NDUFB5

NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 5, 16kDa is a protein that in humans is encoded by the NDUFB5 gene. The NDUFB5 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.
Structure.
The NDUFB5 gene, located on the q arm of chromosome 3 in position 26.33, is 19,713 base pairs long. The NDUFB5 protein weighs 21.7 kDa and is composed of 189 amino acids. NDUFB5 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site. NDUFB5 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I and is of the non-catalytic subunits of the complex. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane.
Function.
The human NDUFB5 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. However, NDUFB5 is an accessory subunit of the complex that is believed not to be involved in catalysis. Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and p"K" shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.


Talose

Talose is an aldohexose sugar. It is an unnatural monosaccharide that is soluble in water and slightly soluble in methanol. Some etymologists suggest that talose's name derives from the automaton of Greek mythology named Talos, but the relevance is unclear.
Talose is a C-2 epimer of galactose and a C-4 epimer of mannose.


Campesterol

Campesterol is a phytosterol whose chemical structure is similar to that of cholesterol, and is one of the ingredients for E number E499.
Natural occurrences.
Many vegetables, fruits, nuts, and seeds contain campesterol, but in low concentrations. Banana, pomegranate, pepper, coffee, grapefruit, cucumber, onion, oat, potato, and lemon grass (citronella) are few examples of common sources containing campesterol at roughly 1–7 mg/100 g of the edible portion. In contrast, canola and corn oils contain as much as 16–100 mg/100 g. Levels are variable and are influenced by geography and growing environment. In addition, different strains have different levels of plant sterols. A number of new genetic strains are currently being engineered with the goal of producing varieties high in campesterol and other plant sterols. It is also found in dandelion coffee.
It is so named because it was first isolated from the rapeseed ("Brassica campestris"). It is thought to have anti-inflammatory effects. It was demonstrated that it inhibits several pro-inflammatory and matrix degradation mediators typically involved in osteoarthritis-induced cartilage degradation.
Precursor of anabolic steroid boldenone.
Being a steroid, campesterol is a precursor of anabolic steroid boldenone. Boldenone undecylenate is commonly used in veterinary medicine to induce growth in cattle, but it is also one of the most commonly abused anabolic steroids in sports. This led to suspicion that some athletes testing positive on boldenone undecylenate did not actually abuse the hormone itself, but consumed food rich in campesterol or similar phytosteroids.
Cardiovascular disease.
Plant sterols were first shown in the 1950s to be beneficial in lowering LDLs and cholesterol. Since then, numerous studies have also reported the beneficial effects of the dietary intake of phytosterols, including campesterol.
The campesterol molecules are thought to compete with cholesterol, thus reducing the absorption of cholesterol in the human intestine. Plant sterols may also act directly on intestinal cells and affect transporter proteins. In addition, an effect on the synthesis of cholesterol-transporting proteins may occur in the liver cells through processes including cholesterol esterification and lipoprotein assembly, cholesterol synthesis, and apolipoprotein (apo) B100-containing lipoprotein removal.
Serum levels of campesterol and the ratio of campesterol to cholesterol have been proposed as measures of cardiac risk. Some studies have suggested that higher levels predict lower cardiac risk. However, extremely high levels are thought to be indicative of higher risk, as indicated by genetic disorders such as sitosterolemia. Study results of serum levels have been conflicting. A recent meta-analysis suggests that no clear relationship exists, and that perhaps previous studies have been confounded by other factors. For example, people who have a higher campesterol level related to a diet high in fruits and nuts may be consuming a Mediterranean-style diet, thus have lower risk because of other lipids or lifestyle factors. Intestinal absorption of cholesterol varies between individuals due to variations in the genes that encode for two proteins. The NPC1L1 protein which sits on the luminal side of the enterocyte is responsible for sterol absorption. Its counterpart, the ABCG5/G8 ATP Binding Cassette protein which also sits on the luminal side of the enterocyte, and on the bile canaliculi side of the hepatocyte, is responsible for sterol efflux. Variations in each of these proteins causes variation in absorption and efflux of dietary and biliary sterols - both cholesterol and plant sterols.
Although studies in humans have shown that consumption of phytosterols may reduce LDL levels, evidence to recommend them as a treatment for hypercholesterolemia is insufficient. Larger trials are needed to provide such evidence, and are underway. Animal studies have shown that campesterol and other phytosterols can reduce the size of atherogenic plaques, but no data yet show that consumption of phytosterols results in any clinical benefit such as a reduction in atherosclerosis, heart disease, cardiac events, or mortality.
Adverse effects.
Nutrient levels.
Excessive supplementation with plant sterols may be associated with reductions in beta-carotene and lycopene levels. Excessive long-term consumption of plant sterols might have a deleterious effect on vitamin E.
Increased risk of disease.
Excessive use of plant sterols has been associated with an increased risk of cardiovascular disease, and genetic conditions that cause extremely elevated levels of some phytosterols, such as sitosterol, are associated with higher risks of cardiovascular disease. However, this is an active area of debate, and no data suggest that modestly elevated levels of campesterol have a negative cardiac impact.


Cyclase

A cyclase is an enzyme, almost always a lyase, that catalyzes a chemical reaction to form a cyclic compound. Important cyclase enzymes include:


Star Wars Pez

A "Star Wars" Pez is a Pez candy dispenser themed after the "Star Wars" movies, and is one of the company's most prominent merchandising deals. Over fifty dispensers have been released on the market from 1997 to 2020, among the many collectibles spawned by the franchise.
The extreme interest of marketing executives in all things "Star Wars" has spawned a scholarly interest in the "materializing fantasy media" such as these PEZ dispensers. It has also led to several museums to feature such Stars Wars memorabilia in their exhibits and/or gift shops, as well as media attention on this fairly odd phenomena.
In museum exhibits and gift shops.
In recent years, several museums around the United States have featured Star Wars Pez in their exhibits and/or gift shops. These products are displayed and exhibited because they are classic Americana. Despite the dispensers' "popularity and cult status," the manufacturer's original factory in Austria does not give tours or sell fancifully-shaped memorabilia. Only in January 2012, this group of dispensers became prominently displayed at the company's new North American headquarters in Orange, Connecticut: one travelogue wrote, "The company has been making the cartoonish plastic heads for 60 years now, representing everything from Star Wars to U.S. presidents to the Geico chameleon."
The Clayton Historical Museum, in Clayton, California opened a new exhibit on the history of candy manufacture in January 2012 that featured these confectionery dispensers.
Pez with "Star Wars" characters have been featured prominently in the Star Wars Museum in Maryland. The "Star Wars" Pez dispensers are pictured on a fan website, which describes them as "some Candy Heads from 1980".
The Pacific Science Center sold Pez at a popular exhibit about "Star Wars".
These branded dispensers were among the "top sellers" at the gift shop at the Burlingame Museum of Pez Memorabilia, outside San Francisco. The museum also displayed "a whole lot of "Star Wars" Pez," in Plexiglas displays. This "unofficial shrine" to the collectibles is unaffiliated with Pez Candy, Inc., and the manufacturer sued the Burlingam museum in 2009 for copyright infringement. There was a notorious, giant Pez sculpture of C-3PO and Chewbacca locked in a slash fiction kiss. As of December 2019, the museum is now closed.
Another Pez museum in Easton, Pennsylvania also has featured prominently their obligatory "Star Wars" memorabilia, ("Of course, we had to include the Star Wars Pez Dispensers"), including an oversize Darth Vader figurine. As of early 2012, this museum appears to have closed to the public.
Other influences.
Carrie Fisher's "Princess Leia Pez dispenser" is one of the "merchandising horrors" she discusses in her one-woman show "Wishful Drinking".
These candy dispensers are featured prominently in the 2010 Emmy Award-winning fan film, "Star Wars Uncut".
"Star Wars" Pez has a gateway drug-like effect for some young collectors. One fan of Pez dispensers started her huge horde with "Star Wars" figurines at the age of three. Another fan calls Pez dispensers generally "a 'gateway drug' to hardcore collecting". "Pezheads" shopping for new dispensers frequently place "Star Wars" first on their shopping lists.
Chronology of releases.
Five Star Wars Pez were released in 1997:
Four Star Wars Pez were released in 1999 "in advance" of the May 19 premier of "":
Also released in 1999 was a Jar Jar Binks Pez Hander battery operated toy.
Three Star Wars Pez were released in 2002 for "":
Fourteen Giant Pez were released in 2005 to "commemorate" "":
Pez also released five standard-size dispensers in 2005 for the "" movie release:
For the 2009 animated release of "", Pez released three dispensers:
Pez released two dispensers in 2012 for the 3D release of ":"
One Star Wars Pez was released in 2013, a re-issued and re-painted Boba Fett – now with a green base.
Four limited edition crystal Star Wars Pez were released in 2015 as a gift tin:
In 2016 a "Rogue One" gift tin was released containing four dispensers:
From 2016 - 2017, seven individual Pez were released for "" and "Rogue One":
In 2017 a "Millennium Falcon" gift tin was released containing four dispensers:
For the 2018 theatrical release of " a gift tin containing four dispensers was released:
For the 2019 theatrical release of " four dispensers were released:
For the 2019 holiday season, a limited edition gift tin of which "only 75,000 tins" were produced, was released for ":
PEZ released 3 new dispensers in 2020. A giant Darth Vader to commemorate the 40th Anniversary of " and a gift set for "The Mandalorian"


Surfactant protein A

Surfactant protein A is an innate immune system collectin. It is water-soluble and has collagen-like domains similar to SP-D. It is part of the innate immune system and is used to opsonize bacterial cells in the alveoli marking them for phagocytosis by alveolar macrophages. SP-A may also play a role in negative feedback limiting the secretion of pulmonary surfactant. SP-A is not required for pulmonary surfactant to function but does confer immune effects to the organism.
During parturition.
The role of surfactant protein A (SP-A) in childbirth is indicated in studies with mice. Mice which gestate for 19 days typically show signs of SP-A in amniotic fluid at around 16 days. If SP-A is injected into the uterus at 15 days, mice typically deliver early. Inversely, an SP-A inhibitor injection causes notable delays in birth.
The presence of surfactant protein A seemed to trigger an inflammatory response in the uterus of the mice, but later studies found an anti-inflammatory response in humans. In fact, the level of SP-A in a human uterus typically decreases during labor.
Immune functions.
Research on SP-A has been done mainly in rodents including mice and rats. This research has shown that mice deficient in SP-A are more susceptible to infections from group B Streptoccoal organisms, Pseudomonas aeruginosa, and likely other organisms. The immune functions of SP-A are time, temperature, and concentration dependant.
Location.
SP-A is found in the pulmonary surfactant in lungs. SP-A and SP-D are also present in extrapulmonary tissues.


Beta bend ribbon

The beta bend ribbon, or beta-bend ribbon, is a structural feature in polypeptides and proteins. The shortest possible has six amino acid residues (numbered "i" to "i+5") arranged as two overlapping hydrogen bonded beta turns in which the carbonyl group of residue "i" is hydrogen-bonded to the NH of residue "i+3" while the carbonyl group of residue "i+2" is hydrogen-bonded to the NH of residue "i+5". In longer ribbons, this bonding is continued in peptides of 8, 10, etc., amino acid residues. A beta bend ribbon can be regarded as an aberrant 310 helix (3/10-helix) that has lost some of its hydrogen bonds. Two websites are available to facilitate finding and examining these features in proteins: Motivated Proteins; and PDBeMotif.
The four main types of hydrogen-bonded beta turns are types I, I’, II and II’. Beta bend ribbons may be formed from any of these types but type I is the commonest in proteins, as it is for single beta turns. Beta bend ribbons made from type I or I’ turns are somewhat twisted, while beta bend ribbons made from type II or II’ beta turns are flat. Beta bend ribbons with mixtures of different beta turn types also occur.
Type I beta-bend ribbons regularly occur in leucine-rich repeats, in the environments sometimes occupied by helices. A protein with a stack of these features is the extracellular ligand-binding domain of the Nogo receptor. Another beta bend ribbon occurs in the GTPase-activating protein for Rho in the active, but not the inactive, form of the enzyme. The beta bend ribbon, which incorporates the catalytic arginine, allows its side-chain guanidino group to approach the active site and enhance enzyme activity.
Polypeptides consisting of repeats of the dipeptide (α-amino-γ-lactam plus a conventional amino acid) have been shown to adopt a beta bend ribbon conformation.


Adenylthiomethylpentose

Adenylthiomethylpentose is a sulfur-containing nucleoside that was formerly known as vitamin L2. This chemical is an intermediate in the methylthioadenosine (MTA) cycle, better known as the methionine salvage pathway that is universal to aerobic life.
In 1912, an adenine nucleoside was isolated by Hunter "et al." from yeast that were grown without phosphorus or sulfur. Later that substance was shown by Levene and Sobotkal to be adenylthiomethylpentose.
In 1936, W. Nakahara "et al." did experiments on rats that suggested that vitamin L2 deficiency inhibits the ability of rats to lactate. In 1942 they identified vitamin L2 to be adenylthiomethylpentose. Later studies by Folley "et al" refuted Nakahara's claims and demonstrated that L is not necessary for lactation and thus L2 is not considered a vitamin today.
Hecht found in 1937 that the body temperature of rabbits, cats and guinea pigs were lowered by 1 to 2 degrees after he gave them adenylthiomethylpentose at a dose of 0.2 g/kg. Kühn "et al." replicated this in guinea pigs in 1941.


3-hydroxybutyryl-CoA epimerase

In enzymology, a 3-hydroxybutyryl-CoA epimerase () is an enzyme that catalyzes the chemical reaction
Hence, this enzyme has one substrate, (S)-3-hydroxybutanoyl-CoA, and one product, (R)-3-hydroxybutanoyl-CoA.
This enzyme belongs to the family of isomerases, specifically those racemases and epimerases acting on hydroxy acids and derivatives. The systematic name of this enzyme class is 3-hydroxybutanoyl-CoA 3-epimerase. Other names in common use include 3-hydroxybutyryl coenzyme A epimerase, and 3-hydroxyacyl-CoA epimerase. This enzyme participates in fatty acid metabolism and butanoate metabolism.
Structural studies.
As of late 2007, four structures have been solved for this class of enzymes, with PDB accession codes , , , and .


Liposomal daunorubicin

Liposomal daunorubicin (trade name DaunoXome) is a chemotherapy drug that is FDA approved to treat AIDS related Kaposi's sarcoma. It is also commonly used to treat specific types of leukaemia and non-Hodgkin lymphoma. Liposomal daunorubicin is intravenously administered. It utilizes the liposomal carrier system that provides a favorable pharmacokinetic profile at the site of KS lesions resulting in a 10-fold increase in concentrations compared to that which is achieved with conventional preparations.
External links.
[[Category:Topoisomerase inhibitors]]


Nucleoside

Nucleosides are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nucleobase (also termed a nitrogenous base) and a five-carbon sugar (ribose or 2'-deoxyribose) whereas a nucleotide is composed of a nucleobase, a five-carbon sugar, and one or more phosphate groups. In a nucleoside, the anomeric carbon is linked through a glycosidic bond to the N9 of a purine or the N1 of a pyrimidine. Examples of nucleosides include cytidine, uridine, adenosine, guanosine, thymidine and inosine.
While a nucleoside is a nucleobase linked to a sugar, a nucleotide is composed of a nucleoside "and" one or more phosphate groups. Thus, nucleosides can be phosphorylated by specific kinases in the cell on the sugar's primary alcohol group (-CH2-OH) to produce nucleotides. Nucleotides are the molecular building-blocks of DNA and RNA.
Source.
Nucleosides can be produced from nucleotides "de novo", particularly in the liver, but they are more abundantly supplied via ingestion and digestion of nucleic acids in the diet, whereby nucleotidases break down "nucleotides" (such as the thymidine monophosphate) into "nucleosides" (such as thymidine) and phosphate. The nucleosides, in turn, are subsequently broken down in the lumen of the digestive system by nucleosidases into nucleobases and ribose or deoxyribose. In addition, nucleotides can be broken down inside the cell into nitrogenous bases, and ribose-1-phosphate or deoxyribose-1-phosphate.
Use in medicine and technology.
In medicine several nucleoside analogues are used as antiviral or anticancer agents. The viral polymerase incorporates these compounds with non-canonical bases. These compounds are activated in the cells by being converted into nucleotides. They are administered as nucleosides since charged nucleotides cannot easily cross cell membranes.
In molecular biology, several analogues of the sugar backbone exist. Due to the low stability of RNA, which is prone to hydrolysis, several more stable alternative nucleoside/nucleotide analogues that correctly bind to RNA are used. This is achieved by using a different backbone sugar. These analogues include locked nucleic acids (LNA), morpholinos and peptide nucleic acids (PNA).
In sequencing, dideoxynucleotides are used. These nucleotides possess the non-canonical sugar dideoxyribose, which lacks 3' hydroxyl group (which accepts the phosphate). It therefore cannot bond with the next base and terminates the chain, as DNA polymerases cannot distinguish between it and a regular deoxyribonucleotide.
Prebiotic synthesis of ribonucleosides.
In order to understand how life arose, knowledge is required of the chemical pathways that permit formation of the key building blocks of life under plausible prebiotic conditions. According to the RNA world hypothesis free-floating ribonucleosides and ribonucleotides were present in the primitive soup. Molecules as complex as RNA must have arisen from small molecules whose reactivity was governed by physico-chemical processes. RNA is composed of purine and pyrimidine nucleotides, both of which are necessary for reliable information transfer, and thus Darwinian natural selection and evolution. Nam et al. demonstrated the direct condensation of nucleobases with ribose to give ribonucleosides in aqueous microdroplets, a key step leading to RNA formation. Also, a plausible prebiotic process for synthesizing pyrimidine and purine ribonucleosides and ribonucleotides using wet-dry cycles was presented by Becker et al.


Cold-shock domain

In molecular biology, the cold-shock domain (CSD) is a protein domain of about 70 amino acids which has been found in prokaryotic and eukaryotic DNA-binding proteins. Part of this domain is highly similar to the RNP-1 RNA-binding motif.
When "Escherichia coli" is exposed to a temperature drop from 37 to 10 degrees Celsius, a 4–5 hour lag phase occurs, after which growth is resumed at a reduced rate. During the lag phase, the expression of around 13 proteins, which contain cold shock domains is increased 2–10 fold. These so-called 'cold shock' proteins are thought to help the cell to survive in temperatures lower than optimum growth temperature, by contrast with heat shock proteins, which help the cell to survive in temperatures greater than the optimum, possibly by condensation of the chromosome and organisation of the prokaryotic nucleoid.


Alpha,alpha-trehalase

In enzymology, an alpha,alpha-trehalase () is an enzyme with system name "alpha,alpha-trehalose glucohydrolase". This enzyme catalyzes the chemical reaction
Thus, the two substrates of this enzyme are alpha,alpha-trehalose and H2O, whereas its product is D-glucose.
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 alpha,alpha-trehalose glucohydrolase. This enzyme is also called trehalase. This enzyme participates in starch and sucrose metabolism.
Structural studies.
As of late 2007, two structures have been solved for this class of enzymes, with PDB accession codes and .


National Prion Clinic (UK)

History.
Prion diseases comprise Creutzfeldt–Jakob disease (CJD), Gerstmann–Sträussler–Scheinker syndrome, fatal familial insomnia and related disorders. A specialist prion disease clinic was established by Professor John Collinge at St Mary's Hospital, London, in 1997. This was designated the NHS National Prion Clinic (NPC) in March 2001 by the UK Department of Health. In August 2004, following the relocation of the Medical Research Council (MRC) Prion Unit from Imperial College to University College London (UCL), the NPC relocated to the National Hospital for Neurology and Neurosurgery at Queen Square, part of the University College London Hospitals NHS Foundation Trust. The NPC is closely integrated with the MRC Prion Unit, a relationship of fundamental importance to the missions of both organisations. The NPC receives UK-wide and international referrals of all forms of suspected CJD or other prion diseases. It is internationally unique and has developed considerable experience in the clinical management of prion disease.
In addition to providing a national NHS centre of expertise for the management of all forms of CJD and other prion diseases, the clinic was established to facilitate research in both diagnostics and therapeutics including the organisation of clinical trials. The Health Services Director at the NHS Executive wrote to all UK hospitals to inform them of the clinic, and encourage referral to it. The clinic liaises closely with the National CJD Surveillance Unit in Edinburgh, Scotland (NCJDSU) to ensure that both centres are aware of all UK prion disease patients.
Referrals and staff.
Aside from patients with Creutzfeldt–Jakob disease and other prion diseases, referrals are welcome of healthy but at-risk individuals from families with inherited prion disease. With some of these large pedigrees a clinical relationship has been fostered for around two decades since mutations in the prion protein gene and their use in diagnosis and genetic counseling were first reported from 1989. Through collaboration with the UK Health Protection Agency referrals are received from individuals at risk of variant Creutzfeldt–Jakob disease through blood transfusion.
In 2020 the clinic staff comprise consultant neurologists Professor John Collinge, Professor Simon Mead and Dr Peter Rudge, Clinical Research Fellows, Senior Clinical Psychologist, Lead Nurse, Clinical Nurse Specialists a Cohort Manager and administrator.


Dentyne Mints

Dentyne mints (pronounced "Den-TEEN") are a brand of breath mint manufactured by Cadbury Adams, a division of Cadbury-Schweppes.
Description.
The mints are produced in two flavors: Ice (mint flavored) and Fire (cinnamon flavored). The form is a white (Dentyne Ice Mints) or red (Dentyne Fire Mints) pillow shape (slightly rounded square with rounded top and bottom). The mints are plain, with no printing or embossing.
Dentyne Mints are packed in a plastic box in the form of a rectangular solid with corners slightly rounded (along the X and Y axes only). Along the top of the top is a square hole with a sliding cover. Sliding this cover away from the hole allows access to the mints. The box uses no hinges.
50 mints are contained in each package.
Dentyne mints are not true mints, as they contain no mint oil.
Nomenclature.
The classification of Dentyne Fire as a "mint" can be questioned, as they contain (natural and artificial) cinnamon flavor, rather than mint flavor. Cadbury Adams, however, identifies both Dentyne Ice and Dentyne Fire as "mints".
Dentyne gum.
Dentyne Mints should not be confused with Dentyne gum, which is also made in Ice and Fire flavors, is sold in packaging similar to Dentyne Mints, and has a generally similar form.


Messenger RNP

Messenger RNP (messenger ribonucleoprotein) is mRNA with bound proteins. mRNA does not exist "naked" "in vivo" but is always bound by various proteins while being synthesized, spliced, exported, and translated in the cytoplasm.
Messenger RNPs were first discovered in Alexander S. Spirin's laboratory in Moscow, Russia in 1964. The discovery was based in their study of fish embryo cytoplasm extracts, where they found these mRNPs. This finding was discovered after the mRNA of the fish embryo was centrifuged. The mRNA liquid separated into two parts, having the scientists question what is separate of the mrNA from the ribosomes. Spirin and his collaborators analyzed the mRNA against CsCl density gradients and discovered that parts of the mRNA were coated in proteins. The weight ratio of mRNPs was found to be 1:3, mRNA to protein. mRNPs were thus denoted as "informosomes" by the lab.
There are three major informosomes found in mammalian cells: nuclear ribonucleoproteins, cytoplasmic informosomes, and polyribosomal messenger ribonucleoproteins. It was hypothesized by researchers that major roles of informosomes are to assist in mRNAs translocation from the nucleus to the cytoplasm, protect the mRNA against degradation, and help regulate protein formation.
When mRNA is being synthesized by RNA polymerase, this nascent mRNA is already bound by RNA 5′ end 7-methyl-guanosine capping enzymes. Later, the pre-mRNA is bound by the spliceosome containing exon and intron definition complexes and proteins and RNA that catalyze the chemical reactions of splicing. Joan Steitz and Michael Lerner and collaborators showed that the small nuclear RNAs (snRNAs) are complexed into small nuclear Ribonuclear Proteins (snRNPs). Christine Guthrie and collaborators showed that specific snRNAs encoded by single copy genes in yeast base pair with the pre-mRNA and direct each step in splicing. The spliced mRNA is bound by another set of proteins which help in export from the nucleus to the cytoplasm. In vertebrates exon-exon junction are marked by exon junction complexes which in the cytosol can trigger nonsense mediated decay if the exon-exon junction is more than 50-55 nt downstream of the stop codon.
Neurodegenerative diseases in RNP granules are caused by genetic mutations. RNP granules store specific types of mRNAs under tight translational control while forming different types. Neuronal RNP granules that are connected to RNA binding proteins show signs of causing neurodevelopment, neurodegeneration or neuropsychiatric disorders. An example of one of these diseases would be spinal muscular atrophy (SMA) which affect the small nuclear ribonucleoprotein (snRNP). Although it is still unknown, increasing evidence ties neurodegeneration diseases with altered RNP granule homeostasis creating a concept of hypo and hyper-assembly diseases of RNPs. Hyper-assembly of RNP granule can be caused by two effects, one by mutations in the RNA binding protein while the other being an expansion of nucleotide repeats in the RNA. Another neurodegenerative disease amyotrophic lateral sclerosis (ALS) which is affected by the hyper assemble of RNP granule components. Even though neuronal cells are more susceptible to hypo- or hyper- assembly of RNP components there is still much unknown in terms of the full mutation process.
Neuronal RNP granules assembly and regulation with flexible spatio-temporal that compartmentalize gene expression. The advanced technology that is present today helps uncover the behavior of neuronal RNP granules. It was recently discovered in a "vitro" study that the dynamic properties and structure of these RNP granules is fluid and generated through liquid-liquid phase separation. Post-translational modification (PTM) of granule components have the means to modulate binding affinities that can do both condensation and dissolution.


Trypsin inhibitor

A trypsin inhibitor (TI) is a protein and a type of serine protease inhibitor (serpin) that reduces the biological activity of trypsin by controlling the activation and catalytic reactions of proteins. Trypsin is an enzyme involved in the breakdown of many different proteins, primarily as part of digestion in humans and other animals such as monogastrics and young ruminants. When trypsin inhibitor is consumed it acts as an irreversible and competitive substrate.
It competes with proteins to bind to trypsin and therefore renders it unavailable to bind with proteins for the digestion process. As a result, protease inhibitors that interfere with digestion activity have an antinutritional effect. Therefore, trypsin inhibitor is considered an anti-nutritional factor or ANF. Additionally, trypsin inhibitor partially interferes with chymotrypsin function.
Trypsinogen is an inactive form of trypsin, its inactive form ensures protein aspects of the body, such as the pancreas and muscles, are not broken down. It is formed in the pancreas and activated to trypsin with enteropeptidase Chymotrypsinogen is the inactive form of chymotrypsin and has similar functions as trypsin.
The presence of trypsin inhibitor has been found to result in delayed growth as well as metabolic and digestive diseases. Additionally, pancreatic hypertrophy is a common occurrence with trypsin inhibitor consumption The presence of trypsin inhibitor in a product reduces the protein efficiency and therefore results in the consumers body not being able to efficiently and fully utilize the protein.
Function.
Trypsin inhibitor is present in various foods such as soybeans, grains, cereals and various additional legumes. The main function of trypsin inhibitors in these foods is to act as a defense mechanism. By having this harmful component wild animals learn that any food that contains trypsin inhibitor is a food to avoid. Trypsin inhibitor can also be essential for biological processes within the plant.
Trypsin inhibitor can also naturally occur in the pancreas of species such as the bovine. The function of this is to protect the animal from any accidental activation of trypsinogen and/or chymotrypsinogen
Inactivation.
Trypsin inhibitor is heat liable, therefore by exposing these foods to heat, the trypsin inhibitor is removed and the food subsequently becomes safe to eat. Boiling soybeans for 14 minutes inactivates about 80% of the inhibitor, and for 30 minutes, about 90%. At higher temperatures, e.g. in pressure cookers, shorter cooking times are needed. ELISA tests can be used to measure the degree of deactivation achieved.
Applications in commercial industries.
The most prominent application of trypsin inhibitor is livestock feed. Soybeans are a popular ingredient in livestock feed therefore trypsin inhibitor can be a concern due to the presence of it in soybeans. The majority of soybeans used in livestock feed is converted to soybean meal and through the process the trypsin inhibitor is removed due to the heat treatment. However, experiments have been done concerning animals who consume active trypsin inhibitor and they consistently have decreased weights.
A study revealing that a protease inhibitor from the eggs of the freshwater snail "Pomacea canaliculata", interacting as a trypsin inhibitor with the protease of potential predators, was reported in 2010, the first direct evidence for this mechanism in the animal kingdom.
Clinical significance.
The peptide tumor-associated trypsin inhibitor (TATI) has been used as a marker of mucinous ovarian carcinoma, urothelial carcinoma, and renal cell carcinoma. TATI is metabolised by the kidneys and is, thus, elevated in patients with kidney failure. It may be elevated in non-neoplastic processes such as pancreatitis and can be used as a prognostic marker in this setting (levels above 70 micrograms/L are associated with poor prognosis).
Fifty percent of stage I mucinous ovarian carcinomas are associated with elevated TATI, and nearly 100% of stage IV tumors show elevated TATI.
Eighty-five to 95% of pancreatic adenocarcinomas are associated with increased TATI (but elevation in pancreatitis limits the clinical utility of TATI in this setting; see above).
Sixty percent of gastric adenocarcinomas show elevated TATI, in particular tumors of diffusely infiltrative/signet ring type. TATI, thus, complements CEA, which is elevated exclusively in intestinal type adenocarcinoma of the stomach.
In urothelial carcinoma, TATI expression varies with stage, ranging from 20% in low-stage tumors to 80% of high-stage tumors.
TATI sensitivity in the setting of renal cell carcinoma is approximately 70%. Elevated TATI is more likely to be seen in patients with advanced-stage disease.
In nearly all tumor types studied, TATI is a marker of poor prognosis.


Adenosine kinase

Adenosine kinase (AdK; EC 2.7.1.20) is an enzyme that catalyzes the transfer of gamma-phosphate from Adenosine triphosphate (ATP) to adenosine (Ado) leading to formation of Adenosine monophosphate (AMP). In addition to its well-studied role in controlling the cellular concentration of Ado, AdK also plays an important role in the maintenance of methylation reactions. All S-adenosylmethionine-dependent transmethylation reactions in cells lead to production of S-adenosylhomocysteine (SAH), which is cleaved by SAH hydrolase into Ado and homocysteine. The failure to efficiently remove these end products (Ado removed by phosphorylation by AdK) can result in buildup of SAH, which is a potent inhibitor of all transmethylation reactions. The disruption of AdK gene (-/-) in mice causes neonatal hepatic steatosis, a fatal condition characterized by rapid microvesicular fat infiltration, leading to early postnatal death. The liver was the main organ affected in these animals and in it the levels of adenine nucleotides were decreased, while those of SAH were elevated. Recently, missense mutations in the AdK gene in humans which result in AdK deficiency have also been shown to cause hypermethioninemia, encephalopathy and abnormal liver function.
Biochemical properties.
AdK is a monomeric protein (~ 38-40 kDa), which works via an ordered Bi-Bi reaction mechanism. It belongs to the phosphofructokinase B (PfkB) family of sugar kinases. Other members of this family (also known as the RK family) include ribokinase (RK), inosine-guanosine kinase, fructokinase, and 1-phosphofructokinase. The members of the PfkB/RK family are identified by the presence of three conserved sequence motifs. The structures of AdK and several other PfK family of proteins have been determined from a number of organisms (see section below) as well as that for RK protein from E. coli. Despite low sequence similarity between AdK and other PfkB family of proteins, these proteins are quite similar at structural levels. Compounds that are substrates for AdK include the N-nucleosides toyocamycin, tubercidin and 6-methylmecaptopurine riboside; the C-nucleosides formycin A, 9-azadenosine, and a large number of other C- and N-nucleoside analogs. The AdK from mammalian sources, in addition to carrying out ATP-dependent phosphorylation of Ado, also catalyzes an Ado-AMP exchange reaction requiring ADP. This activity is an integral part of AdK and it presumably allows a rapid and precise control of Ado concentration in cells. The enzymatic activity of AdK from different sources show a marked dependence on phosphate (Pi) and/or pentavalent ions and it is a conserved property of the PfkB family of proteins. The conserved NXXE motif, which is a distinctive property of the PfkB family of proteins, is involved in Pi (PVI) dependency.
Evolution and Relationship to the PfkB Family of Proteins.
The AdK gene/protein is mainly found in eukaryotic organisms and its primary sequence shows a high degree of conservation (>55% aa similarity). However, AdK sequences exhibit low (~ 20-25%), but significant similarity to other PfkB family of proteins such as RK and phosphofructokinases, which are also found in prokaryotic organisms. Although a protein exhibiting AdK activity has been reported in Mycobacterium tuberculosis, sequence and biochemical characteristics of this enzyme reveal it to be an atypical enzyme that is more closely related to ribokinase and fructokinase (35%) than to other ADKs (less than 24%).
Gene and isoforms.
The AdK gene in humans is located on chromosome 10 in the 10q11-10q24 region. In contrast to its coding sequence (about 1 Kb), the AdK gene in mammalian species is unusually large (~546 Kb in humans) and it consists of 11 exons (36 to 173 bp in length) and 10 introns whose lengths vary from 4.2 Kb to 128.6 Kb (average ~50Kb). The ratio of the non-coding to coding sequence for human ADK (>550) is the highest known for any gene. The AdK gene in mammalian organisms is also linked in a head to head manner to the gene for the long isoform of AdK to the gene for μ3A adaptor protein, and both these genes are transcribed from a single bi-directional promoter. The large size of the AdK gene and its linkage to the gene for μ3A adaptor protein are apparently unique characteristic of the amniotes (e.g. various mammals, birds, and reptiles). In contrast, the AdK genes in other eukaryotic organisms are much smaller in lengths (1.3 – 20 Kb long). In mammals, two isoforms of Adk are present. These two isoforms show no difference in their biological activity and they differ only at the N-terminus where the long isoform (AdK-long) contains extra 21 amino acids that replace the first 4 amino acids of the short isoform (AdK-short). These two isoforms are independently regulated at the transcriptional level and the promoter for the short isoform is located within the first large AdK intron. It was recently shown that of the two AdK isoforms, the AdK-long isoform is localized in the nucleus, whereas AdK-short is found in the cytoplasm.
Cardio- and neuro-protective roles.
AdK plays a central role in controlling the cellular levels of Ado, which via its interaction with adenosine receptors in mammalian tissues produces a broad range of physiological responses including potent cardioprotective and neuroprotective activities. The overexpression of AdK in the brain, which leads to decreased Ado levels and loss of inhibition of neuronal excitability by astrocytes, has been proposed as the main underlying cause of progression of epilepsy. Hence, the modulation of AdK by external means provides an important strategy for harnessing its potential therapeutic benefits. As such, there is much interest in developing specific inhibitors of AdK. Many AdK inhibitors, some of which show useful analgesic, anti-seizure, and anti-inflammatory properties in animal models have been described.
Studies with mutant mammalian cells.
In cultured mammalian cells, mainly Chinese hamster ovary (CHO) cells, many kinds of mutants that are affected in AdK and show interesting differences in their genetic and biochemical properties have been isolated; One kind of mutant that is obtained at unusually high spontaneous mutant frequency (10−3-10−4) contain large deletions within the AdK gene that leads to the loss of several introns and exons. Many mutants that are affected in the expression of either the expressions of the two AdK isoforms have also been isolated.


Trapidil

Trapidil is a vasodilator and an antiplatelet drug. It also acts as an antagonist of platelet-derived growth factor.


3-demethylubiquinone-9 3-O-methyltransferase

In enzymology, a 3-demethylubiquinone-9 3-O-methyltransferase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are S-adenosyl methionine and 3-demethylubiquinone-9, whereas its two products are S-adenosylhomocysteine and ubiquinone-9.
This enzyme participates in ubiquinone biosynthesis.
Nomenclature.
This enzyme belongs to the family of transferases, specifically those transferring one-carbon group methyltransferases. The systematic name of this enzyme class is S-adenosyl-L-methionine:2-nonaprenyl-3-methyl-5-hydroxy-6-methoxy-1, 4-benzoquinone 3-O-methyltransferase. Other names in common use include 5-demethylubiquinone-9 methyltransferase, OMHMB-methyltransferase, 2-Octaprenyl-3-methyl-5-hydroxy-6-methoxy-1,4-benzoquinone, methyltransferase, S-adenosyl-L-methionine:2-octaprenyl-3-methyl-5-hydroxy-6-methoxy-, and 1,4-benzoquinone-O-methyltransferase.


Pol (HIV)

Pol (DNA polymerase) refers to a gene in retroviruses, or the protein produced by that gene.
Products of pol include:
Reverse transcriptase.
Common to all retroviruses, this enzyme transcribes the viral RNA into double-stranded DNA.
Integrase.
This enzyme integrates the DNA produced by reverse transcriptase into the host's genome.
Protease.
A protease is any enzyme that cuts proteins into segments. HIV's "gag" and "pol" genes do not produce their proteins in their final form, but as larger combination proteins; the specific protease used by HIV cleaves these into separate functional units. Protease inhibitor drugs block this step.


Loganin

Loganin is one of the best-known of the iridoid glycosides. It is named for the Loganiaceae, having first been isolated from the seeds of a member of that plant family, namely those of "Strychnos nux-vomica". It also occurs in "Alstonia boonei" (Apocynaceae), a medicinal tree of West Africa and in the medicinal/entheogenic shrub Desfontainia spinosa (Columelliaceae) native to Central America and South America.
Biosynthesis.
Loganin is formed from loganic acid by the enzyme loganic acid O-methyltransferase (LAMT). Loganin then becomes a substrate for the enzyme secologanin synthase (SLS) to form secologanin, a secoiridoid monoterpene found as part of ipecac and terpene indole alkaloids.


Monocarboxylate transporter 2

Monocarboxylate transporter 2 (MCT2) also known as solute carrier family 16 member 7 (SLC16A7) is a protein that in humans is encoded by the "SLC16A7" gene. MCT2 is a proton-coupled monocarboxylate transporter. It catalyzes the rapid transport across the plasma membrane of many monocarboxylates such as lactate, branched-chain oxo acids derived from leucine, valine and isoleucine, and the ketone bodies acetoacetate and beta-hydroxybutyrate. It also functions as high-affinity pyruvate transporter.
Both Northern blot analysis and inspection of the human expressed sequence tag (EST) database suggest relatively little expression of MCT2 in human tissues. As well, the sequence of MCT2 is far less conserved across species than that of MCT1 or MCT4 and there also appear to be considerable species differences in the tissue expression profile of this isoform.
Of the four known mammalian lactate transporters (MCTs 1-4), MCT2 harbors the highest affinity for lactate. In parallel, MCT2 gene transcription has been demonstrated to respond with high-sensitivity to hypoxia, intracellular pH, and, to lactate.


Olaparib

Olaparib, sold under the brand name Lynparza, is a medication for the maintenance treatment of BRCA-mutated advanced ovarian cancer in adults. It is a PARP inhibitor, inhibiting poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair. It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which include some ovarian, breast, and prostate cancers.
In December 2014, olaparib was approved for use as a single agent by the European Medicines Agency (EMA) in the European Union and by the Food and Drug Administration (FDA) in the United States. The FDA approval was for germline BRCA mutated (gBRCAm) advanced ovarian cancer that has received three or more prior lines of chemotherapy. In January 2018, olaparib became the first PARP inhibitor to be approved by the FDA for gBRCAm metastatic breast cancer. Olaparib was developed and first dosed into patients by the UK-based biotechnology company, KuDOS Pharmaceuticals, that was founded by Stephen Jackson of Cambridge University, UK. Since KuDOS was acquired by AstraZeneca in 2006, the drug has undergone clinical development by AstraZeneca and Merck & Co. Olaparib in combination with temozolomide demonstrated substantial clinical activity in relapsed small cell lung cancer.
Mechanism of action.
Olaparib acts as an inhibitor of the enzyme poly ADP ribose polymerase (PARP), and is termed a PARP inhibitor. BRCA1/2 mutations may be genetically predisposed to development of some forms of cancer, and may be resistant to other forms of cancer treatment. However, these cancers sometimes have a unique vulnerability, as the cancer cells have increased reliance on PARP to repair their DNA and enable them to continue dividing. This means that drugs which selectively inhibit PARP may be of benefit if the cancers are susceptible to this treatment.
Approvals and indications.
In December 2014, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved olaparib as monotherapy. The FDA approval is in germline BRCA mutated (gBRCAm) advanced ovarian cancer that has received three or more prior lines of chemotherapy. The EMA public assessment report, which utilized the same phase II trial data, made reference to both "high grade serous ovarian cancers" and to the use of olaparib "not later than 8 weeks after a course of platinum-based medicines, when the tumour was diminishing in size or had completely disappeared".
In breast cancer, olaparib is approved for gBRCAm HER2-negative metastatic breast cancer patients who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. If patients have hormone receptor positive cancer, they should have received endocrine therapy where appropriate. This approval was based on the OlympiAD randomised phase III trial, which showed a progression-free survival benefit for patients treated with olaparib compared to conventional chemotherapy
In August 2017, olaparib tablets were approved in the United States for the maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy. The formulation was changed from capsules to tablets and the capsules were phased out in the United States. The capsules and tablets are not interchangeable.
The approval in the maintenance setting was based on two randomized, placebo-controlled, double-blind, multicenter trials in patients with recurrent ovarian cancers who were in response to platinum-based therapy. SOLO-2 (NCT01874353) randomized 295 patients with recurrent germline BRCA-mutated ovarian, fallopian tube, or primary peritoneal cancer (2:1) to receive olaparib tablets 300 mg orally twice daily or placebo. SOLO-2 demonstrated a statistically significant improvement in investigator-assessed progression-free survival (PFS) in patients randomized to olaparib compared with those who received placebo, with a hazard ratio (HR) of 0.30 (95% CI: 0.22, 0.41; p<0.0001). Study 19 (NCT00753545) randomized 265 patients regardless of BRCA status (1:1) to receive olaparib capsules 400 mg orally twice daily or placebo. Study 19 demonstrated a statistically significant improvement in investigator-assessed PFS in patients treated with olaparib vs. placebo with a HR of 0.35.
In January 2018, olaparib was approved in the United States for the treatment of patients with certain types of breast cancer that have spread (metastasized) and whose tumors have a specific inherited (germline) genetic mutation, making it the first drug in its class (PARP inhibitor) approved to treat breast cancer, and it is the first time any drug has been approved to treat certain patients with metastatic breast cancer who have a “BRCA” gene mutation. Patients are selected for treatment with Lynparza based on an FDA-approved genetic test, called the BRACAnalysis CDx.
In December 2018, olaparib was approved in the United States for the maintenance treatment of adults with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Adults with gBRCAm advanced epithelial ovarian, fallopian tube or primary peritoneal cancer should be selected for therapy based on an FDA-approved companion diagnostic. Approval was based on SOLO-1 (NCT01844986), a randomized, double-blind, placebo-controlled, multi-center trial that compared the efficacy of olaparib with placebo in patients with BRCA-mutated (BRCAm) advanced ovarian, fallopian tube, or primary peritoneal cancer following first-line platinum-based chemotherapy. Patients were randomized (2:1) to receive olaparib tablets 300 mg orally twice daily (n=260) or placebo (n=131).
In December 2019, olaparib was approved for the maintenance treatment of adults with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) metastatic pancreatic adenocarcinoma, as detected by an FDA-approved test, whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. The FDA also approved the BRACAnalysis CDx test (Myriad Genetic Laboratories, Inc.) as a companion diagnostic for the selection of patients with pancreatic cancer for treatment with olaparib based upon the identification of deleterious or suspected deleterious germline mutations in BRCA1 or BRCA2 genes. Efficacy was investigated in POLO (NCT02184195), a double-blind, placebo-controlled, multi-center trial that randomized (3:2) 154 patients with gBRCAm metastatic pancreatic adenocarcinoma to olaparib 300 mg orally twice daily or placebo until disease progression or unacceptable toxicity.
An April 2020 clinical trial indicated that olaparib treatment resulted in longer survival for patients with metastatic castration-resistant prostate cancer compared to enzalutamide or abiraterone.
Side effects.
Side effects include gastrointestinal effects such as nausea, vomiting, and loss of appetite; fatigue; muscle and joint pain; and low blood counts such as anemia, with occasional leukemia. Somnolence was sometimes seen in clinical trials which used doses higher than the approved schedule.


Farnesyl pyrophosphate cyclase

Farnesyl pyrophosphate cyclase may refer to:


Toroid repeat proteins

A toroid repeat is a protein fold composed of repeating subunits, arranged in circular fashion to form a closed structure.
Structure.
In the case when the N- and C-terminal repeats lie in close physical contact in a tandem repeat domain, the result is a topologically compact, closed structure. Such domains typically display a high rotational symmetry (unlike open repeats that only have translational symmetries), and assume a wheel-like shape. Because of the limitations of this structure, the number of individual repeats is not arbitrary. In the case of WD40 repeats (perhaps the largest family of closed solenoids) the number of repeats can range from 4 to 10 (more usually between 5 and 7). Kelch repeats, beta-barrels and beta-trefoil repeats are further examples for this architecture.
Function.
Closed solenoids frequently function as protein-protein interaction modules: it is possible that all repeats must be present to form the ligand-binding site if it is located at the centre or axis of the domain "wheel". The WD40 repeat is a prime example of this function.
Classification.
The following major sub-classes of toroid repeat proteins can be found:


Glycerate dehydrogenase

In enzymology, a glycerate dehydrogenase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are (R)-glycerate and NAD+, whereas its 3 products are hydroxypyruvate, NADH, and H+. However, in nature these enzymes have the ability to catalyze the reverse reaction as well. That is, hydroxypyruvate, NADH, and H+ can act as the substrates while (R)-glycerate and NAD+ are formed as products. Additionally, NADPH can take the place of NADH in this reaction.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-OH group of donor with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is (R)-glycerate:NAD+ oxidoreductase. Other names in common use include D-glycerate dehydrogenase, and hydroxypyruvate reductase (due to the reversibility of the reaction). This enzyme participates in glycine, serine and threonine metabolism and glyoxylate and dicarboxylate metabolism.
Enzyme structure.
This class of enzyme is part of a larger superfamily of enzymes known as D-2-hydroxy-acid dehydrogenases.
Many organisms from "Hyphomicrobium methylovorum" to humans have some form of the glycerate dehydrogenase protein. There are currently several structures that have been solved for this class of enzyme including those for the two mentioned above with PDB access code , D-glycerate dehydrogenase, and the human homolog Glyoxylate reductase/Hydroxypyruvate reductase (GRHPR), .
These studies have yielded a better understanding of the structure and function of these enzymes. It has been shown that these proteins are homodimeric enzymes. This means that 2 identical proteins are linked forming one larger complex. The active site is found in each subunit between the two distinct α/β/α globular domains, the substrate binding domain and the coenzyme binding domain. This coenzyme binding domain is slightly larger than the substrate binding domain and contains a NAD(P) Rossmann fold along with the "dimerisation loop" which holds the two subunits of the homodimer together. In addition to linking the two proteins together, the "dimerisation loop" of each subunit protrudes into the active site of the other subunit increasing the specificity of the enzyme, by preventing the binding of pyruvate as a substrate. Hydroxypyruvate is still able to bind to the active site due to extra stabilization from hydrogen bonds with neighboring amino-acid residues.
Glyoxylate reductase/Hydroxypyruvate reductase.
Biological relevance.
Glyoxylate reductase/Hydroxypyruvate reductase (GRHPR) is the glycerate dehydrogenase found, predominantly in the liver, of humans encoded by the gene GRHPR. Under physiological conditions, the production of D-glycerate is favored over its consumption as a substrate. It can then be converted to 2-phosphoglycerate, which can then enter into glycolysis, gluconeogenesis, or the serine pathway.
As the name suggests, in addition to the glycerate dehydrogenase and hydroxypyruvate reductase activity, the protein also exhibits glyoxylate reductase activity. The ability of GRHPR to reduce glyoxylate to glycolate is found in other glycerate dehydrogenase homologs as well. This is important for the intracellular regulation of glyoxylate levels, which has important medical ramifications. As mentioned earlier, these enzymes have the ability to use either NADH or NADPH as the coenzyme. This gives them an advantage over other enzymes that can only use a single form of the coenzyme. Lactate dehydrogenase(LDH) is one such enzyme that directly competes with GRHPR for substrates and converts glyoxylate to oxalate. However, due to the relatively large concentration of NADPH compared to NADH under normal cellular concentration, the GRHPR activity is greater than that of LDH so the production of glycolate is dominant.
Medical relevance.
Primary hyperoxaluria is a condition that results in the overproduction of oxalate which combines with calcium to generate calcium oxalate, the main component of kidney stones. Primary Hyperoxaluria type 2 is caused by any one of several mutations to the GRHPR gene and results in the accumulation of calcium oxalate in the kidneys, bones, and many other organs. The mutations to GRHPR prevent it from converting glyoxylate to glycolate, leading to a build-up of glyoxylate. This excess glyoxylate is then oxidized by lactate dehydrogenase to produce the oxalate that is characteristic of hyperoxaluria.


Niche (protein structural motif)

In the area of protein structural motifs, niches are three or four amino acid residue features in which main-chain CO groups are bridged by positively charged or δ+ groups. The δ+ groups include groups with two hydrogen bond donor atoms such as NH2 groups and water molecules. In typical proteins, 7% of amino acid residues belong to niches bound to a δ+ group, while another 7% have the conformation but no single cationic bridging group is detected.
Niches are of two kinds, distinguished as niche3 (3 residues, i to i+2) and niche4 (4 residues, i to i+3). In a niche3 motif the δ+-binding carbonyl groups are from residues i and i+2 while in a niche4 motif they are from residues i and i+3.
A niche3 has the α conformation for residue i+1 and the β conformation for residue i+2; a niche4 has the α conformation for residues i+1 and i+2 and the β conformation for residue i+3.
A niche occurs commonly at the C-terminus of α-helices, and especially of 310 helices.
Metal ions that occur bound to niches in proteins are Na+, K+, Ca++ and Mg++. Proteins with regulatory cations often employ niches for metal binding (thrombin, Na+; annexin, Ca++; pyruvate dehydrogenase, K+).
A major cation transporter in cells is calcium ATPase. In the Ca++-bound crystal structures the two calcium ions side-by-side within the transmembrane domain are thought to be at the halfway stage of being transported. As well as being bound by various side chain carbonyl groups, one of these calcium ions is bound by a niche3/niche4 (both in the one motif) at residues 304–307 at the C-terminus of an α-helix.
A lysine side chain in the nuclear export receptor CRM1 is recognised specifically by a niche conformation that has to be adopted as a key part of the nuclear export signal of proteins exiting the nucleus.
A sodium ion in the Fluc fluoride channel is situated at the dyad axis of the dimer, bound tetrahedrally by two niche4s, one from each subunit.
The Hsp70 interdomain linker region of 10 residues enables allosteric communication between two folded domains. The N-terminal part of the linker has a niche4 structure that is water-bound.
In the scorpion toxin BeM9 the side chain of arginine 60 binds the carbonyls of residues 61 and 63 as a niche3. The motif, loss of which alters the specificity of the protein for voltage-gated sodium channels, is named "arginine hand". The slightly unusual dihedral angles for a niche3 are because this niche3 accommodates two separate NH groups from the arginine's guanidino group.
Another small tripeptide motif that binds cations or δ+ groups via main-chain CO groups is called the catgrip.


6-Ketoprogesterone

6-Ketoprogesterone is an orally active oxidized form of progesterone that contains a keto group at position-6.


Irsogladine

Irsogladine is a phosphodiesterase inhibitor.


9alpha-copalyl-diphosphate diphosphate-lyase

9alpha-copalyl-diphosphate diphosphate-lyase may refer to:


GCOA

GCOA may refer to:


Ethinylestradiol/Segesterone acetate


Glycoside hydrolase family 22

In molecular biology, glycoside hydrolase family 22 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 22 CAZY GH_22 comprises lysozyme type C () lysozyme type i () and alpha-lactalbumins. Asp and/or the carbonyl oxygen of the C-2 acetamido group of the substrate acts as the catalytic nucleophile/base.
Alpha-lactalbumin, is a milk protein that acts as the regulatory subunit of lactose synthetase, acting to promote the conversion of galactosyltransferase to lactose synthase, which is essential for milk production. In the mammary gland, alpha-lactalbumin changes the substrate specificity of galactosyltransferase from N-acetylglucosamine to glucose.
Lysozymes act as bacteriolytic enzymes by hydrolyzing the beta(1->4) bonds between N-acetylglucosamine and N-acetylmuramic acid in the peptidoglycan of prokaryotic cell walls. It has also been recruited for a digestive role in certain ruminants and colobine monkeys. There are at least five different classes of lysozymes: C (chicken type), G (goose type), phage-type (T4), fungi (Chalaropsis), and bacterial ("Bacillus subtilis"). There are few similarities in the sequences of the different types of lysozymes.
Lysozyme type C and alpha-lactalbumin are similar both in terms of primary sequence and structure, and probably evolved from a common ancestral protein. Around 35 to 40% of the residues are conserved in both proteins as well as the positions of the four disulphide bonds. There is, however, no similarity in function. Another significant difference between the two enzymes is that all lactalbumins have the ability to bind calcium, while this property is restricted to only a few lysozymes.
The binding site was deduced using high resolution X-ray structure analysis and was shown to consist of three aspartic acid residues. It was first suggested that calcium bound to lactalbumin stabilised the structure, but recently it has been claimed that calcium controls the release of lactalbumin from the golgi membrane and that the pattern of ion binding may also affect the catalytic properties of the lactose synthetase complex.


Kelch-like protein 20

Kelch-like protein 20 is a protein that in humans is encoded by the "KLHL20" gene.
The protein encoded by this gene is a member of the kelch family of proteins, which is characterized by a 44-56 amino acid repeat motif. The kelch motif appears in many different polypeptide contexts and contains multiple potential protein-protein contact sites. Members of this family are present both throughout the cell and extracellularly, with diverse activities.


Prednylidene

Prednylidene is a glucocorticoid for systemic use.
Substitution at position 16 also leads to more potent corticosteroids. The additional steric bulk introduced by such substituents adjacent to the dihydroxyacetone side chain also protects that moiety against metabolic degradation.


Acylphosphatase

In enzymology, an acylphosphatase () is an enzyme that catalyzes the following chemical reaction:
Thus, the two substrates of this enzyme are acylphosphate and H2O, whereas its two products are carboxylate and phosphate.
Function.
This enzyme belongs to the family of hydrolases, specifically those acting on acid anhydrides in phosphorus-containing anhydrides. The systematic name of this enzyme class is acylphosphate phosphohydrolase. Other names in common use include acetylphosphatase, 1,3-diphosphoglycerate phosphatase, acetic phosphatase, Ho 1-3, and GP 1-3.
This enzyme participates in 3 metabolic pathways:
Structural studies.
Structures of this enzyme have been solved by both NMR and X-ray crystallography. See the links to PDB structures in the info boxes on the right for a current list of structures available in the PDB. The protein contains a beta sheet stacked on two alpha helices described by CATH as an Alpha-Beta Plait fold. The active site sits between sheet and helices and contains an arginine and an asparagine. Most structures are monomeric
Isozymes.
Humans express the following two acylphosphatase isozymes:


Acetylxylan esterase

In enzymology, an acetylxylan esterase () is an enzyme that catalyzes a chemical reaction, the deacetylation of xylans and xylo-oligosaccharides.
This enzyme belongs to the family of hydrolases, specifically those acting on carboxylic ester bonds. The systematic name of this enzyme class is likewise acetylxylan esterase.
Structural studies.
As of late 2007, 4 structures have been solved for this class of enzymes, with PDB accession codes , , , and .


Testican

Testican is a type of proteoglycan. Testican-1 is a highly conserved, multidomain proteoglycan that is most prominently expressed in the thalamus of the brain, and is upregulated in activated astroglial cells of the cerebrum. Several functions of this gene product have now been demonstrated in vitro including membrane-type matrix metalloproteinase inhibition, cathepsin L inhibition, and low-affinity calcium binding. The purified gene product has been shown to inhibit cell attachment and neurite extensions in culture. Functions of testican in vivo have yet to be demonstrated in knockout mice or other models. Testican has been shown to carry substantial amounts of chondroitin sulfate as well as other oligosaccharides, but the biological significance of these embellishments is not yet known.
In humans there are three testicans:
Medicinal Roles.
Testican-1 is known to play a role in lapatinib resistance, which is a drug used to treat HER2-positive gastric cancer. Testican-1 is involved in the pathway for this drug, and leads to drug resistance when upregulated. When testican-1 levels are artificially reduced, sensitivity towards lapatinib was once again increased. This shows the potential for future use in combatting drug resistance.
Testican-1 has also shown to be useful when studying sepsis in patients. A study revealed that patients with more advanced sepsis exhibited higher levels of testican-1. This is useful in determining the severity of sepsis in a clinical setting and could allow healthcare professionals to formulate a better treatment plan.


3-methyl-2-oxobutanoate dehydrogenase

In enzymology, a 3-methyl-2-oxobutanoate dehydrogenase () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are 3-methyl-2-oxobutanoate, dihydrolipoyllysine-residue (2-methylpropanoyl)transferase, and lipoyllysine, whereas its 3 products are dihydrolipoyllysine-residue (2-methylpropanoyl)transferase, S-(2-methylpropanoyl)dihydrolipoyllysine, and CO2.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the aldehyde or oxo group of donor with a disulfide as acceptor.
This enzyme participates in valine, leucine and isoleucine degradation. It employs one cofactor, thiamin diphosphate. It is the E1 subunit of a catalytic complex.
Structural studies.
As of late 2007, twenty-nine structures have been solved for this class of enzymes, with PDB accession codes , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .


Dicer

Dicer, also known as endoribonuclease Dicer or helicase with RNase motif, is an enzyme that in humans is encoded by the "DICER1" gene. Being part of the RNase III family, Dicer cleaves double-stranded RNA (dsRNA) and pre-microRNA (pre-miRNA) into short double-stranded RNA fragments called small interfering RNA and microRNA, respectively. These fragments are approximately 20-25 base pairs long with a two-base overhang on the 3' ends. Dicer facilitates the activation of the RNA-induced silencing complex (RISC), which is essential for RNA interference. RISC has a catalytic component Argonaute, which is an endonuclease capable of degrading messenger RNA (mRNA).
Discovery.
Dicer was given its name in 2001 by Stony Brook PhD student Emily Bernstein while conducting research in Gregory Hannon's lab at Cold Spring Harbor Laboratory. Bernstein sought to discover the enzyme responsible for generating small RNA fragments from double-stranded RNA. Dicer's ability to generate ~22 nucleotide RNA fragments was discovered by separating it from the RISC enzyme complex after initiating the RNAi pathway with dsRNA transfection. This experiment showed that RISC was not responsible for generating the observable small nucleotide fragments. Subsequent experiments testing RNase III family enzymes abilities to create RNA fragments narrowed the search to "Drosophila" CG4792, now named Dicer.
Dicer orthologs are present in many other organisms. In the moss "Physcomitrella patens" DCL1b, one of four DICER proteins, is not involved in miRNA biogenesis but in dicing miRNA target transcripts. Thus, a novel mechanism for regulation of gene expression, the epigenetic silencing of genes by miRNAs, was discovered.
In terms of crystal structure, the first Dicer to be explored was that from the protozoan "Giardia intestinalis". A PAZ domain and two RNase III domains were discovered by X-ray crystallography. The protein size is 82 kDa, while it is larger in other organisms; for example, it is 219 kDa in humans. The difference in size from humans to "G. intestinalis" Dicer is due to at least five different domains being present within human Dicer. These domains are important in Dicer activity regulation, dsRNA processing, and RNA interference protein factor functioning.
Functional domains.
Human dicer (also known as hsDicer or DICER1) is classified a Ribonuclease III because it contains both helicase and PAZ (Piwi/Argonaute/Zwille) domains. In addition to these domains, hsDicer contains four other functional domains: two RNaseIII domains and two double stranded RNA binding domains (DUF283 and dsRBD).
Current research suggests the PAZ domain is capable of binding the 2 nucleotide 3' overhang of dsRNA while the RNaseIII catalytic domains form a pseudo-dimer around the dsRNA to initiate cleavage of the strands. This results in a functional shortening of the dsRNA strand. The distance between the PAZ and RNaseIII domains is determined by the angle of the connector helix and influences the length of the micro RNA product. The dsRBD domain binds the dsRNA, although the specific binding site of the domain has not been defined. It is possible that this domain works as part of a complex with other regulator proteins (TRBP in humans, R2D2, Loqs in Drosophila) in order to effectively position the RNaseIII domains and thus control the specificity of the sRNA products. The helicase domain has been implicated in processing long substrates.
Role in RNA interference.
Micro RNA.
RNA interference is a process where the breakdown of RNA molecules into miRNA inhibits gene expression of specific host mRNA sequences. miRNA is produced within the cell starting from primary miRNA (pri-miRNA) in the nucleus. These long sequences are cleaved into smaller precursor miRNA (pre-miRNA), which are usually 70 nucleotides with a hairpin structure. Pri-miRNA are identified by DGCR8 and cleaved by Drosha to form the pre-miRNA, a process that occurs in the nucleus. These pre-miRNA are then exported to the cytoplasm, where they are cleaved by Dicer to form mature miRNA.
Small Interfering RNA.
Small interfering RNA (siRNA) are produced and function in a similar manner to miRNA by cleaving double-stranded RNA with Dicer into smaller fragments, 21 to 23 nucleotides in length. Both miRNAs and siRNAs activate the RNA-induced silencing complex (RISC), which finds the complementary target mRNA sequence and cleaves the RNA using RNase. This in turn silences the particular gene by RNA interference. siRNAs and miRNAs differ in the fact that siRNAs are typically specific to the mRNA sequence while miRNAs aren't completely complementary to the mRNA sequence. miRNAs can interact with targets that have similar sequences, which inhibits translation of different genes. In general, RNA interference is an essential part of normal processes within organisms such as humans, and it is an area being researched as a diagnostic and therapeutic tool for cancer targets.
Disease.
Macular degeneration.
Age related macular degeneration is a prominent cause of blindness in developed countries. Dicer's role in this disease became apparent after it was discovered that affected patients showed decreased levels of Dicer in their retinal pigment epithelium (RPE). Mice with Dicer knocked out, lacking Dicer only in their RPE, exhibited similar symptoms. However, other mice lacking important RNAi pathway proteins like Drosha and Pasha, did not have symptoms of macular degeneration as Dicer-knockout mice. This observation suggested a Dicer specific role in retinal health that was independent of the RNAi pathway and thus not a function of si/miRNA generation. A form of RNA called Alu RNA (the RNA transcripts of alu elements)) was found to be elevated in patients with insufficient Dicer levels. These non coding strands of RNA can loop forming dsRNA structures that would be degraded by Dicer in a healthy retina. However, with insufficient Dicer levels, the accumulation of alu RNA leads to the degeneration of RPE as a result of inflammation.
Cancer.
Altered miRNA expression profiles in malignant cancers suggest a pivotal role of miRNA and thus dicer in cancer development and prognosis. miRNAs can function as tumor suppressors and therefore their altered expression may result in tumorigenesis. In analysis of lung and ovarian cancer, poor prognosis and decreased patient survival times correlate with decreased dicer and drosha expression. Decreased dicer mRNA levels correlate with advanced tumor stage. However, high dicer expression in other cancers, like prostate and esophageal, has been shown to correlate with poor patient prognosis. This discrepancy between cancer types suggests unique RNAi regulatory processes involving dicer differ amongst different tumor types.
Dicer is also involved in DNA repair. DNA damage increases in mammalian cells with decreased Dicer expression as a result of decreased efficiency of DNA damage repair and other mechanisms. For example, siRNA from double strand breaks (produced by Dicer) may act as guides for protein complexes involved in the double strand break repair mechanisms and can also direct chromatin modifications. Additionally, miRNAs expression patterns change as a result of DNA damage caused by ionizing or ultraviolet radiation. RNAi mechanisms are responsible for transposon silencing and in their absence, as when Dicer is knocked out/down, can lead to activated transposons that cause DNA damage. Accumulation of DNA damage may result in cells with oncogenic mutations and thus the development of a tumor.
Other conditions.
Multinodular goiter with schwannomatosis has been shown to be an autosomal dominant condition associated with mutations in this gene.
Viral pathogenesis.
Infection by RNA viruses can trigger the RNAi cascade. It is likely dicer is involved in viral immunity as viruses that infect both plant and animal cells contain proteins designed to inhibit the RNAi response. In humans, the viruses HIV-1, influenza, and vaccinia encode such RNAi suppressing proteins. Inhibition of dicer is beneficial to the virus as dicer is able to cleave viral dsRNA and load the product onto RISC resulting in targeted degradation of viral mRNA; thus fighting the infection. Another potential mechanism for viral pathogenesis is the blockade of dicer as a way to inhibit cellular miRNA pathways.
In insects.
Insects can use Dicer as a potent antiviral. This finding is especially significant given that mosquitoes are responsible for the transmission of many viral diseases including the potentially deadly arboviruses: West Nile virus, dengue fever and yellow fever. While mosquitoes, more specifically the "Aedes aegypti" species, serve as the vectors for these viruses, they are not the intended host of the virus. Transmission occurs as a result of the female mosquito's need for vertebrate blood to develop her eggs. The RNAi pathway in insects is very similar to that of other animals; Dicer-2 cleaves viral RNA and loads it onto the RISC complex where one strand serves as a template for the production of RNAi products and the other is degraded. Insects with mutations leading to non-functional components of their RNAi pathway show increased viral loads for viruses they carry or increased susceptibility to viruses for which they are hosts. Similarly to humans, insect viruses have evolved mechanisms to avoid the RNAi pathway. As an example, Drosophila C virus encodes for protein 1A which binds to dsRNA thus protecting it from dicer cleavage as well as RISC loading. "Heliothis virescens" ascovirus 3a encodes an RNase III enzyme similar to the RNase III domains of dicer which may compete for dsRNA substrate as well as degrade siRNA duplexes to prevent RISC loading.
Diagnostic and therapeutic applications.
Dicer can be used to identify whether tumors are present within the body based on the expression level of the enzyme. A study showed that many patients that had cancer had decreased expression levels of Dicer. The same study showed that lower Dicer expression correlated with lower patient survival length. Along with being a diagnostic tool, Dicer can be used for treating patients by injecting foreign siRNA intravenously to cause gene silencing.
The siRNA was shown to be delivered in two ways in mammalian species such as mice. One way would be to directly inject into the system, which would not require Dicer function. Another way would be to introduce it by plasmids that encode for short hairpin RNA, which are cleaved by Dicer into siRNA.
One of the advantages of using Dicer to produce siRNA therapeutically would be the specificity and diversity of targets it can affect compared to what is currently being used such as antibodies or small molecular inhibitors. In general, small molecular inhibitors are difficult in terms of specificity along with unendurable side effects. Antibodies are as specific as siRNA, but it is limited by only being able to be used against ligands or surface receptors. On the other hand, low efficiency of intracellular uptake is the main obstacle of injection of siRNA. Injected SiRNA has poor stability in blood and causes stimulations of non-specific immunity. Also, producing miRNA therapeutically lacks in specificity because only 6-8 nucleotide base pairing is required for miRNA to attach to mRNA.
Dicer-like proteins.
Plant genomes encode for dicer like proteins with similar functions and protein domains as animal and insect dicer. For example, in the model organism Arabidopsis thaliana, four dicer like proteins are made and are designated DCL1 to DCL4. DCL1 is involved with miRNA generation and sRNA production from inverted repeats. DCL2 creates siRNA from cis-acting antisense transcripts which aid in viral immunity and defense. DCL3 generates siRNA which aids in chromatin modification and DCL4 is involved in trans-acting siRNA metabolism and transcript silencing at the post-transcriptional level. Additionally, DCL 1 and 3 are important for Arabidopsis flowering. In Arabidopsis, DCL knockout does not cause severe developmental problems.
Rice and grapes also produce DCLs as the dicer mechanism is a common defense strategy of many organisms. Rice has evolved other functions for the 5 DCLs it produces and they play a more important role in function and development than in Arabidopsis. Additionally, expression patterns differ among the different plant cell types of rice while expression in Arabidopsis is more homogeneous. Rice DCL expression can be effected by biological stress conditions including drought, salinity, and cold, thus, these stressors may decrease a plants viral resistance. Unlike Arabidopsis, loss of function of DCL proteins causes developmental defects in rice.


PHD finger

The PHD finger was discovered in 1993 as a Cys4-His-Cys3 motif in the plant homeodomain (hence PHD) proteins HAT3.1 in "Arabidopsis thaliana" and maize ZmHox1a.
The PHD finger motif resembles the metal binding RING domain (Cys3-His-Cys4) and FYVE domain. It occurs as a single finger, but often in clusters of two or three, and it also occurs together with other domains, such as the chromodomain and the bromodomain.
Role in epigenetics.
The PHD finger, approximately 50-80 amino acids in length, is found in more than 100 human proteins. Several of the proteins it occurs in are found in the nucleus, and are involved in chromatin-mediated gene regulation. The PHD finger occurs in proteins such as the transcriptional co-activators p300 and CBP, Polycomb-like protein (Pcl), Trithorax-group proteins like ASH1L, ASH2L and MLL, the autoimmune regulator (AIRE), Mi-2 complex (part of histone deacetylase complex), the co-repressor TIF1, the JARID1-family of demethylases and many more.
Structure.
The NMR structure of the PHD finger from human WSTF (Williams Syndrome Transcription Factor) shows that the conserved cysteines and histidine coordinate two Zn2+ ions. In general, the PHD finger adopts a globular fold, consisting of a two-stranded beta-sheet and an alpha-helix. The region consisting of these secondary structures and the residues involved in coordinating the zinc-ions are very conserved among species. The loop regions I and II are variable and could contribute functional specificity to the different PHD fingers.
Function.
The PHD fingers of some proteins, including ING2, YNG1 and NURF, have been reported to bind to histone H3 tri-methylated on lysine 4 (H3K4me3), while other PHD fingers have tested negative in such assays. A protein called KDM5C has a PHD finger, which has been reported to bind histone H3 tri-methylated lysine 9 (H3K9me3). Based on these publications, binding to tri-methylated lysines on histones may therefore be a property widespread among PHD fingers. Domains that bind to modified histones, are called "epigenetic readers" as they specifically recognize the modified version of the residue and binds to it. The modification H3K4me3 is associated with the transcription start site of active genes, while H3K9me3 is associated with inactive genes. The modifications of the histone lysines are dynamic, as there are methylases that add methyl groups to the lysines, and there are demethylases that remove methyl groups. KDM5C is a histone H3 lysine 4 demethylase, which means it is an enzyme that can remove the methyl groups of lysine 4 on histone 3 (making it H3K4me2 or H3K4me1). One can only speculate if the H3K9me3-binding of KDM5C PHD domain provides a crosstalk between trimethylation of H3K9 and the demethylation of H3K4me3. Such crosstalks have been suggested earlier with other domains involved in chromatin regulation, and may provide a strictly coordinated regulation.
Another example is the PHD finger of the BHC80/PHF21A protein, which is a component of the LSD1 complex. In this complex, LSD1 specifically demethylates H3K4me2 to H3K4me0, and BHC80 binds H3K4me0 through its PHD finger to stabilize the complex at its target promoters, presumably to prevent further re-methylation. This is the first example of a PHD finger recognizing lysine methyl-zero status.


DPNH-ubiquinone reductase

DPNH-ubiquinone reductase may refer to:


Hydrocortisone butyrate

Hydrocortisone butyrate is a corticosteroid that comes in one of the following forms:
It is a group IV corticosteroid under US classification.


Aldolase C

Aldolase C, fructose-bisphosphate (ALDOC, or ALDC), is an enzyme that, in humans, is encoded by the "ALDOC" gene on chromosome 17. This gene encodes a member of the class I fructose-bisphosphate aldolase gene family. Expressed specifically in the hippocampus and Purkinje cells of the brain, the encoded protein is a glycolytic enzyme that catalyzes the reversible aldol cleavage of fructose 1,6-bisphosphate and fructose-1-phosphate to dihydroxyacetone phosphate and either glyceraldehyde 3-phosphate or glyceraldehyde, respectively.[provided by RefSeq, Jul 2008]
Structure.
ALDOC is one of the three aldolase isozymes (A, B, and C), encoded by three different genes. The amino acid sequence of ALDOC is highly similar to those of the other isozymes, sharing a 68% identity with ALDOB and 78% identity with ALDOA. In particular, the residues Asp33, Arg42, Lys107, Lys146, Glu187, Ser271, Arg303, and Lys229 are all conserved in the active sites of the three isozymes. This active site is located in the center of the homotetrameric αβ-barrel structure of these aldolases. However, several structural details set ALDOC apart. For instance, the Arg303 residue in ALDOC adopts an intermediate conformation between the liganded and unliganded structures observed in the other isozymes. Also, the C-terminal region between Glu332 and Lys71 forms a salt bridge with the barrel region that is absent in the A and B isoforms. Moreover, the electrostatic surface of ALDOC is more negatively charged, which may serve as an acidic binding site or as a docking site to accommodate the C-terminal conformations. Four ALDOC-specific residues (N90, V92, R96 and D100) may be key for ALDOC-specific functions.
Function.
ALDOC is a key enzyme in the fourth step of glycolysis, as well as in the reverse pathway gluconeogenesis. It catalyzes the reversible conversion of fructose-1,6-bisphosphate to glyceraldehydes-3-phosphate (G3P), or glyceraldehyde, and dihydroxyacetone phosphate (DHAP) by aldol cleavage. As a result, it is a crucial player in ATP biosynthesis. As an aldolase, ALDOC putatively also contributes to other "moonlighting" functions, though its exact involvements remain unclear. For instance, it binds less tightly to the cytoskeleton than the other isozymes do, likely due to its more acidic pI. In addition, ALDOC participates in the stress-response pathway for lung epithelial cell function during hypoxia and in the resistance of cerebellar Purkinje cells against excitotoxic insult.
ALDOC is ubiquitously expressed in most tissues, though it is predominantly expressed in brain, smooth muscle, and neuronal tissue. However, since the ALDOA isoform is co-expressed with ALDOC in the central nervous system (CS), it is suggested that ALDOC contributes to CNS function outside of glycolysis. Moreover, its presence within other cell types, such as platelets and mast cells (MCs), may serve as a failsafe in the case that the other predominant aldolase isozymes become inactivated. Within cells, it localizes to the cytoplasm.
Clinical significance.
This aldolase has been associated with cancer.
ALDOC is found to be upregulated in the brains of schizophrenia (SCZ) patients. Notably, while ALDOC is differentially expressed in the anterior cingulate cortex (ACC) of male SCZ patients, it displays no significant changes in female SCZ patients, indicating that different regulatory mechanisms may be involved in male versus female SCZ patients. It is likely that ALDOC is involved in SCZ through its role in glycolysis, which is a central biochemical pathway in SCZ.
Furthermore, ALDOC is reported to undergo oxidation in brains affected by mild cognitive impairment (MCI) and Alzheimer's disease (AD). This oxidative modification inhibits ALDOC activity, causing the accumulation of fructose 1,6- bisphosphate and driving the reverse reaction, in the direction of gluconeogenesis rather than glycolysis, thus halting ATP production.


Gemopatrilat

Gemopatrilat (INN) is an experimental drug that was never marketed. It acts as a vasopeptidase inhibitor. It inhibits both angiotensin-converting enzyme (ACE) and neutral endopeptidase (neprilysin).


3,4-dihydroxy-2-butanone-4-phosphate synthase

In molecular biology, 3,4-dihydroxy-2-butanone 4-phosphate synthase (DHBP synthase) (RibB) is an enzyme which catalyses the conversion of D-ribulose 5-phosphate to formate and 3,4-dihydroxy-2-butanone 4-phosphate, the latter serving as the biosynthetic precursor for the xylene ring of riboflavin. In "Photobacterium leiognathi", the riboflavin synthesis genes ribB (DHBP synthase), ribE (riboflavin synthase), ribH (lumazine synthase) and ribA (GTP cyclohydrolase II) all reside in the lux operon. RibB is sometimes found as a bifunctional enzyme with GTP cyclohydrolase II that catalyses the first committed step in the biosynthesis of riboflavin. No sequences with significant homology to DHBP synthase are found in the metazoa.


Benzoyl-beta-D-glucoside

Benzoyl-"beta"--glucoside is a benzoyl glucoside, a natural substance that can be found in "Pteris ensiformis".


Acetylcholinesterase inhibitor

Acetylcholinesterase inhibitors (AChEIs) also often called cholinesterase inhibitors, inhibit the enzyme acetylcholinesterase from breaking down the neurotransmitter acetylcholine into choline and acetate, thereby increasing both the level and duration of action of acetylcholine in the central nervous system, autonomic ganglia and neuromuscular junctions, which are rich in acetylcholine receptors. Acetylcholinesterase inhibitors are one of two types of cholinesterase inhibitors; the other being butyryl-cholinesterase inhibitors.
Acetylcholinesterase is the primary member of the cholinesterase enzyme family.
Acetylcholinesterase inhibitors are classified as reversible, irreversible, or quasi-irreversible (also called pseudo-irreversible).
Mechanism of action.
Organophosphates.
Organophosphates like TEPP and sarin inhibit cholinesterases, enzymes that hydrolyze the neurotransmitter acetylcholine.
The active centre of cholinesterases feature two important sites, namely the anionic site and the esteratic site. After the binding of acetylcholine to the anionic site of the cholinesterase, the acetyl group of acetylcholine can bind to the esteratic site. Important amino acid residues in the esteratic site are a glutamate, a histidine, and a serine. These residues mediate the hydrolysis of the acetylcholine.
At the esteratic site the acetylcholine is cleaved, which results in a free choline moiety and an acetylated cholinesterase. This acetylated state requires hydrolysis to regenerate itself.
Inhibitors like TEPP modify the serine residue in the esteratic site of the cholinesterase.
This phosphorylation inhibits the binding of the acetyl group of the acetylcholine to the esteratic site of the cholinesterase. Because the acetyl group can’t bind the cholinesterase, the acetylcholine can’t be cleaved. Therefore the acetylcholine will remain intact and will accumulate in the synapses. This results in continuous activation of acetylcholine receptors, which leads to the acute symptoms of TEPP poisoning. The phosphorylation of cholinesterase by TEPP (or any other organophosphate) is irreversible. This makes the inhibition of the cholinesterase permanent.
The cholinesterase gets irreversible phosphorylated according to the following reaction scheme
<chem>E + PX <=> E-PX ->[k_3] EP + X </chem>
In this reaction scheme the E indicates the cholinesterase, PX the TEPP molecule, E–PX the reversible phosphorylated cholinesterase, "k"3 the reaction rate of the second step, EP the phosphorylated cholinesterase and X the leaving group of the TEPP.
The irreversible phosphorylation of the cholinesterase occurs in two steps. In the first step the cholinesterase gets reversibly phosphorylated. This reaction is very fast. Then the second step takes place. The cholinesterase forms a very stable complex with TEPP, in which TEPP is covalently bound to the cholinesterase. This is a slow reaction. But after this step the cholinesterase is irreversibly inhibited.
The time dependent irreversible inhibition of the cholinesterase can be described by the following equation.
In this formula, "E" is the remaining enzyme activity, "E"0 is the initial enzyme activity, "t" is the time interval after mixing of the cholinesterase and the TEPP, "K""I" is the dissociation constant for cholinesterase-TEPP complex (E–PX) and I is the TEPP concentration.
The reaction mechanism and the formula above are both also compatible for other organophosphates. The process occurs in the same way.
Furthermore, certain organophosphates can cause OPIDN, organophosphate-induced delayed polyneuropathy. This is a disease, which is characterized by degeneration of axons in the peripheral and central nervous system. This disease will show a few weeks after contamination with the organophosphate. It is believed that the neuropathy target esterase (NTE) is affected by the organophosphate which induces the disease. However, there are no references found, which indicate that TEPP is one of the organophosphates that can cause OPIDN.
Uses.
Acetylcholinesterase inhibitors:
Guideline recommendations.
The clinical guidelines for medication management in people with dementia recommend trialing an AChE inhibitor for people with early to mid stage dementia. These guidelines, known as the Medication Appropriateness Tool for Comorbid Health conditions in Dementia (MATCH-D), suggest that these medicines are at least considered.
Side effects.
Some major effects of cholinesterase inhibitors:
Administration of reversible cholinoesterase inhibitors is contraindicated with those that have urinary retention due to urethral obstruction.
Examples.
Reversible inhibitor.
Compounds which function as reversible competitive or noncompetitive inhibitors of cholinesterase are those most likely to have therapeutic uses. These include:
Quasi-irreversible inhibitor.
Compounds which function as quasi-irreversible inhibitors of cholinesterase are those most likely to have use as chemical weapons or pesticides.