3-hydroxybutyryl-CoA dehydratase

In enzymology, a 3-hydroxybutyryl-CoA dehydratase () is an enzyme that catalyzes the chemical reaction
Hence, this enzyme has one substrate, (3R)-3-hydroxybutanoyl-CoA, and two products, crotonoyl-CoA and H2O.
This enzyme belongs to the family of lyases, specifically the hydro-lyases, which cleave carbon-oxygen bonds. The systematic name of this enzyme class is (3R)-3-hydroxybutanoyl-CoA hydro-lyase (crotonoyl-CoA-forming). Other names in common use include D-3-hydroxybutyryl coenzyme A dehydratase, D-3-hydroxybutyryl-CoA dehydratase, enoyl coenzyme A hydrase (D), and (3R)-3-hydroxybutanoyl-CoA hydro-lyase. This enzyme participates in butanoate metabolism.


DNA polymerase (disambiguation)

DNA polymerase may refer to:


Ankyrin repeat

The ankyrin repeat is a 33-residue motif in proteins consisting of two alpha helices separated by loops, first discovered in signaling proteins in yeast Cdc10 and "Drosophila" Notch. Domains consisting of ankyrin tandem repeats mediate protein–protein interactions and are among the most common structural motifs in known proteins. They appear in bacterial, archaeal, and eukaryotic proteins, but are far more common in eukaryotes. Ankyrin repeat proteins, though absent in most viruses, are common among poxviruses. Most proteins that contain the motif have four to six repeats, although its namesake ankyrin contains 24, and the largest known number of repeats is 34, predicted in a protein expressed by "Giardia lamblia".
Ankyrin repeats typically fold together to form a single, linear solenoid structure called ankyrin repeat domains. These domains are one of the most common protein–protein interaction platforms in nature. They occur in a large number of functionally diverse proteins, mainly from eukaryotes. The few known examples from prokaryotes and viruses may be the result of horizontal gene transfers. The repeat has been found in proteins of diverse function such as transcriptional initiators, cell cycle regulators, cytoskeletal, ion transporters, and signal transducers. The ankyrin fold appears to be defined by its structure rather than its function, since there is no specific sequence or structure that is universally recognised by it.
Considering the atomic structures of individual ankyrin repeats, the loop is often a type 1 beta bulge loop, while both alpha-helices commonly have a Schellman loop at their N-terminus.
Role in protein folding.
The ankyrin-repeat sequence motif has been studied using multiple sequence alignment to determine conserved amino acid residues critical for folding and stability. The residues on the wide lateral surface of ankyrin repeat structures are variable, often hydrophobic, and involved mainly in mediating protein–protein interactions. An artificial protein design based on a consensus sequence derived from sequence alignment has been synthesized and found to fold stably, representing the first designed protein with multiple repeats. More extensive design strategies have used combinatorial sequences to "evolve" ankyrin-repeats that recognize particular protein targets, a technique that has been presented as an alternative to antibody design for applications requiring high-affinity binding. A structure-based study involving a range of ankyrin proteins of known structures, shows that consensus-based ankyrin proteins are very stable since they maximize the energetic gap between the folding and unfolding structures, encoding a densely connected network of favourable interactions among conserved sequence motifs, like the TPLX motif. The same study shows that insertions in the canonical framework of ankyrin repeats are enriched in conflictive interactions, that are related to function. The same applies to interactions surrounding deletion hotspots. These might be related to complex folding/unfolding transitions that are important to the partner recognition and interaction.
Ankyrin-repeat proteins present an unusual problem in the study of protein folding, which has largely focused on globular proteins that form well-defined tertiary structure stabilized by long-range, nonlocal residue-residue contacts. Ankyrin repeats, by contrast, contain very few such contacts (that is, they have a low contact order). Most studies have found that ankyrin repeats fold in a two-state folding mechanism, suggesting a high degree of folding cooperativity despite the local inter-residue contacts and the evident need for successful folding with varying numbers of repeats. Some evidence, based on synthesis of truncated versions of natural repeat proteins, and on the examination of phi values, suggests that the C-terminus forms the folding nucleation site.
Clinical significance.
Ankyrin-repeat proteins have been associated with a number of human diseases. These proteins include the cell cycle inhibitor p16, which is associated with cancer, and the Notch protein (a key component of cell signalling pathways) which can cause the neurological disorder CADASIL when the repeat domain is disrupted by mutations.
A specialized family of ankyrin proteins known as muscle ankyrin repeat proteins (MARPs) are involved with the repair and regeneration of muscle tissue following damage due to injury and stress.
A natural variation between glutamine and lysine at position 703 in the 11th ankyrin repeat of ANKK1, known as the TaqI A1 allele, has been credited with encouraging addictive behaviours such as obesity, alcoholism, nicotine dependency and the Eros love style while discouraging juvenile delinquency and neuroticism-anxiety. The variation may affect the specificity of protein interactions made by the ANKK1 protein kinase through this repeat.
Human proteins containing this repeat.
ABTB1; ABTB2; ACBD6; ACTBL1; ANK1; ANK2; ANK3; ANKAR;
ANKDD1A; ANKEF1; ANKFY1; ANKHD1; ANKIB1; ANKK1; ANKMY1; ANKMY2; ANKRA2;
ANKRD1; ANKRD10; ANKRD11; ANKRD12; ANKRD13; ANKRD13A; ANKRD13B; ANKRD13C;
ANKRD13D; ANKRD15; ANKRD16; ANKRD17; ANKRD18A; ANKRD18B; ANKRD19; ANKRD2;
ANKRD20A1; ANKRD20A2; ANKRD20A3; ANKRD20A4; ANKRD21; ANKRD22; ANKRD23; ANKRD24; ANKRD25;
ANKRD26; ANKRD27; ANKRD28; ANKRD30A; ANKRD30B; ANKRD30BL; ANKRD32; ANKRD33; ANKRD35;
ANKRD36; ANKRD36B; ANKRD37; ANKRD38; ANKRD39; ANKRD40; ANKRD41; ANKRD42;
ANKRD43; ANKRD44; ANKRD45; ANKRD46; ANKRD47; ; ANKRD50;
ANKRD52; ANKRD53; ANKRD54; ANKRD55; ANKRD56; ANKRD57; ANKRD58; ANKRD60;
ANKRD6; ANKRD7; ANKRD9; ANKS1A; ANKS3; ANKS4B; ANKS6; ANKZF1; ASB1;
ASB10; ASB11; ASB12; ASB13; ASB14; ASB15; ASB16; ASB2;
ASB3; ASB4; ASB5; ASB6; ASB7; ASB8; ASB9; ASZ1;
BARD1; BAT4; BAT8; BCL3; BCOR; BCORL1; BTBD11;
CAMTA1; CAMTA2; CASKIN1; CASKIN2; CCM1;
CDKN2A; CDKN2B; CDKN2C; CDKN2D; CENTB1; CENTB2; CENTB5; CENTG1;
CENTG2; CENTG3; CLIP3; CLIP4; CLPB; CTGLF1; CTGLF2; CTGLF3;
CTGLF4; CTGLF5; CTTNBP2; DAPK1; DDEF1; DDEF2; DDEFL1; DGKI;
DGKZ; DP58; DYSFIP1; DZANK; EHMT1; EHMT2; ESPN; FANK1; FEM1A;
FEM1B; GABPB2; GIT1; GIT2; GLS; GLS2; HACE1; HECTD1;
IBTK; ILK; INVS; KIDINS220; KRIT1; LRRK1;
MAIL; MIB1; MIB2; MPHOSPH8; MTPN; MYO16;
NFKB1; NFKB2; NFKBIA; NFKBIB; NFKBIE; NFKBIL1; NFKBIL2; NOTCH1;
NOTCH2; NOTCH3; NOTCH4; NRARP; NUDT12; OSBPL1A; OSTF1; PLA2G6;
POTE14; POTE15; POTE8; PPP1R12A; PPP1R12B; PPP1R12C; PPP1R13B; PPP1R13L;
PPP1R16A; PPP1R16B; PSMD10; RAI14; RFXANK; RIPK4; RNASEL; SHANK1;
SHANK2; SHANK3; SNCAIP; TA-NFKBH; TEX14; TNKS; TNKS2; TNNI3K; TP53BP2; TRP7; TRPA1; TRPC3; TRPC4; TRPC5; TRPC6; TRPC7; TRPV1; TRPV2; TRPV3; TRPV4; TRPV5; TRPV6; UACA; USH1G; ZDHHC13; ZDHHC17;


Jacalin

Jacalin is a plant-based lectin, but not a legume lectin, found in jackfruit. It has been studied for capturing O-glycoproteins such as mucins and IgA1, for potential applications in human immunology.
Jacalin belongs to a family of galactose-binding lectins containing the Jacalin-like lectin domain and it has a tetrameric two-chain structure with a weight of 66 kDa
Jacalin is preferably used in applications to isolate IgA from human serum, isolating human plasma glycoproteins and for applications in histochemistry. The lectin is blood group non-specific after neuraminidase treatment and agglutinates human erythrocytes at a concentration of ≥ 7,8 µg/ml.
A post-translational proteolytic modification of Jacalin gives the lectin a novel carbohydrate-binding site involving the N terminus of the a-chain. The relative affinities of the lectin for galactose derivatives, as well as the structural basis of its T-antigen specificity, are explained by its protein structure


Collagenase

Collagenases are enzymes that break the peptide bonds in collagen. They assist in destroying extracellular structures in the pathogenesis of bacteria such as "Clostridium". They are considered a virulence factor, facilitating the spread of gas gangrene. They normally target the connective tissue in muscle cells and other body organs.
Collagen, a key component of the animal extracellular matrix, is made through cleavage of pro-collagen by collagenase once it has been secreted from the cell. This stops large structures from forming inside the cell itself.
In addition to being produced by some bacteria, collagenase can be made by the body as part of its normal immune response. This production is induced by cytokines, which stimulate cells such as fibroblasts and osteoblasts, and can cause indirect tissue damage.
Therapeutic uses.
Collagenases have been approved for medical uses for
The MEROPS M9 family.
This group of metallopeptidases constitutes the MEROPS peptidase family M9, subfamilies M9A and M9B (microbial collagenase, clan MA(E)). The protein fold of the peptidase domain for members of this family resembles that of thermolysin, the type example for clan MA and the predicted active site residues for members of this family and thermolysin occur in the motif HEXXH.
Microbial collagenases have been identified from bacteria of both the "Vibrio" and "Clostridium" genera. Collagenase is used during bacterial attack to degrade the collagen barrier of the host during invasion. "Vibrio" bacteria are sometimes used in hospitals to remove dead tissue from burns and ulcers. "Clostridium histolyticum" is a pathogen that causes gas gangrene; nevertheless, the isolated collagenase has been used to treat bed sores. Collagen cleavage occurs at an in "Vibrio" bacteria and at bonds in "Clostridium" collagenases.
Analysis of the primary structure of the gene product from "Clostridium perfringens" has revealed that the enzyme is produced with a stretch of 86 residues that contain a putative signal sequence. Within this stretch is found PLGP, an amino acid sequence typical of collagenase substrates. This sequence may thus be implicated in self-processing of the collagenase.
Metalloproteases are the most diverse of the seven main types of protease, with more than 50 families identified to date. In these enzymes, a divalent cation, usually zinc, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. The known metal ligands are His, Glu, Asp, or Lys and at least one other residue is required for catalysis, which may play an electrophillic role. Of the known metalloproteases, around half contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site. The HEXXH motif is relatively common, but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases.
Other uses.
Collagenases may be used for tenderizing meat in a manner similar to widely used tenderizers papain, bromelain and ficain.


Adenosylhomocysteine nucleosidase

In enzymology, an adenosylhomocysteine nucleosidase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are S-adenosyl-L-homocysteine and H2O, whereas its two products are S-(5-deoxy-D-ribos-5-yl)-L-homocysteine and adenine.
This enzyme belongs to the family of hydrolases, specifically those glycosylases that hydrolyse N-glycosyl compounds. The systematic name of this enzyme class is S-adenosyl-L-homocysteine homocysteinylribohydrolase. Other names in common use include S-adenosylhomocysteine hydrolase (ambiguous), S-adenosylhomocysteine nucleosidase, 5'-methyladenosine nucleosidase, S-adenosylhomocysteine/5'-methylthioadenosine nucleosidase, and AdoHcy/MTA nucleosidase. This enzyme participates in methionine metabolism.
Structural studies.
As of late 2007, 8 structures have been solved for this class of enzymes, with PDB accession codes , , , , , , , and .


BtpA protein

In molecular biology, the BtpA protein family is a family of proteins which includes BtpA. BtpA appears to play a role in the stabilisation of photosystem I . It is an extrinsic membrane protein located on the cytoplasmic side of the thylakoid membrane. Homologs of BtpA are found in the crenarchaeota and euryarchaeota, where their function remains unknown. The Ycf4 protein is firmly associated with the thylakoid membrane, presumably through a transmembrane domain. Ycf4 co-fractionates with a protein complex larger than PSI upon sucrose density gradient centrifugation of solubilised thylakoids. The Ycf3 protein is loosely associated with the thylakoid membrane and can be released from the membrane with sodium carbonate. This suggests that Ycf3 is not part of a stable complex and that it probably interacts transiently with its partners. Ycf3 contains a number of tetratricopeptide repeats (TPR); TPR is a structural motif present in a wide range of proteins, which mediates protein-protein interactions.


Cocamide

Cocamide is a mixture of amides manufactured from the fatty acids obtained from coconut oil. As coconut oil contains about 50% of lauric acid, in formulas only the 12-carbon chains tend to be considered. Therefore the formula of cocamide can be written as 3(CH2)10CH2, though the number of carbon atoms in the chains varies (it is always even).
Cocamide is the structural basis of many surfactants. Common are ethanolamines (cocamide MEA, cocamide DEA), betaine compounds (cocamidopropyl betaine), and hydroxysultaines (cocamidopropyl hydroxysultaine).


(3S)-2,3-epoxy-2,3-dihydrosqualene mutase

(3S)-2,3-epoxy-2,3-dihydrosqualene mutase may refer to:


Holin superfamily I

The Holin Superfamily I (aka the CDD phage holin1 superfamily) is a superfamily of integral membrane transport proteins. It is one of the seven different holin superfamilies in total. In general, these proteins are thought to play a role in regulated cell death, although functionality varies between families and individual members.
Its main constituent is the Phi11 Holin (φ11 Holin) Family. This family is made up of over 270 putative pore-forming proteins, all from "Firmicutes". On average, proteins belonging to the holin I superfamily are about 100 amino acyl residues (aas) in length, although a large size variation exists among proteins of this superfamily. There does not seem to be deviation from the standard two transmembrane segments that these proteins possess.


3-hydroxy-2-methylpyridine-4,5-dicarboxylate 4-decarboxylase

In enzymology, a 3-hydroxy-2-methylpyridine-4,5-dicarboxylate 4-decarboxylase () is an enzyme that catalyzes the chemical reaction
Hence, this enzyme has one substrate, 3-hydroxy-2-methylpyridine-4,5-dicarboxylate, and two products, 3-hydroxy-2-methylpyridine-5-carboxylate and CO2.
This enzyme belongs to the family of lyases, specifically the carboxy-lyases, which cleave carbon-carbon bonds. The systematic name of this enzyme class is 3-hydroxy-2-methylpyridine-4,5-dicarboxylate 4-carboxy-lyase (3-hydroxy-2-methylpyridine-5-carboxylate-forming). This enzyme is also called 3-hydroxy-2-methylpyridine-4,5-dicarboxylate 4-carboxy-lyase. This enzyme participates in vitamin B6 metabolism.


Ribose 5-phosphate

Ribose 5-phosphate (R5P) is both a product and an intermediate of the pentose phosphate pathway. The last step of the oxidative reactions in the pentose phosphate pathway is the production of ribulose 5-phosphate. Depending on the body's state, ribulose 5-phosphate can reversibly isomerize to ribose 5-phosphate. Ribulose 5-phosphate can alternatively undergo a series of isomerizations as well as transaldolations and transketolations that result in the production of other pentose phosphates as well as fructose 6-phosphate and glyceraldehyde 3-phosphate (both intermediates in glycolysis).
The enzyme ribose-phosphate diphosphokinase converts ribose-5-phosphate into phosphoribosyl pyrophosphate.
Structure.
R5P consists of a five-carbon sugar, ribose, and a phosphate group at the five-position carbon. It can exist in open chain form or in furanose form. The furanose form is most commonly referred to as ribose 5-phosphoric acid.
Biosynthesis.
The formation of R5P is highly dependent on the cell growth and the need for NADPH (Nicotinamide adenine dinucleotide phosphate), R5P, and ATP (Adenosine triphosphate). Formation of each molecule is controlled by the flow of glucose 6-phosphate (G6P) in two different metabolic pathways: the pentose phosphate pathway and glycolysis. The relationship between the two pathways can be examined through different metabolic situations.
Pentose Phosphate Pathway.
R5P is produced in the pentose phosphate pathway in all organisms. The pentose phosphate pathway (PPP) is a metabolic pathway that runs parallel to glycolysis. It is a crucial source for NADPH generation for reductive biosynthesis (e.g. fatty acid synthesis) and pentose sugars. The pathway consists of two phases: an oxidative phase that generates NADPH and a non-oxidative phase that involves the interconversion of sugars. In the oxidative phase of PPP, two molecules of NADP+ are reduced to NADPH through the conversion of G6P to ribulose 5-phosphate (Ru5P). In the non-oxidative of PPP, Ru5P can be converted to R5P through ribose-5-phosphate isomerase enzyme catalysis.
When demand for NADPH and R5P is balanced, G6P forms one Ru5P molecule through the PPP, generating two NADPH molecules and one R5P molecule.
Glycolysis.
When more R5P is needed than NADPH, R5P can be formed through glycolytic intermediates. Glucose 6-phosphate is converted to fructose 6-phosphate (F6P) and glyceraldehyde 3-phosphate (G3P) during glycolysis. Transketolase and transaldolase convert two molecules of F6P and one molecule of G3P to three molecules of R5P. During rapid cell growth, higher quantities of R5P and NADPH are needed for nucleotide and fatty acid synthesis, respectively. Glycolytic intermediates can be diverted toward the non-oxidative phase of PPP by the expression of the gene for pyruvate kinase isozyme, PKM. PKM creates a bottleneck in the glycolytic pathway, allowing intermediates to be utilized by the PPP to synthesize NADPH and R5P. This process is further enabled by triosephosphate isomerase inhibition by phosphoenolpyruvate, the PKM substrate.
Function.
R5P and its derivatives serve as precursors to many biomolecules, including DNA, RNA, ATP, coenzyme A, FAD (Flavin adenine dinucleotide), and histidine.
Nucleotide biosynthesis.
Nucleotides serve as the building blocks for nucleic acids, DNA and RNA. They are composed of a nitrogenous base, a pentose sugar, and at least one phosphate group. Nucleotides contain either a purine or a pyrimidine nitrogenous base. All intermediates in purine biosynthesis are constructed on a R5P "scaffold". R5P also serves as an important precursor to pyrimidine ribonucleotide synthesis.
During nucleotide biosynthesis, R5P undergoes activation by ribose-phosphate diphosphokinase (PRPS1) to form phosphoribosyl pyrophosphate (PRPP). Formation of PRPP is essential for both the de novo synthesis of purines and for the purine salvage pathway. The de novo synthesis pathway begins with the activation of R5P to PRPP, which is later catalyzed to become phosphoribosylamine, a nucleotide precursor. During the purine salvage pathway, phosphoribosyltransferases add PRPP to bases.
PRPP also plays an important role in pyrimidine ribonucleotide synthesis. During the fifth step of pyrimidine nucleotide synthesis, PRPP covalently links to orotate at the one-position carbon on the ribose unit. The reaction is catalyzed by orotate phosphoriboseyltransferase (PRPP transferase), yielding orotidine monophosphate (OMP).
Histidine biosynthesis.
Histidine is an essential amino acid that is not synthesized de novo in humans. Like nucleotides, biosynthesis of histidine is initiated by the conversion of R5P to PRPP. The step of histidine biosynthesis is the condensation of ATP and PRPP by ATP-phosphoribosyl transferase, the rate determining enzyme. Histidine biosynthesis is carefully regulated by feedback inhibition/
Other functions.
R5P can be converted to adenosine diphosphate ribose, which binds and activates the TRPM2 ion channel. The reaction is catalyzed by ribose-5-phosphate adenylyltransferase
Disease relevance.
Diseases have been linked to R5P imbalances in cells. Cancers and tumors show upregulated production of R5P correlated to increased RNA and DNA synthesis. Ribose 5-phosphate isomerase deficiency, the rarest disease in the world, is also linked to an imbalance of R5P. Although the molecular pathology of the disease is poorly understood, hypotheses included decreased RNA synthesis.
Another disease linked to R5P is gout Higher levels of G6P lead to a buildup of glycolytic intermediates, that are diverted to R5P production. R5P converts to PRPP, which forces an overproduction of purines, leading to uric acid build up.
Accumulation of PRPP is found in Lesch-Nyhan Syndrome. The build up is caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT), which leads to decreased nucleotide synthesis and an increase of uric acid production.
Superactivity in PRPS1, the enzyme that catalyzes the R5P to PRPP, has also been linked to gout, as well as neurodevelopmental impairment and sensorineural deafness.


GTP cyclohydrolase I

GTP cyclohydrolase I (GTPCH) () is a member of the GTP cyclohydrolase family of enzymes. GTPCH is part of the folate and biopterin biosynthesis pathways. It is responsible for the hydrolysis of guanosine triphosphate (GTP) to form 7,8-dihydroneopterin triphosphate (7,8-DHNP-3'-TP, 7,8-NH2-3'-TP).
Gene.
GTPCH is encoded by the gene "GCH1". Several alternatively spliced transcript variants encoding different isoforms have been described; however, not all of the variants give rise to a functional enzyme.
Clinical significance.
Mutations in this gene are associated with malignant phenylketonuria (PKU) and hyperphenylalaninemia (HPA), as well as GTP cyclohydrolase I deficiency. Deficiency of GTP cyclohydrolase I can occur in a recessive and in a dominant form and lead to a lack of certain neurotransmitters (dopamine, norepinephrine, epinephrine and serotonin). The dominant form, with mutation in only one of the two alleles for GTP cyclohydrolase I, causes dopamine-responsive dystonia, characterized by childhood-onset dystonia. Patients with the recessive form have mutations in both alleles for GTP cyclohydrolase I. Patients present with developmental delays and neurological dysfunction with trunk hypotonia, hypertonia of the extremities, abnormal movements, tremors, convulsions, and sometimes autonomic dysfunction. Response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype/phenotype correlation and outcome of these diseases their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders (iNTD).
Function.
The transcribed protein is the first and rate-limiting enzyme in tetrahydrobiopterin (THB, BH4) biosynthesis, catalyzing the conversion of GTP into 7,8-DHNP-3'-TP. THB is an essential cofactor required by the aromatic amino acid hydroxylase (AAAH) and nitric oxide synthase (NOS) enzymes in the biosynthesis of the monoamine neurotransmitters serotonin (5-hydroxytryptamine (5-HT)), melatonin, dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), and nitric oxide (NO), respectively.
GTPCH (GCH1) and tetrahydrobiopterin were found to protect against cell death by ferroptosis. Tetrahydrobiopterin (BH4) acts as a potent, diffusable antioxidant that resists oxidative stress and enables cancer cell survival.


3-Isopropylmalate dehydratase

3-Isopropylmalate dehydratase (E.C.4.2.1.33) is an aconitase homologue, which catalyses the isomerisation of 2-isopropylmalate to 3-isopropylmalate, via dehydration, in the biosynthesis of leucine.


Carbonic anhydrase inhibitor

Carbonic anhydrase inhibitors are a class of pharmaceuticals that suppress the activity of carbonic anhydrase. Their clinical use has been established as anti-glaucoma agents, diuretics, antiepileptics, in the management of mountain sickness, gastric and duodenal ulcers, idiopathic intracranial hypertension, neurological disorders, or osteoporosis.
Medical uses.
Carbonic anhydrase inhibitors are primarily used for the treatment of glaucoma. They may also be used to treat seizure disorder and acute mountain sickness. Because they encourage solubilization and excretion of uric acid, they can be used in the treatment of gout.
Glaucoma.
Acetazolamide is an inhibitor of carbonic anhydrase. It is used for glaucoma, epilepsy (rarely), idiopathic intracranial hypertension, and altitude sickness.
For the reduction of intraocular pressure (IOP), acetazolamide inactivates carbonic anhydrase and interferes with the sodium pump, which decreases aqueous humor formation and thus lowers IOP. Systemic effects include increased loss of sodium, potassium, and water in the urine, secondary to the drug's effects on the renal tubules, where valuable components of filtered blood are re-absorbed in the kidney. Arterial Blood gases may show a mild hyperchloremic metabolic acidosis.
Methazolamide is also a carbonic anhydrase inhibitor. It has a longer elimination half-life than acetazolamide and is less associated with adverse effects to the kidney.
Dorzolamide is a sulfonamide and topical carbonic anhydrase II inhibitor. It is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension and who are insufficiently responsive to beta-blockers. Inhibition of carbonic anhydrase II in the ciliary processes of the eye decreases aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport.
Brinzolamide (trade names Azopt, Alcon Laboratories, Inc, Befardin Fardi Medicals) is a carbonic anhydrase inhibitor used to lower intraocular pressure in patients with open-angle glaucoma or ocular hypertension. It exists as a number of isoenzymes, the most active of which is carbonic anhydrase II (CA-II). The combination of brinzolamide with timolol is marketed under the trade name Azarga.
Diuretic.
Some diuretics inhibit the activity of carbonic anhydrase in proximal convoluted tubules and prevent reabsorption of bicarbonates from renal tubules. Lowered reabsorption of bicarbonates results in decreased activity of the apical sodium hydrogen exchanger, causing diuresis due to retention of sodium in the renal tubules. Acetazolamide is a carbonic anhydrase inhibitor. Other examples are;
Epilepsy.
Acetazolamide is effective in the treatment of most types of seizures, including generalized tonic-clonic and focal seizures and especially absence seizures, although it has limited utility because tolerance develops with chronic use. The drug is occasionally used on an intermittent basis to prevent seizures in catamenial epilepsy.
The sulfur-containing antiseizure and antimigraine drug topiramate is a weak inhibitor of carbonic anhydrase, particularly subtypes II and IV.
Whether carbonic anhydrase inhibition contributes to its clinical activity is not known. In rare cases, the inhibition of carbonic anhydrase may be strong enough to cause metabolic acidosis of clinical importance. Zonisamide is another sulfur containing antiseizure drug that weakly inhibits carbonic anhydrase.
Sultiame is also an example of an anticonvulsant drug of this class.
Altitude sickness.
At high altitude, the partial pressure of oxygen is lower and people have to breathe more rapidly to get adequate oxygen. When this happens, the partial pressure of CO2 in the lungs (pCO2) decreases (is "blown off"), causing a respiratory alkalosis. This would normally be compensated by the kidney excreting bicarbonate and causing compensatory metabolic acidosis, but this mechanism takes several days. A more immediate treatment is carbonic anhydrase inhibitors, which prevent bicarbonate uptake in the kidney and help correct the alkalosis. Carbonic anhydrase inhibitors have also been shown to improve chronic mountain sickness.
Adverse effects.
Loss of bicarbonate may result in metabolic acidosis.
Natural sources.
Ellagitannins extracted from the pericarps of "Punica granatum", the pomegranate, such as punicalin, punicalagin, granatin B, gallagyldilactone, casuarinin, pedunculagin and tellimagrandin I, are carbonic anhydrase inhibitors.


Flavodoxin fold

The flavodoxin fold is a common α/β protein fold, second only to the TIM barrel fold. It has three layers, with two α-helical layers sandwiching a 5-stranded parallel β-sheet. The order of strands within the sheet is 21345.


Allantoicase

Allantoicase is an enzyme () that in humans is encoded by the "ALLC" gene. Allantoicase catalyzes the chemical reaction
Thus, the two substrates of this enzyme are allantoate and H2O, whereas its two products are (S)-ureidoglycolate and urea.
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 allantoate amidinohydrolase. This enzyme participates in purine metabolism by facilitating the utilization of purines as secondary nitrogen sources under nitrogen-limiting conditions. While purine degradation converges to uric acid in all vertebrates, its further degradation varies from species to species. Uric acid is excreted by birds, reptiles, and some mammals that do not have a functional uricase gene, whereas other mammals produce allantoin. Amphibians and microorganisms produce ammonia and carbon dioxide using the uricolytic pathway. Allantoicase performs the second step in this pathway catalyzing the conversion of allantoate into ureidoglycolate and urea.
Structural studies.
As of late 2007, two structures have been solved for this class of enzymes, with PDB accession codes and .
The structure of allantoicase is best described as being composed of two repeats (the allantoicase repeats: AR1 and AR2), which are connected by a flexible linker. The crystal structure, resolved at 2.4A resolution, reveals that AR1 has a very similar fold to AR2, both repeats being jelly-roll motifs, composed of four-stranded and five-stranded antiparallel beta-sheets. Each jelly-roll motif has two conserved surface patches that probably constitute the active site.


DEP domain

In molecular biology, the DEP domain (Dishevelled, Egl-10 and Pleckstrin domain) is a globular protein domain of about 80 amino acids that is found in over 50 proteins involved in G-protein signalling pathways. It was named after the three proteins it was initially found in:
Mammalian regulators of G-protein signalling also contain these domains, and regulate signal transduction by increasing the GTPase activity of G-protein alpha subunits, thereby driving them into their inactive GDP-bound form. It has been proposed that the DEP domain could play a selective role in targeting DEP domain-containing proteins to specific subcellular membranous sites, perhaps even to specific G protein-coupled signaling pathways. Nuclear magnetic resonance spectroscopy has revealed that the DEP domain comprises a three-helix bundle, a beta-hairpin 'arm' composed of two beta-strands and two short beta-strands in the C-terminal region.


Harmine

Harmine is a beta-carboline and a harmala alkaloid. It occurs in a number of different plants, most notably the Syrian rue and "Banisteriopsis caapi". Harmine reversibly inhibits monoamine oxidase A (MAO-A), an enzyme which breaks down monoamines, making it a RIMA. Harmine does not inhibit MAO-B. Harmine is also known as banisterine, telepathine, leucoharmine and yageine.
Biosynthesis.
The coincident occurrence of β-carboline alkaloids and serotonin in "Peganum harmala" indicates the presence of two very similar, interrelated biosynthetic pathways, which makes it difficult to definitively identify whether free tryptamine or L-tryptophan is the precursor in the biosynthesis of harmine. However, it is postulated that L-tryptophan is the most likely precursor, with tryptamine existing as an intermediate in the pathway.
The following figure shows the proposed biosynthetic scheme for harmine. The Shikimate acid pathway yields the aromatic amino acid, L-tryptophan. Decarboxylation of L-tryptophan by aromatic L-amino acid decarboxylase (AADC) produces tryptamine (I), which contains a nucleophilic center at the C-2 carbon of the indole ring due to the adjacent nitrogen atom that enables the participation in a Mannich-type reaction. Rearrangements enable the formation of a Schiff base from tryptamine, which then reacts with pyruvate in II to form a β-carboline carboxylic acid. The β-carboline carboxylic acid subsequently undergoes decarboxylation to produce 1-methyl β-carboline III. Hydroxylation followed by methylation in IV yields harmaline. The order of O-methylation and hydroxylation have been shown to be inconsequential to the formation of the harmaline intermediate. In the last step V, the oxidation of harmaline is accompanied by the loss of water and effectively generates harmine.
The difficulty distinguishing between L-tryptophan and free tryptamine as the precursor of harmine biosynthesis originates from the presence of the serotonin biosynthetic pathway, which closely resembles that of harmine, yet necessitates the availability of free tryptamine as its precursor. As such, it is unclear if the decarboxylation of L-tryptophan, or the incorporation of pyruvate into the basic tryptamine structure is the first step of harmine biosynthesis. However, feeding experiments involving the feeding of one of tryptamine to hairy root cultures of "P. harmala" showed that the feeding of tryptamine yielded a great increase in serotonin levels with little to no effect on β-carboline levels, confirming that tryptamine is the precursor for serotonin, and indicating that it is likely only an intermediate in the biosynthesis of harmine; otherwise, comparable increases in harmine levels would have been observed.
Uses.
Monoamine oxidase inhibitor.
Harmine is a RIMA, as it reversibly inhibits monoamine oxidase A (MAO-A), but not MAO-B. Oral or intravenous harmine doses ranging from 30 to 300 mg may cause agitation, bradycardia or tachycardia, blurred vision, hypotension, paresthesias. Serum or plasma harmine concentrations may be measured as a confirmation of diagnosis. The plasma elimination half-life of harmine is on the order of 1–3 hours.
Medically significant amounts of harmine occur in the plants Syrian rue and "Banisteriopsis caapi". These plants also contain notable amounts of harmaline, which is also a RIMA. The psychoactive ayahuasca brew is made from "B. caapi" stem bark usually in combination with dimethyltryptamine (DMT) containing "Psychotria viridis" leaves. DMT is a psychedelic drug, but it is not orally active unless it is ingested with RIMAs. This makes harmine a vital component of the ayahuasca brew with regard to its ability to induce a psychedelic experience. Syrian rue or synthetic harmine is sometimes used to substitute "B. caapi" in the oral use of DMT.
Other.
Harmine is useful fluorescent pH indicator. As the pH of its local environment increases, the fluorescence emission of harmine decreases.
Due to its MAO-A specific binding, carbon-11 labeled harmine can be used in positron emission tomography to study MAO-A dysregulation in several psychiatric and neurologic illnesses.
Harmine was used as an antiparkinsonian medication since the late 1920s until the early 1950s. It was replaced by other medications.
Research.
Anti-cancer.
"Harmine showed cytotoxicity against HL60 and K562 cell lines. This could explain the cytotoxic effect of "Peganum harmala" on these cells." Beta-carboline MAO inhibitors, such as harmine, bind with DNA and also exhibit anti-tumor properties. Harmine has been shown to bind one hundred times more effectively than its close analogue harmaline. The consequences of this are currently not well understood.
Effects on bone and cartilage.
Harmine has been shown to promote differentiation of osteoblasts (bone-forming cells), and chondrocytes (cells in the cartilage)." Harmine was also shown to inhibit the formation of osteoclasts (bone resorbing cells).
Pancreatic islet cell proliferation.
Harmine is currently the only known drug that induces proliferation (rapid mitosis and subsequent mass growth) of pancreatic alpha (α) and beta (β) cells in adult humans. These islet sub-cells are normally very resistant to growth stimulation in the adult stage of a human's life, as the cell mass plateaus at around age 10 and remains virtually unchanged from there on. Other similar drugs have been successful in triggering beta cell proliferation in rats/mice and pigs, however these drugs were met with very limited to no success in human subjects. Harmine was found to increase the diminished beta cell mass of diabetic people to clinically significant levels for a short time: this property proves very useful in a possible harmine-based treatment for both type 1 and type 2 diabetes.
Harmine is known to be a potent inhibitor of the DYRK1A enzyme pathway. This is thought to be the main mechanism by which harmine can induce alpha and beta cell proliferation "in vivo". DYRK1A is an enzyme that plays a definitive role in suppressing/regulating cell proliferation, therefore it makes sense that the partial blocking of DYRK1A increases the growth of certain cells, including pancreatic α and β cells. The alteration of many other enzymes and genes that are implicated in cell proliferation have shown no significant results in humans, hence it is still unknown why DYRK1A inhibition specifically can force α and β cells to divide and grow, in humans no less.
Other.
Harmine found in root secretions of "Oxalis tuberosa" has been found to have insecticidal properties.
Harmine has been found to increase EAAT2 glutamate pump expression in central nervous system, therefore reducing glutamate toxicity.
Natural sources.
Harmine is found in a wide variety of different organisms, most of which are plants.
Alexander Shulgin lists about thirty different species known to contain harmine, including seven species of butterfly in the family Nymphalidae.
The harmine-containing plants include tobacco, "Peganum harmala", two species of passiflora, and numerous others. Lemon balm ("Melissa officinalis") contains harmine.
In addition to "B. caapi", at least three members of the Malpighiaceae contain harmine, including two more "Banisteriopsis" species and the plant "Callaeum antifebrile". Callaway, Brito and Neves (2005) found harmine levels of 0.31-8.43% in "B. caapi" samples.
The family Zygophyllaceae, which "P. harmala" belongs to, contains at least two other harmine-bearing plants: "Peganum nigellastrum" and "Zygophyllum fabago".
History.
J. Fritzche was the first to isolate and name harmine. He isolated it from the husks of "Peganum harmala" seeds in 1848. The related harmaline was already isolated and named by Göebel in 1837 from the same plant. The pharmacology of harmine was not studied in detail until 1895. The structures of harmine and harmaline were determined in 1927 by Richard Helmuth Fredrick Manske and colleagues.
In 1905, the Colombian naturalist and chemist, Rafael Zerda-Bayón suggested the name telepathine to the then unknown hallucinogenic ingredient in ayahuasca brew. "Telepathine" comes from "telepathy", as Zerda-Bayón believed that ayahuasca induced telepathic visions. In 1923, the Colombian chemist, Guillermo Fischer-Cárdenas was the first to isolate harmine from "Banisteriopsis caapi", which is an important herbal component of ayahuasca brew. He called the isolated harmine "telepathine". This was solely to honor Zerda-Bayón, as Fischer-Cárdenas found that telepathine had only mild non-hallucinogenic effects in humans. In 1925, Barriga Villalba, professor of chemistry at the University of Bogotá, isolated harmine from "B. caapi", but named it "yajéine", which in some texts is written as "yageine". In 1927, F. Elger, who was a chemist working at Hoffmann-La Roche, isolated harmine from "B. caapi". With the assistance of Professor Robert Robinson in Manchester, Elger showed that harmine (which was already isolated in 1848) was identical with telepathine and yajéine. In 1928, Louis Lewin isolated harmine from "B. caapi", and named it "banisterine", but this supposedly novel compound was soon also shown to be harmine.
Legal status.
Australia.
Harmala alkaloids are considered Schedule 9 prohibited substances under the Poisons Standard (October 2015). A Schedule 9 substance is a substance which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities.
Exceptions are made when in herbs, or preparations, for therapeutic use such as: (a) containing 0.1 per cent or less of harmala alkaloids; or (b) in divided preparations containing 2 mg or less of harmala alkaloids per recommended daily dose.


Dipeptidase E

Dipeptidase E (, "aspartyl dipeptidase", "peptidase E", "PepE gene product (Salmonella typhimurium)") is an enzyme. This enzyme catalyses the following chemical reaction
A free carboxy group is not absolutely required in the substrate.


Teneligliptin

Teneligliptin (INN; trade name Tenelia) is a pharmaceutical drug for the treatment of type 2 diabetes mellitus. It belongs to the class of anti-diabetic drugs known as dipeptidyl peptidase-4 inhibitors or "gliptins".
Creation.
It was created by Mitsubishi Tanabe Pharma and launched in September 2012 by both Mitsubishi Tanabe Pharma and Daiichi Sankyo in Japan.
Licensing and use.
Japan/Korea/India/Argentina.
It is approved for use in Japan, Argentina, Korea and India.
Pharmacology.
Teneligliptin has unique J shaped or anchor locked domain structure because of which it has a potent inhibition of DPP 4 enzyme.
Teneligliptin significantly controls glycemic parameters with safety. No dose adjustment is required in renally impaired patients.


Cytochrome c assembly protein family

In molecular biology, the cytochrome c assembly protein family includes various proteins involved in cytochrome c assembly from mitochondria and bacteria. Members of this family include: CycK from "Rhizobium leguminosarum", CcmC from "Escherichia coli" and "Paracoccus denitrificans", and orf240 from "Triticum aestivum" (Wheat) mitochondria. The members of this family are probably integral membrane proteins with six predicted transmembrane helices that may comprise the membrane component of an ABC (ATP binding cassette) transporter complex. This transporter may be necessary for transport of some component needed for cytochrome c assembly. One member, "R. leguminosarum" CycK, contains a putative haem-binding motif. Wheat orf240 also contains a putative haem-binding motif and is a proposed ABC transporter with c-type haem as its proposed substrate. However it seems unlikely that all members of this family transport haem or c-type apocytochromes because "P. denitrificans" CcmC transports neither.


4-hydroxybenzoyl-CoA reductase

In enzymology, a 4-hydroxybenzoyl-CoA reductase () is an enzyme found in some bacteria and archaea that catalyzes the chemical reaction
The 3 substrates of this enzyme are benzoyl-CoA, acceptor, and H2O, whereas its two products are 4-hydroxybenzoyl-CoA and reduced acceptor.
This enzyme participates in benzoate degradation via coa ligation.
Nomenclature.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-CH group of donor with other acceptors. The systematic name of this enzyme class is benzoyl-CoA:acceptor oxidoreductase. Other names in common use include:


ATP synthase gamma subunit

Gamma subunit of ATP synthase F1 complex forms the central shaft that connects the Fo rotary motor to the F1 catalytic core. F-ATP synthases (also known as F1Fo ATPase, or H(+)-transporting two-sector ATPase) () are composed of two linked complexes: the F1 ATPase complex is the catalytic core and is composed of 5 subunits (alpha, beta, gamma, delta, epsilon), while the Fo ATPase complex is the membrane-embedded proton channel that is composed of at least 3 subunits (A-C), nine in mitochondria (A-G, F6, F8).
The human ATP synthase gamma subunit is encoded by the gene ATP5C1.
Molecular Interactions.
Both the F1 and Fo complexes are rotary motors that are coupled back-to-back. In the F1 complex, the central gamma subunit forms the rotor inside the cylinder made of the alpha(3)beta(3) subunits, while in the Fo complex, the ring-shaped C subunits forms the rotor. The two rotors rotate in opposite directions, but the Fo rotor is usually stronger, using the force from the proton gradient to push the F1 rotor in reverse in order to drive ATP synthesis. These ATPases can also work in reverse to hydrolyse ATP to create a proton gradient.
The ATPase F1 complex gamma subunit forms the central shaft that connects the Fo rotary motor to the F1 catalytic core. The gamma subunit functions as a rotary motor inside the cylinder formed by the alpha(3)beta(3) subunits in the F1 complex. The best-conserved region of the gamma subunit is its C-terminus, which seems to be essential for assembly and catalysis.


AEE788

AEE788 is a multitargeted human epidermal receptor (HER) 1/2 and vascular endothelial growth factor receptor (VEGFR) 1/2 receptor family tyrosine kinases inhibitor with IC50 of 2, 6, 77, 59 nM for EGFR, ErbB2, KDR, and Flt-1. In cells, growth factor-induced EGFR and ErbB2 phosphorylation was also efficiently inhibited with IC50s of 11 and 220 nM, respectively. It efficiently inhibited growth factor-induced EGFR and ErbB2 phosphorylation in tumors for >72 h, a phenomenon correlating with the antitumor efficacy of intermittent treatment schedules. It also inhibits VEGF-induced angiogenesis in a murine implant model. It has potential as an anticancer agent targeting deregulated tumor cell proliferation as well as angiogenic parameters.


Matrilin-3

Matrilin-3 is a matrilin protein that in humans is encoded by the "MATN3" gene.


Methazolamide

Methazolamide (trade name Neptazane) is a potent carbonic anhydrase inhibitor. It is indicated in the treatment of increased intraocular pressure (IOP) in chronic open-angle glaucoma and secondary glaucoma. Also it is used preoperatively in acute angle-closure (narrow-angle) glaucoma where lowering the IOP is desired before surgery.


Tetratricopeptide repeat

The tetratricopeptide repeat (TPR) is a structural motif. It consists of a degenerate 34 amino acid tandem repeat identified in a wide variety of proteins. It is found in tandem arrays of 3–16 motifs, which form scaffolds to mediate protein–protein interactions and often the assembly of multiprotein complexes. These alpha-helix pair repeats usually fold together to produce a single, linear solenoid domain called a TPR domain. Proteins with such domains include the anaphase-promoting complex (APC) subunits cdc16, cdc23 and cdc27, the NADPH oxidase subunit p67-phox, hsp90-binding immunophilins, transcription factors, the protein kinase R (PKR), the major receptor for peroxisomal matrix protein import PEX5, protein arginine methyltransferase 9 (PRMT9), and mitochondrial import proteins.
Structure.
The structure of the PP5 protein was the first structure to be determined. The structure solved by X-ray crystallography by Das and colleagues showed that the TPR sequence motif was composed of a pair of antiparallel alpha helices. The PP5 structure contained 3 tandem TPR repeats which showed the sequential TPR repeats formed an alpha-helical solenoid structure.
A typical TPR structure is characterized by interactions between helices A and B of the first motif and helix A’ of the next TPR. Although the nature of such interactions may vary, the first two helices of the TPR motif typically have a packing angle of ~24 degrees within a single motif. Repeats of more than three TPR motifs generate a right handed superhelix characterized by both a concave and a convex face, of which the concave face is usually involved in ligand binding.
In terms of sequence, a TPR possesses a mixture of small and large hydrophobic residues, nonetheless, no positions are fully invariant. There are however certain residues that are usually conserved including Tryptophan 4, Leucine 7, Glycine 8, Tyrosine 11, Alanine 20, Phenylalanine 24, Alanine 27 and Proline 32. Among those 8, Alanine at positions 8, 20 and 27 tend to be more conserved. The other positions have a stronger preference for either small, large or aromatic amino acids rather than a specific residue. In between helices, residue conservation plays more of a structural role with helix breaking residues present. Between adjacent TPR, residues have roles with both structural and functional implications.
TPR containing peptides.
Hop.
The Hop adaptor protein mediates the association of the molecular chaperones Hsp70 and Hsp90. It contains three 3-TPR repeats each with its own peptide-binding specificity. Its TPR1 domain is known to recognize the C-terminal of Hsp70 while TPR2 binds to the C-terminal of Hsp90. Both C-terminal sequences end with an EEVD motif and the nature of the interaction is both electrostatic and hydrophobic.
PEX5.
The PEX5 protein is a receptor for PTS1 (peroxisomal targeting signal tripeptide which directs proteins into peroxisomes). It interacts with the signal via TPR motifs. Most of its contacts with the C-terminal tripeptide PTS1 are in the concave face of TPRs 1, 2 and 3.
Neutrophil cytosolic factor 2.
Neutrophil cytosolic factor 2 is an essential to NADPH oxidase complex which in turn produces superoxides in response to microbial infection. The binding of the Rac GTPase is a key step into the assembly of the complex and the TPRs in the phox unit mediate the assembly of the multiprotein complex by acting a binding scaffold.
Examples.
Human genes encoding proteins containing this motif include:


Metrizamide

Metrizamide is a non-ionic iodine-based radiocontrast agent. It is also a density gradient medium for the centrifugation of biological particles.
Historically metrizamide replaced iofendylate (trade names: Pantopaque, Myodil) as the contrast agent of choice for myelography (an X-ray study of the spine now largely replaced by MRI). The radio opacity characteristics are such that finer detail is displayed with metrizamide, as well as the advantage of reabsorption from spinal fluid and excretion from the body – since unlike iofendylate, metrizamide is a water-soluble substance.
Both agents are administered by lumbar puncture (also referred to as a spinal tap or cisternal puncture), at the cervicocranial junction. The human patient is rolled from the lateral decubitus (lying on the side) to prone. Ankles are strapped to the end of a hard X-ray, CT, or MRI table. To obtain images of the cervical region the patient is then carefully tilted in the Trendelenberg position (head down) so the contrast agent (particularly iofendylate) can enter the neck region. Care is given to prevent spilling dye into the posterior cranial fossa (back of the head) or to enter the cranial cavity in general. This speaks to the inability to remove the heavier or more viscous iofendylate without aspirating it with spinal fluid through a lumbar puncture needle in the low back (sticking up vertically) or back of the neck. Removal of iofendylate is necessary since it is not water-soluble. With metrizamide the issue is that if entering the cranial cavity and high dose exposure to the blood brain barrier, side effects are more likely encountered. Issues related to absorption into the general circulation are also encountered.
History.
Metrizamide was approved in the US in 1978. Its marketing is discontinued as of 2021.


RU-2309

RU-2309, also known as 18-methylmetribolone, δ9,11-17α,18-dimethyl-19-nortestosterone, or 17α,18-dimethylestr-4,9,11-trien-17β-ol-3-one, is a 17α-alkylated androgen/anabolic steroid (AAS) of the 19-nortestosterone group which was never marketed. It is the C18 methyl or C13β ethyl derivative of metribolone. The compound is closely related to tetrahydrogestrinone (THG), which has the same chemical structure as RU-2309 except for possessing an ethyl group at the C17α position instead of a methyl group. Hence, it could also be referred to as 17α-methyl-THG. RU-2309 shows high affinity for the androgen, progesterone, and glucocorticoid receptors.


Allyl-alcohol dehydrogenase

In enzymology, an allyl-alcohol dehydrogenase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are allyl alcohol and NADP+, whereas its 3 products are acrolein, 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 allyl-alcohol:NADP+ oxidoreductase.


Dammaradiene synthase

Dammaradiene synthase () is an enzyme with systematic name "squalene mutase (cyclizing, dammara-20,24-diene-forming)". This enzyme catalyses the following chemical reaction: squalene formula_1 dammara-20,24-diene


Erythrose

Erythrose is a tetrose saccharide with the chemical formula C4H8O4. It has one aldehyde group, and is thus part of the aldose family. The natural isomer is -erythrose.
Erythrose was first isolated in 1849 from rhubarb by the French pharmacist Louis Feux Joseph Garot (1798-1869), and was named as such because of its red hue in the presence of alkali metals (ἐρυθρός, "red").
Erythrose 4-phosphate is an intermediate in the pentose phosphate pathway and the Calvin cycle.
Oxidative bacteria can be made to use erythrose as its sole energy source.


Deoxycytidylate kinase

Deoxycytidylate kinase may refer to one of two enzymes:


Dipeptidyl peptidase-4 inhibitor

Inhibitors of dipeptidyl peptidase 4 (DPP-4 inhibitors or gliptins) are a class of oral hypoglycemics that block the enzyme dipeptidyl peptidase-4 (DPP-4). They can be used to treat diabetes mellitus type 2.
The first agent of the class – sitagliptin – was approved by the FDA in 2006.
Glucagon increases blood glucose levels, and DPP-4 inhibitors reduce glucagon and blood glucose levels. The mechanism of DPP-4 inhibitors is to increase incretin levels (GLP-1 and GIP), which inhibit glucagon release, which in turn increases insulin secretion, decreases gastric emptying, and decreases blood glucose levels.
A 2018 meta-analysis found no favorable effect of DPP-4 inhibitors on all-cause mortality, cardiovascular mortality, myocardial infarction or stroke in patients with type 2 diabetes.
Examples.
Drugs belonging to this class are:
Other chemicals which may inhibit DPP-4 include:
Adverse effects.
In those already taking sulphonylureas, there is an increased risk of low blood sugar when taking a medicine in the DPP-4 drug class.
Adverse effects include nasopharyngitis, headache, nausea, heart failure, hypersensitivity and skin reactions.
The U.S. Food and Drug Administration (FDA) is warning that the type 2 diabetes medicines like sitagliptin, saxagliptin, linagliptin, and alogliptin may cause joint pain that can be severe and disabling. FDA has added a new Warning and Precaution about this risk to the labels of all medicines in this drug class, called dipeptidyl peptidase-4 (DPP-4) inhibitors. However, studies assessing risk of rheumatoid arthritis among DPP-4 inhibitor users have been inconclusive.
A 2014 review found increased risk of heart failure with saxagliptin and alogliptin, prompting the FDA in 2016 to add warnings to the relevant drug labels.
A 2018 meta analysis showed that use of DPP-4 inhibitors was associated with a 58% increased risk of developing acute pancreatitis compared with placebo or no treatment.
A 2018 observational study suggested an elevated risk of developing inflammatory bowel disease (specifically, ulcerative colitis), reaching a peak after three to four years of use and decreasing after more than four years of use.
Cancer.
In response to a report of precancerous changes in the pancreases of rats and organ donors treated with the DPP-4 inhibitor sitagliptin, the United States FDA and the European Medicines Agency each undertook independent reviews of all clinical and preclinical data related to the possible association of DPP-4 inhibitors with pancreatic cancer. In a joint letter to the New England Journal of Medicine, the agencies stated that they had not yet reached a final conclusion regarding a possible causative relationship.
A 2014 meta-analysis found no evidence for increased pancreatic cancer risk in people treated with DPP-4 inhibitors, but owing to the modest amount of data available, was not able to completely exclude possible risk.
Combination drugs.
Some DPP-4 inhibitor drugs have received approval from the FDA to be used with metformin concomitantly with additive effect to increase the level of glucagon-like peptide 1 (GLP-1) which also decreases hepatic glucose production.


Solenoid protein domain

Solenoid protein domains are a highly modular type of protein domain. They consist of a chain of nearly identical folds, often simply called tandem repeats. They are extremely common among all types of proteins, though exact figures are unknown.
"Repeats" in molecular biology.
In proteins, a "repeat" is any sequence block that returns more than one time in the sequence, either in an identical or a highly similar form. Repetitiveness does not in itself indicate anything about the structure of the protein. As a "rule of thumb", short repetitive sequences (e.g. those below the length of 10 amino acids) may be intrinsically disordered, and not part of any folded protein domains. Repeats that are at least 30 to 40 amino acids long, are far more likely to be folded as part of a domain. Such long repeats are frequently indicative of the presence of a solenoid domain in the protein.
Examples of disordered repetitive sequences include the 7-mer peptide repeats found in the RPB1 subunit of RNA polymerase II, or the tandem beta-catenin or axin binding linear motifs in APC (adenomatous polyposis coli). Examples of short repeats exhibiting ordered structures include the three-residue collagen repeat or the five-residue pentapeptide repeat that forms a beta helix structure.
Architecture of solenoid domains.
Due to the identical form of their building blocks, solenoid domains can only assume a limited number of shapes. Two main topologies are possible: linear (or open, generally with some degree of helical curvature) and circular (or closed).
Linear (open) solenoids.

If the two terminal repeats in a solenoid do not physically interact, it leads to an open or linear structure. Members of this group are frequently rod- or crescent-shaped. The number of individual repeats can range from 2 to over 50. A clear advantage of this topology is that both the N- and C-terminal ends are free to add new repeats and folds, or even remove existing ones during evolution without any gross impact on the structural stability of the entire domain. This type of domain is extremely common among extracellular segments of receptors or cell adhesion molecules. A non-exhaustive list of examples include: EGF repeats, cadherin repeats, leucine-rich repeats, HEAT repeats, ankyrin repeats, armadillo repeats, tetratricopeptide repeats, etc. Whenever a linear solenoid domain structure participates in protein-protein interactions, frequently at least 3 or more repetitive subunits form the ligand-binding sites. Thus - while individual repeats might have a (limited) ability to fold on their own – they usually cannot perform the functions of the entire domain alone.
Circular (closed) solenoids.
In the case when the N- and C-terminal repeats lie in close physical contact in a solenoid domain, the result is a topologically compact, closed structure. Such domains typically display a high rotational symmetry (unlike open solenoids 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. 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".
Repetitive supradomain modules.
As common in biology, there are several borderline cases between solenoid architectures and regular protein domains. Proteins that contain tandem repeats of ordinary domains are very common in eukaryotes. Even if these domains are perfectly capable of folding on their own, some of them might bind together and assume a rigidly fixed orientation in the full protein. These supradomain modules can perform functions that its individual constituents are incapable of . A famous example is the case of tandem BRCT domains, found in the tumor suppressor protein BRCA1. While individual BRCT domains are found in certain proteins (e.g. some DNA ligases) binding DNA, these tandem BRCT domains evolved a novel function: phosphorylated linear motif binding. In the case of BRCA1 (and MDC1), the peptide-binding groove lies in a cleft formed by the junction of the two domains. This elegantly explains why individual constituents of this supradomain block are incapable of ligand binding, while their proper assembly endows them with a novel function. Therefore, tandem BRCT domains can be regarded as a form of a single, linear solenoid domain as well.


NLRC4

NLR family CARD domain-containing protein 4 is a protein that in humans is encoded by the "NLRC4" gene.
Structure.
The NLRC4 protein is highly conserved across mammalian species. It bears homology to the C. elegans Ced4 protein. It contains an n-terminal CARD domain, a central nucleotide binding/NACHT domain, and a c-terminal leucine rich repeat (LRR) domain. It belongs to a family of NLR proteins that includes the transcriptional co-activator CIITA and the canonical inflammasome protein NLRP3. A truncated murine NLRC4 was the first member of this family whose crystal structure was solved.
Function.
NLRC4 is best associated with triggering formation of the inflammasome. Unlike NLRP3, certain inflammasome-dependent functions of NLRC4 may be carried out independently of the inflammasome scaffold ASC. Human Ced4 homologs include APAF1, NOD1 (CARD4), and NOD2 (CARD15). These proteins have at least 1 N-terminal CARD domain followed by a centrally located nucleotide-binding domain (NBD or NACHT) and a C-terminal regulatory domain, found only in mammals, that contains either WD40 repeats or leucine-rich repeats (LRRs). CARD12 is a member of the Ced4 family and can induce apoptosis.
Interactions.
NLRC4 has been shown to interact with NAIP (there is one human NAIP but mice express at least 4 distinct NAIP proteins). The NAIP/NLRC4 interaction may determine the ligand specificity. NLRC4-dependent inflammasome activity activates CASP1. Under certain circumstances, NLRC4 and NLRP3 may occupy the same inflammasome complex.
Clinical significance.
Humans bearing activating mutations in NLRC4 can develop an autoinflammatory syndrome characterized by acute fever, hepatitis, very high serum ferritin, and other features suggestive of Macrophage Activation Syndrome (MAS). Some patients also developed a potentially life-threatening enterocolitis that abated during early childhood. In these patients, chronic and extraordinary elevation of serum IL-18 is found, in distinction from patients with NLRP3 mutations who develop Cryopyrin Associated Periodic Syndromes. A large Japanese family had much milder disease associated with cold-induced urticaria that was caused by a dominantly inherited NLRC4 mutation.


Very long-chain acyl-coenzyme A dehydrogenase deficiency

Very long-chain acyl-coenzyme A dehydrogenase deficiency is a fatty-acid metabolism disorder which prevents the body from converting certain fats to energy, particularly during periods without food.
Those affected by this disorder have inadequate levels of an enzyme that breaks down a group of fats called very long-chain fatty acids.
Signs and symptoms.
Signs and symptoms can include:
Causes.
VLCAD (very long-chain-acyl-dehydrogenase) deficiency is exclusively linked to genetic mutations in DNA. A change of the gene that codes for very long-chain-acyl-CoA-dehydrogenase (VLCAD) results in a deficiency or malfunction of the produced VLCAD enzyme. This mutation occurs on chromosome 17 and can be altered via a variety of pathways. These can range from frameshift mutations, deletion mutations, insertion mutations, and missense mutations. All of which cause the enzyme to function differently in the mitochondria, or in some cases not at all. Due to this mutation, effective levels of very long-chain-acyl-CoA-dehydrogenase are low or absent in the body, giving rise to the array of symptoms listed above.
Genetics.
Mutations in the "ACADVL" gene lead to inadequate levels of an enzyme called very long-chain acyl-coenzyme A (CoA) dehydrogenase. Without this enzyme, long-chain fatty acids from food and fats stored in the body cannot be degraded and processed. As a result, these fatty acids are not converted into energy, which can lead to characteristic signs and symptoms of this disorder, such as lethargy and hypoglycemia. Levels of very long-chain fatty acids or partially degraded fatty acids may build up in tissues and can damage the heart, liver, and muscles, causing more serious complications.
VLCAD deficiency is characterized as an inherited genetic disorder. The mutations that occur within the gene itself are recessive, meaning that an individual has to acquire both recessive mutated genes in order for the disease to manifest. There are various forms of the disease that can be manifested in infancy, adolescence, and adulthood. However, it is still unknown at to what causes the disease to manifest itself in the different life stages.
Diagnosis.
Typically, initial signs and symptoms of this disorder occur during infancy and include low blood sugar (hypoglycemia), lack of energy (lethargy), and muscle weakness. There is also a high risk of complications such as liver abnormalities and life-threatening heart problems. Symptoms that begin later in childhood, adolescence, or adulthood tend to be milder and usually do not involve heart problems. Episodes of very long-chain acyl-coenzyme A dehydrogenase deficiency can be triggered by periods of fasting, illness, and exercise.
It is common for babies and children with the early and childhood types of VLCAD to have episodes of illness known as metabolic crises. Some of the first symptoms of a metabolic crisis are: extreme sleepiness, behavior changes, irritable mood, poor appetite.
Some of these other symptoms of VLCAD in infants may also follow: fever, nausea, diarrhea, vomiting, hypoglycemia. Evaluation of symptom combinations can aid in a positive diagnosis of VLCAD. Since symptoms vary depending on age and onset of the patient, consultation with a metabolic specialist should be considered. Diagnosis is further confirmed through genetic analysis of the VLCAD gene.
Treatment.
Treatment and management of VLCAD deficiency involve dietary restrictions as well as implementation of proper hydration to avoid further complications. Hospitalization due to VLCAD deficiency can be treated with intravenous (IV) glucose for hydration and alkalization of urine and prevention of renal malfunction or failure. Avoidance of fasting periods, high-fat diets, and dehydration is recommended for those who are affected. A diet consisting of low-fat intake and supplemental calories is common for management of VLCAD deficiency. If a metabolic crisis is not treated, a child with VLCAD can develop: breathing problems, seizures, coma, sometimes leading to death.
Prognosis.
Medical screening can confirm occurrences of VLCAD most often in neonatal and infancy stages. Approximately half of all patients show signs of VLCAD deficiency during the neonatal period, one-fourth present later in the first year of infancy, and the final quarter is split between manifestations in childhood and adulthood. Comorbidity of cardiomyopathy, arrhythmias and rhabdomyolysis are extremely common in patients under 1 year old which can lead to complications later in life. Loss of awareness or seizure can occur from hypoketotic hypoglycemia, which is often fatal if not caught in screening. However, prompt treatment shows high promise for improvement. Late-onset myopathic sufferers may only experience muscle-related, vague, sporadic symptoms, and may never be diagnosed. There is an extremely high genotype-phenotype correlation in a presentation. Mitigation of VLCAD symptoms can be achieved through dietary management.


Glycoside hydrolase family 48

In molecular biology, glycoside hydrolase family 48 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 48 CAZY GH_48 comprises enzymes with several known activities; endoglucanase (); cellobiohydrolase ().
An example of an enzyme containing a domain belonging to this family is one of the cellulases (celA) from the genome of the thermophilic anaerobic bacterium "Caldocellum saccharolyticum". The celA gene product is a polypeptide of 1751 amino acids; this has a multidomain structure comprising two catalytic domains and two cellulose-binding domains, linked by Pro-Thr-rich regions. The N-terminal domain encodes an endoglucanase activity on carboxymethylcellulose, consistent with its similarity to several endo-1, 4-beta-D-glucanase sequences, and is a member of the glycoside hydrolase family 9. The C-terminal domain belongs to this family shows similarity to a cellulase from "Clostridium thermocellum" (CelS), which acts synergistically with a second component to hydrolyse crystalline cellulose.


Stevioside

Stevioside is a glycoside derived from the stevia plant, which can be used as a sweetener. Evidence of benefit is lacking for long term effects on weight loss and heart disease risks.
Origin.
Stevioside is the main sweetener with rebaudioside A, found in the leaves of "Stevia rebaudiana", a plant originating in South America. Dried leaves, as well as aqueous extracts, have been used for decades as a sweetener in many countries, notably in Latin America and Asia (Japan, China). Stevioside was discovered in 1931 by French chemists who gave it its name. The sweetening power of stevioside was estimated to be about 300 times stronger than cane sugar.


DXP reductoisomerase

DXP reductoisomerase (1-deoxy--xylulose 5-phosphate reductoisomerase or DXR) is an enzyme that interconverts 1-deoxy-D-xylulose 5-phosphate (DXP) and 2-C-methyl-D-erythritol 4-phosphate (MEP).
It is classified under . It is normally abbreviated DXR, but it is sometimes named IspC, as the product of the "ispC" gene.
DXR is part of the MEP pathway (nonmevalonate pathway) of isoprenoid precursor biosynthesis. DXR is inhibited by fosmidomycin.
This enzyme is required for terpenoid biosynthesis in some organisms, since it is a key enzyme on the MEP pathway for the production of the isoprenoid precursors IPP and DMAPP. In "Arabidopsis thaliana" 1-deoxy-D-xylulose 5-phosphate reductoisomerase is the first committed enzyme of the MEP pathway for isoprenoid precursor biosynthesis. The enzyme requires Mn2+, Co2+ or Mg2+ for activity, with Mn2+ being most effective.


Nodosome

Nodosome refers to protein complexes involving pattern recognition receptors and intracellular pathogen sensors NOD2 and CARD8. Their activation leads to regulation of caspase-1 and NF-kappa-B.


P-glycoprotein

P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein of the cell membrane that pumps many foreign substances out of cells. More formally, it is an ATP-dependent efflux pump with broad substrate specificity. It exists in animals, fungi, and bacteria, and it likely evolved as a defense mechanism against harmful substances.
P-gp is extensively distributed and expressed in the intestinal epithelium where it pumps xenobiotics (such as toxins or drugs) back into the intestinal lumen, in liver cells where it pumps them into bile ducts, in the cells of the proximal tubule of the kidney where it pumps them into urinary filtrate (in the proximal tubule), and in the capillary endothelial cells composing the blood–brain barrier and blood-testis barrier, where it pumps them back into the capillaries.
P-gp is a glycoprotein that in humans is encoded by the "ABCB1" gene. P-gp is a well-characterized ABC-transporter (which transports a wide variety of substrates across extra- and intracellular membranes) of the MDR/TAP subfamily. The normal excretion of xenobiotics back into the gut lumen by P-gp pharmacokinetically reduces the efficacy of some pharmaceutical drugs (which are said to be P-gp substrates). In addition, some cancer cells also express large amounts of P-gp, further amplifying that effect and rendering these cancers multidrug resistant. Many drugs inhibit P-gp, typically incidentally rather than as their main mechanism of action; some foods do as well. Any such substance can sometimes be called a P-gp inhibitor.
P-gp was discovered in 1971 by Victor Ling.
Gene.
A 2015 review of polymorphisms in "ABCB1" found that "the effect of "ABCB1" variation on P-glycoprotein expression (messenger RNA and protein expression) and/or activity in various tissues (e.g. the liver, gut and heart) appears to be small. Although polymorphisms and haplotypes of "ABCB1" have been associated with alterations in drug disposition and drug response, including adverse events with various ABCB1 substrates in different ethnic populations, the results have been majorly conflicting, with limited clinical relevance."
Protein.
P-gp is a 170 kDa transmembrane glycoprotein, which includes 10-15 kDa of N-terminal glycosylation. The N-terminal half of the molecule contains 6 transmembrane domains, followed by a large cytoplasmic domain with an ATP-binding site, and then a second section with 6 transmembrane domains and an ATP-binding site that shows over 65% of amino acid similarity with the first half of the polypeptide. In 2009, the first structure of a mammalian P-glycoprotein was solved (3G5U). The structure was derived from the mouse MDR3 gene product heterologously expressed in "Pichia pastoris" yeast. The structure of mouse P-gp is similar to structures of the bacterial ABC transporter MsbA (3B5W and 3B5X) that adopt an inward facing conformation that is believed to be important for binding substrate along the inner leaflet of the membrane. Additional structures (3G60 and 3G61) of P-gp were also solved revealing the binding site(s) of two different cyclic peptide substrate/inhibitors. The promiscuous binding pocket of P-gp is lined with aromatic amino acid side chains.
Through Molecular Dynamic (MD) simulations, this sequence was proved to have a direct impact in the transporter's structural stability (in the nucleotide-binding domains) and defining a lower boundary for the internal drug-binding pocket.
Species, tissue, and subcellular distribution.
P-gp is expressed primarily in certain cell types in the liver, pancreas, kidney, colon, and jejunum. P-gp is also found in brain capillary endothelial cells.
Function.
Substrate enters P-gp either from an opening within the inner leaflet of the membrane or from an opening at the cytoplasmic side of the protein. ATP binds at the cytoplasmic side of the protein. Following binding of each, ATP hydrolysis shifts the substrate into a position to be excreted from the cell. Release of the phosphate (from the original ATP molecule) occurs concurrently with substrate excretion. ADP is released, and a new molecule of ATP binds to the secondary ATP-binding site. Hydrolysis and release of ADP and a phosphate molecule resets the protein, so that the process can start again.
The protein belongs to the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. P-gp is an ATP-dependent drug efflux pump for xenobiotic compounds with broad substrate specificity. It is responsible for decreased drug accumulation in multidrug-resistant cells and often mediates the development of resistance to anticancer drugs. This protein also functions as a transporter in the blood–brain barrier. Mutations in this gene are associated with colchicine resistance and Inflammatory bowel disease 13. Alternative splicing and the use of alternative promoters results in multiple transcript variants.
P-gp transports various substrates across the cell membrane including:
Its ability to transport the above substrates accounts for the many roles of P-gp including:
It is inhibited by many drugs, such as amiodarone, azithromycin, captopril, clarithromycin, cyclosporine, piperine, quercetin, quinidine, quinine, reserpine, ritonavir, tariquidar, and verapamil.
Regulation of expression and function of P-gp in cancer cells.
At the transcriptional level, the expression of P-gp has been intensively studied, and numerous transcription factors and pathways are known to play roles. A variety of transcription factors, such as p53, YB-1, and NF-κB are involved in the direct regulation of P-gp by binding to the promoter regions of the P-gp gene. Many cell signaling pathways are also involved in transcriptional regulation of P-gp. For example, the PI3K/Akt pathway and the Wnt/β-catenin pathway were reported to positively regulate the expression of P-gp. Mitogen-activated protein kinase (MAPK) signaling includes three pathways: the classical MAPK/ERK pathway, the p38 MAPK pathway, and the c-Jun N-terminal kinase (JNK) pathway, all of which were reported to have implications in the regulation of the expression of P-gp. Studies suggested that the MAPK/ERK pathway is involved in the positive regulation of P-gp; the p38 MAPK pathway negatively regulates the expression of the P-gp gene; and the JNK pathway was reported to be involved in both positive regulation and negative regulation of P-gp.
After 2008, MicroRNAs (miRNAs) were identified as new players in regulating the expression of P-gp in both transcriptional and post-transcriptional levels. Some miRNAs decrease the expression of P-gp. For example, miR-200c down-regulates the expression of P-gp through the JNK signaling pathway or ZEB1 and ZEB2; miR-145 down-regulates the mRNA of P-gp by directly binding to the 3'-UTR of the gene of P-gp and thus suppresses the translation of P-gp. Some other miRNAs increase the expression of P-gp. For example, miR-27a up-regulates P-gp expression by suppressing the Raf kinase inhibitor protein (RKIP); alternatively, miR-27a can also directly bind to the promoter of the P-gp gene, which works in a similar way with the mechanism of action of transcriptional factors.
The expression of P-gp is also regulated by post-translational events, such as post-transcriptional modification, degradation, and intracellular trafficking of P-gp. Pim-1 protects P-gp from ubiquitination and the following degradation in the proteasome. Small GTPases Rab5 down-regulates the endocytotic trafficking of P-gp and thus increases the functional P-gp level on the cell membrane; while Small GTPases Rab4 work in an opposite way: Rab4 down-regulates the exocytotic trafficking of P-gp from intracellular compartments to the cell membrane, and therefore decreases the functional P-gp level on the cell membrane.
Clinical significance.
Drug interactions.
Some common pharmacological inhibitors of P-glycoprotein include: amiodarone, clarithromycin, ciclosporin, colchicine, diltiazem, erythromycin, felodipine, ketoconazole, lansoprazole, omeprazole and other proton-pump inhibitors, nifedipine, paroxetine, reserpine, saquinavir, sertraline, quinidine, tamoxifen, verapamil, and duloxetine. Elacridar and CP 100356 are other common P-gp inhibitors. Zosuquidar and tariquidar were also developed with this in mind. Lastly, valspodar and reversan are other examples of such agents. ABCB1 is linked to the daily dose of warfarin required to maintain the INR to a target of 2.5. Patients with the GT or TT genotypes of the 2677G>T SNP require around 20% more warfarin daily.
Common pharmacological inducers of P-glycoprotein include carbamazepine, dexamethasone, doxorubicin, nefazodone, phenobarbital, phenytoin, prazosin, rifampicin, St. John's wort, tenofovir, tipranavir, trazodone, and vinblastine.
Substrates of P-glycoprotein are susceptible to changes in pharmacokinetics due to drug interactions with P-gp inhibitors or inducers. Some of these substrates include colchicine, ciclosporin, dabigatran, digoxin, diltiazem, fexofenadine, indinavir, morphine, and sirolimus.
Diseases (non-cancer).
Decreased P-gp expression has been found in Alzheimer's disease brains.
Altered P-gp function has also been linked to inflammatory bowel diseases (IBD); however, due to its ambivalent effects in intestinal inflammation many questions remain so far unanswered. While decreased efflux activity may promote disease susceptibility and drug toxicity, increased efflux activity may confer resistance to therapeutic drugs in IBD. Mice deficient in MDR1A develop chronic intestinal inflammation spontaneously, which appears to resemble human ulcerative colitis.
Cancer.
P-gp efflux activity is capable of lowering intracellular concentrations of otherwise beneficial compounds, such as chemotherapeutics and other medications, to sub-therapeutic levels. Consequently, P-gp overexpression is one of the main mechanisms behind decreased intracellular drug accumulation and development of multidrug resistance in human multidrug-resistant (MDR) cancers.
History.
P-gp was first characterized in 1976. P-gp was shown to be responsible for conferring multidrug resistance upon mutant cultured cancer cells that had developed resistance to cytotoxic drugs.
The structure of mouse P-gp, which has 87% sequence identity to human P-gp, was resolved by x-ray crystallography in 2009. The first structure of human P-gp was solved in 2018, with the protein in its ATP-bound, outward-facing conformation.
Research.
Radioactive verapamil can be used for measuring P-gp function with positron emission tomography.
P-gp is also used to differentiate transitional B cells from naive B cells. Dyes such as rhodamine 123 and MitoTracker dyes from Invitrogen can be used to make this differentiation.
MDR1 as a drug target.
It has been suggested that MDR1 inhibitors might treat various diseases, especially cancers, but none have done well in clinical trials.
Single nucleotide polymorphism "rs1045642".
Single Nucleotide Polymorphism are important for the differential activity of the PGP pump.
Homozygous subjects, identified with the TT genotype, are usually more able to extrude xenobiotics from the cell. A Homozygous genotype for the allele ABCB1/MDR1 is capable of a higher absorption from the blood vessels and a lower extrusion into the lumen.
Xenobiotics are extruded at a lower rate with heterozygous (CT) alleles compared to homozygous ones.


Kalirin

Kalirin, also known as Huntingtin-associated protein-interacting protein (HAPIP), protein duo (DUO), or serine/threonine-protein kinase with Dbl- and pleckstrin homology domain, is a protein that in humans is encoded by the "KALRN" gene. Kalirin was first identified in 1997 as a protein interacting with huntingtin-associated protein 1. Is also known to play an important role in nerve growth and axonal development.
Kalirin is a member of the Dbl family of proteins and is a Rho guanine nucleotide exchange factor.
It is named after the multiple-handed Hindu goddess Kali for its ability to interact with numerous other proteins. Kalirin's other name, DUO, comes from the fact that it is 98% identical to rat DUO protein and 80.6% identical to a human protein named TRIO. Unlike TRIO, which is expressed in numerous tissues, Kalirin isoforms are mainly found in the brain.
Clinical significance.
Several isoforms of Kalirin are produced through alternative splicing. One of the isoforms, Kalirin-7, was found to be necessary for the remodeling of synapses in mature cortical neurons and is thought to be important in the development of schizophrenia, as demonstrated by adolescent development of schizophrenia-like symptoms in kalirin knockout mice. Alzheimer's disease may also be linked to kalirin-7.
The KALRN gene, has been linked to multiple neurological disorders both through large exome and genome sequencing efforts, as well as post mortem and clinical studies.
Several mutations within KALRN have been linked to neurological disease. In autism spectrum disorder a frameshift mutation was found that is likely to lead to transcript decay, and heterozygosity. Another, found within the second GEF domain, is predicted to be highly deleterious to RhoA-GEF activity and likely affects the function of kalirin9 and 12 isoforms early in neuronal development. A patient harboring a homozygous mutation in kalirin’s spectrin repeat domain was found to have severe intellectual disability, and both truncating and missense mutations have been identified in patients with developmental delay. Several intronic variants have been associated with addiction and were found to alter the function of brain regions responsible for reward anticipation. This link to addiction is supported by animal models, where loss of kalirin results in altered cocaine self-administration and synaptic and expression changes in response to cocaine. Perhaps the most compelling genetic links are between kalirin and schizophrenia. Numerous missense mutations in KALRN have been identified in exome sequencing studies of schizophrenia cohorts that are predicted to be deleterious to protein function.
Neuronal studies have provided insight into the mechanisms of some missense mutations, particularly within the GEF domains of KALRN. A mutation found within the Rac-GEF domain was found to induce strong reductions in Rac activation, neuronal branching and spine density. These effects were mirrored by mutations in the RhoA-GEF domain, producing similar neuronal deficits, but by "promoting" RhoA-GEF activity. In addition to exome sequencing, post-mortem studies have consistently found alterations in kalirin transcript levels within the brain further supporting a role for kalirin in the etiology of schizophrenia.
In addition to neurodevelopmental disorders, kalirin has been found to be underexpressed in the post-mortem Alzheimer’s brain. This loss of kalirin expression was recapitulated in animal models of Alzheimer’s disease. Moreover, introduction of kalirin7 into culture or animal models of Alzheimer’s disease was able to rescue synaptic and behavioral deficits, suggesting an important role for kalirin in regulating synapse loss and cognitive impairment in Alzheimer’s disease.
Function.
The majority of kalirin’s effects are induced through its catalytic GEF domain signaling. By promoting the release of GDP from Rac and RhoA , it acts as an activator of GTPase signaling within the cell. Although able to activate Rac and RhoA, much of its activity in regulating neuronal morphology has been attributed to Rac-PAK pathway activation. kalirin has found been found to exert control over dendritic arborization, axonal growth, dendritic spine formation and synaptic activity and plasticity. These effects are regulated by protein-protein interactions and post-translational modifications within the non-catalytic domains, and have been shown to exert control over kalirin subcellular targeting and activation.
Kalirin has been found to play a critical role in synaptic activity and plasticity. Loss of KALRN results in decreased nMDAr and AMPAr-mediated mEPSC, and kalirin7 knockout animals show strong deficits in NMDAr mediated long term potentiation and long term depression. This may be linked to the ability to regulate RAC-PAK signaling and actin dynamics, which in turn can regulate the size and density of dendritic spines. Within dendritic spines, kalirin interacts with multiple disease related proteins to regulate synapse strength. It directly interacts with the schizophrenia risk factor DISC1 that can act to suppress kalirin function within the spine. Furthermore, kalirin7 directly interacts with the GluN2B subunit of the NMDA receptor and PSD95 within the post-synaptic density.
The importance of KALRN in neurodevelopment is supported by knockout animal models that display profound deficiencies in multiple behavioral tasks. Kalirin knockout animals display reduced GEF activity, dendritic arborization and spine density. These deficits may be linked to the observed reductions in prepulse inhibition, sociability and increased locomotor activity. Notably, loss of kalirin results in deficits in working memory, but not reference memory. The generation of a kalirin7 specific knockout animal model revealed similar deficits in spine density, suggesting a central role of kalirin7 in regulating neuronal connectivity. Both full and kalirin7 specific knockout animals show decreased anxiety-like behavior and impaired contextual fear learning.
Expression.
Multiple isoforms, arising from alternate splicing and promoter usage, display varying tissue and developmental expression. Control over kalirin expression is exerted through the use of alternate promoters which produce alternate start sites and restrict expression to specific neuronal subpopulations, and alter kalirin activity within neurons. During early development, the long kalirin9 and 12 isoforms are predominant in the brain. These isoforms contain both a Rac and a RhoA selective GEF domain, and control axonal growth and dendritic branching. Kalirin9 and 12 are also expressed ubiquitously throughout the body and have functions outwith the brain. However, during neurodevelopment the kalirin7 isoform is preferentially expressed during periods of synaptogenesis, and this isoform displays highly restricted cortical expression. Kalirin7 expresses only the N-terminal domains, including the Rac-GEF domain along with a c-terminal PDZ-binding domain that strongly targets kalirin7 to the post-synaptic density. It is likely this subcellular distribution is vital to kalirin7 function, as this isoform exerts control dendritic spine density and synaptic plasticity. It is likely that mutations that result in deregulation of kalirin function within the brain is responsible for the role of kalirin within multiple neurological disorders.


Endo-alpha-N-acetylgalactosaminidase

Endo-alpha-N-acetylgalactosaminidase may refer to:


RGD motif

The tripeptide Arg-Gly-Asp (RGD) consists of Arginine, Glycine, and Aspartate. It was originally identified as the amino acid sequence within the extracellular matrix protein fibronectin that mediates cell attachment. The RGD cell binding sequence has since been identified in other extracellular matrix proteins, including vitronectin and laminin. The family of membrane proteins known as integrins act as receptors for these cell adhesion molecules via the RGD motif. A subset of the integrins recognize the RGD motif within their ligands, the binding of which mediates both cell-substratum and cell-cell interactions. These integrins include αvβ3, α5β1 and αIIbβ3.
The RGD domain is both sufficient and indispensable for cell membrane binding. As such, the RGD cell binding motif has supreme relevance in the fields of oncology, tissue engineering and regenerative medicine. Because of their cell-adhesive activity, RGD peptides are frequently incorporated into biomaterials designed to promote wound healing. RGD is also an important peptide sequence often used in Targeted therapy. For example, the RGD peptide can be used to target cancer cells on which cell membrane integrins are up-regulated compared to healthy cells.
Though the minimum sequence peptide RGD retains the property of cell adhesion, integrin-RGD bonds are considerably weaker than integrin-fibronectin bonds. The reduced adhesion strength is likely due to both lack of secondary structure and other synergistic domains, namely PHSRN, present in the full-length protein. Furthermore, full length protein domains differentially mediate cell morphology, cell migration and cell proliferation compared to RGD alone.
Other minimum sequence motifs have been identified, including the GFOGER 30 amino acid sequence from collagen 1 and the YGISR and A5G81 sequences from laminin.