucky guess that the molecular geometry was assigned to (+)-glyceraldehyde in the late 19th century, as confirmed by X-ray crystallography in 1951.
Nomenclature.
In the , glyceraldehyde is used as the configurational standard for carbohydrates. Monosaccharides with an absolute configuration identical to ("R")-glyceraldehyde at the "last" stereocentre, for example C5 in glucose, are assigned the stereo-descriptor . Those similar to ("S")-glyceraldehyde are assigned an .
Chemical synthesis.
Glyceraldehyde can be prepared, along with dihydroxyacetone, by the mild oxidation of glycerol, for example with hydrogen peroxide and a ferrous salt as catalyst. Dihydroxyacetone, the simplest ketose, is an isomer of glyceraldehyde.
Biosynthesis.
The enzyme glycerol dehydrogenase (NADP+) has two substrates, glycerol and NADP+, and 3 products, D-glyceraldehyde, NADPH and H+.
Biochemical role.
The interconversion of the phosphates of glyceraldehyde (glyceraldehyde 3-phosphate) and dihydroxyacetone (dihydroxyacetone phosphate), catalyzed by the enzyme triosephosphate isomerase, is an important intermediate step in glycolysis.


Asparagusate reductase

Asparagusate reductase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are 3-mercapto-2-mercaptomethylpropanoate and nicotinamide adenine dinucleotide ion, whereas its 3 products are asparagusate, nicotinamide adenine dinucleotide, and hydrogen ion.
This enzyme belongs to the family of oxidoreductases, specifically those acting on a sulfur group of donors with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is 3-mercapto-2-mercaptomethylpropanoate:NAD+ oxidoreductase. Other names in common use include asparagusate dehydrogenase, asparagusic dehydrogenase, asparagusate reductase (NADH2), and NADH2:asparagusate oxidoreductase.


Ipragliflozin

Ipragliflozin (INN, trade names Suglat) is a pharmaceutical drug for treatment of type 2 diabetes. Ipragliflozin, jointly developed by Astellas Pharma and Kotobuki Pharmaceutical, was approved in Japan on January 17, 2014, and in Russia on May 22, 2019.
Ipragliflozin is a Sodium/glucose cotransporter 2 (SGLT2) inhibitor (gliflozin). These membrane proteins are on the cell surface and transfer glucose into the cells. SGLT2 is one subtype of SGLTs and plays a key role in the reuptake of glucose in the proximal tubule of the kidneys. Ipragliflozin reduces blood glucose levels by inhibiting the reuptake of glucose by selectively inhibiting SGLT2.
Clinical trials.
The efficacy and safety of ipragliflozin were both observed in a Phase III study in monotherapy and clinical studies used in combination with other hypoglycemic agents (6 types) in Japan.
One placebo-controlled, double-blind study was carried out at 18 different sites in Korea and 12 in Taiwan. Patients were above 20 and had type 2 diabetes for atlas 12 weeks. They were given an 8-week period to clear their systems of all other drugs (besides metformin). Patients received either 50 mg ipragliflozin or a placebo. The drugs were identical in all physical forms. The patients were prohibited from using any other anti diabetic drugs, other than metformin. The study ran for 24 weeks along with a 4-week follow-up period.
The standard deviation in hemoglobin A1c were −0.94% and −0.47% in the ipragliflozin and placebo groups, respectively (between-group difference −0.46%, "p" <0.001). The changes in fasting plasma glucose and bodyweight were also significantly greater in the ipragliflozin group, with between-group differences of −14.1 mg/dL and −1.24 kg, respectively (both "p" <0.001). The most common adverse events that appeared were upper respiratory infections and urinary tract infections. From this it was concluded that ipragliflozin is both efficacious as well as safe.
However, ipragliflozin is currently in Observational Case Control clinical trial to see the long-term (over three years) safety of using ipragliflozin. The estimated completion of this trial is October 2018.
Ipragliflozin was also in development for type 2 diabetes mellitus in the U.S., Europe and other countries, and three phase II trials were completed in combination with metformin. This was since discontinued.
Commercialization.
As of 2014, Suglat was the top reimbursed drug in Japan. Peak sales reached 515 million with 800,000 and the cost per patient reached 644 per year.
In 2014, the market for selective SGLT2 inhibitors in Japan was around 9 billion yen. Suglat's share of this market was around 49%.
In 2015, sales of Suglat grew 77.8% to 7.3 billion yen, following the availability of long-term prescriptions from May 2015. Suglat's share of the market for selective SGLT2 inhibitors in Japan was around 39%.
The projected sales in 2016 is to jump all the way to 12.5 billion yen.
Marketing.
Ipragliflozin was the first drug of its kind sold by any company in Japan. Therefore, Astellas will focus their marketing in order to maintain the top share of this market that it holds. Astellas has been building up post-marketing data in regard to the efficacy and safety of ipragliflozin. By supplying information based on this data, Astellas aims to increase the market penetration of ipragliflozin in the Japanese market.
In 2015, Astellas additionally launched Suglat in the Republic of Korea and Feburic in Thailand.
Intellectual Property.
In May 2013, Boehringer Ingelheim of Germany applied for a Methods of Treatment, Pharmaceutical Compositions and uses thereof patent. This patent application included SGLT2 inhibitor ipragliflozin.
In April 2014, Boehringer Ingelheim applied for usage of SGLT2 inhibitors in equine animals. The usage of these inhibitors in an animal study allows for progression in the application in humans for more than just diabetes.
The National Institute of Biological Science out of Beijing filed a similar patent in September 2015.
In January 2016, the Dalian University of Technology filed a patent on the synthetic method of ipragliflozin.
There are additional patents for the synthesis of the intermediates leading up to these types of inhibitors.


Glycerol-3-phosphate dehydrogenase (disambiguation)

Glycerol-3-phosphate dehydrogenase may refer to:


Keratin 7

Keratin, type II cytoskeletal 7 also known as cytokeratin-7 (CK-7) or keratin-7 (K7) or sarcolectin (SCL) is a protein that in humans is encoded by the "KRT7" gene. Keratin 7 is a type II keratin. It is specifically expressed in the simple epithelia lining the cavities of the internal organs and in the gland ducts and blood vessels.
Function.
Keratin-7 is a member of the keratin gene family. The type II cytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues. This type II cytokeratin is specifically expressed in the simple epithelia lining the cavities of the internal organs and in the gland ducts and blood vessels. The genes encoding the type II cytokeratins are clustered in a region of chromosome 12q12-q13. Alternative splicing may result in several transcript variants; however, not all variants have been fully described.
Keratin-7 is found in simple glandular epithelia, and in transitional epithelium. Epithelial cells of the lung and breast both contain keratin-7, but some other glandular epithelia, such as those of the colon and prostate, do not. Because the keratin-7 antigen is found in both healthy and neoplastic cells, antibodies to CK7 can be used in immunohistochemistry to distinguish ovarian and transitional cell carcinomas (staining positive) from colonic and prostate cancers (negative), respectively. It is commonly used together with CK20 when making such diagnoses.
Model organisms.
Model organisms have been used in the study of KRT7 function. A conditional knockout mouse line called "Krt7tm1b(KOMP)Wtsi" was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping


Thymidine kinase from herpesvirus

Thymidine kinase from herpesvirus is a sub-family of thymidine kinases.
Its presence in herpesvirus-infected cells is used to activate a range of antivirals against herpes infection, and thus specifically target the therapy towards infected cells only.
Such antivirals include:
Mutations in the gene coding thymidine kinase in herpes viruses can endow the virus with resistance to aciclovir. In these situations, alternative medications that are of use include other guanine analogues such as famciclovir, valaciclovir and penciclovir.


Cyclin-dependent kinase regulatory subunit family

In molecular biology, the cyclin-dependent kinase regulatory subunit family is a family of proteins consisting of the regulatory subunits of cyclin-dependent protein kinases.
In eukaryotes, cyclin-dependent protein kinases interact with cyclins to regulate cell cycle progression, and are required for the G1 and G2 stages of cell division. The proteins bind to a regulatory subunit, cyclin-dependent kinase regulatory subunit (CKS), which is essential for their function. This regulatory subunit is a small protein of 79 to 150 residues. In yeast (gene CKS1) and in fission yeast (gene suc1) a single isoform is known, while mammals have two highly related isoforms. The regulatory subunits exist as hexamers, formed by the symmetrical assembly of 3 interlocked homodimers, creating an unusual 12-stranded beta-barrel structure. Through the barrel centre runs a 12A diameter tunnel, lined by 6 exposed helix pairs. Six kinase units can be modelled to bind the hexameric structure, which may thus act as a hub for cyclin-dependent protein kinase multimerisation.
This family includes the CKS1B and CKS2 genes in mammals.


Fumarate reductase

Fumarate reductase is the enzyme that converts fumarate to succinate, and is important in microbial metabolism as a part of anaerobic respiration.
Succinate + acceptor <=> fumarate + reduced acceptor
Fumarate reductases can be divided into two classes depending on the electron acceptor:


TOC complex


Trametenolic acid

Trametenolic acid is an anti-inflammatory sterol isolated from "Inonotus obliquus".


Pepsinogen


Alpha,alpha-trehalose-phosphate synthase

Alpha,alpha-trehalose-phosphate synthase may refer to:


Chondrocalcin

Chondrocalcin comes from a family of pro-collagen molecules. This protein is found in the bone and is involved in calcium-binding, which occurs in order to harden (or calcify) the cartilage. Another one of its roles is to assemble the triple collagen helix, which is predominately entails the linkage of glycine and proline amino acids and then the twisting of those linkages. Chondrocalcin is important because cartilage calcification of the growth plate is one of the main occurrences in endochondral bone formation. Because of its importance, it is one of the most highly created polypeptides in human cartilage.
This calcium-binding protein comes from chondrocytes, which are cells that produce and maintain cartilage. Some examples of chondrocytes include collagen and proteoglycans. The chondrocytes that produce chondrocalcin are typically found in growing bone matrices that have not yet matured. These immature bone matrices are found in the epiphyseal plate at both the lower hypertrophic zone and the longitudinal septa of the cartilaginous matrix.
One study was conducted on fetal cartilage discovered that the chondrocalcin protein exists as a dimer with 35,000 g/mol subunits. The reason why fetal cartilage was used is because chondrocalcin cannot be detected in mature bone.
Another investigation was conducted to determine the mechanism behind calcium binding in chondrocalcin. It was discovered that along with cartilage building, the protein also had a role in cartilage destruction.


Clitocine

Clitocine is a mushroom nucleoside isolate with anticancer activity "in vitro".


Transporter associated with antigen processing

Transporter associated with antigen processing (TAP) protein complex belongs to the ATP-binding-cassette transporter family. It delivers cytosolic peptides into the endoplasmic reticulum (ER), where they bind to nascent MHC class I molecules.
The TAP structure is formed of two proteins: TAP-1 and TAP-2, which have one hydrophobic region and one ATP-binding region each. They assemble into a heterodimer, which results in a four-domain transporter.
Function.
The TAP transporter is found in the ER lumen associated with the "peptide-loading complex" (PLC). This complex of β2 microglobulin, calreticulin, ERp57, TAP, tapasin, and MHC class I acts to keep hold of MHC molecules until they have been fully loaded with peptides.
Peptide transport.
TAP-mediated peptide transport is a multistep process. The peptide-binding pocket is formed by TAP-1 and TAP-2. Association with TAP is an ATP-independent event, ‘in a fast bimolecular association step, peptide binds to TAP, followed by a slow isomerisation of the TAP complex’. It is suggested that the conformational change in structure triggers ATP hydrolysis and so initiates peptide transport.
Both nucleotide-binding domains (NBDs) are required for peptide translocation, as each NBD cannot hydrolyse ATP alone. The exact mechanism of transport is not known; however, findings indicate that ATP binding to TAP-1 is the initial step in the transport process, and that ATP bound to TAP-1 induces ATP binding in TAP-2. It has also been shown that undocking of the loaded MHC class I is linked to the transport cycle of TAP caused by signals from the TAP-1 subunit.
Transport of mRNA out of the nucleus.
Yeast protein Mex67p and human NXF1, also-called TAP, are the two best-characterized NXFs (nuclear transport factors). TAPs mediate the interaction of the messenger ribonucleoprotein particle (mRNP) and the nuclear pore complex (NPC).NXFs bear no resemblance to prototypical nuclear transport receptors of the importin – exportin (karyopherin) family and lack the characteristic Ran-binding domain found in all karyopherins.
Specificity.
The ATPase activity of TAP is highly dependent on the presence of the correct substrate, and peptide binding is prerequisite for ATP hydrolysis. This prevents waste of ATP via peptide-independent hydrolysis.
The specificity of TAP proteins was first investigated by trapping peptides in the ER using glycosylation. TAP binds to 8- to 16-residue peptides with equal affinity, while translocation is most efficient for peptides that are 8 to 12 residues long. Efficiency reduces for peptides longer than 12 residues. However, peptides with more than 40 residues were translocated, albeit with low efficiency. Peptides with low affinity for the MHC class I molecule are transported out of the ER by an efficient ATP-dependent export protein. These outlined mechanisms may represent a mechanism for ensuring that only high-affinity peptides are bound to MHC class I.


ABCA7

ATP-binding cassette sub-family A member 7 is a protein that in humans is encoded by the "ABCA7" gene.
Function.
The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies: ABC1, MDR/TAP, CFTR/MRP, ALD (adrenoleukodystrophy), OABP, GCN20, and White. This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. This full transporter has been detected predominantly in myelo-lymphatic tissues with the highest expression in peripheral leukocytes, thymus, spleen, and bone marrow. The function of this protein is not yet known; however, the expression pattern suggests a role in lipid homeostasis in cells of the immune system. Alternative splicing of this gene results in two transcript variants.
Lack of ABCA7 gene exhibits phenotypes in mice, such as moderate decrease in plasma HDL and adipose tissues only in female, while release of cellular cholesterol and phospholipid is not impaired.
Accordingly, decrease in plasma lectin level was also reported.
Reduction of CD3 or CD1d may lead to dysfunction of T cells by deletion of ABCA7.
On the other hand, transfected and expressed ABCA7, but not endogenous ABCA7, mediates release of cell phospholipid and cholesterol to generate HDL-like particles but contain less cholesterol than those generated by ABCA1.
ABCA7-generated HDL is smaller and appears as a single peak in a molecular sieve HPLC analysis in comparison to HDL generated by ABCA1 that shows twin peaks of small and poor in cholesterol and large and rich in cholesterol.
ABCA7 mRNA generates full length cDNA and a spliced form of cDNA, and only the former is capable of generating HDL when transfected.
ABCA7 was shown associated with cellular phagocytotic activity. The promoter of ABCA7 contains sterol regulatory element (SRE) so that ABCA7 is down-regulated by cell cholesterol through sterol regulatory element binding protein (SREBP) 2. Therefore, ABCA7 expression and phagocytosis are up-regulated by use of HMG-reductase inhibitors (statins). In addition, ABCA7 is stabilized like ABCA1 by helical apolipoproteins such as apoA-I, and phagocytosis is accordingly increased in such a condition.
In summary, ABCA7 is a substantially related protein to ABCA1 but it does not mediate cell cholesterol release by generation of HDL unless it is externally transfected and expressed in vitro. ABCA7 is shown associated with cellular phagocytotic function in vivo and in vitro, and expression of the ABCA7 gene is regulated by cell cholesterol mainly through the SRE/SREBP system in a negative feed-back fashion in contrast to positive feedback by the LXR/RXR system for ABCA1. ABCA7 thus links cholesterol metabolism to host defense system.
Clinical significance.
In 2011, two genome-wide association studies (GWAS) identified ABCA7 as a new susceptibility locus for late-onset Alzheimer's disease. The finding was also confirmed by other meta-analysis investigations later. Such association of ABCA7 variants was reported on more specific findings of the disease such as memory decline and incident mild cognitive impairment or cortical and hippocampal atrophy.
Protein-disrupting variants in ABCA7 have been shown to predispose to Alzheimer's disease. The Icelandic database of Decode Genetics has shown a doubled probability of developing Alzheimer's disease when inactive variants of the ABCA7 gene are present.
By using the knock-out mice, ABCA7 was indicated involved in generation and processing of amyloid β (Aβ) peptides. In the brain of the amyloid precursor protein transgenic mice, deletion of ABCA7 resulted in accumulation of Aβ40 and Aβ42 in the early stage apparently by accelerating Aβ production. More rapid endocytosis of amyloid precursor protein was observed in primary microglia from ABCA7 deficient mice. Roles of ABCA7 are also implicated for microglial phagocytotic function and immune responses. Although the direct target of ABCA7 function is unclear, the findings are so far mechanistically consistent with the increased Aβ production.
The data can be summarized as 1) loss of function of ABCA7 is associated a risk for late onset Alzheimer's disease, 2) one of its molecular backgrounds can be enhanced production/decreased processing of Aβ peptides, and 3) ABCA7 is at least shown to increase phagocytosis including that of microglia. Since ABCA7 gene is down-regulated by cell cholesterol via the SRE/SREBP system, the data accumulated are consistent with clinical implication that use of statins, HMG-CoA reductase inhibitors, reduces risk for Alzheimer's disease.


Malonyltransferase

Malonyltransferase can refer to:


NotI

NotI is a restriction enzyme isolated from the bacterium "Nocardia otitidis".


Dipalmitoylphosphatidylethanolamine

Dipalmitoylphosphatidylethanolamine is a phosphatidylethanolamine. Like other phospholipids, it has been used as part of model bilayer membranes.


Desmolase

A desmolase is any of various enzymes that catalyze the formation or destruction of carbon-carbon bonds within a molecule. These enzymes play a significant role in cellular respiration and in fermentation. Desmolases are involved in steroidogenesis.
Examples of desmolases are:


Nonspecific dipeptidase

Nonspecific dipeptidase may refer to:


DNAJA3

DnaJ homolog subfamily A member 3, mitochondrial, also known as Tumorous imaginal disc 1 (TID1), is a protein that in humans is encoded by the "DNAJA3" gene on chromosome 16. This protein belongs to the DNAJ/Hsp40 protein family, which is known for binding and activating Hsp70 chaperone proteins to perform protein folding, degradation, and complex assembly. As a mitochondrial protein, it is involved in maintaining membrane potential and mitochondrial DNA (mtDNA) integrity, as well as cellular processes such as cell movement, growth, and death. Furthermore, it is associated with a broad range of diseases, including neurodegenerative diseases, inflammatory diseases, and cancers.
Structure.
As a member of the DNAJ/Hsp40 protein family, DNAJA3 contains a conserved DnaJ domain, which includes an HPD motif that interacts with Hsp70 to perform its cochaperone function. The DnaJ domain is composed of tetrahelical regions containing a tripeptide of histidine, proline and aspartic acid situated between two helices. In addition, this protein contains a glycine/phenylalanine (G/F) rich linker region and a central cysteine-rich region similar to a zinc finger repeat, both characteristic of type I DnaJ molecular chaperones. The mitochondrial targeting sequence at its N-terminal directs the localization of the protein to the mitochondrial matrix.
DNAJA3 possesses two alternatively spliced forms: a long isoform of 43 kDa and a short isoform of 40 kDa. The long isoform contains an additional 33 residues at its C-terminal compared to the short isoform, and this region is predicted to hinder the long isoform from regulating membrane potential.
Function.
DNAJA3 is a member of the DNAJ/Hsp40 protein family, which stimulates the ATPase activity of Hsp70 chaperones and plays critical roles in protein folding, degradation, and multiprotein complex assembly. DNAJA3 localizes to the mitochondria, where it interacts with the mitochondrial Hsp70 chaperone (mtHsp70) to carry out the chaperone system. This protein is crucial for maintaining a homogeneous distribution of mitochondrial membrane potential and the integrity of mtDNA. DNAJA3 homogenizes membrane potential through regulation of complex I aggregation, though the mechanism for maintaining mtDNA remains unknown. These functions then allow DNAJA3 to mediate mitochondrial fission through DRP1 and, by extension, cellular processes such as cell movement, growth, proliferation, differentiation, senescence, and apoptosis. However, though both isoforms of DNAJA3 are involved with cell survival, they are also observed to influence two opposing outcomes. The proapoptotic long isoform induces apoptosis by stimulating cytochrome C release and caspase activation in the mitochondria, whereas the antiapoptotic short isoform prevents cytochrome C release and, thus, apoptosis. In neuromuscular junctions, only the short isoform clusters acetylcholine receptors for efficient synaptic transmission. The two isoforms also differ in their specific mitochondrial localization, which may partially account for their different functions.
Before localization to the mitochondria, DNAJA3 is transiently retained in the cytosol, where it can also interact with cytosolic proteins and possibly function to transport these proteins.
Clinical significance.
This protein is implicated in several cancers, including skin cancer, breast cancer, and colorectal cancer. It is a key player in tumor suppression through interactions with oncogenic proteins, including ErbB2 and the p53 tumor suppressor protein. Under hypoxic conditions, DNAJA3 may directly influence p53 complex assembly or modification, or indirectly ubiquitinylate p53 through ubiquitin ligases like MDM2. Moreover, both p53 and DNAJA3 must be present in the mitochondria in order to induce apoptosis in the cell. In head and neck squamous cell carcinoma (HNSCC) cancer, DNAJA3 suppresses cell proliferation, anchorage-independent growth, cell motility, and cell invasion by attenuating EGFR and, downstream the signaling pathway, AKT. Thus, treatments promoting DNAJA3 expression and function may greatly aid the elimination of tumors.
Additionally, DNAJA3 is implicated in neurodegenerative diseases like Parkinson's disease by virtue of its key roles in chaperoning mitochondrial proteins and mediating mitochondrial morphology in conjunction with mtHsp70. Another disease, psoriasis, is a chronic inflammatory skin disease that results from the absence of DNAJA3 activity, which then results in the activation of MK5, increased phosphorylation of HSP27, increased actin cytoskeleton organization, and hyperthickened skin.
Interactions.
DNAJA3 has been shown to interact with:


Permease

The permeases are membrane transport proteins, a class of multipass transmembrane proteins that allow the diffusion of a specific molecule in or out of the cell in the direction of a concentration gradient, a form of facilitated diffusion.
The permease binding is first step of translocation. LacY protein from Escherichia coli is an example of a permease.
See also.
It was originally discovered in the 1930s by Joy Adames. It is a transporter protein that helps in various aspects of cellular life including DNA replication, translation of RNA, and diffusion.
A permease (porter) is a protein or protein complex that catalyzes a vectorial reaction, irrespective of whether or not it also catalyzes a chemical or electron transfer reaction that drives the vectorial process.


BURP domain

In molecular biology, the BURP domain is a ~230-amino acid protein domain, which has been named for the four members of the group initially identified, BNM2, USP, RD22, and PG1beta. It is found in the C-terminal part of a number of plant cell wall proteins, which are defined not only by the BURP domain, but also by the overall similarity in their modular construction. The BURP domain proteins consists of either three or four modules: (i) an N-terminal hydrophobic domain - a presumptive transit peptide, joined to (ii) a short conserved segment or other short segment, (iii) an optional segment consisting of repeated units which is unique to each member, and (iv) the C-terminal BURP domain. Although the BURP domain proteins share primary structural features, their expression patterns and the conditions under which they are expressed differ. The presence of the conserved BURP domain in diverse plant proteins suggests an important role for this domain. It is possible that the BURP domain represents a general motif for localization of proteins within the cell wall matrix. The other structural domains associated with the BURP domain may specify other target sites for intermolecular interactions.
Some proteins known to contain a BURP domain are listed below:


Protein Z-related protease inhibitor

Protein Z-dependent protease inhibitor is a protein circulating in the blood which inhibits factors Xa and XIa of the coagulation cascade. It is a member of the class of the serine protease inhibitors (serpins). Its name implies that it requires protein Z, another circulating protein, to function properly, but this only applies to its inhibition of factor X.
It is about 72 kDa heavy and 444 amino acids large. It is produced by the liver.
Role in disease.
Water "et al." found deficiency of ZPI in 4.4% of a cohort of patients with thrombophilia (a tendency to thrombosis).
History.
Han "et al." first described ZPI in 1998. The same group further characterised it in 2000.


Endoplasmic-reticulum-associated protein degradation

Endoplasmic-reticulum-associated protein degradation (ERAD) designates a cellular pathway which targets misfolded proteins of the endoplasmic reticulum for ubiquitination and subsequent degradation by a protein-degrading complex, called the proteasome.
Mechanism.
The process of ERAD can be divided into three steps:
Recognition of misfolded or mutated proteins in the endoplasmic reticulum.
The recognition of misfolded or mutated proteins depends on the detection of substructures within proteins such as exposed hydrophobic regions, unpaired cysteine residues and immature glycans.
In mammalian cells for example, there exists a mechanism called glycan processing. In this mechanism, the lectin-type chaperones calnexin/calreticulin (CNX/CRT) provide immature glycoproteins the opportunity to reach their native conformation. They can do this by way of reglucosylating these glycoproteins by an enzyme called UDP-glucose-glycoprotein glucosyltransferase also known as UGGT. Terminally misfolded proteins, however, must be extracted from CNX/CRT. This is carried out by members of the EDEM (ER degradation-enhancing α-mannosidase-like protein) family (EDEM1-3) and ER mannosidase I. This mannosidase removes one mannose residue from the glycoprotein and the latter is recognized by EDEM. Eventually EDEM will target the misfolded glycoproteins for degradation by facilitating binding of ERAD lectins OS9 and XTP3-B.
Retro-translocation into the cytosol.
Because the ubiquitin–proteasome system (UPS) is located in the cytosol, terminally misfolded proteins have to be transported from the endoplasmic reticulum back into cytoplasm. Most evidence suggest that the Hrd1 E3 ubiquitin-protein ligase can function as a retrotranslocon or dislocon to transport substrates into the cytosol. Hrd1 is not required for all ERAD events, so it is likely that other proteins contribute to this process. For example, glycosylated substrates are recognized by the E3 Fbs2 lectin. Further, this translocation requires a driving force that determines the direction of transport. Since polyubiquitination is essential for the export of substrates, it is widely thought that this driving force is provided by ubiquitin-binding factors. One of these ubiquitin-binding factors is the Cdc48p-Npl4p-Ufd1p complex in yeast. Humans have the homolog of Cdc48p known as valosin-containing protein (VCP/p97) with the same function as Cdc48p. VCP/p97 transports substrates from the endoplasmic reticulum to the cytoplasm with its ATPase activity.
Ubiquitin-dependent degradation by the proteasome.
The ubiquitination of terminally misfolded proteins is caused by a cascade of enzymatic reactions. The first of these reactions takes place when the ubiquitin-activating enzyme E1 hydrolyses ATP and forms a high-energy thioester linkage between a cysteine residue in its active site and the C-terminus of ubiquitin. The resulting activated ubiquitin is then passed to E2, which is a ubiquitin-conjugating enzyme. Another group of enzymes, more specifically ubiquitin protein ligases called E3, bind to the misfolded protein. Next they align the protein and E2, thus facilitating the attachment of ubiquitin to lysine residues of the misfolded protein. Following successive addition of ubiquitin molecules to lysine residues of the previously attached ubiquitin, a polyubiquitin chain is formed. A polyubiquitinated protein is produced and this is recognized by specific subunits in the 19S capping complexes of the 26S proteasome. Hereafter, the polypeptide chain is fed into the central chamber of the 20S core region that contains the proteolytically active sites. Ubiquitin is cleaved before terminal digestion by deubiquitinating enzymes. This third step is very closely associated with the second one, since ubiquitination takes place during the translocation event. However, the proteasomal degradation takes place in the cytoplasm.
ERAD ubiquitination machinery.
The ER membrane anchored RING finger containing ubiquitin ligases Hrd1 and Doa10 are the major mediators of substrate ubiquitination during ERAD. The tail anchored membrane protein Ubc6 as well as Ubc1 and the Cue1 dependent membrane bound Ubc7 are the ubiquitin conjugating enzymes involved in ERAD.
Checkpoints.
As the variation of ERAD-substrates is enormous, several variations of the ERAD mechanism have been proposed. Indeed, it was confirmed that soluble, membrane and transmembrane proteins were recognized by different mechanisms. This led to the identification of 3 different pathways that constitute in fact 3 checkpoints.
Diseases associated with ERAD-malfunctioning.
As ERAD is a central element of the secretory pathway, disorders in its activity can cause a range of human diseases. These disorders can be classified into two groups.
The first group is the result of mutations in ERAD components, which subsequently lose their function. By losing their function, these components are no longer able to stabilize aberrant proteins, so that the latter accumulate and damage the cell. An example of a disease caused by this first group of disorders is Parkinson's disease. It is caused by a mutation in the parkin gene. Parkin is a protein that functions in complex with CHIP as a ubiquitin ligase and overcomes the accumulation and aggregation of misfolded proteins.
[There are numerous theories addressing the causes of Parkinson's disease, besides the one presented here. Many of these can be found in the section of Wikipedia devoted to Parkinson's disease.]
In contrast to this first group of disorders, the second group is caused by premature degradation of secretory or membrane proteins. In this way, these proteins aren't able to be deployed to distal compartments, as is the case in cystic fibrosis.
ERAD and HIV.
As described before, the addition of polyubiquitin chains to ERAD substrates is crucial for their export. HIV uses an efficient mechanism to dislocate a single-membrane-spanning host protein, CD4, from the ER and submits it to ERAD. The Vpu protein of HIV-1 is a protein on the ER membrane and targets newly made CD4 in the endoplasmic reticulum for degradation by cytosolic proteasomes. Vpu only utilizes part of the ERAD process to degrade CD4. CD4 is normally a stable protein and is not likely to be a target for ERAD. However, HIV produces the membrane protein Vpu that binds to CD4. The Vpu protein mainly retains the CD4 in the ER by SCFβ-TrCP-dependent ubiquitination of the CD4 cytosolic tail and transmembrane domain (TMD) interactions. The CD4 Gly415 is a contributor to CD4-Vpu interactions, several TMD-mediated mechanisms by HIV-1 Vpu are necessary to downregulate CD4 and thus promote viral pathogenesis. CD4 retained in the ER will be a target for a variant ERAD pathway rather than predominantly appearing at the plasma membrane without the presence of Vpu through the RESET pathway. Vpu mediates the CD4 retention in the ER and the addition of degradation. As Vpu is phosphorylated, it mimics substrates for the E3 complex SCFβTrCP. In cells that are infected with HIV, SCFβTrCP interacts with Vpu and ubiquitinates CD4, which is subsequently degraded by the proteasome. Vpu itself escapes from the degradation.
Questions.
The big open questions related to ERAD are:


NuA4 histone acetyltransferase complex

The NuA4 histone acetyltransferase complex is a protein complex that has histone acetylase activity on chromatin, as well as ATPase, DNA helicase and structural DNA binding activities. The complex is thought to be involved in double-strand DNA break repair. Subunits of the human complex include HTATIP/TIP60, TRRAP, RUVBL1, RUVBL2, beta-actin and BAF53/ACTL6A. In yeast, the complex has 13 subunits, including the catalytic subunit Esa1 (homologous to human Tip60).
Post-translational acetylation of the histone H4 N-terminal tail in chromatin has been associated with several
nuclear processes including transcription. Purification and characterization of a native multi-subunit complex (NuA4) from yeast that acetylates nucleosomal histone H4 have been reported. NuA4 has an apparent molecular mass of 1.3 MDa. All four conserved lysines of histone H4 can be acetylated by NuA4. The catalytic subunit of the complex has been identified as the product of ESA1, an essential gene required for cell cycle progression in yeast. Antibodies against Esa1p specifically immunoprecipitate NuA4 activity whereas the complex purified from a temperature-sensitive esa1 mutant loses its acetyltransferase activity at the restrictive temperature. Additionally, another subunit of the complex has been identified as the product of TRA1, an ATM-related essential gene homologous to human TRRAP, an essential cofactor for c-Myc- and E2F-mediated oncogenic transformation. Finally, the ability of NuA4 to stimulate GAL4–VP16-driven transcription from chromatin templates in vitro is also lost in the temperature-sensitive esa1 mutant. The function of the essential Esa1 protein as the HAT subunit of NuA4 and the presence of Tra1p, a putative transcription activator-interacting subunit, supports an essential link between nuclear H4 acetylation, transcriptional regulation and cell cycle control.


Dihydrobunolol dehydrogenase

In enzymology, a dihydrobunolol dehydrogenase () is an enzyme that catalyzes the chemical reaction
The three substrates of this enzyme are (+/−)-5-[(tert-butylamino)-2'-hydroxypropoxy]-1,2,3,4-tetrahydro-1-naphthol, and NADP+, whereas its 4 products are (+/−)-5-[(tert-butylamino)-2'-hydroxypropoxy]-3,4-dihydro-1(2H)-, naphthalenone, NADPH, and H+.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-OH group of donor with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is (+/−)-5-[(tert-butylamino)-2'-hydroxypropoxy]-1,2,3,4-tetrahydro-1-n aphthol:NADP+ oxidoreductase. This enzyme is also termed bunolol reductase.


DHHC domain

In molecular biology the DHHC domain is a protein domain that acts as an enzyme, which adds a palmitoyl chemical group to proteins in order to anchor them to cell membranes. The DHHC domain was discovered in 1999 and named after a conserved sequence motif found in its protein sequence. Roth and colleagues showed that the yeast Akr1p protein could palmitoylate Yck2p "in vitro" and inferred that the DHHC domain defined a large family of palmitoyltransferases. In mammals twenty three members of this family have been identified and their substrate specificities investigated. Some members of the family such as ZDHHC3 and ZDHHC7 enhance palmitoylation of proteins such as PSD-95, SNAP-25, GAP43, Gαs. Others such as ZDHHC9 showed specificity only toward the H-Ras protein. However, a recent study questions the involvement of classical enzyme-substrate recognition and specificity in the palmitoylation reaction. Several members of the family have been implicated in human diseases.
Sequence motifs.
Conserved motifs within protein sequences point towards the most important amino acid residues for function. In the DHHC domain there is a tetrapeptide motif composed of aspartate-histidine-histidine-cysteine. However this short sequence is embedded in a larger region of about fifty amino acids in length that shares many more conserved amino acids. The canonical DHHC domain can be described with the following sequence motif:
 C-x2-C-x9-HC-x2-C-x2-C-x4-DHHC-x5-C-x4-N-x3-F (x shows region of unconserved residues)
However many examples of DHHC domains are known that do not contain all these conserved residues. In addition to the central DHHC domain three further sequence motifs have been identified in members of the DHHC family. A "DPG" (aspartate-proline-glycine) motif has been identified just to the C-terminus of the second transmembrane region. A "TTxE" (threonine-threonine-any-glutamate) motif has also been identified after the fourth transmembrane helix. A third motif towards the C-terminus of many proteins has been identified that contains a conserved aromatic amino acid, a glycine and an asparagine called the PaCCT motif (PAlmitoiltransferase Conserved C-Terminus motif).
Structure and mechanism.
Several structures of the DHHC domain has been solved, and it is known to run on a linearly-arranged catalytic triad of Asp153, His154, and Cys156. It runs on a ping-pong mechanism, where the cysteine attacks the acyl-CoA to form an S-acylated DHHC, and then the acyl group is transferred to the substrate. DHHR enzymes exist exist, and it (as well as some DHHC enzymes) may use a ternary complex mechanism instead.
Chemical inhibitors.
In 2006, five chemical classes of small molecules were discovered which were shown to act against palmitoyltransferases.
Further studies in 2009 showed that of the 5 classes studied, 2-(2-hydroxy-5-nitro-benzylidene)-benzo[b]thiophen-3-one was shown to behave similarly to 2-Bromopalmitate and were identified as able to inhibit the palmitoylation reaction of a range of DHHC domain containing proteins. Inhibition with 2-Bromopalmitate was found to be irreversible, the other however was found to be mostly reversible. Because of the roles of DHHC domain proteins in human diseases it has been suggested that chemical inhibitors of specific DHHC proteins may be a potential route to treatment of disease.
In human disease.
Several proteins containing DHHC domains have been implicated in human disease. Two missense mutations within the DHHC domain of ZDHHC9 were identified in X-linked mental retardation associated
with a Marfanoid Habitus. A potential link of ZDHHC11 with bladder cancer has been suggested by the discovery that 5 out of 9 high-grade bladder cancer samples surveyed contained a duplication of the 5p15.33 genomic region. However, this region contains another gene TPPP which may be the causative gene. The HIP14 palmitoyltransferase is responsible for palmitoylating the Huntingtin protein. Expansions of the triplet repeat in the huntington's gene leads to loss of interaction with HIP14 which Yanai and colleagues speculate is involved in the pathology of Huntington's disease. A gene knockout experiment of the mouse homologue of ZDHHC13 showed hair loss, severe osteoporosis, and systemic amyloidosis, both of AL and AA depositions.
Human proteins containing this domain.
ZDHHC1; ZDHHC2; ZDHHC3; ZDHHC4; ZDHHC5; ZDHHC6; ZDHHC7; ZDHHC8; ZDHHC9; ZDHHC11; ZDHHC11B; ZDHHC12; ZDHHC13; ZDHHC14; ZDHHC15; ZDHHC16; ZDHHC17; ZDHHC18; ZDHHC19; ZDHHC20; ZDHHC21; ZDHHC22; ZDHHC23; ZDHHC24;


BZIP Maf

bZIP Maf is a domain found in Maf transcription factor proteins. It contains a leucine zipper (bZIP) domain, which mediates the transcription factor's dimerization and DNA binding properties. The Maf extended homology region (EHR) is present at the N-terminus of the protein. This region (shown in yellow in the adjacent image) exists only within the Maf family and allows the family to recognize longer DNA motifs than other leucine zippers. These motifs are termed the Maf recognition element (MARE) and is 13 or 14 base pairs long. In particular, the two residues at the beginning of helix H2 are positioned to recognise the flanking region of the DNA. Small Maf proteins heterodimerize with Fos and may act as competitive repressors of the NF2-E2 transcription factor.
In mouse, Maf1 may play an early role in axial patterning. Defects in these proteins are a cause of autosomal dominant retinitis pigmentosa. Neural retina-specific leucine zipper proteins belong to this family.


Olamkicept

Olamkicept, also known as soluble gp130Fc or sgp130Fc (other designations are FE 999301, FE301, TJ301) is an immunosuppressive drug candidate, which selectively blocks activities of the cytokine Interleukin-6, which are mediated by the soluble Interleukin-6. Interleukin-6 is a cytokine, which plays a dominant role in the regulation of the immune response and also in autoimmunity. Furthermore, Interleukin-6 has been demonstrated to be involved in the regulation of metabolism and body. Interleukin-6 also has many activities on neural. The biochemical principle was invented by the German biochemist Stefan Rose-John and it was further developed into a biotech compound by the Conaris Research Institute AG, which gave an exclusive world-wide license to the Swiss-based biopharmaceutical company. In December 2016, Ferring and the biotech company I-MAB signed a licensing agreement granting I-MAB exclusive rights in Asia to Olamkicept for the treatment of autoimmune disease.
Mechanism of action.
On cells, Interleukin-6 binds to an Interleukin-6 receptor, which, however, is not signaling. The complex of Interleukin-6 and the Interleukin-6 receptor binds to a second receptor protein, gp130, which thereupon dimerizes and initiates intracellular. The gp130 receptor is present on all cells of the human body, whereas the Interleukin-6 receptor is only expressed by some cells such as hepatocytes and some leukocytes. Since Interleukin-6 exhibits only measurable affinity to the Interleukin-6 receptor but not to gp130, only cells which express the Interleukin-6 receptor can respond to Interleukin-6. It was found that the Interleukin-6 receptor can be cleaved from the cell membrane by the protease ADAM17 generating a soluble receptor. Interestingly, the soluble Interleukin-6 receptor can still bind Interleukin-6 and the complex of Interleukin-6 and Interleukin-6 receptor can bind to gp130 even on cells, which do not express the membrane-bound Interleukin-6 receptor. This mode of signaling has named Interleukin-6 trans-signaling. The protein Olamkicept consists of the extracellular portion of gp130 fused (and thereby dimerized) to the constant portion of a human IgG1 antibody. Like membrane bound gp130, the protein Olamkicept does not bind Interleukin-6 alone but only the complex of Interleukin-6 and soluble Interleukin-6 receptor. Therefore, Olamkicept only inhibits Interleukin-6 trans-signaling but not Interleukin-6 signaling via the membrane-bound Interleukin-6 receptor. It has been shown that Interleukin-6 activities via the membrane-bound Interleukin-6 receptor are regenerative and protect from bacterial infections whereas Interleukin-6 activities via the soluble Interleukin-6 receptor are considered pro-inflammatory. Therefore, Olamkicept only blocks the pro-inflammatory activities of the cytokine Interleukin-6.
Research.
In many animal disease models of human pathologies it was tested whether the specific blockade of Interleukin-6 trans-signaling by the Olamkicept protein was superior to a global blockade with an Interleukin-6 or an Interleukin-6 receptor neutralizing antibody. It turned out that the specific blockade of Interleukin-6 trans-signaling was superior to global Interleukin-6 blockade in models of e.g. sepsis, of acute lung injury after severe acute pancreatitis and of abdominal aortic aneurysm. Furthermore, it was shown that Interleukin-6 trans-signaling plays a dominant role in colon cancer and lung cancer.
Medical use.
The Olamkicept protein underwent phase I clinical studies in healthy volunteers and a small cohort of largely inactive patients with IBD in 2013/14, an open label phase IIa study in Germany and is currently investigated in a placebo-controlled, phase II clinical trial in patients with ulcerative colitis in China, Taiwan and South Korea. The results of the German phase IIa clinical trial were published and demonstrated target engagement through olamkicept exposure over 12 weeks in patients with active inflammatory bowel disease. Most interestingly some patients developed a complete remission while others went into response. The molecular analysis revealed an olamkicept-specific signature in influencing disease pathophysiology. It is expected that the results of the placebo controlled trial in China/Taiwan/South Korea are released during the 2021 Digestive Disease Week (DDW) or the 2021 annual meeting of the European Crohn’s and Colitis Organization (ECCO).


Dimethylmalate dehydrogenase

In enzymology, a dimethylmalate dehydrogenase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are (R)-3,3-dimethylmalate and NAD+, whereas its 3 products are 3-methyl-2-oxobutanoate, CO2, and NADH.
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 (R)-3,3-dimethylmalate:NAD+ oxidoreductase (decarboxylating). This enzyme is also called beta,beta-dimethylmalate dehydrogenase. This enzyme participates in pantothenate and coa biosynthesis. It has 5 cofactors: ammonia, manganese, cobalt, potassium, and NH4+.


Acetylesterase

In enzymology, an acetylesterase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are acetic ester and H2O, whereas its two products are alcohol and acetate.
This enzyme belongs to the family of hydrolases, specifically those acting on carboxylic ester bonds. The systematic name of this enzyme class is acetic-ester acetylhydrolase. Other names in common use include C-esterase (in animal tissues), acetic ester hydrolase, chloroesterase, p-nitrophenyl acetate esterase, and Citrus acetylesterase.
Structural studies.
As of late 2007, 3 structures have been solved for this class of enzymes, with PDB accession codes , , and .


Oxynitrilase

Oxynitrilase may refer to:


Laura Manuelidis

Laura Manuelidis is a physician and neuropathologist at Yale University.
Career.
Dr. Manuelidis earned her B.A. degree from Sarah Lawrence College, where she studied poetry, and her M.D. from Yale Medical School. She is head of the section of Neuropathology in the department of Surgery at Yale. She is also on the faculty of Neurosciences and Virology. Her major contributions include the discovery of complex repeated DNAs at centromeres and on chromosome arms (LINES) in large Giemsa bands that define tissue specific genes. She also illuminated the compact 3-D organization and structure of individual chromosomes in the interphase nucleus (not spaghetti-like chromatin) by developing high resolution non-isotopic in-situ hybridization, and further demonstrated positional specificity in different functional cell types, such as neurons and glia
Achievements.
The Manuelidis lab was the first to serially transmit any form of human Creutzfeldt–Jakob disease (CJD) to small rodents. This made it possible to elucidate fundamental mechanisms of infection, including infectious agent uptake and spread by myeloid cells of the blood, lack of maternal transmission, and major strain differences of human Transmissible Spongiform Encephalopathy (TSE) agents such as sporadic CJD, kuru of New Guinea, bovine-linked vCJD in the UK, and Asiatic CJD. Her development of monotypic tissue cultures infected by many different human and sheep scrapie TSE strains along with rapid quantitative assays of infectivity showed that PrP band patterns are cell-type dependent and not specific for the agent-strain. TSE agents replicate every 24 hrs in culture in contrast to their slow replication in brain that has many complex host immune system controls.
Prion Hypothesis.
She has challenged the dominant explanation that the host prion protein (PrP), without any nucleic acid, is the causal infectious agent in TSEs. The prion hypothesis was put forth by Stanley B. Prusiner, who won the 1997 Nobel Prize in Physiology or Medicine. In contrast to the amyloid or "infectious form of host PrP", Manuelidis and colleagues showed that infectious CJD brain particles separated from most prion protein with a homogeneous viral density and size, and disruption of CJD nucleic acid-protein complexes destroys infectivity. Comparable 25 nm particles were identified within CJD and scrapie infected cell cultures, but not in uninfected controls. As with 25 nm brain particles, the culture particles did not bind PrP antibodies.
Manuelidis stated that, "Although much work remains to be done, there is a reasonable possibility these are the long sought viral particles that cause transmissible spongiform encephalopathies. The [prion] is probably not infectious, but is a pathological result [of] an infectious virus binding to this host protein.". Much additional recent evidence points to an exogenous source of infectious TSE agents and the claim that recombinant PrP can be made infectious has not been reproduced. In fact, one can remove all detectable forms of PrP from infectious brain particles, yet the brain particles retain their high infectivity. Thus, PrP may not be an integral component of the infectious agent, but instead a host susceptibility factor. Additionally, nucleases that have no effect on PrP are able to obliterate particle-associated nucleic acids and destroy >99% of their infectivity. These findings suggest that TSE agents are viruses that require protected genetic material to infect their hosts. Although novel circular SPHINX DNAs from the microbiome were identified in isolated infectious particles, their role in infection and/or disease is not yet clear.


Peptidoglycan recognition protein 2

Peptidoglycan recognition protein 2 (PGLYRP2) is an enzyme (EC 3.5.1.28), N-acetylmuramoyl-L-alanine amidase (NAMLAA), that hydrolyzes bacterial cell wall peptidoglycan and is encoded by the "PGLYRP2" gene.
Discovery.
The "N"-acetylmuramoyl-L-alanine amidase enzymatic activity was first observed in human and mouse serum in 1981 by Branko Ladešić and coworkers. The enzyme (abbreviated NAMLAA) was then purified from human serum by this and other groups. The sequence of 15 N-terminal amino acids of NAMLAA was identified, but the cDNA for the protein was not cloned and the gene encoding NAMLAA was not known.
In 2000, Dan Hultmark and coworkers discovered a family of 12 Peptidoglycan Recognition Protein (PGRP) genes in "Drosophila" "melanogaster" and by homology searches of available human and mouse sequences predicted the presence of long forms of human and mouse PGRPs, which they named PGRP-L by analogy to long forms of insect PGRPs.
In 2001, Roman Dziarski and coworkers discovered and cloned three human PGRPs, named PGRP-L, PGRP-Iα, and PGRP-Iβ (for long and intermediate size transcripts), and established that human genome codes for a family of 4 PGRPs: PGRP-S (short PGRP) and PGRP-L, PGRP-Iα, and PGRP-Iβ. Subsequently, the Human Genome Organization Gene Nomenclature Committee changed the gene symbols of PGRP-S, PGRP-L, PGRP-Iα, and PGRP-Iβ to "PGLYRP1" (peptidoglycan recognition protein 1), "PGLYRP2" (peptidoglycan recognition protein 2), "PGLYRP3" (peptidoglycan recognition protein 3), and "PGLYRP4" (peptidoglycan recognition protein 4), respectively, and this nomenclature is currently also used for other mammalian PGRPs. Sergei Kiselev and coworkers also independently cloned mouse PGLYRP2 (which they named TagL).
In 2003 Håkan Steiner and coworkers and Roman Dziarski and coworkers discovered that mouse and human PGLYRP2 (PGRP-L) proteins encoded by the mouse and human "PGLYRP2" genes are "N"-acetylmuramoyl-L-alanine amidases. Recombinant and native human PGLYRP2 proteins were then further shown to be identical with the previously identified and purified serum NAMLAA.
Tissue distribution and secretion.
Human and mouse PGLYRP2 is constitutively expressed in the adult and fetal liver, from where it is secreted into the blood. PGLYRP2 (NAMLAA) is present in human plasma at 100 to 200 µg/ml and at lower concentrations in saliva, milk, cerebrospinal fluid, and synovial fluid. PGLYRP2 is also expressed to a much lower level in the colon, lymph nodes, spleen, thymus, heart, and polymorphonuclear leukocyte granules. PGLYRP2 is differentially expressed in the developing brain and this expression is influenced by the intestinal microbiome. Bacteria and cytokines induce low level of PGLYRP2 expression in the skin and gastrointestinal and oral epithelial cells, and also in intestinal intraepithelial T lymphocytes, dendritic cells, NK (natural killer) cells, and inflammatory macrophages. Some mammals, e.g. pigs, express multiple splice forms of PGLYRP2 with differential expression.
Bacteria and cytokines induce expression of PGLYRP2 in epithelial cells through the p38 mitogen activated protein kinase (MAPK) and IRAK1 (interleukin-1 receptor-associated kinase 1) signaling pathways. Constitutive and induced expression of PGLYRP2 is controlled by different transcription factors whose binding sequences are located in different regions of the "PGLYRP2" promoter. Constitutive expression of "PGLYRP2" in hepatocytes is regulated by transcription factors c-Jun and ATF2 (activating transcription factor 2) through sequences in the proximal region of the promoter. Induced expression of "PGLYRP2" in keratinocytes is regulated by transcription factors NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and Sp1 (specificity protein 1) through sequences in the distal region of the promoter.
Structure.
PGLYRP2 has one canonical carboxy-terminal catalytic peptidoglycan-binding type 2 amidase domain (also known as a PGRP domain) with predicted peptidoglycan-binding and catalytic cleft with walls formed by α-helices and the floor by a β-sheet. PGLYRP2 also has a long N-terminal segment that comprises two thirds of the PGLYRP2 sequence, has two hydrophobic regions, is not found in other mammalian PGLYRP1, PGLYRP3, and PGLYRP4 and in invertebrate PGRPs, and is unique with no identifiable functional motifs or domains. The C-terminal segment is also longer than in other mammalian PGLYRPs. PGLYRP2 has two pairs of cysteines in the PGRP domain that are conserved in all human PGRPs and are predicted to form two disulfide bonds. Human PGLYRP2 is glycosylated and secreted, and forms non-disulfide-linked homodimers.
PGLYRP2, similar to all other amidase-active PGRPs (invertebrate and vertebrate), has a conserved Zn2+-binding site in the peptidoglycan-binding cleft, which is also present in bacteriophage type 2 amidases and consists of two histidines, one tyrosine, and one cysteine (His411, Tyr447, His522, Cys530 in human PGLYRP2).
Functions.
The PGLYRP2 protein plays an important role in the innate immune responses.
Peptidoglycan binding and hydrolysis.
PGLYRP2 is an enzyme (EC 3.5.1.28), "N"-acetylmuramoyl-L-alanine amidase, that binds and hydrolyzes bacterial cell wall peptidoglycan. Peptidoglycan is the main component of bacterial cell wall and is a polymer of β(1-4)-linked "N"-acetylglucosamine (GlcNAc) and "N"-acetylmuramic acid (MurNAc) with MurNAc-attached short peptides, typically composed of alternating L and D amino acids, that cross-link the adjacent polysaccharide chains.
PGLYRP2 hydrolyzes the amide bond between the MurNAc and L-Ala, the first amino acid in the stem peptide. This hydrolysis separates the crosslinking peptides from the polysaccharide chains and solubilizes cross-linked bacterial peptidoglycan into uncross-linked polysaccharide chains. The minimal peptidoglycan fragment hydrolyzed by PGLYRP2 is MurNAc-tripeptide.
The peptidoglycan-binding site, which is also the amidase catalytic domain, is located in the C-terminal PGRP domain. This PGRP domain is sufficient for the enzymatic activity of PGLYRP2, although this activity of the isolated C-terminal fragment is diminished compared with the entire PGLYRP2 molecule. Zn2+ and Zn2+-binding amino acids (His411, Tyr447, and Cys530 in human PGLYRP2) are required for the amidase activity. Cys419 in human PGLYRP2, which is broadly conserved in invertebrate and vertebrate PRGPs, forms a disulfide bond with Cys425 (in human PGLYRP2) and is required for the amidase activity, as this disulfide bond is essential for the structural integrity of the PGRP domain. Cys530 is conserved in all amidase-active vertebrate and invertebrate PGRPs, whereas non-catalytic PGRPs (including mammalian PGLYRP1, PGLYRP3, and PGLYRP4) have serine in this position, and thus the presence of Cys or Ser in this position can be used to predict amidase activity of PGRPs. However, Cys530 and seven other amino acids that are all required for the amidase activity of PGRPs are not sufficient for the amidase activity, which requires additional so far unidentified amino acids.
Defense against infections.
PGLYRP2 plays a limited role in host defense against infections. "PGLYRP2"-deficient mice are more sensitive to "Pseudomonas aeruginosa"-induced keratitis and "Streptococcus pneumoniae"-induced pneumonia and sepsis. However, "PGLYRP2"-deficient mice did not show a changed susceptibility to systemic "Escherichia coli", "Staphylococcus aureus", and "Candida" "albicans" infections or intestinal "Salmonella enterica" infection, although the latter was accompanied by increased inflammation in the cecum.
Although PGLYRP2 is not directly bacteriolytic, it has antibacterial activity against both Gram-positive and Gram-negative bacteria and "Chlamydia" "trachomatis".
Maintaining microbiome.
Mouse PGLYRP2 plays a role in maintaining healthy microbiome, as "PGLYRP2"-deficient mice have significant changes in the composition of their intestinal microbiome, which affect their sensitivity to colitis.
Effects on inflammation.
PGLYRP2 directly and indirectly affects inflammation and plays a role in maintaining anti- and pro-inflammatory homeostasis in the intestine, skin, joints, and brain.
Hydrolysis of peptidoglycan by PGLYRP2 diminishes peptidoglycan’s pro-inflammatory activity. This effect is likely due to amidase activity of PGLYRP2, which separates the stem peptide from MurNAc in peptidoglycan and destroys the motif required for the peptidoglycan-induced activation of NOD2 (nucleotide-binding oligomerization domain-containing protein 2), one of the proinflammatory peptidoglycan receptors.
"PGLYRP2"-deficient mice are more susceptible than wild type mice to dextran sodium sulfate (DSS)-induced colitis, which indicates that PGLYRP2 protects mice from DSS-induced colitis. Intestinal microbiome is important for this protection, because this increased sensitivity to colitis could be transferred to wild type germ-free mice by microbiome transplant from "PGLYRP2"-deficient mice.
"PGLYRP2"-deficient mice are more susceptible than wild type mice to the development of experimentally induced psoriasis-like inflammation, which indicates that PGLYRP2 is anti-inflammatory and protects mice from this type of skin inflammation. This pro-inflammatory effect is due to increased numbers and activity of T helper 17 (Th17) cells and decreased numbers of T regulatory (Treg) cells. "PGLYRP2"-deficient mice are more susceptible than wild type mice to "S. enterica"-induced intestinal inflammation, which indicates that PGLYRP2 also has anti-inflammatory effect in the intestinal tract.
However, PGLYRP2 also has opposite effects. "PGLYRP2"-deficient mice are more resistant than wild type mice to the development of arthritis induced by systemic administration of peptidoglycan or MurNAc-L-Ala-D-isoGln peptidoglycan fragment (muramyl dipeptide, MDP). In this model, PGLYRP2 is required for the production of chemokines and cytokines that attract neutrophils to the arthritic joints. "PGLYRP2"-deficient mice are also more resistant than wild type mice to bacterially induced keratitis and inflammation in "S. pneumoniae"-induced lung infection. These results indicate that under certain conditions PGLYRP2 has pro-inflammatory effects.
"PGLYRP2"-deficient mice also show higher sociability and decreased levels of anxiety-like behaviors compared with wild type mice, which indicate that PGLYRP2 affects behavior in mice.
Medical relevance.
Genetic "PGLYRP2" variants or changed expression of PGLYRP2 are associated with some diseases. Patients with inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, have significantly more frequent missense variants in "PGLYRP2" gene (and also in the other three "PGLYRP" genes) than healthy controls. These results suggest that PGLYRP2 protects humans from these inflammatory diseases, and that mutations in "PGLYRP2" gene are among the genetic factors predisposing to these diseases. "PGLYRP2" variants are also associated with esophageal squamous cell carcinoma and Parkinson’s disease.
Decreased expression of PGLYRP2 is associated with HIV-associated tuberculosis, Lyme disease, hepatocellular carcinoma, and myocardial infarction.


Triose

A triose is a monosaccharide, or simple sugar, containing three carbon atoms. There are only three possible trioses (including dihydroxyacetone): -glyceraldehyde and -glyceraldehyde, the two enantiomers of glyceraldehyde, which are aldotrioses because the carbonyl group is at the end of the chain, and dihydroxyacetone, the only ketotriose, which is symmetrical and therefore has no enantiomers.
Trioses are important in cellular respiration. During glycolysis, fructose-1,6-bisphosphate is broken down into glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. Lactic acid and pyruvic acid are later derived from these molecules.


Smaug (protein)

Smaug is a RNA binding protein in "Drosophila" that helps in maternal to zygotic transition (MZT). The protein is named after the fictional character Smaug, the dragon in J.R.R. Tolkien's 1937 novel "The Hobbit". The MZT ends with the midblastula transition (MBT), which is defined as the first developmental event in "Drosophila" that depends on zygotic mRNA. In Drosophila, the initial developmental events are controlled by maternal mRNAs like "Hsp83", "nanos", "string", "Pgc", and "cyclin B" mRNA. Degradation of these mRNAs, which is expected to terminate maternal control and enable zygotic control of embryogenesis, happens at interphase of nuclear division cycle 14. During this transition smaug protein targets the maternal mRNA for destruction using miRs. Thus activating the zygotic genes. Smaug is expected to play a role in expression of three miRNAs – "miR-3, miR-6, miR-309" and "miR-286" during MZT in Drosophila. Among them smaug dependent expression of "miR-309" is needed for destabilization of 410 maternal mRNAs. In smaug mutants almost 85% of maternal mRNA is found to be stable. Smaug also binds to 3′ untranslated region (UTR) elements known as "SMG response elements" (SREs) on "nanos" mRNA and represses its expression by recruiting a protein called Cup "(an eIF4E-binding protein that blocks the binding of eIF4G to eIF4E)". There after it recruits deadenylation complex CCR4-Not on to the nanos mRNA which leads to deadenylation and subsequent decay of the mRNA. It is also found to be involved in degradation and repression of maternal Hsp83 mRNA by recruiting CCR4/POP2/NOT deadenylase to the mRNA. The human Smaug protein homologs are SAMD4A and SAMD4B.


Leucyl/cystinyl aminopeptidase

Leucyl/cystinyl aminopeptidase, also known as cystinyl aminopeptidase (CAP), insulin-regulated aminopeptidase (IRAP), human placental leucine aminopeptidase (PLAP), oxytocinase, and vasopressinase, is an enzyme of the aminopeptidase group that in humans is encoded by the "LNPEP" gene.
This gene encodes a zinc-dependent aminopeptidase (metalloexopeptidase) that cleaves vasopressin, oxytocin, lys-bradykinin, met-enkephalin, dynorphin A and other peptide hormones. The protein can be secreted in maternal serum, reside in intracellular vesicles with the insulin-responsive glucose transporter GLUT4, or form a type II integral membrane glycoprotein. The protein catalyzes the final step in the conversion of angiotensinogen to angiotensin IV (AT4) and is also a receptor for AT4. Alternative splicing results in multiple transcript variants encoding different isoforms.
Mutations in this gene have been associated to psoriasis risk.(doi:10.1038/jid.2013.317)
Interactions.
Cystinyl aminopeptidase has been shown to interact with TNKS2.


Baicalein 7-O-glucuronosyltransferase

Baicalein 7-O-glucuronosyltransferase (, "UBGAT") is an enzyme with systematic name "UDP-D-glucuronate:5,6,7-trihydroxyflavone 7-O-glucuronosyltransferase ". This enzyme catalyses the following chemical reaction
The enzyme is specific for UDP-D-glucuronate as a sugar donor.


KDM4A

Lysine-specific demethylase 4A is an enzyme that in humans is encoded by the "KDM4A" gene.
Function.
This gene is a member of the Jumonji domain 2 (JMJD2) family and encodes a protein with a JmjN domain, a JmjC domain, a JD2H domain, two TUDOR domains, and two PHD-type zinc fingers. This nuclear protein belongs to the alpha-ketoglutarate-dependent hydroxylase superfamily. It functions as a trimethylation-specific demethylase, converting specific trimethylated histone on histone H3 lysine 9 and 36 residues to the dimethylated form and lysine 9 dimethylated residues to monomethyl, and as a transcriptional repressor.
Alterations in this gene have been found associated with chromosomal instability that leads to cancer.
In humans, the role of "Kdm4a" as an oncogene, or cancer associated gene, is well established. It is implicated in prostate tumors, where it is overexpressed, and stimulates cell proliferation in colon cancer cells, where it promotes formation of the tumor itself. In lung cancer cell lines, where "Kdm4a" is also overexpressed, it coordinates with other oncogenes (like "Ras") to transform normal cells into cancerous cells by inhibiting tumor suppressor pathways such as p53. Suppression of "Kdm4a" in breast cancer cell lines has shown to reduce cancer cell proliferation through cell cycle arrest, and decrease tumor migration and invasion.
In mice models, "Kdm4a" influences various processes leading up to implantation of the embryo. The expression of this gene is observed in all tissues critical to the female reproductive system, including the hypothalamus, pituitary, ovary, oviducts, and uterus, as well as embryonic development. A knockout of this gene in female mice has shown to negatively interfere with maintaining a maternal uterine environment suitable to receive and implant the blastocyst. It also interferes in the early embryonic development of the female mice's pups prior to implantation, leading to infertility. While mechanisms of normal ovulation and fertilization remain unaffected, infertility may also be partly due to decreased levels of Prolactin, a hormone crucial during the process of pregnancy. A knockout of "Kdm4a" has no effect on the fertility or viability of male pups.


Recognition sequence

A recognition sequence is a DNA sequence to which a structural motif of a DNA-binding domain exhibits binding specificity. Recognition sequences are palindromes.
The transcription factor Sp1 for example, binds the sequences 5'-(G/T)GGGCGG(G/A)(G/A)(C/T)-3', where (G/T) indicates that the domain will bind a guanine or thymine at this position.
The restriction endonuclease PstI recognizes, binds, and cleaves the sequence 5'-CTGCAG-3'.
A recognition sequence is different from a recognition site. A given recognition sequence can occur one or more times, or not at all, on a specific DNA fragment. A recognition site is specified by the position of the site. For example, there are two PstI recognition sites in the following DNA sequence fragment, starting at base 9 and 31 respectively. A recognition sequence is a specific sequence, usually very short (less than 10 bases). Depending on the degree of specificity of the protein, a DNA-binding protein can bind to more than one specific sequence. For PstI, which has a single sequence specificity, it is 5'-CTGCAG-3'. It is always the same whether at the first recognition site or the second in the following example sequence. For Sp1, which has multiple (16) sequence specificity as shown above, the two recognition sites in the following example sequence fragment are at 18 and 32, and their respective recognition sequences are 5'-GGGGCGGAGC-3' and 5'-TGGGCGGAAC-3'.
5'-AACGTTAGCTGCAGTC"GGGGCGGAGC"TAGGCTGCAGGAAT"TGGGCGGAAC"CT-3'


Envelysin

Envelysin (, "sea-urchin-hatching proteinase", "hatching enzyme", "chorionase", "chorion-digesting proteinase", "chymostrypsin", "sea urchin embryo hatching enzyme") is an enzyme. This enzyme catalyses the following chemical reaction
This enzyme is a glycoprotein from various members of the class "Echinoidea".


Enoyl-(acyl-carrier-protein) reductase (NADPH, B-specific)

In enzymology, an enoyl-[acyl-carrier-protein] reductase (NADPH, B-specific) () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are acyl-[acyl-carrier-protein] and NADP+, whereas its 3 products are trans-2,3-dehydroacyl-[acyl-carrier-protein], NADPH, and H+.
This enzyme belongs to the family of oxidoreductases, to be specific, those acting on the CH-CH group of donor with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is acyl-[acyl-carrier-protein]:NADP+ oxidoreductase (B-specific). Other names in common use include acyl-ACP dehydrogenase, reductase, enoyl-[acyl carrier protein] (reduced nicotinamide, adenine dinucleotide phosphate), NADPH 2-enoyl Co A reductase, enoyl acyl-carrier-protein reductase, enoyl-ACP reductase, and enoyl-[acyl-carrier-protein] reductase (NADPH, B-specific). This enzyme participates in fatty acid biosynthesis.
Structural studies.
As of late 2007, two structures have been solved for this class of enzymes, with PDB accession codes and .


Hemagglutinin-neuraminidase

Hemagglutinin-neuraminidase refers to a single viral protein that has both hemagglutinin and (endo) neuraminidase activity. This is in contrast to the proteins found in influenza, where both functions exist but in two separate proteins. Its neuraminidase domain has the CAZy designation glycoside hydrolase family 83 (GH83).
It does show a structural similarity to influenza viral neuraminidase and has a six-bladed beta-propeller structure. This Pfam entry also matches measles hemagglutinin (cd15467), which has a "dead" neuraminidase part repurposed as a receptor binding site.
Hemagglutinin-neuraminidase allows the virus to stick to a potential host cell, and cut itself loose if necessary. Hemagglutinin-neuraminidase can be found in a variety of paramyxoviruses including mumps virus, human parainfluenza virus 3, and the avian pathogen Newcastle disease virus.
Types include:
Hemagglutinin-neuraminidase inhibitors have been investigated and suggest that there may applications for human use in the future.


3-deoxy-manno-octulosonic acid transferase

3-deoxy-manno-octulosonic acid transferase may refer to:


Silvermints

Silvermints is an Irish sugar-based peppermint-flavoured hard candy.
Silvermints, traditionally sold in the foil packed tube, is as of 2006 sold in a 120g cello bag.
Clarendon Confectionery, part of the Jacob Fruitfield Food Group, first introduced Silvermints in the 1920s.


Matrilin

Matrilins are proteoglycan-associated proteins that are major components of extracellular matrix of various tissues. They include:


Glycosylase

Glycosylases () are enzymes that hydrolyze glycosyl compounds. They are a type of hydrolase (EC 3). In turn, glycosylases are divided into two groups: glycosidases—enzymes that hydrolyze O- and S-glycosyl compounds (EC 3.2.1) -- and enzymes that hydrolyze N-glycosyl compounds (EC 3.2.2).