SIM2

Single-minded homolog 2 is a protein that in humans is encoded by the "SIM2" gene. It plays a major role in the development of the central nervous system midline as well as the construction of the face and head.
Function.
SIM1 and SIM2 genes are "Drosophila" single-minded (sim) gene homologs. The Drosophila sim gene encodes a transcription factor that is a master regulator of neurogenesis of midline cells in the central nervous system. SIM2 maps within the so-called Down syndrome chromosomal region, specifically on the q arm of chromosome 21, band 22.2. Based on the mapping position, its potential function as transcriptional repressor and similarity to Drosophila sim, it is proposed that SIM2 may contribute to some specific Down syndrome phenotypes
Interactions.
SIM2 has been shown to interact with Aryl hydrocarbon receptor nuclear translocator.
When the SIM2 gene is tranfected into PC12 cells, it effects the normal cycle of cell maturation. SIM2 inhibits the expression of cyclin E, which in turn inhibits the cell's ability to pass through the G1/S checkpoint and suppresses the cell's proliferation ability. it also up-regulates the presence of p27, a growth inhibitor protein. The presence of p27 inhibits the activation of cell cycle regulatory kinases.
Disease state.
There are three states of the gene: +/+, +/-, and -/-. When the gene is expressed as SIM2 -/-, it is considered disrupted and many physical malformations are seen, particularly in the craniofacial area. Individuals with SIM2 -/- have either a full or partial secondary palate cleft and malformations in the tongue and pterygoid processes of the sphenoid bone. These malformations cause aerophagia, or the swallowing of air, and postnatal death. Severe aerophagia leads to accumulation of air in the gastrointestinal tract, causing the belly to be distended.
It is thought that the over-expression of the SIM2 gene brings about some of the phenotypic deformities that are characteristic of Down syndrome. The presence of SIM2 mRNA in many parts of the brain known to show deformities in individuals with Down syndrome, as well as in the palate, oral and tongue epithelia, mandibular and hyoid bones.
SIM2 Short (SIM2s).
There are two known isoforms of SIM2 which play different roles in various tissues. The isoform SIM2 Short (SIM2s) has been shown to be specifically expressed in mammary gland tissue. SIM2s is a splice variant which lacks exon 11 of SIM2. It has been researched that SIM2s acts in mammary gland development and has tumor suppressive characteristics specifically in breast cancer. In a mouse specimen, when SIM2s was not expressed in mammary epithelial cells there were development defects leading to cancer-like characteristics in the cells. The defects were increased cell proliferation, cellular invasion of local stroma, loss of cellular polarity, and loss of E-cadherin cellular adhesion molecules. These observations suggest that SIM2s is essential for proper mammary gland development. Experiments reintroducing SIM2s in human breast cancer cells allowed for the tumor suppressive characteristics to be observed. Comparing normal human breast cells to human breast cancer cells with immunohistochemical staining showed that SIM2s was expressed more in the normal than the cancerous. Reintroducing SIM2s expression in breast cancer cells showed a decrease in growth, proliferation, and invasiveness. SIM2s represses the actions of the matrix metalloprotease-3 gene (MMP3) which include cell migration, cancer progression, and epithelial to mesenchymal transitions (EMT). SIM2s also represses the SLUG transcription factor which in turn suppresses EMT. EMT suppression allows for E-cadherin to remain and for the cell to not undergo pathological EMT associated with tumor formation. These actions show the tumor suppressive effects of SIM2s in mammary epithelium.
Knockout model.
Scientists can purposefully "knockout" or cause the gene to be disrupted. To do this, they perform homologous recombination and eliminate the predicted start codon and the following 47 amino acids. Then the EcoRI restriction site is introduced into the chromosome.


Nigerose

Nigerose, also known as sakebiose, is an unfermentable sugar obtained by partial hydrolysis of nigeran, a polysaccharide found in black mold, but is also readily extracted from the dextrans found in rice molds and many other fermenting microorganisms, such as "L. mesenteroides". It is a disaccharide made of two glucose residues, connected with a 1->3 link. It is a product of the caramelization of glucose.


Ent-sandaracopimaradiene synthase

Ent-sandaracopimaradiene synthase (, "OsKS10", "ent-sandaracopimara-8(14),15-diene synthase") is an enzyme with systematic name "ent-copalyl-diphosphate diphosphate-lyase (ent-sandaracopimara-8(14),15-diene-forming)". This enzyme catalyses the following chemical reaction
ent-Sandaracopimaradiene is a precursor of the rice oryzalexins A-F.


Alkylphenol

Alkylphenols are a family of organic compounds obtained by the alkylation of phenols. The term is usually reserved for commercially important propylphenol, butylphenol, amylphenol, heptylphenol, octylphenol, nonylphenol, dodecylphenol and related "long chain alkylphenols" (LCAPs). Methylphenols and ethylphenols are also alkylphenols, but they are more commonly referred to by their specific names, cresols and xylenols.
Production.
The long-chain alkylphenols are prepared by alkylation of phenol with alkenes:
In this way, about 500M kg/y are produced.
Environmental controversy over nonylphenols.
Alkylphenols are xenoestrogens. The European Union has implemented sales and use restrictions on certain applications in which nonylphenols are used because of their alleged "toxicity, persistence, and the liability to bioaccumulate" but the United States EPA has taken a slower approach to make sure that action is based on sound science.
Uses of long-chain alkylphenols.
The long-chain alkylphenols are used extensively as precursors to the detergents, as additives for fuels and lubricants, polymers, and as components in phenolic resins. These compounds are also used as building block chemicals that are also used in making fragrances, thermoplastic elastomers, antioxidants, oil field chemicals and fire retardant materials. Through the downstream use in making alkylphenolic resins, alkylphenols are also found in tires, adhesives, coatings, carbonless copy paper and high performance rubber products. They have been used in industry for over 40 years.


Glycitin

Glycitin (glycitein 7-"O"-glucoside) is an isoflavone found in soy, and remain to various degrees in soy products like tofu and soymilk. as well as fermented soy sauce. Although glycitin has its own health associated properties (below), it can be transformed to glycitein by human intestinal flora by the action of beta-glucosidases.
Properties.
Some interesting effects of glycitin include human dermal fibroblast cell proliferation and migration via TGF‐β signaling, glycitin treatment produces anti-photoaging effects such as collagen type I and collagen type III increase at both the mRNA and protein levels. Other noted effects decreased elastase, and decreased β‐galactosidase activation. In conjunction with 4′,6,7-trimethoxyisoflavone (TMF), an isoflavone that promotes fibroblast migration but not proliferation, wound healing and anti-scarring activity (reorganization and wound fibrosis inhibition) were significantly and synergistically boosted in both "in vivo" mice and "in vitro".


XbaI

"Xba"I is a restriction enzyme isolated from the bacterium "Xanthomonas badrii"


Galactitol 2-dehydrogenase

In enzymology, a galactitol 2-dehydrogenase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are galactitol and NAD+, whereas its 3 products are D-tagatose, NADH, and H+.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-OH group of donor with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is galactitol:NAD+ 2-oxidoreductase. This enzyme is also called dulcitol dehydrogenase. This enzyme participates in galactose metabolism.


Melibiulose

Melibiulose is a disaccharide formed from fructose and galactose similar to melibiose


Diiodophenylpyruvate reductase

In enzymology, a diiodophenylpyruvate reductase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are 3-(3,5-diiodo-4-hydroxyphenyl)lactate and NAD+, whereas its 3 products are 3-(3,5-diiodo-4-hydroxyphenyl)pyruvate, NADH, and H+.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-OH group of donor with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is 3-(3,5-diiodo-4-hydroxyphenyl)lactate:NAD+ oxidoreductase. Other names in common use include aromatic alpha-keto acid, KAR, and 2-oxo acid reductase.


6-Pyruvoyltetrahydropterin synthase

In enzymology, a 6-pyruvoyltetrahydropterin synthase (PTPS) () is an enzyme that catalyzes the following chemical reaction:
7,8-Dihydroneopterin triphosphate formula_1 6-pyruvoyltetrahydropterin + triphosphate
This reaction is the second step (shown above) in the biosynthesis of tetrahydrobiopterin from GTP, which is used as a cofactor in the synthesis of aromatic amino acid monooxygenases and nitric oxide synthase PTPS converts 7,8-dihydroneopterin triphosphate to 6-pyruvoyltetrahydropterin (PTP) through the loss of the triphosphate group, a stereospecific reduction of the double bond between the top right nitrogen and carbon in the ring on the triphosphate on the right, the oxidation of the hydroxyl groups located on the first and second carbons of the side chain, and an internal base-catalyzed hydrogen transfer. ] 6-pyruvoyltetrahydropterin synthase (PTPS) can be found in the cytoplasm as well as the nucleus of cells according to immunohistochemical studies conducted. It has also been found that in higher species 6-pyruvoyltetrahydropterin synthase (PTPS) can undergo post-translational modification.
This enzyme participates in tetrahydrobiopterin biosynthesis.
Nomenclature.
This enzyme belongs to the family of lyases, to be specific, those carbon-oxygen lyases acting on phosphates. The systematic name of this enzyme class is 6-[(1S,2R)-1,2-dihydroxy-3-triphosphooxypropyl]-7,8-dihydropterin triphosphate-lyase (6-pyruvoyl-5,6,7,8-tetrahydropterin-forming). Other names in common use include 2-amino-4-oxo-6-[(1S,2R)-1,2-dihydroxy-3-triphosphooxypropyl]-7,8-, and dihydroxypteridine triphosphate lyase.
Structure.
6-pyruvoyltetrahydropterin synthase (PTPS) is a hexamer with "D"3 symmetry, and dimensions 60 × 60 × 60 A ̊. It is composed of identical subunits formed from a dimer of trimers. A 12-stranded antiparallel b-barrel is formed by the trimer of dimers and creates a pore within PTPS, with a 6 to 12 A ̊ diameter. The trimers are connected by contact between the β-sheets of monomers, which are perpendicular to each other, separated by less than 4 Angstroms, and connected in three locations residues 20–24, 48–51, and 89–91.
One enzymatic active site is located where the three monomers come together in each subunit of the hexamer. Three histidine residues: His23, His48 and His50 create a transition metal binding site where Zn(II) binds and is the cause of enzymatic activity in the center of the pore. Above the Zn(II) ion are GluA133 and CysA42, which are catalytically important because they are close to the metal but do not bind to it. The lack of binding implies that the substrate binds to the Zn(II) inside the pore during catalysis.
Genetics.
This enzyme 6-pyruvoyltetrahydropterin synthase is encoded by the PTS gene. A mutation in the 6-PTS gene may be the cause of a hereditary dystonic disorder. There have been four mutations of the 6-PTS gene found. The mutations include two homozygous mutations, R25Q and I114V, and two compound heterozygous mutations, R16C and K120stop. The deficiency is only associated with the recessive gene being passed on from parent to child.
Clinical significance.
A lack of 6-pyruvoyltetrahydropterin synthase (PTPS) is the most common cause of a deficiency of tetrahydrobiopterin. Tetrahydrobiopterin deficiency leads to hyperphenylalaninemia and the inability to make neurotransmitters such as dopamine and serotonin. PTPS deficiency has been shown to lead to severe mental retardation, delayed motor development, and seizures. Low levels of tetrahydrobiopterin production, opposed to near complete lack of tetrahydrobiopterin may cause fluctuations in the symptoms experienced throughout the day.


Phospholipase A

Phospholipase A can refer to:
An enzyme that displays both phospholipase A1 and phospholipase A2 activities is called a Phospholipase B (see main article on phospholipases).


Z-FA-FMK

Z-FA-FMK, abbreviating for benzyloxycarbonyl-phenylalanyl-alanyl-fluoromethyl ketone, is a very potent irreversible inhibitor of cysteine proteases, including cathepsins B, L, and S, cruzain, and papain. It also selectively inhibits effector caspases 2, 3, 6, and 7 but not caspases 8 and 10. This compound has been shown to block the production of IL1-α, IL1-β, and TNF-α induced by LPS in macrophages by inhibiting NF-κB pathways.


Haloacid dehydrogenase superfamily

The haloacid dehydrogenase superfamily (HAD superfamily) is a superfamily of enzymes that include phosphatases, phosphonatases, P-type ATPases, beta-phosphoglucomutases, phosphomannomutases, and dehalogenases, and are involved in a variety of cellular processes ranging from amino acid biosynthesis to detoxification.
Examples.
A HAD domain is found in several distinct proteins including:
Human genes encoding proteins that contain this domain include:


Indoleacetate decarboxylase

Indoleacetate decarboxylase (IAD) is a glycyl radical enzyme (therefore member of the GRE superfamily ) that catalyses the decarboxylation of indoleacetate to form skatole, which is a malodorous organic compound that gives animal faeces their characteristic smell. This decarboxylation is the last step of the tryptophan fermentation in some types of anaerobic bacteria.
Tryptophan (Trp), Tyrosine (Tyr) and Phenylalanine (Phe) are aromatic aminoacids that can be degraded by certain types of fermenting bacteria. These bacteria create indoleacetate, p-hydroxyphenylacetate and phenylacetate, respectively. In addition, some bacteria carry out a further step, decarboxylating these compounds and creating skatole, cresol and toluene, respectively, which are volatile aromatic compounds. Out of these three compounds, skatole is the most noticeable as its distinct faecal malodour is detectable at the lowest concentration of 0.00056 parts per million (0.0030 mg/m3).
Discovery.
The study that led to the discovery of the indoleacetate decarboxylase enzyme was published in 2018., and was carried out by an international research team, co-led by Huimin Zhao, from the A*STAR Institute of Chemical and Engineering Sciences.
The researchers compared the genoma of two skatole producers bacteria, "Clostridium scatologenes" ("Cs") and "Olsenella scatoligenes" ("Os"), isolated from acidic sediment and swine manure respectively, in order to identify a candidate GRE with IAD activity. The team found two proteins that share approximately half of the sequence identity, suggesting they might have the same function as well: A0A0E3M8P3 in "Cs" (CsIAD) and A0A100YXA1 in "Os" (OsIAD). To confirm their biochemical activity, the researchers recombinantly produced the enzyme OsIAD and its protein neighborhood, in which it was its activating enzyme, OsIADAE. Once the enzyme was conveniently activated, it was incubated with indoleacetate, and this process resulted in the generation of skatole, proving that OsAID was an IAD. This enzyme was also incubated with phenylacetate and p-hydroxyphenylacetate and there was no activity, indicating high substrate specificity.
Structure.
The structure of the IAD hasn't been discovered yet, but as a glycyl radical enzyme (GRE) it is known that its core structure is formed by a 10-stranded β-barrel surrounded by α-helices.
Reaction mechanism.
Indoleacetate decarboxylase takes part in the tryptophan fermentation, which involves two steps. The first one consists of the degradation of the amino acid into indole-3-acetate. And in the second step, the IAD catalyses the decarboxylation of the indole-3-acetate to form the final product, skatole.
The decarboxylation of indole-3-acetate is chemically difficult since it leaves an unstable carbanion because of the direct elimination of CO2. This chemical reaction is promoted by 1-electron oxidation of indole-3-acetate through a proton-coupled electron transfer (PCET), which requires the transfer of the indolic-NH proton to a suitably positioned base, producing an indoleacetate anion radical intermediate.
Biological relevance.
The discovery of IAD provides a way to identify the skatole-producing bacteria and helps us understand the fermentation pathways and their products, which had not been found in previous studies.
Fermentation of aromatic amino acids (in this case tryptophan) leads to a large variety of products that remain with their stable aromatic rings. When this fermentation takes place in the human or animal gut, these compounds can accumulate in the host bloodstream and have global physiological or pathological effects.
Several analysis in humans showed the presence of IAD in two more bacteria: "Olsenella uli" from the gingival crevice, and "Faecalicatena contorta" from gangrenous appendicitis. This enzyme also contributes to halitosis, since it is present in certain sequenced human oral bacteria, and this discovery could open some doors to treat this condition. Furthermore, the mosquitoes that cause Japanese encephalitis and West Nile virus are known to be attracted by skatole, so blocking the production of this molecule might help to combat the spread of this infections
In the farming industry, skatole is a major component of the manure smell and the source of some bovine respiratory diseases. Skatole causes acute bovine pulmonary edema (ABPD, a condition caused by excess fluid in the lungs) and emphysema (condition that causes shortness of breath) in cattle. It is also responsible for the intense offensive odor and taste that can be evident when cooking or eating pork. Many ruminants are susceptible to ABPE, a disease in which skatole acts as a very selective pneumotoxin that causes the degeneration of certain lung tissues. Therefore, by knowing the IAD mechanism, the skatole products could be suppressed and with them the unpleasant smell of animal feaces and the other pathological effects that has on many living creatures.


Cimoxatone

Cimoxatone (MD 780515) is a reversible inhibitor of MAO-A (RIMA). It has a significant food interaction–related adverse effect in combination with tyramine. It was never marketed.


Peflin

Peflin is a protein that in humans is encoded by the "PEF1" gene.
PEF1 is a Ca(2+)-binding protein that belongs to the penta-EF hand (PEF) protein family, which includes the calpain small subunit (CAPNS1; MIM 114170), sorcin (SRI; MIM 182520), grancalcin (GCA; MIM 607030), and ALG2 (PDCD6; MIM 601057) (Kitaura et al., 2001).[supplied by OMIM]
Interactions.
PEF1 has been shown to interact with PDCD6.


Na-K-Cl cotransporter

The Na-K-Cl cotransporter (NKCC) is a protein that aids in the secondary active transport of sodium, potassium, and chloride into cells. In humans there are two isoforms of this membrane transport protein, NKCC1 and NKCC2, encoded by two different genes ("SLC12A2" and "SLC12A1" respectively). Two isoforms of the NKCC1/Slc12a2 gene result from keeping (isoform 1) or skipping (isoform 2) exon 21 in the final gene product.
NKCC1 is widely distributed throughout the human body; it has important functions in organs that secrete fluids. NKCC2 is found specifically in the kidney, where it serves to extract sodium, potassium, and chloride from the urine so that they can be reabsorbed into the blood.
Function.
NKCC proteins are membrane transport proteins that transport sodium (Na), potassium (K), and chloride (Cl) ions across the cell membrane. Because they move each solute in the same direction, NKCC proteins are considered symporters. They maintain electroneutrality by moving two positively charged solutes (sodium and potassium) alongside two parts of a negatively charged solute (chloride). Thus the stoichiometry of the transported solutes is 1Na:1K:2Cl. However, there is a notable exception in squid giant axon as the symporter in this special cell has a stoichiometry of 2Na:1K:3Cl, although electroneutrality is still maintained.
NKCC1.
NKCC1 is widely distributed throughout the body, especially in organs that secrete fluids, called exocrine glands. In cells of these organs, NKCC1 is commonly found in the basolateral membrane, the part of the cell membrane closest to the blood vessels. Its basolateral location gives NKCC1 the ability to transport sodium, potassium, and chloride from the blood into the cell. Other transporters assist in the movement of these solutes out of the cell through its apical surface. The end result is that solutes from the blood, particularly chloride, are secreted into the lumen of these exocrine glands, increasing the luminal concentration of solutes and causing water to be secreted by osmosis.
In addition to exocrine glands, NKCC1 is necessary for establishing the potassium-rich endolymph that bathes part of the cochlea, an organ necessary for hearing. Inhibition of NKCC1, as with furosemide or other loop diuretics, can result in deafness.
NKCC1 is also expressed in many regions of the brain during early development, but not in adulthood. This change in NKCC1 presence seems to be responsible for altering responses to the neurotransmitters GABA and glycine from excitatory to inhibitory, which was suggested to be important for early neuronal development. As long as NKCC1 transporters are predominantly active, internal chloride concentrations in neurons is raised in comparison with mature chloride concentrations, which is important for GABA and glycine responses, as respective ligand-gated anion channels are permeable to chloride. With higher internal chloride concentrations, outward driving force for this ions increases, and thus channel opening leads to chloride leaving the cell, thereby depolarizing it. Put another way, increasing internal chloride concentration increases the reversal potential for chloride, given by the Nernst equation. Later in development expression of NKCC1 is reduced, while expression of a KCC2 K-Cl cotransporter increased, thus bringing internal chloride concentration in neurons down to adult values.
NKCC2.
NKCC2 is specifically found in cells of the thick ascending limb of the loop of Henle and the macula densa in nephrons, the basic functional units of the kidney. Within these cells, NKCC2 resides in the apical membrane abutting the nephron's lumen, which is the hollow space containing urine. It thus serves both in sodium absorption and in tubuloglomerular feedback.
The thick ascending limb of the loop of Henle begins at the deeper portion of the renal outer medulla. Here, the urine has a relatively high concentration of sodium. As urine moves towards the more superficial portion of the thick ascending limb, NKCC2 is the major transport protein by which sodium is reabsorbed from the urine. This outward movement of sodium and the lack of water permeability in the thick ascending limb, creates a more diluted urine. According to the stoichiometry outlined above, each molecule of sodium reabsorbed brings one molecule of potassium and two molecules of chloride. Sodium goes on to be reabsorbed into the blood, where it contributes to the maintenance of blood pressure.
Furosemide and other loop diuretics inhibit the activity of NKCC2, thereby impairing sodium reabsorption in the thick ascending limb of the loop of Henle. The action of these loop diuretics also reduces potassium reabsorption through the NKCC2 cotransporter and consequently increases tubular flow rate which enhances potassium secretion and emphasises the hypokalaemic effect.
Impaired sodium reabsorption increases diuresis by three mechanisms:
Loop diuretics therefore ultimately result in decreased blood pressure.
The hormone vasopressin stimulates the activity of NKCC2. Vasopressin stimulates sodium chloride reabsorption in the thick ascending limb of the nephron by activating signaling pathways. Vasopressin increases the traffic of NKCC2 to the membrane and phosphorylates some serine and threonine sites on the cytoplasmic N-terminal of the NKCC2 located in the membrane, increasing its activity. Increased NKCC2 activity aids in water reabsorption in the collecting duct through aquaporin 2 channels by creating a hypo-osmotic filtrate.
Genetics.
NKCC1 and NKCC2 are encoded by genes on the long arms of chromosomes 15 and 5, respectively. A loss of function mutation of NKCC2 produces Bartter syndrome, an autosomal recessive disorder characterized by hypokalemic metabolic alkalosis with normal to low blood pressure.
Kinetics.
The energy required to move solutes across the cell membrane is provided by the electrochemical gradient of sodium. Sodium's electrochemical gradient is established by the Na-K ATPase, which is an ATP-dependent enzyme. Since NKCC proteins use sodium's gradient, their activity is indirectly dependent on ATP; for this reason, NKCC proteins are said to move solutes by way of secondary active transport.
There are three isoforms of NKCC2 created by alternative splicing (NKCC2A, B and F). Each one of these isoforms is expressed at different portions of the thick ascending limb and they have different affinity for sodium that correlates with its localization. The isoform F is more predominant in the deeper portion of the thick ascending limb, where the sodium concentration is very high. NKCC2F is the isoform with the lowest affinity for sodium and this allows the cotransporter to work at this sodium rich environment. Conversely, NKCC2B is expressed at the more superficial portion of the thick ascending limb and the macula densa, and it has the highest affinity for sodium. This permits NKCC2B to function in this sodium-depleted environment without saturating. The NKCC2A isoform shows an intermediate distribution and affinity for sodium. In this way, NKCC2 is able to function properly along the range of sodium concentrations found along the thick ascending limb.


Aldosterone synthase

Aldosterone synthase, also called steroid 18-hydroxylase, corticosterone 18-monooxygenase or P450C18, is a steroid hydroxylase cytochrome P450 enzyme involved in the biosynthesis of the mineralocorticoid aldosterone and other steroids. The enzyme catalyzes sequential hydroxylations of the steroid angular methyl group at C18 after initial 11β-hydroxylation (the enzyme has steroid 18-hydroxylase activity as well as steroid 11 beta-hydroxylase activity). It is encoded by "CYP11B2" gene in humans.
Aldosterone synthase is a protein which is only expressed in the zona glomerulosa of the adrenal cortex and is primarily regulated by the renin–angiotensin system. It is the sole enzyme capable of synthesizing aldosterone in humans and plays an important role in electrolyte balance and blood pressure.
Genetics.
Aldosterone synthase is encoded on chromosome 8q22 by the CYP11B2 gene. The gene contains 9 exons and spans roughly 7000 base pairs of DNA. CYP11B2 is closely related with CYP11B1. The two genes show 93% homology to each other and are both encoded on the same chromosome. Research has shown that calcium ions activate transcription factors at CYP11B2 through well defined interactions at the 5'-flanking region of CYP11B2.
Aldosterone synthase is a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, and other lipids.
Function.
Aldosterone synthase is the enzyme that has steroid 18-hydroxylase activity as well as steroid 11 beta-hydroxylase activity. The 18-hydroxylase activity consists in catalyzing sequential hydroxylations of the steroid angular methyl group at C18.
Whereas steroid 11β-hydroxylase (encoded by "CYP11B1" gene) only catalyzes hydroxylation at position 11 beta (mainly of 11-deoxycorticosterone and 11-deoxycortisol), aldosterone synthase (encoded by "CYP11B2" gene) catalyzes the synthesis of aldosterone from deoxycorticosterone, a process that successively requires hydroxylation at positions 11 beta and 18 and oxidation at position 18.
Adrenocorticotropic hormone is assumed to play a role in the regulation of aldosterone synthase likely through stimulating the synthesis of 11-deoxycorticosterone which is the initial substrate of the enzymatic action in aldosterone synthase.
Metabolism.
Aldosterone synthase converts 11-deoxycorticosterone to corticosterone, to 18-hydroxycorticosterone, and finally to aldosterone:
In human metabolism the biosynthesis of aldosterone largely depends on the metabolism of cholesterol. Cholesterol is metabolized in what is known as the early pathway of aldosterone synthesis and is hydroxylated becoming (20R,22R)-dihydroxycholesterol which is then metabolized as a direct precursor to pregnenolone. Pregnenolone can then followed one of two pathways which involve the metabolism of progesterone or the testosterone and estradiol biosynthesis. Aldosterone is synthesized by following the metabolism of progesterone.
In the potential case where aldosterone synthase is not metabolically active the body accumulates 11-deoxycorticosterone. This increases salt retention leading to increased hypertension.
Substrates.
Aldosterone synthase shows different catalytic activity during metabolism of its substrates. Here are some of the substrates, grouped by catalytic activity of the enzyme:
Methyl oxidase deficiency.
Lack of metabolically active aldosterone synthase leads to corticosterone methyl oxidase deficiency type I and II. The deficiency is characterized clinically by salt-wasting, failure to thrive, and growth retardation. The in-active proteins are caused by the autosomal recessive inheritance of defective CYP11B2 genes in which genetic mutations destroy the enzymatic activity of aldosterone synthase. Deficient aldosterone synthase activity results in impaired biosynthesis of aldosterone while corticosterone in the zona glomerulosa is excessively produced in both corticosterone methyl oxidase deficiency type I and II. The corticosterone methyl oxidase deficiencies both share this effect however type I causes an overall deficiency of 18-hydroxycorticosterone while type II overproduces it.
Enzymatic inhibition.
Inhibition of aldosterone synthase is currently being investigated as a medical treatment for hypertension, heart failure, and renal disorders. Deactivation of enzymatic activity reduces aldosterone concentrations in plasma and tissues which decreases mineralocorticoid receptor-dependent and independent effects in cardiac vascular and renal target organs. Inhibition has shown to decrease plasma and urinary aldosterone concentrations by 70 - 80%, rapid hypokalaemia correction, moderate decrease of blood pressure, and an increase plasma renin activity in patients who are on a low-sodium diet. Ongoing medical research is focusing on the synthesis of second-generation aldosterone synthase inhibitors to create an ideally selective inhibitor as the current, orally delivered, LCl699 has shown to be non-specific to aldosterone synthase.


3-hydroxyanthranilate 4-C-methyltransferase

In enzymology, a 3-hydroxyanthranilate 4-C-methyltransferase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are S-adenosyl methionine and 3-hydroxyanthranilate, whereas its two products are S-adenosylhomocysteine and 3-hydroxy-4-methylanthranilate.
This enzyme belongs to the family of transferases, specifically those transferring one-carbon group methyltransferases. The systematic name of this enzyme class is S-adenosyl-L-methionine:3-hydroxyanthranilate 4-C-methyltransferase. This enzyme is also called 3-hydroxyanthranilate 4-methyltransferase.


6-phospho-beta-glucosidase

In enzymology, a 6-phospho-beta-glucosidase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are 6-phospho-beta-D-glucosyl-(1,4)-D-glucose and H2O, whereas its two products are D-glucose and D-glucose 6-phosphate.
This enzyme belongs to the family of hydrolases, specifically those glycosidases that hydrolyse O- and S-glycosyl compounds. The systematic name of this enzyme class is 6-phospho-beta-D-glucosyl-(1,4)-D-glucose glucohydrolase. Other names in common use include phospho-beta-glucosidase A, phospho-beta-glucosidase, and phosphocellobiase. This enzyme participates in glycolysis / gluconeogenesis.
Structural studies.
As of late 2007, only one structure has been solved for this class of enzymes, with the PDB accession code .


Lupus anticoagulant

Lupus anticoagulant is an immunoglobulin that binds to phospholipids and proteins associated with the cell membrane. Its name is a misnomer, as it is actually a prothrombotic antibody. Lupus anticoagulant in living systems cause an increase in inappropriate blood clotting. The name derives from their properties in vitro, as these antibodies increase laboratory coagulation tests such as the activated partial thromboplastin time (aPTT). Investigators speculate that the antibodies interfere with phospholipids used to induce in vitro coagulation. In vivo, the antibodies are thought to interact with platelet membrane phospholipids, increasing adhesion and aggregation of platelets, which accounts for the in vivo prothrombotic characteristics.
The condition was first described by hematologist C. Lockard Conley in 1952.
Terminology.
Both words in the term "lupus anticoagulant" can be misleading:
Indications for testing.
The main indication for testing for lupus anticoagulant is a suspected antiphospholipid syndrome, whose main manifestations are blood clots (thrombosis) in both arteries and veins as well as pregnancy-related complications such as miscarriage, stillbirth, preterm delivery, and severe preeclampsia.
In a suspected antiphospholipid syndrome, lupus anticoagulant is generally tested in conjunction with anti-apolipoprotein antibodies and anti-cardiolipin antibodies, and diagnostic criteria require one clinical event (i.e. thrombosis or pregnancy complication) and two positive blood test results spaced at least three months apart that detect at least one of the three types of antibodies.
Testing for lupus anticoagulant can also be indicated by a prolonged aPTT test that is unexplained.
Workup.
An aPTT is generally included in a differential diagnosis in vague symptoms, and is a non-specific test of coagulation. In contrast, the prothrombin time (PT), another non-specific coagulation test, is normally unaffected by lupus anticoagulant. Nevertheless, falsely increased PT has been reported, likely by lupus anticoagulant interfering with the phospholipid component of the PT reagent, particularly when using recombinant tissue factor and purified phospholipids.
A mixing test is generally in the initial workup of a prolonged aPTT. In a mixing test, patient plasma is mixed with normal pooled plasma and the clotting is reassessed. If a clotting inhibitor such as a lupus anticoagulant is present, the inhibitor will interact with the normal pooled plasma and the clotting time will generally remain abnormal. However, if the clotting time of the mixed plasma corrects towards normal, the presence of an inhibitor such as the lupus anticoagulant is less likely, instead indicating a deficient quantity of clotting factor (that is replenished by the normal plasma). In case of a corrected mixing test, a lower dose of normal pooled plasma is often used, such as a 4:1 mix (4 times as much patient plasma than normal pooled plasma), as some studies suggest that this method is more sensitive for the detection of a weak lupus anticoagulant that is not enough prevalent or potent to affect a 1:1 mix.
However, only about 60 per cent of patients with lupus anticoagulants have a both a prolonged APTT and APTT mix, making it unsuitable as the only test in case of a high suspicion of the antiphospholipid syndrome. Thus, one or more of the following tests are generally performed to detect lupus anticoagulant if a high suspicion remains, and/or specify lupus anticoagulant as the cause of an abnormal mixing test:
Treatment.
Treatment for a lupus anticoagulant is usually undertaken in the context of documented thrombosis, such as extremity phlebitis or dural sinus vein thrombosis. Patients with a well-documented (i.e., present at least twice) lupus anticoagulant and a history of thrombosis should be considered candidates for indefinite treatment with anticoagulants. Patients with no history of thrombosis and a lupus anticoagulant should probably be observed. Current evidence suggests that the risk of recurrent thrombosis in patients with an antiphospholipid antibody is enhanced whether that antibody is measured on serological testing or functional testing. The Sapporo criteria specify that both serological and functional tests must be positive to diagnose the antiphospholipid antibody syndrome.
Miscarriages may be more prevalent in patients with a lupus anticoagulant. Some of these miscarriages may "potentially" be prevented with the administration of aspirin and unfractionated heparin. The Cochrane Database of Systematic Reviews provide a deeper understanding on the subject.
Thrombosis is treated with anticoagulants (LMWHs and warfarin).


Glycerol dehydrogenase

Glycerol dehydrogenase (, also known as NAD+-linked glycerol dehydrogenase, glycerol: NAD+ 2-oxidoreductase, GDH, GlDH, GlyDH) is an enzyme in the oxidoreductase family that utilizes the NAD+ to catalyze the oxidation of glycerol to form glycerone (dihydroxyacetone). This enzyme is an oxidoreductase, specifically a metal-dependent alcohol dehydrogenase that plays a role in anaerobic glycerol metabolism and has been isolated from a number of bacteria, including "Enterobacter aerogenes," "Klebsiella aerogenes," "Streptococcus faecalis," "Erwinia aeroidea," "Bacillus megaterium," and "Bacillus stearothermophilus." However, most studies of glycerol dehydrogenase have been performed in "Bacillus stearothermophilus," "(B. stearothermophilus)" due to its thermostability and the following structural and functional information will, therefore, refer primarily to the characterization of the enzyme in this bacterium.
Structure.
Glycerol dehydrogenase is a homooctamer composed of eight identical monomer subunits made up of a single polypeptide chain of 370 amino acids (molecular weight 42,000 Da). Each subunit contains 9 beta sheets and 14 alpha helices within two distinct domains (N-terminal, residues 1-162 and C-terminal, residues 163-370). The deep cleft formed between these two domains serves as the enzyme’s active site. This active site consists of one bound metal ion, one NAD+ nicotinamide ring binding site, and a substrate binding site.
Research into the structure of "B. stearothermophilus" shows that the active site contains a divalent cation—zinc ion, Zn2+. This zinc ion forms tetrahedral dipole interactions between the amino acid residues Asp173, His256, and His274 as well as a water molecule.
The NAD+ binding site, resembling the Rossmann fold within the N-terminal domain, extends from the surface of the enzyme to the cleft containing the active site. The nicotinamide ring (the active region of NAD+) binds in a pocket of the cleft consisting of the residues Asp100, Asp123, Ala124, Ser127, Leu129, Val131, Asp173, His174, and Phe247.
Finally, the substrate binding site consists of the residues Asp123, His256, His274 as well as a water molecule.
Function.
Encoded by the gene gldA, the enzyme glycerol dehydrogenase, GlyDH catalyzes the oxidation of glycerol to glycerone. Unlike more common pathways utilizing glycerol, GlyDH effectively oxidizes glycerol in anaerobic metabolic pathways under ATP-independent conditions (a useful mechanism in the breakdown of glycerol in bacteria). In addition, GlyDH selectively oxidizes the C2 hydroxyl group to form a ketone rather than a terminal hydroxyl group to form an aldehyde.
Mechanism.
While the precise mechanism of this specific enzyme has not yet been characterized, kinetic studies support that GlyDH catalysis of the chemical reaction
is comparable to those of other alcohol dehydrogenases. Therefore, the following mechanism offers a reasonable representation of glycerol oxidation by NAD+.
After NAD+ is bound to the enzyme, glycerol substrate binds to the active site in such a way as to have two coordinated interactions between two adjacent hydroxyl groups and the neighboring zinc ion. GlyDH then catalyzes the base-assisted deprotonation of the C2 hydroxyl group, forming an alkoxide. The zinc atom further serves to stabilize the negative charge on the alkoxide intermediate before the excess electron density around the charged oxygen atom shifts to form a double bond with the C2 carbon atom. Hydride is subsequently removed from the secondary carbon and acts as a nucleophile in electron transfer to the NAD+ nicotinamide ring. As a result, the H+ removed by the base is released as a proton into the surrounding solution; followed by the release of the product glycerone, then NADH by GlyDH.
Industrial Implications.
As a result of increasing biodiesel production, formation of the byproduct, crude glycerol, has also increased. While glycerol is commonly used in food, pharmaceuticals, cosmetics, and other industries, increased production of crude glycerol has become very expensive to purify and utilize in these industries. Because of this, researchers are interested in finding new economical ways to utilize low-grade glycerol products. Biotechnology is one such technique: using particular enzymes to break down crude glycerol to form products such as 1,3-propanediol, 1,2-propanediol, succinic acid, dihydroxyacetone (glycerone), hydrogen, polyglycerols, and polyesters. As a catalyst for the conversion of glycerol to glycerone, glycerol dehydrogenase is one such enzyme being investigated for this industrial purpose.
A full list of structures solved and deposited in the PDB for this class of enzyme can be found in the info box.


CAT RNA-binding domain

In molecular biology, the CAT RNA-binding domain (Co-AntiTerminator RNA-binding domain) is a protein domain found at the amino terminus of a family of transcriptional antiterminator proteins. This domain forms a dimer in the crystal structure. Transcriptional antiterminators of the BglG/SacY family are regulatory proteins that mediate the induction of sugar metabolizing operons in Gram-positive and Gram-negative bacteria. Upon activation, these proteins bind to specific targets in nascent mRNAs, thereby preventing abortive dissociation of the RNA polymerase from the DNA template.


Carbonyl reductase (NADPH)

In enzymology, a carbonyl reductase (NADPH) () is an enzyme that catalyzes the chemical reaction
R-CO-R' + NADPH + H+ formula_1 :R-CHOH-R' + NADP+
Thus, the two products of this enzyme are R-CHOH-R' and NADP+, whereas its 3 substrates are R-CO-R', 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 secondary-alcohol:NADP+ oxidoreductase. Other names in common use include aldehyde reductase 1, prostaglandin 9-ketoreductase, xenobiotic ketone reductase, NADPH-dependent carbonyl reductase, ALR3, carbonyl reductase, nonspecific NADPH-dependent carbonyl reductase, aldehyde reductase 1, and carbonyl reductase (NADPH). This enzyme participates in arachidonic acid metabolism, and has recently been shown to catabolize S-Nitrosoglutathione, as a means to degrade NO in an NADPH-dependent manner.
Structural studies.
As of late 2007, 4 structures have been solved for this class of enzymes, with PDB accession codes , , , and .


Curculigoside

Curculigosides are phenols that have been isolated from a variety of plant sources. Curculigoside A, B, C and D can be found in "Curculigo orchioides". Curculigoside B can be isolated by high-speed counter-current chromatography. Curculigosides B and D have "in vitro" activity against β-amyloid aggregation.


BEN domain

In molecular biology, the BEN domain is a protein domain which is found in diverse proteins including:
The BEN domain is predicted to function as an adaptor for the higher-order structuring of chromatin, and recruitment of chromatin modifying factors in transcriptional regulation. It has been suggested to mediate protein-DNA and protein-protein interactions during chromatin organization and transcription. The presence of BEN domains in a poxviral early virosomal protein and in polydnaviral proteins also suggests a possible role in the organisation of viral DNA during replication or transcription. They are generally linked to other globular domains with functions related to transcriptional regulation and chromatin structure, such as BTB, C4DM, and C2H2 fingers.
This domain is predicted to form an all-alpha fold with four conserved helices. Its conservation pattern revealed several conserved residues, most of which have hydrophobic side-chains and are likely to stabilize the fold through helix-helix packing. First human BEN domain (BEND3)structure is solved together with TPR (ERCC6L)domain and Stimulates the ERCC6L translocase and ATPase activities(7).
References.
7 . A novel TPR-BEN domain interaction mediates PICH-BEND3 association.


Helix bundle

A helix bundle is a small protein fold composed of several alpha helices that are usually nearly parallel or antiparallel to each other.
Three-helix bundles.
Three-helix bundles are among the smallest and fastest known cooperatively folding structural domains. The three-helix bundle in the villin headpiece domain is only 36 amino acids long and is a common subject of study in molecular dynamics simulations because its microsecond-scale folding time is within the timescales accessible to simulation. The 40-residue HIV accessory protein has a very similar fold and has also been the subject of extensive study. There is no general sequence motif associated with three-helix bundles, so they cannot necessarily be predicted from sequence alone. Three-helix bundles often occur in actin-binding proteins and in DNA-binding proteins.
Four-helix bundles.
Four-helix bundles typically consist of four helices packed in a coiled-coil arrangement with a sterically close-packed hydrophobic core in the center. Pairs of adjacent helices are often additionally stabilized by salt bridges between charged amino acids. The helix axes typically are oriented about 20 degrees from their neighboring helices, a much shallower incline than in the larger helical structure of the globin fold.
The specific topology of the helices is dependent on the protein – helices that are adjacent in sequence are often antiparallel, although it is also possible to arrange antiparallel links between two pairs of parallel helices. Because dimeric coiled-coils are themselves relatively stable, four-helix bundles can be dimers of coiled-coil pairs, as in the Rop protein. Four-helix bundle can have thermal stability more than 100 °C. Other examples of four-helix bundles include cytochrome, ferritin, human growth hormone, cytokine, and Lac repressor C-terminal. The four-helix bundle fold has proven an attractive target for de novo protein design, with numerous de novo four-helix bundle proteins having been successfully designed by rational and by combinatorial methods. Although sequence is not conserved among four-helix bundles, sequence "patterns" tend to mirror those of coiled-coil structures in which every fourth and seventh residue is hydrophobic.


Glycoside hydrolase family 57

In molecular biology, glycoside hydrolase family 57 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 57 CAZY GH_57 comprises enzymes with several known activities; alpha-amylase (), 4-alpha-glucanotransferase (), α-galactosidase (); amylopullulanase (); branching enzyme (). It includes a thermostable alpha-amylase with a broad substrate specificity from the archaebacterium "Pyrococcus furiosus".


Ribonucleoprotein


Cholestanetriol 26-monooxygenase

In enzymology, a cholestanetriol 26-monooxygenase () is an enzyme that catalyzes the chemical reaction
The 4 substrates of this enzyme are 5beta-cholestane-3alpha,7alpha,12alpha-triol, NADPH, H+, and O2, whereas its 3 products are (25R)-5beta-cholestane-3alpha,7alpha,12alpha,26-tetraol, NADP+, and H2O.
This enzyme belongs to the family of oxidoreductases, specifically those acting on paired donors, with O2 as oxidant and incorporation or reduction of oxygen. The oxygen incorporated need not be derived from O2 with NADH or NADPH as one donor, and incorporation of one atom o oxygen into the other donor. The systematic name of this enzyme class is 5beta-cholestane-3alpha,7alpha,12alpha-triol,NADPH:oxygen oxidoreductase (26-hydroxylating). Other names in common use include 5beta-cholestane-3alpha,7alpha,12alpha-triol 26-hydroxylase, 5beta-cholestane-3alpha,7alpha,12alpha-triol hydroxylase, cholestanetriol 26-hydroxylase, sterol 27-hydroxylase, sterol 26-hydroxylase, cholesterol 27-hydroxylase, CYP27A, CYP27A1, and cytochrome P450 27A1'. This enzyme participates in bile acid biosynthesis and ppar signaling pathway.


Beraprost

Beraprost is a pharmaceutical drug used in several Asian countries, including Japan and South Korea, as a vasodilator and antiplatelet agent. It is classified as a prostacyclin analog.
It has been studied for the treatment of pulmonary hypertension and for use in avoiding reperfusion injury.
Clinical pharmacology.
As an analog of prostacyclin PGI2, beraprost affects vasodilation, which in turn lowers blood pressure. Beraprost also inhibits platelet aggregation, though the role this phenomenon may play in relation to pulmonary hypertension has yet to be determined.
Dosage and administration.
Beraprost is administered orally as a pill available in strength of 20 mcg. Dose ranges from 60 to 180 mcg in divided doses after meals.


Heptad repeat

The heptad repeat is an example of a structural motif that consists of a repeating pattern of seven amino acids:
 "a b c d e f g"
 H P P H C P C
where H represents hydrophobic residues, C represents, typically, charged residues, and P represents polar (and, therefore, hydrophilic) residues. The positions of the heptad repeat are commonly denoted by the lowercase letters "a" through "g".
These motifs are the basis for most coiled coils and, in particular, leucine zippers, which have predominantly leucine in the "d" position of the heptad repeat.


Hydroxynitrile lyase

Hydroxynitrile lyase may refer to:


Choleretic

Choleretics are substances that increase the volume of secretion of bile from the liver as well as the amount of solids secreted.


ACE inhibitor

Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of high blood pressure and heart failure. They work by causing relaxation of blood vessels as well as a decrease in blood volume, which leads to lower blood pressure and decreased oxygen demand from the heart.
ACE inhibitors inhibit the activity of angiotensin-converting enzyme, an important component of the renin–angiotensin system which converts angiotensin I to angiotensin II, and hydrolyses bradykinin. Therefore, ACE inhibitors decrease the formation of angiotensin II, a vasoconstrictor, and increase the level of bradykinin, a peptide vasodilator. This combination is synergistic in lowering blood pressure.
Frequently prescribed ACE inhibitors include benazepril, zofenopril, perindopril, trandolapril, captopril, enalapril, lisinopril, and ramipril.
Medical use.
ACE inhibitors were initially approved for the treatment of hypertension and can be used alone or in combination with other anti-hypertensive medications. Later, they were found useful for other cardiovascular and kidney diseases including:
In treating high blood pressure, ACE inhibitors are often the first drug choice, particularly when diabetes is present, but age can lead to different choices and it is common to need more than one drug to obtain the desired improvement. There are fixed-dose combination drugs, such as ACE inhibitor and thiazide combinations. ACE inhibitors have also been used in chronic kidney failure and kidney involvement in systemic sclerosis (hardening of tissues, as scleroderma renal crisis). In those with stable coronary artery disease, but no heart failure, benefits are similar to other usual treatments.
In 2012, there was a meta-analysis published in the BMJ that described the protective role of ACE inhibitors in reducing the risk of pneumonia when compared to ARBs (Angiotensin II Receptor Blockers). The authors found a decreased risk in patients with previous stroke (54% risk reduction), with heart failure (37% risk reduction), and of Asian descent (43% risk reduction vs 54% risk reduction in non-Asian population). However, no reduced pneumonia related mortality was observed.
Other.
ACE inhibitors may also be used to help decrease excessive water consumption in people with schizophrenia resulting in psychogenic polydipsia. A double-blind, placebo-controlled trial showed that when used for this purpose, enalapril led to decreased consumption (determined by urine output and osmolality) in 60% of people; the same effect has been demonstrated in other ACE inhibitors.
Additionally ACEi are commonly used after renal transplant to manage post-transplant erythrocytosis, a condition characterised by a persistently high hematocrit greater than 51% which often develops 8-24 months after successful transplantation, as ACEi have been shown to decrease erythropoietin production.
Adverse effects.
Common side effects include: low blood pressure, cough, hyperkalemia, headache, dizziness, fatigue, nausea, and kidney impairment.
The main adverse effects of ACE inhibition can be understood from their pharmacological action. The other reported adverse effects are liver problems and effect on the fetus. Kidney problems may occur with all ACE inhibitors that directly follows from their mechanism of action. Patients starting on an ACE inhibitor usually have a modest reduction in glomerular filtration rate (GFR). However, the decrease may be significant in conditions of "pre-existing" decreased renal perfusion, such as renal artery stenosis, heart failure, polycystic kidney disease, or volume depletion. In these patients, the maintenance of GFR depends on angiotensin-II-dependent efferent vasomotor tone. Therefore, renal function should be closely monitored over the first few days after initiation of treatment with ACE inhibitor in patients with decreased renal perfusion. A moderate reduction in renal function, no greater than 30% rise in serum creatinine, that is stabilized after a week of treatment is deemed acceptable as part of the therapeutic effect, providing the residual renal function is sufficient.
Reduced GFR is especially a problem if the patient is concomitantly taking an NSAID and a diuretic. When the three drugs are taken together, the risk of developing renal failure is significantly increased.
High blood potassium is another possible complication of treatment with an ACE inhibitor due to its effect on aldosterone. Suppression of angiotensin II leads to a decrease in aldosterone levels. Since aldosterone is responsible for increasing the excretion of potassium, ACE inhibitors can cause retention of potassium. Some people, however, can continue to lose potassium while on an ACE inhibitor. Hyperkalemia may decrease the velocity of impulse conduction in the nerves and muscles, including cardiac tissues. This leads to cardiac dysfunction and neuromuscular consequences, such as muscle weakness, paresthesia, nausea, diarrhea, and others. Close monitoring of potassium levels is required in patients receiving treatment with ACE inhibitors who are at risk of hyperkalemia.
Another possible adverse effect specific for ACE inhibitors, but not for other RAAS blockers, is an increase in bradykinin level.
A persistent dry cough is a relatively common adverse effect believed to be associated with the increases in bradykinin levels produced by ACE inhibitors, although the role of bradykinin in producing these symptoms has been disputed. Many cases of cough in people on ACE inhibitors may not be from the medication itself, however. People who experience this cough are often switched to angiotensin II receptor antagonists.
Some (0.7%) develop angioedema due to increased bradykinin levels. A genetic predisposition may exist.
A severe rare allergic reaction can affect the bowel wall and secondarily cause abdominal pain.
Blood.
Hematologic effects, such as neutropenia, agranulocytosis and other blood dyscrasias, have occurred during therapy with ACE inhibitors, especially in people with additional risk factors.
Pregnancy.
In pregnant women, ACE inhibitors taken during all the trimesters have been reported to cause congenital malformations, stillbirths, and neonatal deaths. Commonly reported fetal abnormalities include hypotension, renal dysplasia, anuria/oliguria, oligohydramnios, intrauterine growth retardation, pulmonary hypoplasia, patent ductus arteriosus, and incomplete ossification of the skull. Overall, about half of newborns exposed to ACE inhibitors are adversely affected, leading to birth defects.
ACE inhibitors are ADEC pregnancy category D, and should be avoided in women who are likely to become pregnant. In the U.S., ACE inhibitors must be labeled with a boxed warning concerning the risk of birth defects when taken during the second and third trimester. Their use in the first trimester is also associated with a risk of major congenital malformations, particularly affecting the cardiovascular and central nervous systems.
Overdose.
Symptoms and Treatment: There are few reports of ACE inhibitor overdose in the literature. The most likely manifestations are hypotension, which may be severe, hyperkalemia, hyponatremia and renal impairment with metabolic acidosis. Treatment should be mainly symptomatic and supportive, with volume expansion using normal saline to correct hypotension and improve renal function, and gastric lavage followed by activated charcoal and a cathartic to prevent further absorption of the drug. Captopril, enalapril, lisinopril and perindopril are known to be removable by hemodialysis.
Contraindications and precautions.
The ACE inhibitors are contraindicated in people with:
ACE inhibitors should be used with caution in people with:
A combination of ACE inhibitor with other drugs may increase effects of these drugs, but also the risk of adverse effects. The commonly reported adverse effects of drug combination with ACE are acute renal failure, hypotension, and hyperkalemia. The drugs interacting with ACE inhibitor should be prescribed with caution. Special attention should be given to combinations of ACE inhibitor with other RAAS blockers, diuretics (especially potassium-sparing diuretics), NSAIDs, anticoagulants, cyclosporine, DPP-4 inhibitors, and potassium supplements.
Potassium supplementation should be used with caution and under medical supervision owing to the hyperkalemic effect of ACE inhibitors.
Concomitant use with cyclooxygenase inhibitors tends to decrease ACE inhibitor's hypotensive effect.
Mechanism of action.
ACE inhibitors reduce the activity of the renin–angiotensin–aldosterone system (RAAS) as the primary etiologic (causal) event in the development of hypertension in people with diabetes mellitus, as part of the insulin-resistance syndrome or as a manifestation of renal disease.
Renin–angiotensin–aldosterone system.
The renin–angiotensin–aldosterone system is a major blood pressure regulating mechanism. Markers of electrolyte and water imbalance in the body such as hypotension, low distal tubule sodium concentration, decreased blood volume and high sympathetic tone trigger the release of the enzyme renin from the cells of juxtaglomerular apparatus in the kidney.
Renin activates a circulating liver derived prohormone angiotensinogen by proteolytic cleavage of all but its first ten amino acid residues known as angiotensin I. ACE (angiotensin converting enzyme) then removes a further two residues, converting angiotensin I into angiotensin II. ACE is found in the pulmonary circulation and in the endothelium of many blood vessels. The system increases blood pressure by increasing the amount of salt and water the body retains, although angiotensin is also very good at causing the blood vessels to tighten (a potent vasoconstrictor).
Effects.
ACE inhibitors block the conversion of angiotensin I (ATI) to angiotensin II (ATII). They thereby lower arteriolar resistance and increase venous capacity; decrease cardiac output, cardiac index, stroke work, and volume; lower resistance in blood vessels in the kidneys; and lead to increased natriuresis (excretion of sodium in the urine). Renin increases in concentration in the blood as a result of negative feedback of conversion of ATI to ATII. ATI increases for the same reason; ATII and aldosterone decrease. Bradykinin increases because of less inactivation by ACE.
Under normal conditions, angiotensin II has these effects:
During the course of ACE inhibitor use, the production of ATII is decreased, which prevents aldosterone release from the adrenal cortex. This allows the kidney to excrete sodium ions along with obligate water, and retain potassium ions. This decreases blood volume, leading to decreased blood pressure.
Epidemiological and clinical studies have shown ACE inhibitors reduce the progress of diabetic nephropathy independently from their blood pressure-lowering effect. This action of ACE inhibitors is used in the prevention of diabetic renal failure.
ACE inhibitors have been shown to be effective for indications other than hypertension even in patients with normal blood pressure. The use of a maximum dose of ACE inhibitors in such patients (including for prevention of diabetic nephropathy, congestive heart failure, and prophylaxis of cardiovascular events) is justified, because it improves clinical outcomes independently of the blood pressure-lowering effect of ACE inhibitors. Such therapy, of course, requires careful and gradual titration of the dose to prevent the effects of rapidly decreasing blood pressure (dizziness, fainting, etc.).
ACE inhibitors have also been shown to cause a central enhancement of parasympathetic nervous system activity in healthy volunteers and patients with heart failure. This action may reduce the prevalence of malignant cardiac arrhythmias, and the reduction in sudden death reported in large clinical trials.
ACE Inhibitors also reduce plasma norepinephrine levels, and its resulting vasoconstriction effects, in heart failure patients, thus breaking the vicious circles of sympathetic and renin angiotensin system activation, which sustains the downward spiral in cardiac function in congestive heart failure
The ACE inhibitor enalapril has also been shown to reduce cardiac cachexia in patients with chronic heart failure. Cachexia is a poor prognostic sign in patients with chronic heart failure.
ACE inhibitors are under early investigation for the treatment of frailty and muscle wasting (sarcopenia) in elderly patients without heart failure.
Examples.
ACE inhibitors are easily identifiable by their common suffix, '-pril'. ACE inhibitors can be divided into three groups based on their molecular structure of the enzyme binding sites (sulfhydryl, phosphinyl, carboxyl) to the active center of ACE:
Sulfhydryl-containing agents.
These agents appear to show antioxidative properties but may be involved in adverse events such as skin eruptions.
Dicarboxylate-containing agents.
This is the largest group, including:
Comparative information.
All ACE inhibitors have similar antihypertensive efficacy when equivalent doses are administered. The main differences lie with captopril, the first ACE inhibitor. Captopril has a shorter duration of action and an increased incidence of adverse effects. It is also the only ACE inhibitor capable of passing through the blood–brain barrier, although the significance of this characteristic has not been shown to have any positive clinical effects.
In a large clinical study, one of the agents in the ACE inhibitor class, ramipril (Altace), demonstrated an ability to reduce the mortality rates of patients suffering from a myocardial infarction, and to slow the subsequent development of heart failure. This finding was made after it was discovered that regular use of ramipril reduced mortality rates even in test subjects not having suffered from hypertension.
Some believe ramipril's additional benefits may be shared by some or all drugs in the ACE-inhibitor class. However, ramipril currently remains the only ACE inhibitor for which such effects are actually evidence-based.
A meta-analysis confirmed that ACE inhibitors are effective and certainly the first-line choice in hypertension treatment. This meta-analysis was based on 20 trials and a cohort of 158,998 patients, of whom 91% were hypertensive. ACE inhibitors were used as the active treatment in seven trials (n=76,615) and angiotensin receptor blocker (ARB) in 13 trials (n=82,383).
ACE inhibitors were associated with a statistically significant 10% mortality reduction: (HR 0.90; 95% CI, 0.84–0.97; P=0.004). In contrast, no significant mortality reduction was observed with ARB treatment (HR 0.99; 95% CI, 0.94–1.04; P=0.683). Analysis of mortality reduction by different ACE inhibitors showed that perindopril-based regimens are associated with a statistically significant 13% all-cause mortality reduction.