Angiomotin

Angiomotin (AMOT) is a protein that in humans is encoded by the "AMOT" gene. It belongs to the motin family of angiostatin binding proteins, which includes angiomotin, angiomotin-like 1 (AMOTL1) and angiomotin-like 2 (AMOTL2) characterized by coiled-coil domains at N-terminus and consensus PDZ-binding domain at the C-terminus. Angiomotin is expressed predominantly in endothelial cells of capillaries as well as angiogenic tissues such as placenta and solid tumor.
Discovery.
Angiomotin was discovered in 2001 by screening a placenta yeast two-hybrid cDNA library for angiostatin-binding peptides, using a construct encoding the kringle domains 1-4 of angiostatin.
Gene location.
"AMOT" gene is located on human chromosome X:112,021,794-112,066,354, containing 3252 nucleotides in coding sequence as 11 exons.
Protein structure.
Two splice isoforms are known for angiomotin: p80 and p130. The alternative splicing is somewhat tissue specific. Cells expressing p130 contained more actin than those expressing p80. p80 is not the product of cleavage of p130, as p130 contains no potential proteolytic cleavage site for such conversion.
Angiomotin p80 is a 72.54 kD protein of 675 residues, characterized by conserved N-terminal coiled coil domains and C-terminal PDZ binding motifs, with angiostatin binding domain (ABD) located in the central region. It is hypothesized that the ABD is extracellular, while the coiled-coil and the PDZ binding domain are intracellular. The PDZ-binding motif of angiomotin serves as a protein recognition site and deletion of as few as three amino acids from the C-terminal results in complete loss of pro-migratory activity, and endothelial cells expressing such mutant angiomotin failed to migrate or form tubes.
Angiomotin p130 differs from p80 by having an N-terminal cytoplasmic extension of 409 amino acids rich in glutamine, which mediates the binding of p130 to F-actin and tight cell-cell junctions. This binding remains after destabilizing actin with cytochalasin B.
Like other surface-associated proteins that can bind plasminogen and its derivatives, angiomotin does not appear to have a signal sequence, thus its association with the cell surface may be via protein–protein interaction usually referred to as non-classic secretion.
Function.
Role in cell motility and angiogenesis.
Expression of angiomotin p80 in endothelial cells increases the random migration of endothelial cells, as well as the migration of endothelial cells toward growth factors, e.g. bFGF, VEGF and LPA etc. Angiomotin also mediates tube formation of endothelial cells. Angiomotin promotes angiogenesis by both stimulating cell spreading and stabilizing established tubes, e.g. in mouse aortic endothelial (MAE) cells the tubes remained stable for over 30 days, while control tubes started to regress after 3 days. In the presence of angiostatin, endothelial cells expressing angiomotin p80 exhibit reduction in migration as well as reduction in tubules formation in vitro. These observations are consistent with the localization of angiomotin in the leading edge of migrating cells. Angiostatin therefore, is an inhibitor of angiomotin.
Angiomotin p80 locates and binds angiostatin on the cell surface. In primary endothelial of Chinese hamster ovary, it localizes to cell-cell junction, recruits ZO-1 and interacts with MAGI-1. It may play a role in the assembly of endothelial cell-cell junctions, as well.
Angiomotin p130 does not promote cell migration, nor responds to angiostatin. It localizes to cell-cell junction like p80 and regulates paracellular permeability. Its N-terminal domain localizes to actin fibers and stabilizes them, and this effect is not affected by angiostatin. Transfection of p130 angiomotin into MAE cells results in change in cell shape, increased average cell size and stress fiber formation. So p80 is involved in cell migration and expressed during migratory phase. While p130 controls cell shape by interaction with actin, and is expressed during the period of blood vessel stabilization and maturation. The relative expression levels of p80 and p130 regulate a switch between a migratory and a non-migratory cell phenotype, where homo-oligomerization of p80 and hetero-oligomerization of both isoforms are critical for this regulation.
Role in Hippo signaling pathway.
AMOT, AMOTL1 and AMOTL2 play critical roles in the Hippo signaling pathway by regulating the subcellular localization of the co-activators YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif), and activating LATS2 through a novel conserved domain. The activity of YAP and TAZ can be restricted through their interaction with AMOT and AMOTL1, and such interaction depends on the WW domain of TAZ and the Proline-Proline-x–Tyrosine motif at the N-terminus of AMOT.
In position-dependent Hippo signaling, where the outer and inner cells are polar and nonpolar respectively, AMOT and AMOTL2 are essential for Hippo pathway activation and appropriate cell fate specification. In the nonpolar inner cells, AMOT localizes to adherens junctions (AJs), and Ser-176 at the N-terminal domain is phosphorylated by LATS downstream of GPCR signaling, which inhibits actin binding activity and stabilizes the AMOT-LATS interaction to activate the Hippo pathway. Thus, AMOT is a direct substrate of LATS and its phosphorylation at Ser-176 inhibits cell migration and angiogenesis. In the outer cells, the cell polarity sequesters AMOT from basolateral adherens junctions to apical domains, thereby suppressing Hippo signaling. It is therefore proposed AMOT acts as a molecular switch for Hippo pathway and links F-actin with LATS activity.
Along the Hippo pathway, AMOT's binding to Merlin releases its auto-inhibition and promotes Merlin's binding to LATS1/2. Phosphorylation of Ser-518 outside the Merlin's auto-inhibitory tail prevents binding and thus inhibits Hippo pathway kinase activation. USP9x regulates the ubiquitin-mediated turnover of AMOT, and the deubiquitylation of AMOT results in its stabilization and lower YAP/TAZ activity.
Cancer research.
A DNA vaccination targeting angiomotin generated antibodies that detected AMOT on the endothelial cell surface, which inhibited migration. It blocked angiogenesis and prevented growth of transplanted tumors for up to 150 days "in vivo". A combination of DNA vaccines encoding AMOT and the extracellular and transmembrane domains of the human EGF receptor 2 (Her-2)/neu oncogene inhibited breast cancer progression and impaired tumor vascularization in Her-2/neu transgenic mice, showing DNA vaccination targeting AMOT may be used to mimic the effect of angiostatin and no toxicity or impairment of normal blood vessels was detected.
In human breast cancer tissues, AMOT is highly expressed compared with control, and its level is associated with other angiogenesis markers. AMOT links to the proliferation and invasion of breast tumours and the long-term survival of the patients, and could be a potential target for therapy.
For melanoma, AMOT binds a variant of soluble cell adhesion molecule (sCD146) in endothelial progenitor cells (EPC). Silencing AMOT in EPC inhibits the angiogenic effect of sCD146, e.g. EPC migration, proliferation, and capacity to form capillary-like structures in Matrigel.


D-threonine aldolase

D-threonine aldolase (, "D-TA", "DTA", "low specificity D-TA", "low specificity D-threonine aldolase") is an enzyme with systematic name "D-threonine acetaldehyde-lyase (glycine-forming)". This enzyme catalyses the following chemical reaction
This pyridoxal-phosphate protein is activated by divalent metal cations (e.g. Co2+, Ni2+, Mn2+ or Mg2+).


Glycoside hydrolase family 4

In molecular biology, glycoside hydrolase family 4 is a family of glycoside hydrolases.
Glycoside hydrolases are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycoside hydrolases, based on sequence similarity, has led to the definition of >100 different families. This classification is available on the CAZy web site, and also discussed at CAZypedia, an online encyclopedia of carbohydrate active enzymes.
Glycoside hydrolase family 4 CAZY GH_4 comprises enzymes with several known activities; 6-phospho-beta-glucosidase (); 6-phospho-alpha-glucosidase (); alpha-galactosidase (). 6-phospho-alpha-glucosidase requires both NAD(H) and divalent metal (Mn2+, Fe2+, Co2+, or Ni2+) for activity.
External references.
GH4 in CAZypedia


Uncharacterized LOC644249 gene

Uncharacterized LOC644249 gene., also known as RP11-195B21.3, is about 1058 base pairs long and is found in "Homo sapiens" on chromosome 9q12. More specifically, the sequence is located on Chromosome: 9; NC_000009.11(67977457..67987991 bp). This gene’s protein product is the “coiled-coil domain-containing protein 29” which is 291 amino acids long and may contain a conserved domain in the superfamily, pfam 12001. In particular, this conserved domain contains the domain of unknown function DUF3496 which is about 110 amino acids long, functionally uncharacterized, and found in eukaryotes. Other possible motifs for the protein product exist but the DUF3496 remains the most likely. This protein may play a role as a transmembrane protein.
Gene.
Genomic Location.
For humans, this gene is located on chromosome 9q12 (67977457..67987991) bp.
Promoter.
The promoter is predicted to be about 601 bp in length and is about 100 bp upstream from the transcription start site of the primary transcript .
Transcript.
This gene is predicted to have 4 exons, with a very small 3'UTR which is capped with a poly A tail very shortly after the 4th exon.
Protein.
The protein product is the coiled-coil domain-containing protein 29, abbreviated CCDC29, is about 291 amino acids in length and contains the DUF3496 motif. Also, this protein is also predicted to have a possible transmembrane site at about 284 - 291 aa.
Charge Distribution Analysis.
 1 0000000000 0--0-000-0 +0-00+0-00 0++0+0+0-- 000-+-0000 +00000+-00
 61 0000-0000+ +00000-+0- --++00+--0 000+000-00 +0-00+00-0 +0-0--+000
 121 00-+0--000 0-0000-+00 -000+-0000 00++-000+- 0-0+00-0+0 00–000-0-
 181 -0+-000000 +000000++0 0+00++0000 00+000-+-0 0+00000000 ++-0-0000-
 241 00000000++ 0000000+00 0000000000 +000000000 0000000000 0
Motif.
The DUF3496 motif is about 110 aa long and is conserved within eukaryotes. As the name implies, it is currently unknown in function but can be found across different species. On CCDC 29, its relative location is about 153 - 259 aa.
Expression.
This GEO profile of LOC644249 was included in a gene expression profile which was conducted in a study that analyzed adipose tissues of subjects at risk of metabolic syndrome. This GEO profile may suggest that LOC644249 is ubiquitously expressed in adipose tissue but no direct correlation of the effects of the expression levels of LOC644249 with adipose tissue can be made.
Transcript Variant.
Only two transcript variants were predicted to might occur. One transcript variant predicted the loss of exon 4. The loss of exon 4 would lead to the loss of roughly half of the DUF3496 and the entire loss of the transmembrane domain. The other transcript variant predicted the loss of exon 2, which would not lead to the loss of DUF3496 and leaves the reading frame relatively intact.
Homology.
Orthologs of CCDC29 seem to be only limited to primates as shown by the table below. A paralog of CCDC29 which is not only limited to primates, Ankyrin repeat domain-containing protein 26, showed that this paralog is reserved within vertebrate animals only. The most distant ortholog of Ankyrin repeat domain-containing protein 26 was found to be the gallus gallus species.
Protein Post-Modification.
N glycosylation.
One possible N-glycosylation site was predicted, but a signal peptide was not detected. Thus, it is possible that CCDC29 does not undergo this particular modification even though it has the possible site.
Phosphorylation.
A total of 13 likely phosphorylation sites were predicted: Ser: 5 Thr: 6 Tyr: 2
The main concentration of the phosphorylation sites seem to be localized within the DUF3496 motif and the 3' end of the protein.
Protein structure.
The CCDC29, as the name implies, is thought to have the coiled coil motif. Protein structure prediction software confirms this motif 97.6% confidence.
Transmembrane.
CCDC29 is predicted to have one transmembrane helix located at the N terminal 270.
Function.
Currently unknown as of 5/9/2013.


Serum albumin

Serum albumin, often referred to simply as blood albumin, is an albumin (a type of globular protein) found in vertebrate blood. Human serum albumin is encoded by the "ALB" gene. Other mammalian forms, such as bovine serum albumin, are chemically similar.
Serum albumin is produced by the liver, occurs dissolved in blood plasma and is the most abundant blood protein in mammals. Albumin is essential for maintaining the oncotic pressure needed for proper distribution of body fluids between blood vessels and body tissues; without albumin, the high pressure in the blood vessels would force more fluids out into the tissues. It also acts as a plasma carrier by non-specifically binding several hydrophobic steroid hormones and as a transport protein for hemin and fatty acids. Too much or too little circulating serum albumin may be harmful. Albumin in the urine usually denotes the presence of kidney disease. Occasionally albumin appears in the urine of normal persons following long periods of standing (postural albuminuria).
Function.
Albumin functions primarily as a carrier protein for steroids, fatty acids, and thyroid hormones in the blood and plays a major role in stabilizing extracellular fluid volume by contributing to oncotic pressure (known also as colloid osmotic pressure) of plasma.
Because smaller animals (for example rats) function at a lower blood pressure, they need less oncotic pressure to balance this, and thus need less albumin to maintain proper fluid distribution.
Synthesis.
Albumin is synthesized in the liver as preproalbumin which has an N-terminal peptide that is removed before the nascent protein is released from the rough endoplasmic reticulum. The product, proalbumin, is in turn cleaved in the Golgi vesicles to produce the secreted albumin.
Properties.
Albumin is a globular, water-soluble, un-glycosylated serum protein of approximate molecular weight of 65,000 Daltons.
Albumin (when ionized in water at pH 7.4, as found in the body) is negatively charged. The glomerular basement membrane is also negatively charged in the body; some studies suggest that this prevents the filtration of albumin in the urine. According to this theory, that charge plays a major role in the selective exclusion of albumin from the glomerular filtrate. A defect in this property results in nephrotic syndrome leading to albumin loss in the urine. Nephrotic syndrome patients are sometimes given albumin to replace the lost albumin.
Structure.
The general structure of albumin is characterized by several long α helices allowing it to maintain a relatively static shape, which is essential for regulating blood pressure.
Serum albumin contains eleven distinct binding domains for hydrophobic compounds. One hemin and six long-chain fatty acids can bind to serum albumin at the same time.
Types.
Serum albumin is widely distributed in mammals.


Thelephoric acid

Thelephoric acid is a terphenylquinone pigment that is found in several fungi, such as "Omphalotus subilludens" and "Polyozellus multiplex". Thelephoric acid has been shown to inhibit prolyl endopeptidase, an enzyme that has a role in processing proteins (specifically, amyloid precursor protein) in Alzheimer's disease. Chemicals that inhibit prolyl endopeptidase have attracted research interest due to their potential therapeutic effects. It is derived from atromentin, and its precursor can be from cyclovariegatin. Fragmentation patterns have suggested that polymers of thelephoric acid exists.


Corynebacterial porin B

Porins B and C are cell wall channel-forming proteins from "Corynebacterium". Porin B from "Corynebacterium glutamicum" (Brevibacterium flavum) allows the exchange of material across the mycolic acid layer, which is the protective nonpolar barrier. Porin B has an alpha helical core structure consisting of four alpha-helices surrounding a nonpolar interior. There is a disulfide bridge between helices 1 and 4 to form a stable covalently bound ring. The channel of PorB is oligomeric.


Procollagen-proline 3-dioxygenase

In enzymology, a procollagen-proline 3-dioxygenase () is an enzyme that catalyzes the chemical reaction
The enzyme is a member of the alpha-ketoglutarate-dependent hydroxylases superfamily. The 3 substrates of this enzyme are procollagen L-proline, 2-oxoglutarate, and O2, whereas its 3 products are procollagen trans-3-hydroxy-L-proline, succinate, and CO2.
This enzyme belongs to the family of oxidoreductases, specifically those acting on paired donors, with O2 as oxidant and incorporation or reduction of oxygen. The oxygen incorporated need not be derived from O2 with 2-oxoglutarate as one donor, and incorporation of one atom o oxygen into each donor. The systematic name of this enzyme class is procollagen-L-proline,2-oxoglutarate:oxygen oxidoreductase (3-hydroxylating). Other names in common use include proline,2-oxoglutarate 3-dioxygenase, prolyl 3-hydroxylase, protocollagen proline 3-hydroxylase, prolyl-4-hydroxyprolyl-glycyl-peptide, 2-oxoglutarate: oxygen, and oxidoreductase, 3-hydroxylating. It has 2 cofactors: iron, and Ascorbate.


FASTKD5

FAST kinase domain-containing protein 5 (FASTKD5) is a protein that in humans is encoded by the "FASTKD5" gene on chromosome 20. This protein is part of the FASTKD family, which is known for regulating the energy balance of mitochondria under stress. FASTKD5 is also required for RNA granules to process precursor mRNAs not flanked by tRNAs.
Structure.
FASTKD5 shares structural characteristics of the FASTKD family, including an amino terminal mitochondrial targeting domain and three C-terminal domains: two FAST kinase-like domains (FAST_1 and FAST_2) and a RNA-binding domain (RAP). The mitochondrial targeting domain directs FASTKD5 to be imported into the mitochondria. Though the functions of the C-terminal domains are unknown, RAP possibly binds RNA during trans-splicing. This protein forms a 103 kDa protein complex with unidentified proteins.
Function.
As a member of the FASTKD family, FASTKD5 localizes to the mitochondria to modulate their energy balance, especially under conditions of stress. Though ubiquitously expressed in all tissues, FASTKD5 appears more abundantly in skeletal muscle, heart muscle, and other tissues enriched in mitochondria. FASTKD5 also localizes to RNA granules, membraneless bodies containing mRNAs and associated RNA-binding proteins, where it facilitates posttranscriptional RNA processing. This protein is required for the maturation of precursor mRNAs that are not flanked by tRNAs, and thus cannot be processed by the canonical mRNA maturation pathway.
Clinical significance.
Though the link to FASTKD5 remains uncharacterized, the accumulation of abnormal RNA granules can lead to some neurodegenerative diseases.
Interactions.
FASTKD5 has been shown to interact with:


Alanine racemase

In enzymology, an alanine racemase () is an enzyme that catalyzes the chemical reaction
Hence, this enzyme has one substrate, L-alanine, and one product, D-alanine.
This enzyme belongs to the family of isomerases, specifically those racemases and epimerases acting on amino acids and derivatives. The systematic name of this enzyme class is alanine racemase. This enzyme is also called L-alanine racemase. This enzyme participates in alanine and aspartate metabolism and D-alanine metabolism. It employs one cofactor, pyridoxal phosphate. At least two compounds, 3-Fluoro-D-alanine and D-Cycloserine are known to inhibit this enzyme.
The D-alanine produced by alanine racemase is used for peptidoglycan biosynthesis. Peptidoglycan is found in the cell walls of all bacteria, including many which are harmful to humans. The enzyme is absent in higher eukaryotes but found everywhere in prokaryotes, making alanine racemase a great target for antimicrobial drug development. Alanine racemase can be found in some invertebrates.
Bacteria can have one (alr gene) or two alanine racemase genes. Bacterial species with two genes for alanine racemase have one that is continually expressed and one that is inducible, which makes it difficult to target both genes for drug studies. However, knockout studies have shown that without the alr gene being expressed, the bacteria would need an external source of D-alanine in order to survive. Therefore, the alr gene is a feasible target for antimicrobial drugs.
Structural studies.
To catalyze the interconversion of D and L alanine, Alanine racemase must position residues capable of exchanging protons on either side of the alpha carbon of alanine. Structural studies of enzyme-inhibitor complexes suggest that Tyrosine 265 and Lysine 39 are these residues. The alpha-proton of the L-enantiomer is oriented toward Tyr265 and the alpha proton of the D-enantiomer is oriented toward Lys39 (Figure 1). The distance between the enzyme residues and the enantiomers is 3.5A and 3.6A respectively. Structural studies of enzyme complexes with a synthetic L-alanine analog, a tight binding inhibitor and propionate further validate that Tyr265 and Lys39 are catalytic bases for the reaction.
The PLP-L-Ala and PLP-D-Ala complexes are almost superimposability. The regions that do not overlap are the arms connected the pyridine ring of PLP and the alpha carbon of alanine. An interaction between both the phosphate oxygen and pyridine nitrogen atoms to the 5’phosphopyridoxyl region of PLP-Ala probably creates tight binding to the enzyme.
 The structure of alanine racemase from "Bacillus stearothermophilus" (Geobacillus stearothermophilus) was determined by X-ray crystallography to a resolution of 1.9 A. The alanine racemase monomer is composed of two domains, an eight-stranded alpha/beta barrel at the N terminus, and a C-terminal domain essentially composed of beta-strand. A model of the two domain structure is shown in Figure 2. The N-terminal domain is also found in the PROSC (proline synthetase co-transcribed bacterial homolog) family of proteins, which are not known to have alanine racemase activity. The pyridoxal 5'-phosphate (PLP) cofactor lies in and above the mouth of the alpha/beta barrel and is covalently linked via an aldimine linkage to a lysine residue, which is at the C terminus of the first beta-strand of the alpha/beta barrel.
Proposed Mechanism.
Reaction mechanisms are difficult to fully prove by experiment. The traditional mechanism attributed to an alanine racemase reaction is that of a two-base mechanism with a PLP-stabilized carbanion intermediate. PLP is used as an electron sink stabilize the negative charge resulting from the deprotonation of the alpha carbon. The two based mechanism favors reaction specificity compared to a one base mechanism. The second catalytic residue is pre-positioned to donate a proton quickly after a carbanionic intermediate is formed and thus reduces the chance of alternative reactions occurring. There are two potential conflicts with this traditional mechanism, as identified by Watanabe et al. First, Arg219 forms a hydrogen bond with pyridine nitrogen of PLP. The arginine group has a pKa of about 12.6 and is therefore unlikely to protonate the pyridine. Normally in PLP reactions an acidic amino acid residue such as a carboxylic acid group, with a pKa of about 5, protonates the pyridine ring. The protonation of the pyridine nitrogen allows the nitrogen to accept additional negative charge. Therefore, due to the Arg219, the PLP-stabilized carbanion intermediate is less likely to form. Another problem identified was the need for another basic residue to return Lys39 and Tyr265 back to their protonated and unprotonated forms for L-alanine and vice versa for D-alanine. Watanabe et al. found no amino acid residues or water molecules, other than the carboxylate group of PLP-Ala, to be close enough (within 4.5A) to protonate or deprotonate Lys or Tyr. This is shown in Figure 3.
Based on the crystal structures of N-(5’-phosphopyridoxyl) L- alanine (PKP-L-Ala ( and N-(5’-phosphopyridoxyl) D-alanine (PLP-D-Ala)
Watanabe et al. proposed an alternative mechanism in 2002, as seen in the figure 4. In this mechanism the carboxylate oxygen atoms of PLP-Ala directly participates in catalysis by mediating proton transfer between Lys39 and Tyr265. The crystallization structure identified that the carboxylate oxygen of PLP-L-Ala to the OH of Tyr265 was only 3.6A and the carboxylate oxygen of PLP-L-Ala to the nitrogen of Lys39 was only 3.5A. Therefore, both were close enough to cause a reaction.
This mechanism is supported by mutations of Arg219. Mutations changing Arg219 to a carboxylate result in a quinonoid intermediate being detected whereas none was detected with arginine. The arginine intermediate has much more free energy, is more unstable, than the acidic residue mutants. The destabilization of the intermediate promotes specificity of the reaction.


Sprifermin

Sprifermin (INN) (developmental code name AS-902330), also known as recombinant human fibroblast growth factor 18 (rhFGF18), is a recombinant form of human fibroblast growth factor 18 (FGF18) which is under development by Merck and Nordic Bioscience for the treatment of osteoarthritis. As a recombinant form of FGF18, sprifermin is a potent agonist of the FGFR2 and FGFR3.
As of 2017, the drug is in phase II clinical trials for the treatment of osteoarthritis.
2019 outcomes of phase 2 clinical trial for KOA, shows improvement in cartilage thickness, but fails to satisfy tests like the WOMAC, therefore failing to satisfy its primary end points.
However in some subgroups where cartilage thickness is of specific concern, clinical significance might be achieved.


Glycoside hydrolase family 37

In molecular biology, glycoside hydrolase family 37 is a family of glycoside hydrolases.
Glycoside hydrolases are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycoside hydrolases, based on sequence similarity, has led to the definition of >100 different families. This classification is available on the CAZy web site, and also discussed at CAZypedia, an online encyclopedia of carbohydrate active enzymes.
Glycoside hydrolase family 37 CAZY GH_37 comprises enzymes with only one known activity; trehalase (). Trehalase is the enzyme responsible for the degradation of the disaccharide alpha,alpha-trehalose yielding two glucose subunits. It is an enzyme found in a wide variety of organisms and whose sequence has been highly conserved throughout evolution.


RAP6

RAP6 is the abbreviation for Rab5-activating protein 6, a novel endosomal protein with a role in endocytosis. RAP6 was discovered by Alejandro Barbieri and his group of researchers (Christine Hunker, Adriana Galvis, Ivan Kruk, Hugo Giambini, Lina Torres and Maria Luisa Veisaga) working at Florida International University.
This novel human protein has been reported to be involved in membrane trafficking. It has been shown that RAP6 has a guanine nucleotide exchange factor (GEF) activity specific to Rab5 and a GTPase activating protein (GAP) activity specific to RAS.
The original GeneBank Identifications (GIs) have been published in the NCBI Nucleotide databases with GIs 77176718 and 77176720. Since then, many names have been coined to the validated protein such as RabGEF1, GeneID: 27342. RAP6 belongs to the family of the GAPVD1, GeneID: 26130


Gluconate 5-dehydrogenase

In enzymology, a gluconate 5-dehydrogenase () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are D-gluconate, NAD+, and NADP+, whereas its 4 products are 5-dehydro-D-gluconate, NADH, 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 D-gluconate:NAD(P)+ 5-oxidoreductase. Other names in common use include 5-keto-D-gluconate 5-reductase, 5-keto-D-gluconate 5-reductase, 5-ketogluconate 5-reductase, 5-ketogluconate reductase, and 5-keto-D-gluconate reductase.
Structural studies.
As of late 2007, only one structure has been solved for this class of enzymes, with the PDB accession code .


List of intestinal epithelial differentiation genes

Table of genes implicated in development and differentiation of the intestinal epithelium
The table listed below is a running comprehensive list of all intestinal differential genes that have been reported in the literature. The PMID is the pubmed identification number of the papers that support the summarized information in the table corresponding to each row.


Haptoglobin

Haptoglobin (abbreviated as Hp) is the protein that in humans is encoded by the "HP" gene. In blood plasma, haptoglobin binds to "free" hemoglobin, compared to hemopexin that binds to "free" heme, released from erythrocytes with high affinity, and thereby inhibits its deleterious oxidative activity. The haptoglobin-hemoglobin complex will then be removed by the reticuloendothelial system (mostly the spleen).
In clinical settings, the haptoglobin assay is used to screen for and monitor intravascular hemolytic anemia. In intravascular hemolysis, free hemoglobin will be released into circulation and hence haptoglobin will bind the hemoglobin. This causes a decline in haptoglobin levels.
Function.
Hemoglobin that has been released into the blood plasma by damaged red blood cells has harmful effects. The "HP" gene encodes a preproprotein that is processed to yield both alpha and beta chains, which subsequently combines as a tetramer to produce haptoglobin. Haptoglobin functions to bind the free plasma hemoglobin, which allows degradative enzymes to gain access to the hemoglobin while at the same time preventing loss of iron through the kidneys and protecting the kidneys from damage by hemoglobin.
The cellular receptor target of Hp is the monocyte/macrophage scavenger receptor, CD163. Following Hb-Hp binding to CD163, cellular internalization of the complex leads to globin and heme metabolism, which is followed by adaptive changes in antioxidant and iron metabolism pathways and macrophage phenotype polarization.
Differentiation with hemopexin.
When hemoglobin is released from RBCs within the physiologic range of hemopexin, the potential deleterious effects of hemoglobin are prevented. However, during hyper-hemolytic conditions or with chronic hemolysis, hemoglobin is depleted and readily distributes to tissues where it might be exposed to oxidative conditions. In such conditions, heme can be released from ferric (Fe3+-bound) hemoglobin. The free heme can then accelerate tissue damage by promoting peroxidative reactions and activation of inflammatory cascades. Hemopexin (Hx) is another plasma glycoprotein, like hemoglobin, that is able to bind heme with high affinity. Hemopexin sequesters heme in an inert, non-toxic form and transports it to the liver for catabolism and excretion.
Synthesis.
Haptoglobin is produced mostly by hepatic cells but also by other tissues such as skin, lung and kidney. In addition, the haptoglobin gene is expressed in murine and human adipose tissue.
Haptoglobin had been shown to be expressed in adipose tissue of cattle as well.
Structure.
Haptoglobin, in its simplest form, consists of two alpha and two beta chains, connected by disulfide bridges. The chains originate from a common precursor protein, which is proteolytically cleaved during protein synthesis.
Hp exists in two allelic forms in the human population, so-called "Hp1" and "Hp2", the latter one having arisen due to the partial duplication of "Hp1" gene. Three genotypes of Hp, therefore, are found in humans: Hp1-1, Hp2-1, and Hp2-2. Hp of different genotypes have been shown to bind hemoglobin with different affinities, with Hp2-2 being the weakest binder.
In other species.
Hp has been found in all mammals studied so far, some birds, e.g., cormorant and ostrich but also, in its simpler form, in bony fish, e.g., zebrafish. Hp is absent in at least some amphibians ("Xenopus") and neognathous birds (chicken and goose).
Clinical significance.
Mutations in this gene or its regulatory regions cause ahaptoglobinemia or hypohaptoglobinemia. This gene has also been linked to diabetic nephropathy, the incidence of coronary artery disease in type 1 diabetes, Crohn's disease, inflammatory disease behavior, primary sclerosing cholangitis, susceptibility to idiopathic Parkinson's disease, and a reduced incidence of "Plasmodium falciparum" malaria.
Since the reticuloendothelial system will remove the haptoglobin-hemoglobin complex from the body, haptoglobin levels will be decreased in case of intravascular hemolysis or "severe" extravascular hemolysis. In the process of binding to free hemoglobin, haptoglobin sequesters the iron within hemoglobin, preventing iron-utilizing bacteria from benefiting from hemolysis. It is theorized that, because of this, haptoglobin has evolved into an acute-phase protein. HP has a protective influence on the hemolytic kidney.
The different haptoglobin phenotypes differ in their antioxidant, scavenging, and immunomodulatory properties. This aspect of haptoglobin may gain importance in immune suppressed conditions (such as liver cirrhosis) and the various phenotypes may result in different susceptibility levels towards bacterial infections.
Some studies associate certain haptoglobin phenotypes with the risk of developing schizophrenia.
Test protocol.
Measuring the level of haptoglobin in a patient's blood is ordered whenever a patient exhibits symptoms of anemia, such as pallor, fatigue, or shortness of breath, along with physical signs of hemolysis, such as jaundice or dark-colored urine. The test is also commonly ordered as a hemolytic anemia battery, which also includes a reticulocyte count and a peripheral blood smear. It can also be ordered along with a direct antiglobulin test when a patient is suspected of having a transfusion reaction or symptoms of autoimmune hemolytic anemia. Also, it may be ordered in conjunction with a bilirubin.
Interpretation.
A decrease in haptoglobin can support a diagnosis of intravascular hemolytic anemia, especially when correlated with a decreased red blood cell count, hemoglobin, and hematocrit, and also an increased reticulocyte count.
If the reticulocyte count is increased, but the haptoglobin level is normal, this may indicate that cellular destruction is occurring in the spleen and liver, which may indicate an extravascular hemolytic anemia, drug-induced hemolysis, or a red cell dysplasia. The spleen and liver recognize an error in the red cells (either drug coating the red cell membrane or a dysfunctional red cell membrane), and destroy the cell. This type of destruction does not release hemoglobin into the peripheral blood, so the haptoglobin cannot bind to it. Thus, the haptoglobin will stay normal if the hemolysis is not severe. In severe extra-vascular hemolysis, haptoglobin levels can also be low, when large amount of hemoglobin in the reticuloendothelial system leads to transfer of free hemoglobin into plasma.
If there are symptoms of anemia but both the reticulocyte count and the haptoglobin level are normal, the anemia is most likely not due to hemolysis, but instead some other error in cellular production, such as aplastic anemia.
Haptoglobin levels that are decreased but do not accompany signs of anemia may indicate liver damage, as the liver is not producing enough haptoglobin to begin with.
As haptoglobin is indeed an acute-phase protein, any inflammatory process (infection, extreme stress, burns, major crush injury, allergy, etc.) may increase the levels of plasma haptoglobin.


Corticotropin-releasing factor family

Corticotropin-releasing factor family, CRF family is a family of related neuropeptides in vertebrates. This family includes corticotropin-releasing hormone (also known as CRF), urotensin-I, urocortin, and sauvagine. The family can be grouped into 2 separate paralogous lineages, with urotensin-I, urocortin and sauvagine in one group and CRH forming the other group. Urocortin and sauvagine appear to represent orthologues of fish urotensin-I in mammals and amphibians, respectively. The peptides have a variety of physiological effects on stress and anxiety, vasoregulation, thermoregulation, growth and metabolism, metamorphosis and reproduction in various species, and are all released as prohormones.
Corticotropin-releasing hormone (CRH) is a releasing hormone found mainly in the paraventricular nucleus of the mammalian hypothalamus that regulates the release of corticotropin (ACTH) from the pituitary gland. The paraventricular nucleus transports CRH to the anterior pituitary, stimulating adrenocorticotropic hormone (ACTH) release via CRH type 1 receptors, thereby activating the hypothalamic-pituitary-adrenal axis (HPA) and, thus, glucocorticoid release.
CRH is evolutionary-related to a number of other active peptides. Urocortin acts "in vitro" to stimulate the secretion of adrenocorticotropic hormone. Urotensin is found in the teleost caudal neurosecretory system and may play a role in osmoregulation and as a corticotropin-releasing factor. Urotensin-I is released from the urophysis of fish, and produces ACTH and subsequent cortisol release in vivo. The nonhormonal portion of the prohormone is thought to be the urotensin binding protein (urophysin). Sauvagine (), isolated from frog skin, has a potent hypotensive and diuretic effect.
Human proteins from this family.
CRH; UCN;


PARP inhibitor

PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARP).
They are developed for multiple indications, including the treatment of . Several forms of cancer are more dependent on PARP than regular cells, making PARP (PARP1, PARP2 etc) an attractive target for cancer therapy. PARP inhibitors appear to improve progression-free survival in women with recurrent platinum-sensitive ovarian cancer, as evidenced mainly by olaparib added to conventional treatment.
In addition to their use in cancer therapy, PARP inhibitors are considered a potential treatment for acute life-threatening diseases, such as stroke and myocardial infarction, as well as for long-term neurodegenerative diseases.
Mechanism of action.
DNA is damaged thousands of times during each cell cycle, and that damage must be repaired, including in cancer cells. Otherwise the cells may die due to this damage. Chemotherapy and radiation therapy attempt to kill cancer cells by inducing high levels of DNA damage. By inhibiting PARP1 DNA repair, the effectiveness of these therapies can be increased.
BRCA1, BRCA2 and PALB2 are proteins that are important for the repair of double-strand DNA breaks by the error-free homologous recombinational repair, or HRR, pathway. When the gene for one of these proteins is mutated, the change can lead to errors in DNA repair that can eventually cause breast cancer. When subjected to enough damage at one time, the altered gene can cause the death of the cells.
PARP1 is a protein that is important for repairing single-strand breaks ('nicks' in the DNA). If such nicks persist unrepaired until DNA is replicated (which must precede cell division), then the replication itself can cause double strand breaks to form.
Drugs that inhibit PARP1 cause multiple double strand breaks to form in this way, and in tumours with BRCA1, BRCA2 or PALB2 mutations, these double strand breaks cannot be efficiently repaired, leading to the death of the cells. Normal cells that don't replicate their DNA as often as cancer cells, and that lack any mutated BRCA1 or BRCA2 still have homologous repair operating, which allows them to survive the inhibition of PARP.
PARP inhibitors lead to trapping of PARP proteins on DNA in addition to blocking their catalytic action. This interferes with replication, causing cell death preferentially in cancer cells, which grow faster than non-cancerous cells.
Some cancer cells that lack the tumor suppressor PTEN may be sensitive to PARP inhibitors because of downregulation of Rad51, a critical homologous recombination component, although other data suggest PTEN may not regulate Rad51. Hence PARP inhibitors may be effective against many PTEN-defective tumours (e.g. some aggressive prostate cancers).
Cancer cells that are low in oxygen (e.g. in fast growing tumors) are sensitive to PARP inhibitors.
Excessive PARP-1 activity may exacerbate the pathogenesis of stroke, myocardial infarction, neurodegeneration, and a number of other disease conditions due to excessive inflammation. Thus, reduction of inflammation by PARP-1 inhibition can mitigate these conditions.
Examples in clinical trials.
Started Phase III:
Started Phase II:
Currently Discontinued:
Experimental:
Combination with radiotherapy.
The main function of radiotherapy is to produce DNA strand breaks, causing severe DNA damage and leading to cell death. Radiotherapy has the potential to kill 100% of any targeted cells, but the dose required to do so would cause unacceptable side effects to healthy tissue. Radiotherapy therefore can only be given up to a certain level of radiation exposure. Combining radiation therapy with PARP inhibitors offers promise, since the inhibitors would lead to formation of double strand breaks from the single-strand breaks generated by the radiotherapy in tumor tissue with BRCA1/BRCA2 mutations. This combination could therefore lead to either more powerful therapy with the same radiation dose or similarly powerful therapy with a lower radiation dose.


Glycoside hydrolase family 92

In molecular biology, glycoside hydrolase family 92 is a family of glycoside hydrolases.
Glycoside hydrolases are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycoside hydrolases, based on sequence similarity, has led to the definition of >100 different families. This classification is available on the CAZy web site, and also discussed at CAZypedia, an online encyclopedia of carbohydrate active enzymes.
This domain occurs within alpha-1,2-mannosidases, which remove alpha-1,2-linked mannose residues from Man(9)(GlcNAc)(2) by hydrolysis. They are critical for the maturation of N-linked oligosaccharides and ER-associated degradation.
Glycoside hydrolase family 92 includes enzymes with mannosyl-oligosaccharide α-1,2-mannosidase , mannosyl-oligosaccharide α-1,3-mannosidase , mannosyl-oligosaccharide α-1,6-mannosidase , α-mannosidase , α-1,2-mannosidase , α-1,3-mannosidase and α-1,4-mannosidase activities. It includes enzymes critical for the maturation of N-linked oligosaccharides and ER-associated degradation.


ERG4

ERG4 or Delta(24(24(1)))-sterol reductase or Delta(24(28))-sterol reductase is a enzyme that catalyzes the last step of ergosterol biosynthesis pathway in fungi "Saccharomyces cerevisiae" (Baker's yeast), which 5,7,22,24(28)-ergostatetraenol converted into ergosterol.


Bufotalin

Bufotalin is a cardiotoxic bufanolide steroid, cardiac glycoside analogue, secreted by a number of toad species. Bufotalin can be extracted from the skin parotoid glands of several types of toad.
Sources.
"Rhinella marina" (Cane toad), "Rhaebo guttatus" (Smooth-sided toad), "Bufo melanostictus" (Asian toad), and "Bufo bufo" (common European toad) are sources of bufotalin.
Traditional medicine.
Bufotalin is part of Ch'an Su, a traditional Chinese medicine used for cancer. It is also known as Venenum Bufonis or senso (Japanese).
Toxicity.
Specifically, in cats the lethal median dose is 0.13 mg/kg. and in dogs is 0.36 mg/kg (intravenous).
Knowing this it is advisable to monitor those functions continuously using an EKG. As there is no antidote against bufotalin all occurring symptoms need to be treated separately or if possible in combination with others. To increase the clearance theoretically, due to the similarities with digitoxin, cholestyramine, a bile salt, might help. Recent animal studies have shown that taurine restores cardiac functions.
Symptomatic measures include lignocaine, atropine and phenytoin for cardiac toxicity and intravenous potassium compounds to correct hyperkalaemia from its effect on the Na+/K+ ATPase pump.
Pharmacology and mechanism of action.
After a single intravenous injection, bufotalin gets quickly distributed and eliminated from the blood plasma with a half-time of 28.6 minutes and a MRT of 14.7 min. After 30 minutes after an administration of bufotalin, the concentrations within the brain and lungs are significantly higher than those in blood and other tissues. It also increases cancer cell's susceptibility to apoptosis via TNF-α signalling by the BH3 interacting domain death agonist and STAT proteins.
Bufotalin induces apoptosis "in vitro" in human hepatocellular carcinoma Hep 3B cells and might involve caspases and apoptosis inducing factor (AIF). The use of bufotalin as a cancer treating compound is still in the experimental phase. It also arrests cell cycle at G(2)/M, by up- and down- regulation of several enzymes.
Pharmacokinetics.
The mechanism of the biotransformation of bufotalin is still unknown. Researches found, that bufotalin is biotransformed into at least 5 different compounds.
Chemical properties.
If bufotalin is esterified with suberyl arginine, the bufotalin-like steroid bufotoxin is obtained.


Beta-chamigrene synthase

Beta-chamigrene synthase () is an enzyme with systematic name "(2E,6E)-farnesyl diphosphate lyase (cyclizing, (+)-beta-chamigrene-forming)". This enzyme catalyses the following chemical reaction
The recombinant enzyme from the plant "Arabidopsis thaliana" produces (+)-alpha-barbatene, (+)-thujopsene and (+)-beta-chamigrene.


Cyclopentanol dehydrogenase

In enzymology, a cyclopentanol dehydrogenase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are cyclopentanol and NAD+, whereas its 3 products are cyclopentanone, NADH, and H+.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-OH group of donor with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is cyclopentanol:NAD+ oxidoreductase.


Drosha

Drosha is a Class 2 ribonuclease III enzyme that in humans is encoded by the "DROSHA" (formerly "RNASEN") gene. It is the primary nuclease that executes the initiation step of miRNA processing in the nucleus. It works closely with DGCR8 and in correlation with Dicer. It has been found significant in clinical knowledge for cancer prognosis and HIV-1 replication.
History.
Human Drosha was cloned in 2000  when it was identified as a nuclear dsRNA ribonuclease involved in the processing of ribosomal RNA precursors. The other two human enzymes that participate in the processing and activity of miRNA are the Dicer and Argonaute proteins. Recently, proteins like Drosha have been found significant in cancer prognosis and HIV-1 replication.
Function.
Members of the ribonuclease III superfamily of double-stranded (ds) RNA-specific endoribonucleases participate in diverse RNA maturation and decay pathways in eukaryotic and prokaryotic cells. The RNase III Drosha is the core nuclease that executes the initiation step of microRNA (miRNA) processing in the nucleus.
The microRNAs thus generated are short RNA molecules that regulate a wide variety of other genes by interacting with the RNA-induced silencing complex (RISC) to induce cleavage of complementary messenger RNA (mRNA) as part of the RNA interference pathway. MicroRNA molecules are synthesized as long RNA primary transcripts known as a "pri-miRNAs", which are cleaved by Drosha to produce a characteristic stem-loop structure of about 70 base pairs long, known as a "pre-miRNA." Pre-miRNAs, when associated with EXP5, are stabilized due to removal of the 5' cap and 3' poly(A) tail. Drosha exists as part of a protein complex called the Microprocessor complex, which also contains the double-stranded RNA binding protein DGCR8 (called Pasha in "D. melanogaster" and "C. elegans"). DGCR8 is essential for Drosha activity and is capable of binding single-stranded fragments of the pri-miRNA that are required for proper processing. The Drosha complex also contains several auxiliary factors such as EWSR1, FUS, hnRNPs, p68, and p72.
Both Drosha and DGCR8 are localized to the cell nucleus, where processing of pri-miRNA to pre-miRNA occurs. These two proteins homeostatically control miRNA biogenesis by an auto-feedback loop. A 2nt 3' overhang is generated by Drosha in the nucleus recognized by Dicer in the cytoplasm, which couples the upstream and downstream processing events. Pre-miRNA is then further processed by the RNase Dicer into mature miRNAs in the cell cytoplasm. There also exists an isoform of Drosha that does not contain a nuclear localization signal, which results in the generation of c-Drosha. This variant has been shown to localize to the cell cytoplasm rather than the nucleus, but the effects on pri-miRNA processing are yet unclear.
Both Drosha and Dicer also participate in the DNA damage response.
Certain miRNAs have been found to deviate from conventional biogenesis pathways and do not necessarily require Drosha or Dicer, which is because they do not require the processing of pri-miRNA to pre-miRNA. Drosha-independent miRNAs derive from mirtrons, which are genes that encode for miRNAs in their introns and make use of splicing to bypass Drosha cleavage. Simtrons are mirtron-like, splicing-independent, and do require Drosha mediated cleavage, although they do not require most proteins in the canonical pathway such as DGCR8 or Dicer.
Clinical significance.
Drosha and other miRNA processing enzymes may be important in cancer prognosis. Both Drosha and Dicer can function as master regulators of miRNA processing and have been observed to be down-regulated in some types of breast cancer. The alternative splicing patterns of Drosha in The Cancer Genome Atlas have also indicated that c-drosha appears to be enriched in various types of breast cancer, colon cancer, and esophageal cancer. However, the exact nature of the association between microRNA processing and tumorigenesis is unclear, but its function can be effectively examined by siRNA knockdown based on an independent validation.
Drosha and other miRNA processing enzymes may also be important in HIV-1 replication. miRNAs contribute to the innate antiviral defense. This can be shown by the knockdown of two important miRNA processing proteins, Drosha and Dicer, which leads to a significant enhancement of viral replication in PBMCs from HIV-1-infected patients. Thus, Drosha, in conjunction with Dicer, seem to have a role in controlling HIV-1 replication.


STARD4

StAR-related lipid transfer protein 4 (STARD4) is a soluble protein involved in cholesterol transport. It can transfer up to 7 sterol molecules per minute between artificial membranes.
Function.
STARD4 may regulate cholesterol levels in many cells, including in the liver. STARD4 has specifically been linked to the movement of cholesterol to the endoplasmic reticulum. The protein is associated with the endoplasmic reticulum and lipid droplets. Increases in the protein relate to cell stress.
High levels of STARD4 increases the synthesis of bile acids and cholesterol esters in liver hepatocytes. Reductions in cholesterol synthesis by cells increase STARD4 levels while StarD4 declines in mice fed a high cholesterol diet.
Increases in levels of either master gene regulator SREBP-1a or SREBP2, which both promote the production of proteins involved in cholesterol synthesis, increase StarD4 levels in mouse liver. Conversely, increased STARD4 increases active SREBP2 levels.
Loss of the protein in mice has little effect. Mice without functional STARD4 weigh less and females tend to have lower cholesterol profiles. The most dramatic change observed to date is a reduction in NPC-1, a protein involved in bringing cholesterol into cells.
Structure.
The protein is 205 amino acids long in the human (224 in the mouse) and almost entirely consists of a StAR-related transfer (START) domain. It also lends its name to the subgroup of START domain proteins it is part of, StarD4. This subfamily includes STARD5 and STARD6 and is closely related to the StarD1/D3 group.


3-dehydroquinate synthase

In enzymology, a 3-dehydroquinate synthase () is an enzyme that catalyzes the chemical reaction
Hence, this enzyme has one substrate, 3-deoxy-arabino-heptulosonate 7-phosphate, and two products, 3-dehydroquinate and phosphate. The protein uses NAD+ to catalyze the reaction. This reaction is part of the shikimate pathway which is involved in the biosynthesis of aromatic amino acids.
3-Dehydroquinate synthase belongs to the family of lyases, to be specific those carbon-oxygen lyases acting on phosphates. This enzyme participates in phenylalanine, tyrosine, and tryptophan biosynthesis. It employs one cofactor, cobalt (Co2+).
Background.
The shikimate pathway is composed of seven steps, each catalyzed by an enzyme. The shikimate pathway is responsible for producing the precursors for aromatic amino acids, which are essential to our diets because we cannot synthesize them in our bodies. Only plants, bacteria, and microbial eukaryotes are capable of producing aromatic amino acids. The pathway ultimately converts phosphoenolpyruvate and 4-erythrose phosphate into chorismate, the precursor to aromatic amino acids. 3-Dehydroquinate synthase is the enzyme that catalyzes reaction in the second step of this pathway. This second step of the reaction eliminates a phosphate from 3-deoxy-D-arabino-heptulosonate 7-phosphate, which results in 3-dehydroquinate. 3-Dehydroquinate synthase is a monomeric enzyme, and has a molecular weight of 39,000. 3-dehydroquinate synthase is activated by inorganic phosphate, and requires NAD+ for activity, although the reaction in total is neutral when catalyzed by an enzyme.
Function.
3-Dehydroquinate synthase utilizes a complex multi-step mechanism that includes alcohol oxidation, phosphate β-elimination, carbonyl reduction, ring opening, and intramolecular aldol condensation.
Dehydroquinate synthase requires NAD+ and a cobalt cofactor to catalyze the conversion of 3-deoxy-D-arabino-heptulosonate 7-phosphate into 3-dehydroquinate. Dehydroquinate synthase is of particular interest because of its complicated activity relative to its small size. In most bacteria, this enzyme has only one function. However, in fungi and protists, it is part of the pentafunctional AROM complex that comprises steps two, three, four, five and six of the shikimate pathway. Together with 3-dehydroquinate dehydratase, 3-dehydroquinate synthase forms the core of this complex.
Applications.
3-Dehydroquinate synthase catalyzes the second step in the shikimate pathway, which is essential for the production of aromatic amino acids in bacteria, plants, and fungi, but not mammals. This makes it an ideal target for new antimicrobial agents, anti-parasitic agents, and herbicides. Other enzymes in the shikimate pathway have already been targeted and put to use as herbicides. Roundup, a common herbicide made by Monsanto, works by inhibiting another enzyme in the shikimate pathway. The shikimate pathway is an ideal choice for herbicides because this pathway does not exist in animals or people so people are not directly affected. Roundup uses an enzyme inhibitor, glyphosate, to block one of the steps of the shikimate pathway. Glyphosate inhibits 5-enolpyruvylshikimate-3-phosphate synthase (EPSP synthase), which ultimately blocks the production of aromatic amino acids, and, without aromatic amino acids, plants cannot survive. However, Monsanto developed a bacterial form of EPSP synthase that was not inhibited by Roundup. Monsanto introduced this gene into plants using agrobacterium and the result was a plant that was resistant to Roundup. This meant that all plants without the bacterial gene would die, leading a much higher degree of weed control.
Nomenclature.
The systematic name of this enzyme class is 3-deoxy-arabino-heptulonate-7-phosphate phosphate-lyase (cyclizing 3-dehydroquinate-forming). Other names in common use include 5-dehydroquinate synthase, 5-dehydroquinic acid synthetase, dehydroquinate synthase, 3-dehydroquinate synthetase, 3-deoxy-arabino-heptulosonate-7-phosphate phosphate-lyase, (cyclizing), and 3-deoxy-arabino-heptulonate-7-phosphate phosphate-lyase (cyclizing).


4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase

In enzymology, a 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are GDP-beta-L-fucose and 1,4-beta-D-galactosyl-N-acetyl-D-glucosaminyl-R. Its 3 products are GDP, 1,4-beta-D-galactosyl-(alpha-1,3-L-fucosyl)-N-acetyl-D-glucosaminyl-, and R.
This enzyme belongs to the family of glycosyltransferases, specifically the hexosyltransferases. The systematic name of this enzyme class is GDP-beta-L-fucose:1,4-beta-D-galactosyl-N-acetyl-D-glucosaminyl-R 3-alpha-L-fucosyltransferase. Other names in common use include:
This enzyme participates in 3 metabolic pathways: glycosphingolipid biosynthesis - neo-lactoseries, glycosphingolipid biosynthesis - globoseries, and glycan structures - biosynthesis 2.
Structural studies.
As of late 2007, 3 structures have been solved for this class of enzymes, with PDB accession codes , , and .


Alpha-keratin

Alpha-keratin, or α-keratin, is a type of keratin found in vertebrates. This protein is the primary component in hairs, horns, mammalian claws, nails and the epidermis layer of the skin. α-keratin is a fibrous structural protein, meaning it is made up of amino acids that form a repeating secondary structure. The secondary structure of α-keratin is very similar to that of a traditional protein α-helix and forms a coiled coil. Due to its tightly wound structure, it can function as one of the strongest biological materials and has various functions in mammals, from predatory claws to hair for warmth. α-keratin is synthesized through protein biosynthesis, utilizing transcription and translation, but as the cell matures and is full of α-keratin, it dies, creating a strong non-vascular unit of keratinized tissue.
Structure.
 α-keratin is a polypeptide chain, typically high in alanine, leucine, arginine, and cysteine, that forms a right-handed α-helix. Two of these polypeptide chains twist together to form a left-handed helical structure known as a coiled coil. These coiled coil dimers, approximately 45 nm long, are bonded together with disulfide bonds, utilizing the many cysteine amino acids found in α-keratins. The dimers then align, their termini bonding with the termini of other dimers, and two of these new chains bond length-wise, all through disulfide bonds, to form a protofilament. Two protofilaments aggregate to form a protofibril, and four protofibrils polymerize to form the intermediate filament (IF). The IF is the basic subunit of α-keratins. These IFs are able to condense into a super-coil formation of about 7 nm in diameter, and can be type I, acidic, or type II, basic. The IFs are finally embedded in a keratin matrix that either is high in cysteine or glycine, tyrosine, and phenylalanine residues. The different types, alignments, and matrices of these IFs account for the large variation in α-keratin structures found in mammals.
Biochemistry.
Synthesis.
α-keratin synthesis begins near focal adhesions on the cell membrane. There, the keratin filament precursors go through a process known as nucleation, where the keratin precursors of dimers and filaments elongate, fuse, and bundle together. As this synthesis is occurring, the keratin filament precursors are transported by actin fibers in the cell towards the nucleus. There, the alpha-keratin intermediate filaments will collect and form networks of structure dictated by the use of the keratin cell as the nucleus simultaneously degrades. However, if necessary, instead of continuing to grow, the keratin complex will disassemble into non-filamentous keratin precursors that can diffuse throughout the cell cytoplasm. These keratin filaments will be able to be used in future keratin synthesis, either to re-organize the final structure or create a different keratin complex. When the cell has been filled with the correct keratin and structured correctly, it undergoes keratin stabilization and dies, a form of programmed cell death. This results in a fully matured, non-vascular keratin cell. These fully matured, or cornified, alpha-keratin cells are the main components of hair, the outer layer of nails and horns, and the epidermis layer of the skin.
Properties.
The property of most biological importance of alpha-keratin is its structural stability. When exposed to mechanical stress, α-keratin structures can retain their shape and therefore can protect what they surround. Under high tension, alpha-keratin can even change into beta-keratin, a stronger keratin formation that has a secondary structure of beta-pleated sheets. Alpha-keratin tissues also show signs of viscoelasticity, allowing them to both be able to stretch and absorb impact to a degree, though they are not impervious to fracture. Alpha-keratin strength is also affected by water content in the intermediate filament matrix; higher water content decreases the strength and stiffness of the keratin cell due to their effect on the various hydrogen bonds in the alpha-keratin network.
Characterization.
Type I and type II.
Alpha-keratins proteins can be one of two types: type I or type II. There are 54 keratin genes in humans, 28 of which code for type I, and 26 for type II. Type I proteins are acidic, meaning they contain more acidic amino acids, such as aspartic acid, while type II proteins are basic, meaning they contain more basic amino acids, such as lysine. This differentiation is especially important in alpha-keratins because in the synthesis of its sub-unit dimer, the coiled coil, one protein coil must be type I, while the other must be type II. Even within type I and II, there are acidic and basic keratins that are particularly complementary within each organism. For example, in human skin, K5, a type II alpha keratin, pairs primarily with K14, a type I alpha-keratin, to form the alpha-keratin complex of the epidermis layer of cells in the skin.
Hard and soft.
Hard alpha-keratins, such as those found in nails, have a higher cysteine content in their primary structure. This causes an increase in disulfide bonds that are able to stabilize the keratin structure, allowing it to resist a higher level of force before fracture. On the other hand, soft alpha-keratins, such as ones found in the skin, contain a comparatively smaller amount of disulfide bonds, making their structure more flexible.


Probable low affinity copper uptake protein 2

Probable low affinity copper uptake protein 2 is a protein that in humans is encoded by the "SLC31A2" gene.


Reticular fiber

Reticular fibers, reticular fibres or reticulin is a type of fiber in connective tissue composed of type III collagen secreted by reticular cells. Reticular fibers crosslink to form a fine meshwork (reticulin). This network acts as a supporting mesh in soft tissues such as liver, bone marrow, and the tissues and organs of the lymphatic system.
History.
The term reticulin was coined in 1892 by M. Siegfried.
Today, the term reticulin or reticular fiber is restricted to referring to fibers composed of type III collagen. However, during the pre-molecular era, there was confusion in the use of the term "reticulin", which was used to describe two structures:
The history of the reticulin silver stain is reviewed by Puchtler "et al." (1978). The abstract of this paper says:
Maresch (1905) introduced Bielschowsky's silver impregnation technic for neurofibrils as a stain for reticulum fibers, but emphasized the nonspecificity of such procedures. This lack of specificity has been some confirmed repeatedly. Yet, since the 1920s the definition of "reticulin" and studies of its distribution were based solely on silver impregnation technics. The chemical mechanism and specificity of this group of stains is obscure. Application of Gömöri's and Wilder's methods to human tissues showed variations of staining patterns with the fixatives and technics employed. Besides reticulum fibers, various other tissue structures, e.g. I bands of striated muscle, fibers in nervous tissues, and model substances, e.g. polysaccharides, egg white, gliadin, were also stained. Deposition of silver compounds on reticulum fibers was limited to an easily removable substance; the remaining collagen component did not bind silver. These histochemical studies indicate that silver impregnation technics for reticulum fibers have no chemical significance and cannot be considered as histochemical technics for "reticulin" or type III collagen.
Structure.
Reticular fiber is composed of one or more types of very thin and delicately woven strands of type III collagen. These strands build a highly ordered cellular network and provide a supporting network. Many of these types of collagen have been combined with carbohydrate. Thus, they react with silver stains and with periodic acid-Schiff reagent but are not demonstrated with ordinary histological stains such as those using hematoxylin. The 1953 "Science" article mentioned above concluded that the reticular and regular collagenous materials contains the same four sugars – galactose, glucose, mannose, and fucose – but in a much greater concentration in the reticular than in the collagenous material.
In a 1993 paper, the reticular fibers of the capillary sheath and splenic cord were studied and compared in the pig spleen by transmission electron microscopy. This paper attempted to reveal their components and the presence of sialic acid in the amorphous ground substance. Collagen fibrils, elastic fibers, microfibrils, nerve fibers, and smooth muscle cells were observed in the reticular fibers of the splenic cord. On the other hand, only microfibrils were recognized in the reticular fibers of the capillary sheath. The binding of LFA lectin to the splenic cord was stronger than the capillary sheath. These findings suggested that the reticular fibers of the splenic cord include multiple functional elements and might perform an important role during contraction or dilation of the spleen. On the other hand, the reticular fiber of the capillary sheath resembled the basement membrane of the capillary in its components.
Because of their affinity for silver salts, these fibers are called argyrophilic.


2-dehydropantoate aldolase

In enzymology, a 2-dehydropantoate aldolase () is an enzyme that catalyzes the chemical reaction:
Hence, this enzyme has one substrate, 2-dehydropantoate, and two products, 3-methyl-2-oxobutanoate and formaldehyde.
This enzyme belongs to the family of lyases, specifically the aldehyde-lyases, which cleave carbon-carbon bonds. The systematic name of this enzyme class is 2-dehydropantoate formaldehyde-lyase (3-methyl-2-oxobutanoate-forming). Other names in common use include ketopantoaldolase, and 2-dehydropantoate formaldehyde-lyase.


Tiazofurin

Tiazofurin is a drug which acts as an inhibitor of the enzyme IMP dehydrogenase. Tiazofurin and its analogues were under investigation for potential use in the treatment of cancer, though side effects such as pleuropericarditis and a flu-like syndrome precluded further development. They also show antiviral effects and may be reevaluated as potential options in the treatment of newly emerging viral diseases.


Respiratory syncytial virus G protein

Respiratory syncytial virus G protein is a protein produced by respiratory syncytial virus.
It has been proposed as a target for a vaccine.


AGR2

Anterior gradient protein 2 homolog (AGR-2), also known as secreted cement gland protein XAG-2 homolog, is a protein that in humans is encoded by the "AGR2" gene. Anterior gradient homolog 2 was originally discovered in "Xenopus laevis". In "Xenopus" AGR2 plays a role in cement gland differentiation, but in human cancer cell lines high levels of AGR2 correlate with downregulation of the p53 response, cell migration, and cell transformation. However, there have been other observations that AGR2 can repress growth and proliferation.
Discovery in "Xenopus laevis".
The "Xenopus laevis" anterior gradient genes - XAG-1, XAG-2, and XAG-3 - were discovered through dissection of different-aged embryos. They become expressed in the anterior region of the dorsal ectoderm in late gastrula embryos. XAG-2 expression gathers at the anterior region of the dorsal ectoderm, and this region corresponds to the cement gland anlage. Many other homologous proteins have been discovered afterwards in Xenopus.
Tissue distribution.
AGR2 is the human homolog of XAG-2. It is expressed strongly in tissues that secrete mucus or function as endocrine organs, including the lungs, stomach, colon, prostate and small intestine. Its protein expression has been shown to be regulated by both androgens and estrogens.
Structure and function.
AGR2 is a protein disulfide isomerase, with a single CXXS active domain motif for oxidation and reduction reactions. AGR2 forms mixed disulfides in substrates, such as intestinal mucin. AGR2 interacts with Mucin 2 through its thioredoxin-like domain forming a heterodisulfide bond with cysteine residues in MUC2. AGR2 is suggested to play a role in protein folding, and it has a KTEL C-terminal motif similar to KDEL and KVEL endoplasmic reticulum retention sequences.
Clinical significance.
"Agr2" is located on chromosome 7p21, a region that has frequent genetic alterations. It was first identified in estrogen receptor-positive breast cancer cells. Later studies showed elevated levels of AGR2 in adenocarcinomas of the esophagus, pancreas, and prostate. In Barrett's esophagus, "Agr2" expression is elevated by over 70 times compared to normal esophageal epithelia. Thus, this protein alone is enough to distinguish Barrett's esophagus, which is linked to esophageal adenocarcinoma, from a normal esophagus.
Varying AGR2 levels exist in different cancers. In breast cancer, high AGR2 expression is correlated with low survival rate. AGR2 levels are elevated in the preneoplastic tissue Barrett's oesophagus. AGR2 is also associated with prostate cancer, though lower levels are associated with higher Gleason grades.
In contrast to upregulation of AGR2 in various cancers, downregulation of AGR2 is linked with inflammatory bowel disease and increases in the risk of Crohn's disease and ulcerative colitis. This implies the importance of AGR2 in maintaining epithelial barrier function, which is supported by FOXA1 and FOXA2 molecules (transcription factors for epithelial goblet cells) which can activate the AGR2 promoter.
Breast cancer.
In breast cancer, AGR2 and estrogen (ER) expression are positively correlated. Approximately 70% of breast cancer patients have breast cancer cells that heavily express ER and progesterone receptors (PgR). These patients are normally treated with endocrine therapy. Tamoxifen, which blocks the binding of estradiol to its receptor, is the standard treatment for ER-positive breast cancer. However, about one third of patients do not respond to this therapy, and increased AGR2 may be one reason.
There is a positive correlation for a higher level of AGR2 expression with poor therapeutic results in ERα-positive breast cancer patients. "Agr2" mRNA expression is elevated in "in vitro" and "in vivo" studies responding to tamoxifen adjuvant therapy, so AGR2 is likely provides an agonistic effect on tamoxifen. Therefore, AGR2 is a possible predictive biomarker when selecting patients with ER-positive breast cancer to participate this therapy.
Although "Agr2" mRNA levels are correlated with the tamoxifen therapy response, AGR2 protein levels have yet to be statistically associated with the therapy. A combinatorial therapy using the anastrozole and fulvestrant has been shown to prevent binding of the ER to the "Agr2" promoter, and there has been improved prognosis in the patients receiving it, possibly because AGR2 expression in the tumors have been reduced.
What AGR2 does in cancers is poorly understood. In breast cancer, HSP90 is a molecular chaperone expressed in tumor cells when there exists an excess of unfolded protein, and its co-chaperone has been reported to induce expression of AGR2, so AGR2 may be used by the endoplasmic reticulum to assist with protein folding to alleviate proteotoxic stress. AGR2 may help regulate the protein and mRNA levels in a cell overall as well. During late pregnancy and lactation, AGR2 levels peak when milk proteins are produced, and mammary-specific "Agr2" knockout mice had downregulated milk protein mRNA expression.
Prostate cancer.
AGR2 is expressed in relatively high levels for prostate cancer patients. Urine sediment tests determined "Agr2" transcript levels to be elevated. AGR2 expression was increased in metastatic prostate cancer cells cultured in a bone marrow microenvironment, where intense levels of "Agr2" mRNA were detected, suggesting AGR2 is required for bone metastasis of prostate cancer cells. AGR2 transcript levels were lower in metastatic lesions compared to the primary tumor, however. A greater chance of prostate cancer recurrence is linked to relatively lower levels of AGR2.
AGR2 depletion through gene knockdown was shown to result in accumulation of prostate cancer cell lines at the G0/G1 phase of the cell cycle, while forced expression of AGR led to an increase in cell proliferation. AGR2 was determined to be involved in cell adhesion. "Agr2"-silenced prostate cancer cells had a large decrease in association with fibronectin, lost expression of integrin, and reduced tumor cell migration. In addition to these studies, AGR2 was among a set of genes consistently associated with prostate tumour visibility on MRI in a bioinformatic analysis, the analysis found that more visible tumours harboured more aggressive genetic characteristics. The study also found genes involved with cell-ECM interactions to be altered in aggressive MRI-visible tumours, potentially reflecting AGR2's association with cellular adhesion ans integrin signalling.
Pancreatic cancer.
AGR2 mRNA was discovered to be increased in precancerous lesions and neoplastic cells of pancreatic tumors and cancer cell lines. Transient silencing of AGR2 by small interfering RNA and short hairpin RNA significantly reduces cell proliferation and invasion while increasing the effectiveness of gemcitabine treatment in pancreatic cancer cell lines "in vitro", indicating that AGR2 can help pancreatic cancer cells survive and protect tumors from chemotherapeutic treatments for pancreatic cancer. This is critical because pancreatic cancer is well recognized as being highly resistant to therapeutics, and five-year survival rates for pancreatic cancer are extremely low.
Protein interactions.
AGR2 protein has been demonstrated to interact with C4.4A and DAG-1 proteins which are associated with metastasis formation since these transmembrane proteins are involved in cell and matrix interactions between cancer and normal cells. AGR2 is able to suppress p53 activity by preventing phosphorylation after DNA damage. AGR2 has been shown to bind to Reptin, a tumor repressor, in the nucleus.


Armine (chemical)

Armine is an irreversible acetylcholinesterase inhibitor. It is the ethylphosphonate analog of paraoxon.


Chromo shadow domain

In molecular biology, the chromo shadow domain is a protein domain which is distantly related to the chromodomain. It is always found in association with a chromodomain. Proteins containing a chromo shadow domain include "Drosophila" and human heterochromatin protein Su(var)205 (HP1); and mammalian modifier 1 and modifier 2.
Chromo shadow domains self-aggregate, bringing together the nucleosomes to which their proteins are bound and thus condense the chromatin region they are associated with. Condensed chromatin is not able to be transcribed as the transcription factors and enzymes are not able to access to DNA sequence in this form. Hence chromoshadow domain containing proteins repress gene transcription.


Glycoside hydrolase family 25

In molecular biology, glycoside hydrolase family 25 is a family of glycoside hydrolases.
Glycoside hydrolases are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycoside hydrolases, based on sequence similarity, has led to the definition of >100 different families. This classification is available on the CAZy web site, and also discussed at CAZypedia, an online encyclopedia of carbohydrate active enzymes.
Glycoside hydrolase family 25 CAZY GH_25 comprises enzymes with only one known activity; lysozyme (). It has been shown that a number of cell-wall lytic enzymes are evolutionary related and can be classified into a single family. Two residues, an aspartate and a glutamate, have been shown to be important for the catalytic activity of the "Charalopsis" enzyme. These residues as well as some others in their vicinity are conserved in all proteins from this family.


Dihydrolanosterol

Dihydrolanosterol, or 24,25-Dihydrolanosterol, also called Lanostenol, is a sterol and the C24-25 hydrogenated products of lanosterol, dihydrolanosterol can be demethylated by mammal or yeast cytochrome P450 sterol 14alpha-demethylase.


Cis-3,4-dihydrophenanthrene-3,4-diol dehydrogenase

In enzymology, a cis-3,4-dihydrophenanthrene-3,4-diol dehydrogenase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are (+)-cis-3,4-dihydrophenanthrene-3,4-diol and NAD+, whereas its 3 products are phenanthrene-3,4-diol, NADH, and H+.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-CH group of donor with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is (+)-cis-3,4-dihydrophenanthrene-3,4-diol:NAD+ 3,4-oxidoreductase. This enzyme participates in naphthalene and anthracene degradation.


Roxibolone

Roxibolone (INN) (developmental code name BR-906), also known as 11β,17β-dihydroxy-17α-methyl-3-oxoandrosta-1,4-diene-2-carboxylic acid, is a steroidal antiglucocorticoid described as an anticholesterolemic (cholesterol-lowering) and anabolic drug which was never marketed. Roxibolone is closely related to formebolone, which shows antiglucocorticoid activity similarly and, with the exception of having a carboxaldehyde group at the C2 position instead of a carboxylic acid group, roxibolone is structurally almost identical to. The 2-decyl ester of roxibolone, decylroxibolone (developmental code name BR-917), is a long-acting prodrug of roxibolone with similar activity.
In rats, roxibolone counteracts the catabolic effects (control of nitrogen balance) and increased alkaline phosphatase levels induced by the potent glucocorticoid dexamethasone phosphate. It does not bind to the glucocorticoid receptor however, and its antiglucocorticoid activity may instead be mediated by enzyme inhibition. In accordance, 11α- and 11β-hydroxyprogesterone are known to be potent inhibitors of 11β-hydroxysteroid dehydrogenase (11β-HSD), which is responsible for the biosynthesis of the potent endogenous glucocorticoids cortisol and corticosterone (from the precursors deoxycortisol and deoxycorticosterone, respectively). As roxibolone is 11β-hydroxylated similarly, it may act in a likewise fashion. However, formebolone was found to be a very weak inhibitor of 11β-HSD type 2, although this specific isoenzyme is responsible for the inactivation of glucocorticoids rather than their production.
Unlike formebolone, which is additionally an anabolic-androgenic steroid (AAS), roxibolone is devoid of affinity for the androgen receptor and possesses no androgenic or myotrophic activity in animal assays. For this reason, it has been said that roxibolone may be much better tolerated in comparison.


4-hydroxybenzaldehyde dehydrogenase

In enzymology, a 4-hydroxybenzaldehyde dehydrogenase () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are 4-hydroxybenzaldehyde, NAD+, and H2O, whereas its 3 products are 4-hydroxybenzoate, NADH, and H+.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the aldehyde or oxo group of donor with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is 3-hydroxybenzaldehyde:NAD+ oxidoreductase. This enzyme is also called p-hydroxybenzaldehyde dehydrogenase. This enzyme participates in toluene and xylene degradation in bacteria. It is also found in carrots ("Daucus carota").


Diglyceride kinase

Diglyceride kinase may refer to:


Mefruside

Mefruside (INN) is a diuretic indicated for the treatment of edema and hypertension.
It was developed by Bayer A.G. and is sold under the tradename Baycaron.


Push Pop

Push Pop (manufactured by Topps) is an American brand of fruit-flavored lollipops produced in Taiwan (and other Southeast Asian countries). It is a product of the Topps Company Inc. It debuted in 1986 and comes in many flavors.
Overview.
The product's gimmick is that the lollipop takes the form of a long cylinder that retracts into a capped plastic tube, and must be "pushed" out for consumption. Push Pop varieties include Original, spring-loaded Jumbo, Triple Power, Flip-N-Dip, push pop sliderz, and Push Pump Spray.
In 2020, the Push Pop Gummy Roll was added to the line of Push Pop candies. The gummy roll comes in a tape-like dispenser that allows the consumer to pull out a strand of the roll and tear it off to get their desired piece of sanded gummy candy. This new Push pop candy comes in 4 different flavors: Strawberry, Watermelon, Blue Raspberry, and Berry Blast. Creating gummy candy was a bit of a departure for Push Pop, as the brand focuses on creating a fun experience for eating lollipops. The Push Pop Gummy Roll was first announced in May 2019 at the Sweets & Snacks Expo in Chicago.
It has proven to be a popular product with kids, winning the Candy Industry Kid’s Choice award for Best Novelty candy.


Prulifloxacin

Prulifloxacin is an older synthetic antibiotic of the fluoroquinolone class undergoing clinical trials prior to a possible NDA (New Drug Application) submission to the U.S. Food and Drug Administration (FDA). It is a prodrug which is metabolized in the body to the active compound ulifloxacin. It was developed over two decades ago by Nippon Shinyaku Co. and was patented in Japan in 1987 and in the United States in 1989.
It has been approved for the treatment of uncomplicated and complicated urinary tract infections, community-acquired respiratory tract infections in Italy and gastroenteritis, including infectious diarrheas, in Japan. Prulifloxacin has not been approved for use in the United States.
History.
In 1987 a European patent for prulifloxacin was issued to the Japanese-based pharmaceutical company, Nippon Shinyaku Co., Ltd (Nippon). Ten years after the issuance of the European patent, marketing approval was applied for and granted in Japan (March 1997). Subsequent to being approved by the Japanese authorities in 1997 prulifloxacin was co-marketed and jointly developed in Japan with Meiji Seika as licensee (Sword).
In more recent times, Angelini ACRAF SpA, under license from Nippon Shinyaku, has fully developed prulifloxacin, for the European market.
Angelini is the licensee for the product in Italy. Following its launch in Italy, Angelini launched prulifloxacin in Portugal (January 2007) and it has been stated that further approvals will be sought in other European countries.
Prulifloxacin is marketed in Japan and Italy as Quisnon (Nippon Shinyaku); Sword (Meiji); Unidrox (Angelini); Prixina (Angelini) and Glimbax (ITF Hellas) in Greece and generic as Pruquin.
In 1989 and 1992 United States patents (US 5086049) were issued to Nippon Shinyaku for prulifloxacin. It was not until June 2004, when Optimer Pharmaceuticals acquired exclusive rights to discover, develop and commercialize prulifloxacin (Pruvel) in the U.S. from Nippon Shinyaku Co., Ltd., that there were any attempts to seek FDA approval to market the drug in the United States. Optimer Pharmaceuticals
expects to file an NDA (new drug application) for prulifloxacin some time in 2010. As the patent for prulifloxacin has already expired, Optimer Pharmaceuticals has stated that this may have an effect on the commercial prospects of prulifloxacin within the United States market.
Licensed uses.
Prulifloxacin has been approved in Italy, Japan, China, India and Greece (as indicated), for treatment of infections caused by susceptible bacteria, in the following conditions:
Availability.
Prulifloxacin is available as:
In most countries, all formulations require a prescription.
Mechanism of action.
Like other fluoroquinolones, Prulifloxacin prevents bacterial DNA replication, transcription, repair and recombination through inhibition of bacterial DNA gyrase.
Quinolones and fluoroquinolones are bactericidal drugs, eradicating bacteria by interfering with DNA replication.
Quinolones are synthetic agents that have a broad spectrum of antimicrobial activity as well as a unique mechanism of action, resulting in inhibition of bacterial DNA gyrase and topoisomerase IV. Quinolones inhibit the bacterial DNA gyrase or the topoisomerase IV enzyme, thereby inhibiting DNA replication and transcription. For many gram-negative bacteria, DNA gyrase is the target, whereas topoisomerase IV is the target for many gram-positive bacteria. It is believed that eukaryotic cells do not contain DNA gyrase or topoisomerase IV.
Contraindications.
There are only four contraindications found within the package insert:
Special populations.
Pregnancy.
The fluoroquinolones rapidly cross the blood-placenta and blood-milk barrier, and are extensively distributed into the fetal tissues. The fluoroquinolones have also been reported as being present in the mother’s milk and are passed on to the nursing child.
Pediatric population.
Fluoroquinolones are not licensed by the U.S. FDA for use in children due to the risk of permanent injury to the musculoskeletal system, with two exceptions. However, the fluoroquinolones are licensed to treat lower respiratory infections in children with cystic fibrosis in the UK.
Special precautions.
"As with other quinolones, exposure to the sun or ultra-violet rays may cause
phototoxicity reactions in patients treated with prulifloxacin."
"When treated with antibacterial agents of the quinolone group, patients with latent or known deficiencies for the glucose-6-phosphate dehydrogenase activity are predisposed to hemolytic reactions."
Adverse Events.
Within one review prulifloxacin was stated to have a similar tolerability profile to that of ciprofloxacin.
Within another study it was found that prulifloxacin patients experienced a similar number of adverse reactions compared to those in the ciprofloxacin group (15.4% vs 12.7%). There were four serious adverse events in each treatment arm, including 1 death in the prulifloxacin arm. None were considered treatment related by the investigator. If approved in the U.S., prulifloxacin will likely carry a black box warning for tendon damage, as the FDA has determined that this is a class effect of fluoroquinolones.
Prulifloxacin has a reduced effect on the QTc interval compared to other fluoroquinolones and may be a safer choice for patients with pre-existing risk factors for arrhythmia.
Overdose.
In the event of acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage; the patient should be carefully observed and given supportive treatment.
Pharmacokinetics.
Prulifloxacin 600 mg achieves peak plasma concentration (Cmax) of ulifloxacin (1.6μg/mL) in a median time to Cmax (tmax) of 1 hour. Ulifloxacin is ≈45% bound to serum proteins in vivo. It is extensively distributed throughout tissues and shows good penetration into many body tissues. The elimination half-life (t1/2) of ulifloxacin after single-dose prulifloxacin 300–600 mg ranged from 10.6 to 12.1 hours. After absorption from the gastrointestinal tract, prulifloxacin undergoes extensive first-pass metabolism (hydrolysis by esterases, mainly paraoxonase to form ulifloxacin, the active metabolite). Unchanged ulifloxacin is predominantly eliminated by renal excretion. "Quoting from the available package insert."
Bibliography.
PDF File


Vosaroxin

Vosaroxin (AG-7352, SPC-595, SNS 595, voreloxin) is a topoisomerase II inhibitor causing site-selective DNA damage. It is under phase III clinical trial investigation for acute myelogenous leukemia (AML) and ovarian cancer sponsored by Sunesis.
Mechanism of action.
Vosaroxin is a naphthyridine analog of the anticancer quinolone derivatives (AQDs), a class of compounds that has not been used previously for the treatment of cancer. Topoisomerase II enzymes are essential for the survival of eukaryotic cells. Vosaroxin hinders the reunion of topoisomerase II-induced double-strand breaks at selective sites in DNA, resulting in G2 arrest and cell death by apoptosis.


2-acylglycerol-3-phosphate O-acyltransferase

In enzymology, a 2-acylglycerol-3-phosphate O-acyltransferase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are acyl-CoA and 2-acyl-sn-glycerol 3-phosphate, whereas its two products are CoA and 1,2-diacyl-sn-glycerol 3-phosphate.
This enzyme belongs to the family of transferases, specifically those acyltransferases transferring groups other than aminoacyl groups. The systematic name of this enzyme class is acyl-CoA:2-acyl-sn-glycerol 3-phosphate O-acyltransferase. This enzyme is also called 2-acylglycerophosphate acyltransferase. This enzyme participates in glycerophospholipid metabolism.


Arginine repressor ArgR

In molecular biology, the arginine repressor (ArgR) is a repressor of prokaryotic arginine deiminase pathways.
The arginine dihydrolase (AD) pathway is found in many prokaryotes and some eukaryotes, an example of the latter being "Giardia lamblia" ("Giardia intestinalis"). The three-enzyme anaerobic pathway breaks down L-arginine to form 1 mol of ATP, carbon dioxide and ammonia. In some bacteria, the first enzyme, arginine deiminase, can account for up to 10% of total cell protein.
Most prokaryotic arginine deiminase pathways are under the control of a repressor gene, termed ArgR. This is a negative regulator, and will only release the arginine deiminase operon for expression in the presence of arginine. The crystal structure of apo-ArgR from "Bacillus stearothermophilus" has been determined to 2.5A by means of X-ray crystallography. The protein exists as a hexamer of identical subunits, and is shown to have six DNA-binding domains, clustered around a central oligomeric core when bound to arginine. It predominantly interacts with A.T residues in ARG boxes. This hexameric protein binds DNA at its N terminus to repress arginine biosynthesis or activate arginine catabolism. Some species have several ArgR paralogs. In a neighbour-joining tree, some of these paralogous sequences show long branches and differ significantly from the well-conserved C-terminal region.


2-deoxyglucosidase

In enzymology, a 2-deoxyglucosidase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are 2-deoxy-alpha-D-glucoside and H2O, whereas its two products are 2-deoxy-D-glucose and alcohol.
This enzyme belongs to the family of hydrolases, specifically those glycosidases that hydrolyse O- and S-glycosyl compounds. The systematic name of this enzyme class is 2-deoxy-alpha-D-glucoside deoxyglucohydrolase. Other names in common use include 2-deoxy-alpha-glucosidase, and 2-deoxy-alpha-D-glucosidase.


Type II keratin

Type II keratins (or Type II cytokeratins) constitutes the Type II intermediate filaments (IFs) of the intracytoplasmatic cytoskeleton, which is present in all mammalian epithelial cells. The type 2 cytokeratins consist of basic or neutral, high molecular weight proteins which in vivo are arranged in pairs of heterotypic Type I and Type II keratin chains, coexpressed during differentiation of simple and stratified epithelial tissues.
Type II cytokeratins are encoded on chromosome 12q and encompasses: CK1, CK2, CK3, CK4, CK5, CK6, CK7 and CK8. Their molecular weight ranges from 52 kDa (CK8) to 67 kDa (CK18).


Peptide sequence


Testis-specific meiotic arrest complex


Raf kinase inhibitor protein

The Raf kinase inhibitor protein (RKIP) is a kinase inhibitor protein, that regulates many signaling pathways within the cell. RKIP is a member of the phosphatidylethanolamine-binding protein family and has displayed disruptive regulation on the Raf-1-MEK1/2, ERK1/2 and NF-kappaB signalling pathways, by interaction with the Raf-1 kinase.
RKIP has also been shown to inhibit G protein coupled receptor kinases (GRK) when phosphorylated by protein kinase C. Via this mechanism it has been shown to exert beneficial effects on cardiac structure and function.


Beta-secretase 2

Beta-secretase 2 (, also known as Memapsin-1) is an enzyme that cleaves Glu-Val-Asn-Leu!Asp-Ala-Glu-Phe in the Swedish variant of Alzheimer's amyloid precursor protein. BACE2 is a close homolog of BACE1.
Function.
Cerebral deposition of amyloid beta peptide is an early and critical feature of Alzheimer's disease and a frequent complication of Down syndrome. Amyloid beta peptide is generated by proteolytic cleavage of amyloid precursor protein by 2 proteases, one of which is the protein encoded by this gene. This gene localizes to the 'Down critical region' of chromosome 21. The encoded protein, a member of the peptidase A1 protein family, is a type I integral membrane glycoprotein and aspartic protease. Three transcript variants encoding different isoforms have been described for this gene.
It has been reported that BACE2 is the main protease that mediates the release of the amyloidogenic ectodomain of Pmel17 in melanocytes.
Interactions.
BACE2 has been shown to interact with GGA1 and GGA2.


Unoprostone

Unoprostone (INN) is a prostaglandin analogue. Its isopropyl ester, unoprostone isopropyl, was marketed under the trade name Rescula for the management of open-angle glaucoma and ocular hypertension.
It was approved by the Food and Drug Administration in 2000.
In 2009, Sucampo Pharmaceuticals acquired the rights to the drug in the U.S. and Canada.
In 2015, the drug was discontinued in the U.S.


Dideoxyverticillin A

Dideoxyverticillin A, also known as (+)-11,11′-dideoxyverticillin A, is a complex epipolythiodioxopiperazine initially isolated from the marine fungus "Penicillium" sp. in 1999. It has also been found in the marine fungus "Bionectriaceae", and belongs to a class of naturally occurring 2,5-diketopiperazines.
Dideoxyverticillin A potently inhibits the tyrosine kinase activity of the epidermal growth factor receptor (median inhibitory concentration = 0.14 nM), exhibits antiangiogenic activity, and has efficacy against several cancer cell lines. Its reported anticancer mechanism is that it acts as a farnesyl transferase inhibitor. Dozens of semi-synthetic anticancer compounds have been made from dideoxyverticillin A. Dimeric derivatives are reported to have better anticancer activity.
The enantioselective first total synthesis of (+)-11,11′-dideoxyverticillin A, the structure of which contains many sterically congested, contiguous stereogenic centers as well as acid- and base-labile and redox-sensitive functionality, was biosynthetically inspired and achieved with high levels of chemical sophistication.