ATP-binding motif

An ATP-binding motif is a 250-residue sequence within an ATP-binding protein’s primary structure. The binding motif is associated with a protein’s structure and/or function. ATP is a molecule of energy, and can be a coenzyme, involved in a number of biological reactions. ATP is proficient at interacting with other molecules through a binding site. The ATP binding site is the environment in which ATP catalytically actives the enzyme and, as a result, is hydrolyzed to ADP. The binding of ATP causes a conformational change to the enzyme it is interacting with.
The genetic and functional similarity of such a motif demonstrates micro-evolution: proteins have co-opted the same binding sequence from other enzymes rather than developing them independently.
ATP binding sites, which may be representative of an ATP binding motif, are present in many proteins which require an input of energy (from ATP), such sites as active membrane transporters, microtubule subunits, flagellum proteins, and various hydrolytic and proteolytic enzymes.
Primary sequence.
The short motifs involving ATP-binding are the Walker motifs, Walker A, also known as the P-loop, and Walker B, as well as the C motif and switch motif.
Walker A motif.
The Walker site A has a primary amino acid sequence of or . The letter can represent any amino acid.
Walker B motif.
The primary amino acid sequence of the Walker B site is , in which represents any hydrophobic amino acid.
C motif.
The C motif, also known as the signature motif, LSGGQ motif, or the linker peptide, has a primary amino acid sequence of .
Due to the variety of different amino acids that can be used in the primary sequence, of both the Walker site A and B, the non-variant amino acids within the sequence are highly conserved. A mutation of any of these amino acids will affect the binding ATP or interfere with the catalytic activity of the enzyme. The primary amino acid sequence determines the three dimensional structure of each motif.
Structure.
All of the ATP binding domains are made up of an estimated 250 residues and two subunits, creating a dimer. These residues are folded into six α-helices and five β-strands.
Walker A motif.
Structurally, the Walker A motif consists of an α-helix and is always followed by a glycine-rich loop.
Walker B motif.
The Walker B motif is a β-strand. The Walker motifs are connected to each other by a peptide sequence of about 100 residues. Structurally, these connecting residues fold into an α-helical domain.
C motif.
Directly following the Walker B motif, is the signature motif.
Switch motif.
The switch motif has been found to be located at the end of the β4-strand in ATP-binding proteins.
Function.
Each ATP binding motif has a different role to play whether it is directly involved with the binding of ATP or helping with the construction of the ATP-binding cassette (ABC) transporter. The ATP molecule binds to the connecting point of each subunit of the dimer, indicating that ATP is in close proximity to both subunits during catalysis. The two binding motifs that ATP directly interacts with is the residues from the Walker A motif, located on one of the subunits, and the residues from the C binding motif, located on the other subunit. The Walker A binding motif has a lysine side chain, which is essential for the binding of ATP. The lysine residue forms hydrogen bonds with the oxygen atoms of two phosphate groups within ATP, therefore creating proximity and orientation of ATP in the binding site.
In order for the Walker A motif to bind to ATP, the ATP molecule must be in the binding site. The signature motif acts as a signal to the Walker A motif, letting the Walker A know when the ATP molecule has bound to the binding site. The signature motif does this by allowing its residues to extend from the subunit they are located into the other subunit where the Walker A motif is. It is necessary that ATP binds to both nucleotide binding domains in order to complete the catalytically active structure.
The Walker B motif contains the amino acid glutamate within the short sequence. Glutamate can be used to perform a nucleophilic attack on the ATP molecule.
Found in the switch binding motif is a histidine residue. The function of the histidine is to influence the reaction catalytically by contacting the residues across the dimer interface, including the Walker A motif and the Walker B motif. It is the histidine residue that forms the tight coupling between the binding of the ATP molecule and the dimer.
Following the hydrolysis of ADP, a conformational change must occur to separate the ATP-binding cassette. This separation is driven by an electrostatic repulsion by the ADP product that is bound the Walker A motif and the inorganic phosphate product is bound to the C motif.


Prostaglandin D2

Prostaglandin D2 (or PGD2) is a prostaglandin that binds to the receptor PTGDR (DP1), as well as CRTH2 (DP2). It is a major prostaglandin produced by mast cells – recruits Th2 cells, eosinophils, and basophils. In mammalian organs, large amounts of PGD2 are found only in the brain and in mast cells. It is critical to development of allergic diseases such as asthma.
Research carried out in 1989"" found PGD2 is the primary mediator of vasodilation (the "niacin flush") after ingestion of niacin (nicotinic acid).
A 2012 research paper indicates a causal link between elevated levels of localized PGD2 and hair growth inhibition. Applied topically, the researchers found PGD2 prevents hair growth, and mice that were genetically inclined to produce higher levels of PGD2 had inhibited hair growth. The researchers also found PGD2 levels were much higher in balding scalp tissue than nonbalding scalp tissue, through increased levels of prostaglandin D2 synthase. The paper suggested that inhibition of hair growth involved binding of PGD2 to a receptor called GPR44, and that GPR44 therefore would be a therapeutic target for androgenic alopecia in both men and women with hair loss and thinning. Because PGD2's relation to asthma has been known for several years, several drugs that seek to reduce the effect of PGD2 through blocking the GPR44 are already in clinical trials.
Inhibitors.
In silico simulations have predicted the following as potential inhibitors of PGD2 synthase:


SacI

"Sac"I is a restriction enzyme isolated from the bacterium "Streptomyces achromogenes".


Aviculin

Aviculin is a lignan. It is bio-active isolate of "Pseudocydonia sinensis" or "Polygonum aviculare".


Zaprinast

Zaprinast was an unsuccessful clinical drug candidate that was a precursor to the chemically related PDE5 inhibitors, such as sildenafil (Viagra), which successfully reached the market. It is a phosphodiesterase inhibitor, selective for the subtypes PDE5, PDE6, PDE9 and PDE11. IC50 values are 0.76, 0.15, 29.0, and 12.0 "μ"M, respectively.
Zaprinast inhibits the growth of asexual blood-stage malaria parasites ("P. falciparum") "in vitro" with an ED50 value of 35 "μ"M, and inhibits PfPDE1, a "P. falciparum" cGMP-specific phosphodiesterase, with an IC50 value of 3.8 "μ"M.
Zaprinast has also been shown to activate the orphan G-protein coupled receptor known as GPR35, both in rats and humans, however, the clinical significance of this has yet to be determined.


Acetyl-CoA hydrolase

In enzymology, an acetyl-CoA hydrolase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are acetyl-CoA and H2O, whereas its two products are CoA and acetate. It is present in many species including animals (see reference below).
This enzyme belongs to the family of hydrolases, specifically those acting on thioester bonds. The systematic name of this enzyme class is acetyl-CoA hydrolase. Other names in common use include acetyl-CoA deacylase, acetyl-CoA acylase, acetyl coenzyme A hydrolase, acetyl coenzyme A deacylase, acetyl coenzyme A acylase, and acetyl-CoA thiol esterase. This enzyme participates in pyruvate metabolism.
Structural studies.
As of late 2007, only one structure has been solved for this class of enzymes, with the PDB accession code .


Paraoxon

Paraoxon is a parasympathomimetic which acts as an cholinesterase inhibitor. It is an organophosphate oxon, and the active metabolite of the insecticide parathion. It is also used as an ophthalmological drug against glaucoma. Paraoxon is one of the most potent acetylcholinesterase-inhibiting insecticides available, around 70% as potent as the nerve agent sarin, and so is now rarely used as an insecticide due to the risk of poisoning to humans and other animals. Paraoxon has been used by scientists to study acute and chronic effects of organophosphate intoxication. It is easily absorbed through skin, and was allegedly used as an assassination weapon by the apartheid-era South African chemical weapons program Project Coast.


Dipeptidyl carboxypeptidase

Dipeptidyl carboxypeptidase may refer to:


DExD/H box proteins

DEAD box, DEAH, and the SKI families of proteins are all referred to as DExD/H box proteins. They are all quite distinct from one another and there is not one protein that belongs to more than one of these families. It is thought that each family may have a specific role in RNA metabolism, for example both DEAD box and DEAH box proteins NTPase activities become stimulated by RNA, but DEAD box proteins specifically hydrolyze ATP whereas DEAH can hydrolyze ATP and other NTPs.


Asx turn

The Asx turn
is a structural feature in proteins and polypeptides. It consists of three amino acid residues (labeled i, i+1 and i+2) in which residue i is an aspartate (Asp) or asparagine (Asn) that forms a hydrogen bond from its sidechain CO group to the mainchain NH group of residue i+2. About 14% of Asx residues present in proteins belong to Asx turns.
The name "Asx" is used here to represent either of the amino acids aspartate (Asp) or asparagine (Asn).
Types.
Four types of Asx turn can be distinguished: types I, I’, II and II’. These categories correspond to those of the better-known hydrogen-bonded beta turns, which have four residues and a hydrogen bond between the CO of residue i and the NH of residue i+3. Asx turns and beta turns have structurally similar hydrogen-bonded loops and exhibit sidechain-mainchain mimicry in the sense that the sidechain of residue i of the Asx turn mimics the mainchain of residue i of the beta turn. Regarding their occurrence in proteins, they differ in that type I is the commonest of the four beta turns while type II’ is the commonest of the Asx turns.
Occurrence.
Asx and ST turns both occur frequently at the N-termini of α-helices. as part of Asx motifs or ST motifs such that the Asx, serine or threonine is the N cap residue. They are thus often regarded as helix capping features.
Related motifs.
Similar motifs occur with serine or threonine as residue i, which are called ST turns. In spite of serine and threonine having one less sidechain atom, such that the sidechain-mainchain mimicry of β turns is imperfect, these features occur in proteins as the four types in numbers approaching those of Asx turns. They also exhibit a tendency to substitute each other over evolutionary time.
A proportion of Asx turns are accompanied by a mainchain–mainchain hydrogen bond that qualifies them as Asx motifs.


Beta-keratin

β-keratin or beta-keratin is a member of a structural protein family found in the epidermis of reptiles and birds. β-keratins were named so because they are components of epidermal stratum corneum rich in stacked β pleated sheets, in contrast to alpha-keratins, intermediate-filament proteins also found in stratum corneum and rich in alpha helices. Because the accurate use of the term "keratin" is limited to the alpha-keratins, the term "beta-keratins" in recent works is replaced by "corneous beta-proteins" or "keratin-associated beta-proteins."
β-keratins add much more rigidity to reptilian skin than alpha-keratins alone do to mammalian skin. β-keratins are impregnated into the stratum corneum of the reptilian skin, providing waterproofing and the prevention of desiccation.
The scales, beaks, claws and feathers of birds contain β-keratin of the avian family. Phylogenetic studies of β-keratin sequences show that feather β-keratins evolved from scale β-keratins. The scale β-keratins form the basal group in avians. Duplication and divergence events then led to claw β-keratin genes, and further recombination resulted in new feather and feather-like avian β-keratin genes. Evidence for these duplication events comes from the correlation of feather β-keratin clade structure with their genomic loci.
Changes in β-keratins may have also influenced the development of powered flight. A recent study using molecular dating methods to link the evolution of avian β-keratin genes in general to that of feathers specifically reveals that the avian β-keratin family began diverging from the crocodile family about 216 million years ago. It also found that the feather β-keratin family did not begin diverging until 125 million years ago, a date consistent with the adaptive radiation of birds during the Cretaceous. β-keratins found in modern feathers have increased elasticity, a factor that may have contributed to their role in flight. Thus, feathered relatives of birds such as "Anchiornis" and "Archaeopteryx", whose flight capabilities have been questioned, would have had avian, but not feather, β-keratins.
The small alvarezsaurid dinosaur "Shuvuuia deserti" shows evidence of a featherlike skin covering. Analysis by Schweitzer "et al." (1999) showed that these featherlike structures consisted of beta-keratin.
External links.
There are two main forms of keratin, alpha-keratin and beta-keratin. Alpha-keratin is seen in humans and other mammals, beta-keratin is present in birds and reptiles. Beta-keratin is harder than alpha-keratin. Structurally alpha-keratin have alpha-helical coiled coil structure while beta-keratin have twisted beta sheet structure.bIn the case of β-sheets, this allows sterically-unhindered hydrogen bonding between the amino and carboxyl groups of peptide bonds on adjacent protein chains, facilitating their close alignment and strong binding. Fibrous keratin molecules can twist around each other to form helical intermediate filaments.
The secondary structure of silk is an example of the beta pleated sheet. In this structure, individual protein chains are aligned side-by-side with every other protein chain aligned in an opposite direction. The chains are antiparallel, with an alternating C → N orientation. The protein chains are held together by intermolecular hydrogen bonding, that is hydrogen bonding between amide groups of two separate chains. This intermolecular hydrogen bonding in the beta-pleated sheet is in contrast to the intramolecular hydrogen bonding in the alpha-helix.
The hydrogen on the amide of one protein chain is hydrogen bonded to the amide oxygen of the neighboring protein chain. The pleated sheet effect arises form the fact that the amide structure is planar while the "bends" occur at the carbon containing the side chain.
The "side" chain R groups in silk are not very bulky. The basic primary structure of silk consists of a six amino acid unit that repeats itself. The sequence where every other unit is glycine in silk is: -gly-ala-gly-ala-gly-ala-. Although glycine and alanine make up 75-80% of the amino acids in silk, another 10-15% is serine and the final 10% contain bulky side chains such as in tyr, arg, val, asp, and glu.


Trelagliptin

Trelagliptin (trade name Zafatek) is a pharmaceutical drug used for the treatment of type 2 diabetes (diabetes mellitus).
Indications.
It is a highly selective dipeptidyl peptidase-4 inhibitor that is typically used as an add on treatment when the first line treatment of metformin is not achieving the expected glycemic goals; though it has been approved for use as a first line treatment when metformin cannot be used.
Biochemistry.
DPP-4 inhibitors activate T-cells and are more commonly known as T-cell activation antigens (specifically CD26). Chemically, it is a fluorinated derivative of alogliptin.
Development.
Formulated as the salt trelagliptin succinate, it was approved for use in Japan in March 2015. Takeda, the company that developed trelagliptin, chose to not get approval for the drug in the US and EU. The licensing rights that Takeda purchased from Furiex Pharmaceuticals for DPP-4 inhibitors included a clause specific to development of this drug in the US and EU. The clause required that all services done for phase II and phase III clinical studies in the US and EU be purchased through Furiex. Takeda chose to cease development of this drug in the US and EU because of the high costs quoted by Furiex for these services. Gliptins have been on the market since 2006 and there are 8 gliptins currently registered as drugs (worldwide). Gliptins are an emerging market and are thus being developed at an increasing rate; there are currently two gliptins in advanced stages of development that are expected to be on the market in the coming year.
Gliptins are thought to have cardiovascular protective abilities though the extent of these effects is still being studied. They are also being studied for the ability that this class of drugs has at promoting B-cell survival.
Administration and dosing.
Similar drugs in the same class as trelagliptin are administered once daily while trelagliptin is administered once weekly. Alogliptin (Nesina) is the other major DPP-4 inhibitor on the market. It is also owned by Takeda and is administered once daily. A dosing of once per week is advantageous as a reduction in the frequency of required dosing is known to increase patient compliance.
Brand names.
In Bangladesh it is marketed under the trade name "Wedica".


LRRC8E

Leucine-rich repeat-containing protein 8E is a protein that in humans is encoded by the "LRRC8E" gene. Researchers have found out that this protein, along with the other LRRC8 proteins LRRC8A, LRRC8B, LRRC8C, and LRRC8D, is sometimes a subunit of the heteromer protein volume-regulated anion channel. Volume-Regulated Anion Channels (VRACs) are crucial to the regulation of cell size by transporting chloride ions and various organic osmolytes, such as taurine or glutamate, across the plasma membrane, and that is not the only function these channels have been linked to.
While LRRC8E is one of many proteins that can be part of VRAC, research has found that it is not as crucial to the activity of the channel in comparison to LRRC8A and LRRC8D. However, while we know that LRRC8A and LRRC8D are necessary for VRAC function, other studies have found that they are not sufficient for the full range of usual VRAC activity. This is where the other LRRC8 proteins come in, such as LRRC8E, as the different composition of these subunits affects the range of specificity for VRACs.
In addition to its role in VRACs, the LRRC8 protein family is also associated with agammaglobulinemia-5.
Specifically for LRRC8E, there has been a recent study that found that this gene was nominally associated with panic disorder.


DTDP-4-dehydrorhamnose reductase

In enzymology, a dTDP-4-dehydrorhamnose reductase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are dTDP-6-deoxy-L-mannose and NADP+, whereas its 3 products are dTDP-4-dehydro-6-deoxy-L-mannose, NADPH, and H+.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-OH group of donor with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is dTDP-6-deoxy-L-mannose:NADP+ 4-oxidoreductase. Other names in common use include dTDP-4-keto-L-rhamnose reductase, reductase, thymidine diphospho-4-ketorhamnose, dTDP-4-ketorhamnose reductase, TDP-4-keto-rhamnose reductase, and thymidine diphospho-4-ketorhamnose reductase. This enzyme participates in 3 metabolic pathways: nucleotide sugars metabolism, streptomycin biosynthesis, and polyketide sugar unit biosynthesis.
Structural studies.
As of late 2007, 5 structures have been solved for this class of enzymes, with PDB accession codes , , , , and .


Granin

Granin (chromogranin and secretogranin) is a protein family of regulated secretory proteins ubiquitously found in the cores of amine and peptide hormone and neurotransmitter dense-core secretory vesicles.
Function.
Granins (chromogranins or secretogranins) are acidic proteins and are present in the secretory granules of a wide variety of endocrine and neuro-endocrine cells. The exact function(s) of these proteins is not yet settled but there is evidence that granins function as pro-hormones, giving rise to an array of peptide fragments for which autocrine, paracrine, and endocrine activities have been demonstrated in vitro and in vivo. The intracellular biochemistry of granins includes binding of Ca2+, ATP and catecholamines (epinephrine, norepinephrine) within the hormone storage vesicle core. There is also evidence that CgA, and perhaps other granins, regulate the biogenesis of dense-core secretory vesicles and hormone sequestration in neuroendocrine cells.
Structure.
Apart from their subcellular location and the abundance of acidic residues (Asp and Glu), these proteins do not share many structural similarities. Only one short region, located in the C-terminal section, is conserved in all these proteins. Chromogranins and secretogranins together share a C-terminal motif, whereas chromogranins A and B share a region of high similarity in their N-terminal section; this region includes two cysteine residues involved in a disulfide bond.
There are considerable differences in the amino acid composition between different animals. Commercial assays for measuring human CGA can usually not be used for measuring CGA in samples from other species. Some specific parts of the molecule have a higher degree of amino acid homology and methods where the antibodies are directed against specific epitopes can be used to measure samples from different animals. Region-specific assays measuring defined parts of CGA, CGB and SG2 can be used for measurements in samples from cats and dogs.
Members.
Extended group.
Some other proteins are also proposed to belong to the granins based on their physico-chemical properties. These include NESP55 (SgVI), VGF (SgVII), and ProSAAS (SgVIII).


Tetragalacturonic acid hydroxymethylester

Tetragalacturonic acid hydroxymethylester is a local antihemorrhagic. It is derived from apple pectin. It is not used clinically, but research in the 1970s suggests that pectin and analogues may inhibit fibrinolysis "in vitro".


(S)-methylmalonyl-CoA hydrolase

In enzymology, a (S)-methylmalonyl-CoA hydrolase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are (S)-methylmalonyl-CoA and HO, whereas its two products are methylmalonate and CoA.
This enzyme belongs to the family of hydrolases, specifically those acting on thioester bonds. The systematic name of this enzyme class is (S)-methylmalonyl-CoA hydrolase. This enzyme is also called D-methylmalonyl-coenzyme A hydrolase. This enzyme participates in propanoate metabolism.


Ethylmalonyl-CoA decarboxylase

Ethylmalonyl-CoA decarboxylase () is an enzyme with systematic name "(S)-ethylmalonyl-CoA carboxy-lyase (butanoyl-CoA-forming)". This enzyme catalyses the following chemical reaction
The vertebrate enzyme decarboxylates ethylmalonyl-CoA.


HNRPU

Heterogeneous nuclear ribonucleoprotein U is a protein that in humans is encoded by the "HNRNPU" gene.
Function.
This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins that form complexes with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene contains a RNA binding domain and scaffold-associated region (SAR)-specific bipartite DNA-binding domain. This protein is also thought to be involved in the packaging of hnRNA into large ribonucleoprotein complexes. During apoptosis, this protein is cleaved in a caspase-dependent way. Cleavage occurs at the SALD site, resulting in a loss of DNA-binding activity and a concomitant detachment of this protein from nuclear structural sites. But this cleavage does not affect the function of the encoded protein in RNA metabolism. At least two alternatively spliced transcript variants have been identified for this gene.
Interactions.
HNRPU has been shown to interact with:


Minor capsid proteins VP2 and VP3

Minor capsid protein VP2 and minor capsid protein VP3 are viral proteins that are components of the polyomavirus capsid. Polyomavirus capsids are composed of three proteins; the major component is major capsid protein VP1, which self-assembles into pentamers that in turn self-assemble into enclosed icosahedral structures. The minor components are VP2 and VP3, which bind in the interior of the capsid.
Gene expression.
All three capsid proteins are expressed from alternative start sites on a single transcript of the "late region" of the circular viral chromosome (so named because it is transcribed late in the process of viral infection). The VP3 start site is in frame downstream from that of VP2; in consequence VP3's sequence is identical to the C-terminal portion of VP2, which has an additional N-terminal extension. In at least some polyomaviruses, the VP2 N-terminus is myristoylated. Some members of the polyomavirus family, such as Merkel cell polyomavirus, do not appear to encode or express VP3, though VP2 is present.
Structure and interactions.
Both VP2 and VP3 are primarily intrinsically unstructured proteins; they have DNA-binding domains and a nuclear localization signal at their C-terminal ends. Both VP2 and VP3 bind to the interior of VP1 pentamers in the assembled capsid. It is generally believed that the stoichiometry of this interaction is one molecule of VP2 or VP3 to each VP1 pentamer, though higher ratios have sometimes been reported, possibly indicating that pentamers can accommodate associations with two minor proteins.
Function.
VP2 and VP3 are thought to be involved in facilitating viral entry into the host cell, either by mediating associations with and exit from the endoplasmic reticulum or by facilitating the entry of the viral genome into the cell nucleus. However, the precise mechanism of their involvement is unclear, and may vary among polyomaviruses. In most studies, viral propagation is either reduced or abrogated in the absence of one or both proteins, but the apparent mechanisms vary; for example, in JC virus both VP2 and VP3 seem to be essential for packaging the viral chromosome into the capsid, while absence of these proteins in SV40 prevents successful entry into new host cells, with variable effects on packaging reported. In Merkel cell polyomavirus, the effect of VP2 appears to vary depending on the cell type of the infected cell. In murine polyomavirus the minor proteins have been reported to induce apoptosis in the infected cell, and in SV40 they have been identified as viroporins.


BAG domain

In molecular biology, BAG domains are protein domains found in proteins which are modulators of chaperone activity, they bind to HSP70/HSC70 proteins and promote substrate release. The proteins have anti-apoptotic activity and increase the anti-cell death function of BCL-2 induced by various stimuli. BAG-1 binds to the serine/threonine kinase Raf-1 or Hsc70/Hsp70 in a mutually exclusive interaction. BAG-1 promotes cell growth by binding to and stimulating Raf-1 activity. The binding of Hsp70 to BAG-1 diminishes Raf-1 signalling and inhibits subsequent events, such as DNA synthesis, as well as arrests the cell cycle. BAG-1 has been suggested to function as a molecular switch that encourages cells to proliferate in normal conditions but become quiescent under a stressful environment .
BAG-family proteins contain a single BAG domain, except for human BAG-5 which has four BAG repeats. The BAG domain is a conserved region located at the C terminus of the BAG-family proteins that binds the ATPase domain of Hsc70/Hsp70. The BAG domain is evolutionarily conserved, and BAG domain containing proteins have been described and/or proven in a variety of organisms including "Mus musculus" (Mouse), "Xenopus" spp., "Drosophila" spp., "Bombyx mori" (Silk moth), "Caenorhabditis elegans", "Saccharomyces cerevisiae" (Baker's yeast), "Schizosaccharomyces pombe" (Fission yeast), and "Arabidopsis thaliana" (Mouse-ear cress).
The BAG domain has 110-124 amino acids and is composed of three anti-parallel alpha-helices, each approximately 30-40 amino acids in length. The first and second helices interact with the serine/threonine kinase Raf-1 and the second and third helices are the sites of the BAG domain interaction with the ATPase domain of Hsc70/Hsp70. Binding of the BAG domain to the ATPase domain is mediated by both electrostatic and hydrophobic interactions in BAG-1 and is energy requiring.


Cherry Smash

Cherry Smash is a fountain syrup made from cherry syrup along with a blend of other fruit flavors which soda jerks mixed with carbonated water and phosphate. During the 1920s it was available at soda fountains and pharmacies along the East Coast of the United States, but the product is no longer produced in the present day.
History.
Cherry Smash was founded in 1901 by Richmond, Virginia, native John E. Fowler. In 1920, he began to produce it in a former brewery in Arlington, Virginia. He produced it for almost 30 years.
It was sold from ball-shaped dispensers and were common at American drug stores along with other sodas at the time.


IntEnz

IntEnz (Integrated relational Enzyme database) contains data on enzymes organized by enzyme EC number and is the official version of the Enzyme Nomenclature system developed by the International Union of Biochemistry and Molecular Biology.


SLC20A2

Sodium-dependent phosphate transporter 2 is a protein that in humans is encoded by the "SLC20A2" gene.
Genomics.
This gene is found on the short arm of chromosome 8 (8p12-p11) on the minus (Crick) strand. It is 123,077 bases in length. The encoded protein has 652 amino acids and the predicted molecular weight of the protein is 70.392 kiloDaltons.
Function.
The protein acts as a homodimer and is involved in phosphate transport by absorbing phosphate from interstitial fluid for normal cellular functions such as cellular metabolism, signal transduction, and nucleic acid and lipid synthesis.
Clinical significance.
Mutations in the SLC20A2 gene are associated with idiopathic basal ganglia calcification (Fahr's syndrome). This association suggests that familial idiopathic basal ganglia calcification is caused by changes in phosphate homeostasis, since this gene encodes for PIT-2, an inorganic phosphate transporter.


N-carbamoylase

N-carbamoylase may refer to:


Beta bulge

A beta bulge can be described as a localized disruption of the regular hydrogen bonding of beta sheet by inserting extra residues into one or both hydrogen bonded β-strands.
Types.
β-bulges can be grouped according to their length of the disruption, the number of residues inserted into each strand, whether the disrupted β-strands are parallel or antiparallel and by their dihedral angles (which controls the placement of their side chains). Two types occur commonly. One, the "classic beta bulge", occurs within, or at the edge of, antiparallel beta-sheet; the first residue at the outwards bulge typically has the αR, rather than the normal β, conformation.
The other type is the "beta bulge loop" (also named type G1 β-bulge), often occurs in association with an antiparallel sheet, but also in other situations. One residue has the αL conformation and is part of a beta turn or alpha turn, such that the motif sometimes forms the loop of a beta hairpin.
Effects on structure.
At the level of the backbone structure, classic β-bulges can cause a simple aneurysm of the β-sheet, e.g., the bulge in the long β-hairpin of ribonuclease A (residues 88-91). A β-bulge can also cause a β-sheet to fold over and cross itself, e.g., when two residues with left-handed and right-handed α-helical dihedral angles are inserted opposite to each other in a β-hairpin, as occurs at Met9 and Asn16 in pseudoazurin (PDB accession code 1PAZ).
Effect on Functionality of Proteins.
Conserved bulges regularly affect protein functionality. The most basic function of bulges is to accommodate an extra residue added due to mutation etc., while maintaining the bonding pattern and thus the overall protein architecture. Other bulges are involved with protein binding sites. In specific cases like the Immunoglobulin family proteins, conserved bulges help dimerization of the Ig domains. They are also of functional importance in the proteins DHFR (Dihydrofolate Reductase) and SOD (Superoxide Dismutase), where loops containing bulges surround the active site.


Amylosucrase

In enzymology, an amylosucrase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are sucrose and (1,4-alpha-D-glucosyl)n, whereas its two products are D-fructose and (1,4-alpha-D-glucosyl)n+1.
This enzyme belongs to the family of glycosyltransferases, specifically the hexosyltransferases. The systematic name of this enzyme class is sucrose:1,4-alpha-D-glucan 4-alpha-D-glucosyltransferase. Other names in common use include sucrose-glucan glucosyltransferase, and sucrose-1,4-alpha-glucan glucosyltransferase. This enzyme participates in starch and sucrose metabolism.
Structural studies.
As of late 2007, 10 structures have been solved for this class of enzymes, with PDB accession codes , , , , , , , , , and .


Eugenol synthase

Eugenol synthase (, "LtCES1", "EGS1", "EGS2") is an enzyme with systematic name "eugenol:NADP+ oxidoreductase (coniferyl ester reducing)". This enzyme catalyses the following chemical reaction: eugenol + a carboxylate + NADP+ formula_1 a coniferyl ester + NADPH + H+
The enzyme acts in the reverse direction.


Moxaverine

Moxaverine has been used in therapy based on the direct vasodilatory effect of the drug, a phosphodiesterase inhibitor, and on its influence on the rheological properties of red blood cells.
Moxaverine hydrochloride (Kollateral forte®, Ursapharm. Saarbrücken, Germany) has been shown to increase ocular blood flow in patients with age-related macular degeneration, primary open angle glaucoma, and to increase choroidal and retrobulbar blood flow in elderly patients with eye diseases associated with hypo-perfusion. The ocular efficacy of moxaverine has been explored in the clinic.


Aerolysin

In molecular biology, aerolysin is a cytolytic pore-forming toxin exported by "Aeromonas hydrophila", a Gram-negative bacterium associated with diarrhoeal diseases and deep wound infections. The mature toxin binds to eukaryotic cells and aggregates to form holes (approximately 3 nm in diameter) leading to the destruction of the membrane permeability barrier and osmotic lysis. The structure of proaerolysin has been determined to 2.8A resolution and shows the protoxin to adopt a novel fold. Images of an aerolysin oligomer derived from electron microscopy have helped to construct a model of the protein in its heptameric conformation, and to outline a mechanism by which this assembly might insert into lipid bilayers to form ion channels.


5-carboxymethyl-2-hydroxymuconate Delta-isomerase

In enzymology, a 5-carboxymethyl-2-hydroxymuconate Delta-isomerase () is an enzyme that catalyzes the chemical reaction
Hence, this enzyme has one substrate, 5-carboxymethyl-2-hydroxymuconate, and one product, 5-carboxy-2-oxohept-3-enedioate.
This enzyme belongs to the family of isomerases, specifically those intramolecular oxidoreductases transposing C=C bonds. The systematic name of this enzyme class is 5-carboxymethyl-2-hydroxymuconate Delta2,Delta4-2-oxo,Delta3-isomerase. This enzyme participates in tyrosine metabolism and benzoate degradation via hydroxylation.
Structural studies.
As of late 2007, 4 structures have been solved for this class of enzymes, with PDB accession codes , , , and .


CRYAB

Alpha-crystallin B chain is a protein that in humans is encoded by the "CRYAB" gene. It is part of the small heat shock protein family and functions as molecular chaperone that primarily binds misfolded proteins to prevent protein aggregation, as well as inhibit apoptosis and contribute to intracellular architecture. Post-translational modifications decrease the ability to chaperone. Mutations in "CRYAB" cause different cardiomyopathies and skeletal myopathies. In addition, defects in this gene/protein have been associated with cancer and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.
Structure.
Crystallins are separated into two classes: taxon-specific, or enzyme, and ubiquitous. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. Since lens central fiber cells lose their nuclei during development, these crystallins are made and then retained throughout life, making them extremely stable proteins. Mammalian lens crystallins are divided into alpha, beta, and gamma families; beta and gamma crystallins are also considered as a superfamily. Alpha and beta families are further divided into acidic and basic groups.
Seven protein regions exist in crystallins: four homologous motifs, a connecting peptide, and N- and C-terminal extensions. Alpha crystallins are composed of two gene products: alpha-A and alpha-B, for acidic and basic, respectively. These heterogeneous aggregates consist of 30–40 subunits; the alpha-A and alpha-B subunits have a 3:1 ratio, respectively.
Function.
Alpha B chain crystallins (αBC) can be induced by heat shock, ischemia, and oxidation, and are members of the small heat shock protein (sHSP also known as the HSP20) family. They act as molecular chaperones although they do not renature proteins and release them in the fashion of a true chaperone; instead, they bind improperly folded proteins to prevent protein aggregation.
Furthermore, αBC may confer stress resistance to cells by inhibiting the processing of the pro-apoptotic protein caspase-3. Two additional functions of alpha crystallins are an autokinase activity and participation in the intracellular architecture. Alpha-A and alpha-B gene products are differentially expressed; alpha-A is preferentially restricted to the lens and alpha-B is expressed widely in many tissues and organs. Elevated expression of alpha-B crystallin occurs in many neurological diseases; a missense mutation cosegregated in a family with a desmin-related myopathy.
Clinical significance.
Although not yet clearly understood, defective chaperone activity is expected to trigger the accumulation of protein aggregates and underlie the development of α-crystallinopathy, or the failure of protein quality control, resulting in protein deposition diseases such as Alzheimer’s disease and Parkinson’s disease. Mutations in CRYAB could also cause restrictive cardiomyopathy. ER-anchored αBC can suppress aggregate formation mediated by the disease mutant. Thus, modulation of the micromilieu surrounding the ER membrane can serve as a potential target in developing pharmacological interventions for protein deposition disease.
Though expressed highly in eye lens and muscle tissues, αBC can also be found in several types of cancer, among which head and neck squamous cell carcinoma (HNSCC) and breast carcinomas, as well as in patients with tuberous sclerosis. αBC expression is associated with metastasis formation in HNSCC and in breast carcinomas and in other types of cancer, expression is often correlated with poor prognosis as well. The expression of αBC can be increased during various stresses, like heat shock, osmotic stress or exposure to heavy metals, which then may lead to prolonged survival of cells under these conditions.
Interactions.
CRYAB has been shown to interact with:


LRRC23

Leucine-rich repeat-containing protein 23 is a protein that in humans is encoded by the "LRRC23" gene.
Function.
The function of LRRC23 is unknown. It is a member of the leucine-rich repeat family of proteins, which are known for participating in protein-protein interactions. Experimental evidence suggests that LRRC23 interacts with the CD28 protein in a pathway related to the immune system and development of regulatory T cells that control spontaneous autoimmune disease.
Protein sequence.
LRRC23 spans 343 residues containing two varieties of internally repeating sequence. Detected and aligned by RADAR, the most abundant repeat is the leucine-rich repeat, repeating 9 times in bases 89-287. The other repeated sequence occurs twice in bases 3-36. The RADAR program output, below, summarizes the composition and location of all the repeats and aligns them for comparison against each other.
The human genome produces three known variants of LRRC23. The largest splice variant, variant 3, contains 8 exons. Variants 1 and 2 use alternative first exons, and variant 2 excludes the seventh exon, giving it a total of seven exons making up the mRNA.
Protein structure.
Although the actual structure of LRRC23 is unknown, comparison to the crystal structures of various similar proteins such as 2OMW A (e-value 1.00e-17) reveals a structure typical of other leucine-rich repeat proteins. Alternating beta sheets and coils create a spiraled peptide chain forming an arch shape with beta-sheets occupying the concave surface.
The aligned structure of 2OMW_A with LRRC23 spans acids 72-272 of the LRRC23 protein. Conserved asparagines are highlighted in yellow, showing the regularity of spacing and repeat structure within. This model was generated using Cn3D software provided by NCBI.


Oxisopred

Oxisopred is a synthetic glucocorticoid corticosteroid which was never marketed.


SLIT2

Slit homolog 2 protein is a protein that in humans is encoded by the "SLIT2" gene.
Interactions.
SLIT2 has been shown to interact with Glypican 1.


Uridine diphosphate galactose

Uridine diphosphate galactose (UDP-galactose) is an intermediate in the production of polysaccharides. It is important in nucleotide sugars metabolism, and is the substrate for the transferase B4GALT5.


NODAL

Nodal is a secretory protein that in humans is encoded by the "NODAL" gene which is located on chromosome 10q22.1. It belongs to the transforming growth factor beta (TGF-β) superfamily. Like many other members of this superfamily it is involved in cell differentiation in early embryogenesis, playing a key role in signal transfer from the node, in the anterior primitive streak, to lateral plate mesoderm (LPM).
Nodal signaling is important very early in development for mesoderm and endoderm formation and subsequent organization of left-right axial structures. In addition, Nodal seems to have important functions in neural patterning, stem cell maintenance and many other developmental processes, including left/right handedness.
Signaling.
Nodal can bind type I and type II Serine/Threonine kinase receptors, with Cripto-1 acting as its co-receptor. Signaling through SMAD 2/3 and subsequent translocation of SMAD 4 to the nucleus promotes the expression of genes involved in proliferation and differentiation. Nodal also further activates its own expression via a positive feedback loop. It is tightly regulated by inhibitors Lefty A, Lefty B, Cerberus, and Tomoregulin-1, which can interfere with Nodal receptor binding.
Species specific Nodal Ligands.
Nodal is a widely distributed cytokine. The presence of Nodal is not limited to vertebrates, it is also known to be conserved in other deuterostomes (cephalochordates, tunicates and echinoderms) and protostomes such as snails, but neither the nematode "C. elegans" (another protosome) nor the fruit fly "Drosophila" (an arthropod) have a copy of nodal. Although mouse and human only have one "nodal" gene, the zebrafish contain three "nodal" paralogs: "squint , cyclops "and" southpaw," and the frog five (xnr1,2,3,5 and 6). Even though the zebrafish Nodal homologs are very similar, they have specialized to perform different roles; for instance, Squint and Cyclops are important for mesoendoderm formation, whereas the Southpaw has a major role in asymmetric heart morphogenesis and visceral left-right asymmetry. Another example of protein speciation is the case of the frog where Xnr1 and Xnr2 regulate movements in gastrulation in contrast to Xnr5 and Xnr6 that are involved in mesoderm induction. In mouse, Nodal has been implicated in left-right asymmetry, neural pattering and mesoderm induction (see nodal signaling).
Functions.
Nodal signaling regulates mesoderm formation in a species-specific manner. Thus, in Xenopus, Xnr controls dorso-ventral mesoderm formation along the marginal zone. In zebrafish, Squint and Cyclops are responsible for animal-vegetal mesoderm formation. In chicken and mouse, Vg1 and Nodal respectively promote primitive streak formation in the epiblast. In chick development, Nodal is expressed in Koller's sickle. Studies have shown that a nodal knockout in mouse causes the absence of the primitive streak and failure in the formation of mesoderm, leading to developmental arrest just after gastrulation.
Compared to mesoderm specification, endoderm specification requires a higher expression of Nodal. Here, Nodal stimulates mixer homeoproteins, which can interact with SMADs in order to up-regulate endoderm specific genes and repress mesoderm specific genes.
Left-right (LR) asymmetry of visceral organs in vertebrates is also established through nodal signaling. Whereas Nodal is initially symmetrically expressed in the embryo, after gastrulation, Nodal becomes asymmetrically restricted to the left side of the organism. It is highly conserved among deuterostomes. An ortholog of Nodal was found in snails and was shown to be involved in left-right asymmetry as well in 2008.
In order to enable anterior neural tissue development, Nodal signaling needs to be repressed after inducing mesendoderm and LR symmetry.
Recent research on mouse and human embryonic stem cells (hESCs) indicates that Nodal seems to be involved in the maintenance of stem cell self-renewal and pluripotent potentials. Thus, overexpression of Nodal in hESCs lead to the repression of cell differentiation. On the contrary, inhibition of Nodal and Activin signaling enabled the differentiation of hESCs.


Aryl-aldehyde dehydrogenase

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


Beta-propeller

In structural biology, a beta-propeller (β-propeller) is a type of all-β protein architecture characterized by 4 to 8 highly symmetrical blade-shaped beta sheets arranged toroidally around a central axis. Together the beta-sheets form a funnel-like active site.
Structure.
Each beta-sheet typically has four anti-parallel β-strands arranged in the beta-zigzag motif. The strands are twisted so that the first and fourth strands are almost perpendicular to each other. There are five classes of beta-propellers, each arrangement being a highly symmetrical structure with 4–8 beta sheets, all of which generally form a central tunnel that yields pseudo-symmetric axes.
While, the protein's official active site for ligand-binding is formed at one end of the central tunnel by loops between individual beta-strands, protein-protein interactions can occur at multiple areas around the domain. Depending on the packing and tilt of the beta-sheets and beta-strands, the beta-propeller may have a central pocket in place of a tunnel.
The beta-propeller structure is stabilized mainly through hydrophobic interactions of the beta-sheets, while additional stability may come from hydrogen bonds formed between the beta-sheets of the C- and N-terminal ends. In effect this closes the circle which can occur even more strongly in 4-bladed proteins via a disulfide bond. The chaperones Hsp70 and CCT have been shown to sequentially bind nascent beta-propellers as they emerge from the ribosome. These chaperones prevent non-native inter-blade interactions from forming until the entire beta-propeller is synthesized. Many beta-propellers are dependent on CCT for expression. In at least one case, ions have been shown to increase stability by binding deep in the central tunnel of the beta-propeller.
Murzin proposed a geometric model to describe the structural principles of the beta propeller. According to this model the seven bladed propeller was the most favored arrangement in geometric terms.
Despite its highly conserved nature, beta-propellers are well known for their plasticity. Beyond having a variety of allowed beta-sheets per domain, it can also accommodate other domains into its beta-sheets. Additionally, there are proteins that have shown variance in the number of beta-strands per beta-sheet. Rather than having the typical four beta-strands in a sheet, beta-lactamase inhibitor protein-II only has three beta-strands per sheet while the phytase of "Bacillus subtilis" has five beta-strands per beta-sheet.
Function.
Due to its structure and plasticity, protein-protein interactions can form with the top, bottom, central channel, and side faces of the beta-propeller. The function of the propeller can vary based on the blade number. Four-bladed beta-propellers function mainly as transport proteins, and because of its structure, they have a conformation that is favorable for substrate binding. Unlike larger beta-propellers, four-bladed beta-propellers usually cannot perform catalysis themselves, but act instead to aid in catalysis by performing the aforementioned functions. Five-bladed propellers can act as transferases, hydrolases, and sugar binding proteins. Six- and seven-bladed propellers perform a much broader variety of functions in comparison to four- and five-bladed propellers. These functions can include acting as ligand-binding proteins, hydrolases, lyases, isomerases, signaling proteins, structural proteins, and oxidoreductases.
Variations in the larger (five- to eight-bladed) beta-propellers can allow for even more specific functions. This is the case with the C-terminal region of GyrA which expresses a positively charged surface ideal for binding DNA. Two alpha-helices coming out of the six-bladed beta-propeller of serum paraoxonase may provide a hydrophobic region ideal for anchoring membranes. DNA damage-binding protein 1 has three beta-propellers, in which the connection between two of the propellers is inserted into the third propeller potentially allowing for its unique function.
Examples.
Domains.
Repeat domains known to fold into a beta-propeller include WD40, YWTD, Kelch, YVTN, RIVW (PD40), and many more. Their sequences tend to group together, suggesting a close evolutionary link. They are also related to many beta-containing domains.


COQ3

COQ3, also known as ubiquinone biosynthesis O-methyltransferase, mitochondrial is an enzyme that in humans is encoded by the COQ3 gene.


Erythro-3-hydroxyaspartate ammonia-lyase

In enzymology, an erythro-3-hydroxyaspartate ammonia-lyase () is an enzyme that catalyzes the chemical reaction
Hence, this enzyme has one substrate, erythro-3-hydroxy-Ls-aspartate, and two products, oxaloacetate and NH3.
This enzyme belongs to the family of lyases, specifically ammonia lyases, which cleave carbon-nitrogen bonds. The systematic name of this enzyme class is erythro-3-hydroxy-Ls-aspartate ammonia-lyase (oxaloacetate-forming). Other names in common use include 3-hydroxyaspartate dehydratase, erythro-beta-hydroxyaspartate dehydratase, erythro-3-hydroxyaspartate dehydratase, erythro-3-hydroxy-Ls-aspartate hydro-lyase (deaminating), and erythro-3-hydroxy-Ls-aspartate ammonia-lyase. It employs one cofactor, pyridoxal phosphate.


Galectin-3

Galectin-3 is a protein that in humans is encoded by the "LGALS3" gene. Galectin-3 is a member of the lectin family, of which 14 mammalian galectins have been identified.
Galectin-3 is approximately 30 kDa and, like all galectins, contains a carbohydrate-recognition-binding domain (CRD) of about 130 amino acids that enable the specific binding of β-galactosides.
Galectin-3 (Gal-3) is also a member of the beta-galactoside-binding protein family that plays an important role in cell-cell adhesion, cell-matrix interactions, macrophage activation, angiogenesis, metastasis, apoptosis.
Galectin-3 is encoded by a single gene, LGALS3, located on chromosome 14, locus q21–q22. Galectin-3 is expressed in the nucleus, cytoplasm, mitochondrion, cell surface, and extracellular space.
Function.
Galectin-3 has an affinity for beta-galactosides and exhibits antimicrobial activity against bacteria and fungi.
This protein has been shown to be involved in the following biological processes: cell adhesion, cell activation and chemoattraction, cell growth and differentiation, cell cycle, and apoptosis. Given galectin-3's broad biological functionality, it has been demonstrated to be involved in cancer, inflammation and fibrosis, heart disease, and stroke. Studies have also shown that the expression of galectin-3 is implicated in a variety of processes associated with heart failure, including myofibroblast proliferation, fibrogenesis, tissue repair, inflammation, and ventricular remodeling.
Galectin-3 associates with the primary cilium and modulates renal cyst growth in congenital polycystic kidney disease.
The functional roles of galectins in cellular response to membrane damage are rapidly expanding. It has recently shown that Galectin-3 recruits ESCRTs to damaged lysosomes so that lysosomes can be repaired.
Clinical significance.
Fibrosis.
A correlation between galectin-3 expression levels and various types of fibrosis has been found. Galectin-3 is upregulated in cases of liver fibrosis, renal fibrosis, and idiopathic pulmonary fibrosis (IPF). In several studies with mice deficient in or lacking galectin-3, conditions that caused control mice to develop IPF, renal, or liver fibrosis either induced limited fibrosis or failed to induce fibrosis entirely. Companies have developed galectin modulators that block the binding of galectins to carbohydrate structures. The galectin-3 inhibitor, TD139 and GR-MD-02 have the potential to treat fibrosis.
Cardiovascular disease.
Elevated levels of galectin-3 have been found to be significantly associated with higher risk of death in both acute decompensated heart failure and chronic heart failure populations. In normal human, murine, and rat cells galectin-3 levels are low. However, as heart disease progresses, significant upregulation of galectin-3 occurs in the myocardium.
Galectin-3 also may be used as a biomarker to identify at risk individuals, and predict patient response to different drugs and therapies. For instance, galectin-3 levels could be used in early detection of failure-prone hearts and lead to intervention strategies including broad spectrum anti-inflammatory agents. One study concluded that individuals with systolic heart failure of ischaemic origin and elevated galectin-3 levels may benefit from statin treatment. Galectin-3 has also been associated as a factor promoting ventricular remodeling following mitral valve repair, and may identify patients requiring additional therapies to obtain beneficial reverse remodeling.
Cancer.
The wide variety of effects of galectin-3 on cancerous cells are due to the unique structure and various interaction properties of the molecule. Overexpression and changes in the localization of galectin-3 molecules affects the prognosis of the patient and targeting the actions of galectin-3 poses a promising therapeutic strategy for the development of effective therapeutic agents for cancer treatment.
Overexpression and changes in sub- and inter-cellular localization of galectin-3 are commonly seen in cancerous conditions. The many interaction and binding properties of galectin-3 influence various cell activities based on its location. Altered galectin-3 expression can affect cancer cell growth and differentiation, chemoattraction, apoptosis, immunosuppression, angiogenesis, adhesion, invasion and metastasis.
Galectin-3 overexpression promotes neoplastic transformation and the maintenance of transformed phenotypes as well as enhances the tumour cell's adhesion to the extracellular matrix and increase metastatic spreading. Galectin-3 can be either an inhibitory or a promoting apoptotic depending on its sub-cellular localization. In immune regulation, galectin-3 can regulate immune cell activities and helps contribute to the tumour cell's evasion of the immune system. Galectin-3 also helps promote angiogenesis.
The roles of galectins and galectin-3, in particular, in cancer have been heavily investigated. Of note, galectin-3 has been suggested to play important roles in cancer metastasis.
Clinical applications.
As an indicator of Cardiovascular Risk.
Chronic heart failure has been found to be indicated by a galectin-3 tests, using the ARCHITECT immunochemistry platform developed by BG Medicine and marketed by Abbott, helping to determine which patients are most at risk for the disease. This test is also offered on the VIDAS platform marketed by bioMérieux. Pecta-Sol C binds to galectin-3 binding sites on the surfaces of cells as a preventative measure created by Isaac Eliaz in conjunction with EcoNugenics.
Galectin-3 is upregulated in patients with idiopathic pulmonary fibrosis. The cells that receive galectin-3 stimulation (fibroblasts, epithelial cells, and myofibroblasts) upregulated the formation of fibrosis and collagen formation. Fibrosis is necessary in many aspects of intrabody regeneration. The myocardial lining constantly undergoes necessary fibrosis, and the inhibition of galectin-3 interferes with myocardial fibrogenesis. A study concluded that pharmacological inhibition of galectin-3 attenuates cardiac fibrosis, LV dysfunction, and subsequent heart failure development.
Galecto Biotech in Sweden is focused on developing drugs targeting galectin-3 to treat fibrosis, specifically idiopathic pulmonary fibrosis. Galectin Therapeutics in the United States is also targeting galectins for clinical applications. Preclinical studies demonstrate that inhibition of galectin-3 significantly reduces portal hypertension and fibrosis. Galectin Therapeutics galectin-3 inhibitor GR-MD-02 (belapectin) is currently in human clinical trials for nonalcoholic steatohepatitis (NASH) and for increasing the effectiveness and reducing side effects of cancer immunotherapy.
Biomarkers.
Galectin-3 is increasingly being used as a diagnostic marker for different cancers. It can be screened for and used as a prognostic factor to predict the progression of the cancer. Galectin-3 has varying effects in different types of cancer. One approach to cancers with high galectin-3 expression is to inhibit galectin-3 to enhance treatment response.
Interactions.
LGALS3 has been shown to interact with LGALS3BP.
In melanocytic cells LGALS3 gene expression may be regulated by MITF.


Balanol

Balanol is a fungal metabolite produced by the fungus "Verticillium balanoides". It is a potent inhibitor of the serine/threonine kinases protein kinase A (PKA) and protein kinase C (PKC), binding in a similar manner with that of ATP. Balanol was discovered in 1993 in the search for novel inhibitors of PKC, a member of a family of serine/threonine kinases whose overactivation is associated with numerous human diseases of signal transduction including cancer. However, much of the research on balanol focuses on how chemical modifications of the molecular structure affect binding to PKA. Indeed, balanol, its chemically altered analogs, and their interactions with PKA in particular are used to illuminate the roles of selectivity and protein flexibility in the inhibition of kinases. For instance, the X-ray crystal structure of balanol in complex with PKA was used in order to confer selectivity and to improve pharmacological efficacy of inhibitors of the "H. sapiens" Akt (PKB), another serine/threonine protein kinase implicated in the proper functioning of many cellular processes.
Structure.
The chemical structure was initially characterized through a combination of IR spectroscopy, hydrogen-1 NMR, carbon-13 NMR, and 2D NMR spectra data, and the crystal structure of balanol in complex with PKA was solved in 1999. The balanol molecule consists of three regions: a benzophenone, hexahydroazepane, and 4-hydroxy benzoyl moiety. The benzophenone and hexahydroazepane moieties are connected via an ester linkage, and the azepane and benzoyl moieties are connected through an amide linkage. Furthermore, balanol is sometimes referred to as ophiocordin, an antifungal agent produced by the fungus "Cordyceps ophioglossoides" whose structure is regioisometric to that of balanol; that is, in ophiocordin, the benzophenone is linked to the hexahydroazepane instead via an amide; the 4-hydroxy benzoyl group and hexahydroazepane are connected with an ester linkage.
Balanol is a congener of ATP, with distinct regions of its molecular structure able to form bonds like the adenine ring, ribose, and phosphate groups of the ATP molecule. Specifically, balanol's 4-hydroxybenzamide moiety including the amide linker corresponds to the adenine of ATP, the hexahydroazepane moiety to the ribose region, and the benzophenone rings to ATP's triphosphates.
Numerous balanol congeners have been synthesized in order to study the effect of chemical modifications on kinase binding and specificity. For example, modifications of the benzophenone rings, analogs of the phosphate groups of ATP, produce unusually potent and specific protein kinase inhibitors. Additionally, many of these balanol congeners show substantial specificity toward PKA over PKC. Elimination of the hydroxyl group from the benzophenone ring (producing 10"-deoxybalanol), for instance, elicits selectivity two orders of magnitude greater for PKA over PKC. Potent inhibitory activity was also shown to be dependent on the carboxylic acid of the benzophenone ring and the presence of a five- or seven-membered azepane ring.
Balanol's flexible structure also plays an important role in its selectivity. Specifically, balanol's distal benzophenone ring is able to rotate. In fact, in complex with PKA, balanol's distal benzophenone ring was observed to be nearly orthogonal with the neighboring ring. This flexibility could allow balanol to adapt to numerous protein microenvironments in order to exert its inhibitory properties on various protein kinases. Balanol's selectivity for some kinases and not others, in turn, could represent the varying degrees of flexibilities allowed by these kinases' catalytic ATP-binding sites.
Biological activities.
Balanol is one of the most potent, naturally occurring inhibitors of protein kinases PKC and PKA. Balanol was originally discovered to inhibit PKC and many of its isoforms in humans (α, β-Ι, β-ΙΙ, γ, δ, ε, η), with an inhibition profile similar to that of staurosporine.
Balanol prevents functioning by binding competitively to the catalytic domain of PKC and PKA with an affinity (Ki ≥ 4 nM) three orders of magnitude greater than for ATP. Without ATP bound, these kinases are unable to catalyze the transfer of the γ-phosphate from ATP to the kinase's target substrate, and thus function is hindered.
Binding.
Bound balanol extends 17.2 Å from the hydroxyl oxygen atom of its 4-hydroxybenzamide to the most distal carboxyl oxygen atom of its benzophenone moiety, fitting between the large and small catalytic lobes of PKA and extending from the inner edge to the outer mouth of the active-site ATP-binding cleft of the enzyme. The cleft's glycine-rich loop and small lobe allow for tight, induced-fit binding.
Each subsite of the ATP-binding pocket in PKA is occupied by a substituent of the balanol molecule as observed in studies of recombinant mouse catalytic subunit of PKA. The adenine subsite of PKA has hydrophobic components and has the potential to donate and accept electrons to make hydrogen bonds with one or two planar cyclic rings. Specifically, the backbone nitrogen of Val123 and the carbonyl oxygen atom of Glu121 can form hydrogen bonds with balanol's single hydroxyl group of the 4-hydroxyl benzoyl moiety. In the ATP molecule, the Val123 amide hydrogen atom accepts electrons from ATP's purine ring N1 atom while the Glu121 backbone carbonyl oxygen atom donates electrons to the ATP purine ring N6 atom. Mimetics of ATP like balanol can be anchored within the hydrophobic adenine-binding pocket because their planar substituents can make favorable nonpolar interactions. The ribose subsite is occupied by balanol's axepane ring. Specifically, the N1 atom of the azepane ring hydrogen bonds with the backbone carbonyl oxygen atom of Glu170 of the catalytic loop. Atoms within the azepane ring also can make favorable nonpolar contacts with residues Gly50, Flu127, and Glu170. While other interactions also occur, most of the polar and nonpolar interactions involve the benzophenone substituent of balanol, which interacts with residues comprising the phosphate-binding subsite. For instance, balanol's benzophenone ring interacts with numerous highly conserved residues in PKA such as Gly52, Phe54, Asp184 among others in addition to various nonconserved residues such as Leu74 and Gln84. Most of the conserved residues in PKA interact with ATP whereas interactions of ATP with the nonconserved residues do not occur.
Six ordered water molecules also play critical roles in balanol binding to PKA. Several PKA residues such as Leu49 and Tyr330 hydrogen bond with conserved water molecules. These water molecules also mediate interactions between balanol and the residues of the catalytic cleft of PKA; for example, two water molecules form a bridge to allow balanol's N1’ atom to interact with the hydroxyl group of Tyr330.
However, the tight interaction of balanol with the ATP-binding site that leads to balanol's potency as an inhibitor is not due to hydrogen bonding but rather because of the predominant nonpolar interactions the molecule makes. For instance, balanol's benzophenone rings are positioned beside the glycine-rich loop and further from the more polar catalytic loop. Compared to ATP's triphosphates, accommodating balanol's benzophenone rings induces the rearrangement of catalytic side-chains Phe54 and Ser53, enabling favorable polar and nonpolar interactions and likely contributing to balanol's potent inhibitory effect on these kinases.
Action against other protein kinases.
As balanol acts specifically at the ATP-binding site in the catalytic core of PKA and PKC, it was initially hypothesized that balanol could inhibit all serine/threonine kinases sharing a conserved ATP-binding site. However, balanol does not inhibit all serine/threonine kinases uniformly. Affinity to balanol varies greatly (Ki = 1.6–742 nM), with several members of the serine/threonine protein kinase family not being affected at all, even though affinity of these kinases to ATP varies little (13–60 μM). Balanol exhibits the most potent inhibitory effect (Ki = 1.6–6.4  nM) on cGMP-dependent protein kinase (PKG), PKA, and PKC, including isoforms. It exerts much less of an effect (Ki = 30 – 742 nM), if any, on Ca2+-calmodulin-regulated kinases, mitogen-activating protein kinase (MAPK/Erk1), and certain cyclin-dependent kinases. Furthermore, balanol does not inhibit two tyrosine protein kinases, the SC kinase, nor the epidermal growth factor receptor kinase.


NTP binding site

An NTP binding site is a type of binding site found in nucleoside monophosphate (NMP) kinases, N can be adenosine or guanosine. A P-loop is one of the structural motifs common for nucleoside triphosphate (NTP) binding sites, it interacts with the bound nucleotide's phosphoryl groups. For the binding site to be able to bind a nucleotide, the nucleotide must be complex bound to Mg2+ or Mn2+. Nucleotide binding will cause conformational changes in the protein because the P-loop will bend.
NTP binding sites play a role in poliovirus RNA replication.


Keratin 6A

Keratin 6A is one of the 27 different type II keratins expressed in humans. Keratin 6A was the first type II keratin sequence determined. Analysis of the sequence of this keratin together with that of the first type I keratin led to the discovery of the four helical domains in the central rod of keratins. In humans Keratin 6A is encoded by the "KRT6A" gene.
Keratins.
Keratins are the intermediate filament proteins that form a dense meshwork of filaments throughout the cytoplasm of epithelial cells. Keratins form heteropolymers consisting of a type I and a type II keratin. Keratins are generally expressed in particular pairs of type I and type II keratin proteins in a tissue-specific and cellular differentiation-specific manner.
The keratin proteins of epithelial tissues are commonly known as "keratins" or are sometimes referred to as "epithelial keratins" or "cytokeratins". The specialized keratins of hair and nail are known as "hard keratins" or "trichocyte keratins". Trichocytes are the specialized epithelial cells from which hair and nail are composed. Trichocyte keratins are similar in their gene and protein structure to keratins except that they are especially rich in the sulfur-containing amino acid cysteine, which facilitates chemical cross-linking of the assembled hard keratins to form a more structurally resilient material.
Both epithelial keratins and hard keratins can be further subdivided into type I (acidic) keratins and type II (neutral-basic) keratins. The genes for the type I keratins are located in a gene cluster on human chromosome 17q, whereas the genes for type II keratins are located in a cluster on human chromosome 12q (the exception being K18, a type I keratin located in the type II gene cluster).
Keratin 6A.
Keratin 6A (protein name K6A; gene name "KRT6A"), is a type II cytokeratin, one of a number of isoforms of keratin 6 encoded by separate genes located within the type II keratin gene cluster on human chromosome 12q. It is found with keratin 16 and/or keratin 17 in the palm and sole epidermis, the epithelial cells of the nail bed, the filiform papillae of the tongue, the epithelial lining of oral mucosa and esophagus, as well as the hair follicles. This keratin 6 isoform is thought to be the most abundant of the K6 isoforms.
The "KRT6A" gene consists of 9 exons separated by 8 introns and is located in the type II keratin gene cluster on human "chromosome" 12q. Keratin 6B and keratin 6C are encoded by the neighbouring genes, which are identical in intron-exon organization to "KRT6A" and are more than 99% identical in their DNA coding sequences.
Keratin 6A has been shown to have antimicrobial properties, and is the main antimicrobial factor in the eye.
Genetic disorders.
Mutations in the genes expressing this protein is associated with the PC-K6A subtype of pachyonychia congenita, an inherited disorder of the epithelial tissues in which keratin 6A is expressed, particularly leading to structural abnormalities of the nails, the epidermis of the palms and soles, and oral epithelia.
Immunohistochemistry.
The expression of keratin 6A is often tested together with keratin 5, using CK5/6 antibodies, which target both keratin forms.


Volasertib

Volasertib (also known as BI 6727) is an experimental small molecule inhibitor of the PLK1 (polo-like kinase 1) protein being developed by Boehringer Ingelheim for use as an anti-cancer agent. Volasertib is the second in a novel class of drugs called dihydropteridinone derivatives.
Volasertib was awarded breakthrough drug status in September 2013 and orphan drug status for acute myeloid leukemia in April 2014.
Mechanism of action.
Volasertib is a novel small-molecule targeted therapy that blocks cell division by competitively binding to the ATP-binding pocket of the PLK1 protein. PLK1 proteins are found in the nuclei of all dividing cells and control multiple stages of the cell cycle and cell division.
 The levels of the PLK1 protein are tightly controlled and are raised in normal cells that are dividing. Raised levels of the PLK1 protein are also found in many cancers including; breast, non-small cell lung, colorectal, prostate, pancreatic, papillary thyroid, ovarian, head and neck and Non-Hodgkin’s Lymphoma.
 Raised levels of PLK1 increase the probability of improper segregation of chromosomes which is a critical stage in the development of many cancers. Raised levels of PLK1 have been associated with a poorer prognosis and overall survival in some cancers
 In addition to its role in cell division, there is evidence that PLK1 also interacts with components of other pathways involved in cancer development including the K-Ras oncogene and the retinoblastoma and p53 tumour suppressors These observations have led to PLK1 being recognised as an important target in the treatment of cancer.
Volasertib can be taken either orally or via intravenous infusion, once circulating in the blood stream it is distributed throughout the body, crosses the cell membrane and enters the nucleus of cells where it binds to its target; PLK1. Volasertib inhibits PLK1 preventing its roles in the cell-cycle and cell division which leads to cell arrest and programmed cell death. Volasertib binds to and inhibits PLK1 at nanomolar doses however, it has also been shown to inhibit other PLK family members; PLK2 and PLK3 at higher; micromolar doses. The roles of PLK2 and PLK3 are less well understood; however they are known to be active during the cell cycle and cell division.
Volasertib inhibits PLK1 in both cancer and normal cells; however it only causes irreversible inhibition and cell death in cancer cells, because inhibition of PLK1 in cancer cells arrests the cell cycle at a different point to normal, non-cancer cells. In cancer cells PLK1 inhibition results in G2/M cell cycle arrest followed by programmed cell death, however, in normal cells inhibition of PLK1 only causes temporary, reversible G1 and G2 arrest without programmed cell death. This specificity for cancer cells improves the efficacy of the drug and minimizes the drug related toxicity.
Adverse effects.
One of the undesirable effects of small-molecule drugs is that they can lack specificity for their target; hence bind to similar targets in other unrelated proteins, which can result in undesirable drug-related side effects. However, pre-clinical studies have shown volasertib binds in a highly selective manner to the kinase domain of the PLK family, without binding to other proteins with a kinase domain. Clinical studies have shown that at the maximum tolerated dose, side effects of volasertib include; anaemia (22%), thrombocytopenia, neutropenia and febrile neutropenia. Common side effects as seen with other antimitotic agents such as vinca alkaloids and taxanes which include neuropathy, have not been observed with volasertib.
Studies.
Preclinical studies on volasertib have demonstrated that it is highly effective at binding to and blocking PLK1 function and causing programmed cell death in colon and non-small cell lung cancer cells both "in vitro" and "in vivo". Volasertib can also cause cell death in cancer cells that have are no longer sensitive to existing anti-mitotic drugs such as vinca alkaloids and taxanes. This suggests that volasertib may be effective when used as a second line treatment in patients who have developed resistance to vinca alkaloid and taxane chemotherapeutics.
A first in man trial of volasertib in 65 patients with solid cancers reported that the drug is safe to administer to patients and is stable in the bloodstream. This study also reported favourable anti-cancer activity of the drug; three patients achieved a partial response, 48% of patients achieved stable disease and 6 patients achieved progression free survival of greater than 6 months. A further phase 1 trial of volasertib in combination with cytarabine in patients with relapsed / refractory acute myeloid leukemia reported that 5 of 28 patients underwent a complete response, 2 achieved a partial response and a further 6 patients no worsening of their disease.
Clinical trials.
Volasertib is currently undergoing investigation in phase I and II trials and has yet to be licensed by the FDA. Volasertib may be effective in several malignancies evidenced by the fact that its target PLK1 is overexpressed in up to 80% of malignancies, where it has been associated with a poorer treatment outcome and reduced overall survival. Further phase 1 and 2 trials are active, investigating the effects of Volasertib both as a single agent and in combination with other agents in solid tumors and hematological malignancies including; ovarian cancer, urothelial cancer and acute myeloid leukaemia, lymphomas, myelodysplastic syndromes, and non-small call lung cancer.
 it is in one phase III trial (for AML in over 65s), due to complete in February 2017.


Carboxypeptidase P

The term carboxypeptidase P may refer to:


Wheat germ agglutinin

Wheat germ agglutinin (WGA) is a lectin that protects wheat ("Triticum") from insects, yeast and bacteria. An agglutinin protein, it binds to N-acetyl-D-glucosamine and Sialic acid. Succinylated WGA is selective for β-GlcNAc, making it a useful tool for detecting "O"-GlcNAc. N-acetyl-D-glucosamine in the natural environment of wheat is found in the chitin of insects, and the cell membrane of yeast & bacteria. WGA is found abundantly—but not exclusively—in the wheat kernel, where it got the 'germ' name from. In mammals the N-acetyl-D-glucosamine that WGA binds to is found in cartilage and cornea among other places. In those animals sialic acid is found in mucous membranes, e.g. the lining of the inner nose, and digestive tract.
In solution, WGA exists mostly as a heterodimer of 38,000 daltons. It is cationic at physiological pH. It contains a Carbohydrate-binding module called CBM18.
Use in molecular biology.
WGA is also widely used in biological research. Since WGA binds to glycoconjugates in can be used to label cell membranes and fibrotic scar tissue for imaging and analysis.


NADH-coenzyme Q reductase

NADH-coenzyme Q reductase may refer to:


Multidrug and toxin extrusion protein 2

Multidrug and toxin extrusion protein 2 is a protein which in humans is encoded by the "SLC47A2" gene.
Function.
This gene encodes a protein belonging to a family of transporters involved in excretion of toxic electrolytes, both endogenous and exogenous, through urine and bile. This transporter family shares homology with the bacterial MATE (multi antimicrobial extrusion protein or multidrug and toxic compound extrusion) protein family responsible for drug resistance. This gene is one of two members of the MATE transporter family located near each other on chromosome 17. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene.
Discovery.
The multidrug efflux transporter NorM from "V. parahaemolyticus" which mediates resistance to multiple antimicrobial agents (norfloxacin, kanamycin, ethidium bromide etc.) and its homologue from "E. coli" were identified in 1998. NorM seems to function as drug/sodium antiporter which is the first example of Na+-coupled multidrug efflux transporter discovered. NorM is a prototype of a new transporter family and Brown "et al". named it the multidrug and toxic compound extrusion family. The X-ray structure of the NorM was determined to 3.65 Å, revealing an outward-facing conformation with two portals open to the outer leaflet of the membrane and a unique topology of the predicted 12 transmembrane helices distinct from any other known multidrug resistance transporter.


Medium-chain acyl-coenzyme A dehydrogenase deficiency

Medium-chain acyl-CoA dehydrogenase deficiency (MCAD deficiency or MCADD), is a disorder of fatty acid oxidation that impairs the body's ability to break down medium-chain fatty acids into acetyl-CoA. The disorder is characterized by hypoglycemia and sudden death without timely intervention, most often brought on by periods of fasting or vomiting.
Prior to expanded newborn screening, MCADD was an underdiagnosed cause of sudden death in infants. Individuals who have been identified prior to the onset of symptoms have an excellent prognosis.
MCADD is most prevalent in individuals of Northern European Caucasian descent, with an incidence of 1:4000 to 1:17,000 depending on the population. Treatment of MCADD is mainly preventive, by avoiding fasting and other situations where the body relies on fatty acid oxidation to supply energy.
Signs and symptoms.
MCADD presents in early childhood with hypoketotic hypoglycemia and liver dysfunction, often preceded by extended periods of fasting or an infection with vomiting. Infants who are exclusively breast-fed may present in this manner shortly after birth, due to poor feeding. In some individuals the first manifestation of MCADD may be sudden death following a minor illness. A number of individuals with MCADD may remain completely asymptomatic, provided they never encounter a situation that sufficiently stresses their metabolism. With the advent of expanded newborn screening, some mothers have been identified with MCADD after their infants had positive newborn screens for low carnitine levels.
The enzyme "MCAD" is responsible for the dehydrogenation step of fatty acids with chain lengths between 6 and 12 carbons as they undergo beta-oxidation in the mitochondria. Fatty acid beta-oxidation provides energy after the body has used up its stores of glucose and glycogen. This oxidation typically occurs during periods of extended fasting or illness when caloric intake is reduced, and energy needs are increased.
Genetics.
MCADD is inherited in an autosomal recessive manner, meaning an affected individual must inherit a mutated allele from both of their parents. "ACADM" is the gene involved, located at 1p31, with 12 exons and coding for a protein of 421 amino acids. There is a common mutation among Northern European Caucasians, 985A>G, which results in a lysine being replaced by a glutamic acid at position 304 of the protein. Other mutations have been identified more commonly since newborn screening has expanded the mutation spectrum. The 985A>G common mutation is present in the homozygous state in 80% of Caucasian individuals who presented clinically with MCADD and in 60% of the population identified by screening.
An individual's genotype does not correlate well with their clinical phenotype for MCADD. The clinical presentation of an individual with MCADD depends not only on the presence of the mutations in the "ACADM" gene, but also on the presence of environmental or physiological stressors that require the body to depend on fatty acid oxidation for energy. Some mutations, identified through newborn screening programs and associated with higher residual enzyme activity have not been seen in individuals with clinical symptoms of MCADD. Despite this, treatment with fasting avoidance remains the norm for all those diagnosed with MCADD.
Diagnosis.
Clinically, MCADD or another fatty acid oxidation disorder is suspected in individuals who present with lethargy, seizures, coma and hypoketotic hypoglycemia, particularly if triggered by a minor illness. MCADD can also present with acute liver disease and hepatomegaly, which can lead to a misdiagnosis of Reye syndrome. In some individuals, the only manifestation of MCADD is sudden, unexplained death often preceded by a minor illness that would not usually be fatal.
In areas with expanded newborn screening using tandem mass spectrometry (MS/MS), MCADD is usually detected shortly after birth, by the analysis of blood spots collected on filter paper. Acylcarnitine profiles with MS/MS will show a very characteristic pattern of elevated hexanoylcarnitine (C6), octanoylcarnitine (C8), decanoylcarnitine (C10) or decenoylcarnitine (C10:1), with C8 being greater than C6 and C10. Secondary carnitine deficiency is sometimes seen with MCADD, and in these cases, acylcarnitine profiles may not be informative. Urine organic acid analysis by gas chromatography-mass spectrometry (GC-MS) will show a pattern of dicarboxylic aciduria with low levels of ketones. Traces of acylglycine species may also be detected. Asymptomatic individuals may have normal biochemical lab results. For these individuals, targeted analysis of acylglycine species by GC-MS, specifically hexanoylglycine and suberylglycine can be diagnostic. After biochemical suspicion of MCADD, molecular genetic analysis of "ACADM" can be used to confirm the diagnosis. The analysis of MCAD activity in cultured fibroblasts can also be used for diagnosis.
In cases of sudden death where the preceding illness would not usually have been fatal, MCADD is often suspected. The autopsy will often show fatty deposits in the liver. In cases where MCADD is suspected, acylcarnitine analysis of bile and blood can be undertaken postmortem for diagnosis. Where samples are not available, residual blood from newborn screening may be helpful. Biochemical testing of asymptomatic siblings and parents may also be informative. MCADD and other fatty acid oxidation disorders have been recognized in recent years as undiagnosed causes of sudden infant death syndrome.
Treatment.
As with most other fatty acid oxidation disorders, individuals with MCADD need to avoid fasting for prolonged periods of time. During illnesses, they require careful management to stave off metabolic decompensation, which can result in death. Supplementation of simple carbohydrates or glucose during illness is key to prevent catabolism. The duration of fasting for individuals with MCADD varies with age, infants typically require frequent feedings or a slow release source of carbohydrates, such as uncooked cornstarch. Illnesses and other stresses can significantly reduce the fasting tolerance of affected individuals.
Individuals with MCADD should have an "emergency letter" that allows medical staff who are unfamiliar with the patient and the condition to administer correct treatment properly in the event of acute decompensation. This letter should outline the steps needed to intervene in a crisis and have contact information for specialists familiar with the individual's care.
Misdiagnosis issues
Prognosis.
A 1994 study of the entire population of New South Wales (Australia) found 20 patients. Of these, 5 (25%) had died at or before 30 months of age. Of the survivors, 1 (5%) was severely disabled and the remainder had either suffered mild disability or were making normal progress in school. A 2006 Dutch study followed 155 cases and found that 27 individuals (17%) had died at an early age. Of the survivors, 24 (19%) suffered from some degree of disability, of which most were mild. All the 18 patients diagnosed neonatally were alive at the time of the follow-up.
Incidence.
MCADD is most prevalent in individuals of Northern European Caucasian descent. The incidence in Northern Germany is 1:4000, currently the highest in the world. Northern Europe is also the origin of the common mutation in MCADD. For populations without origins in Northern Europe, the incidence is significantly lower, 1:51,000 in Japan and 1:700,000 in Taiwan. The common mutation has not been identified in MCADD cases identified in Asian populations.


Monocarboxylate transporter 9

Monocarboxylate transporter 9 (MCT9, solute carrier family 16, member 9, SLC16A9) is a protein that in humans is encoded by the "SLC16A9" gene.
Clinical relevance.
Mutations in the SLC16A9 gene have been associated with carnitine levels in blood.


Agmatine deiminase

In enzymology, an agmatine deiminase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are agmatine and H2O, whereas its two products are N-carbamoylputrescine and NH3.
This enzyme belongs to the family of hydrolases, those acting on carbon-nitrogen bonds other than peptide bonds, specifically in linear amidines. The systematic name of this enzyme class is agmatine iminohydrolase. This enzyme is also called agmatine amidinohydrolase. This enzyme participates in urea cycle and metabolism of amino groups.
Structural studies.
As of late 2007, 4 structures have been solved for this class of enzymes, with PDB accession codes , , , and .


Cyclin-dependent kinase inhibitor protein

A cyclin-dependent kinase inhibitor protein is a protein which inhibits the enzyme cyclin-dependent kinase (CDK). Several function as tumor suppressor proteins. Cell cycle progression is delayed or stopped by cyclin-dependent kinase inhibitors, abbreviated CDIs, CKIs or CDKIs. CDIs are involved in cell cycle arrest at the G1 phase.
Seven cyclin-dependent kinase inhibitor proteins have thus far been identified. They are named by the small letter "p" followed by their molecular weight in kilodaltons. They are p15, p16, p18, p19, p21, p27, and p57.