HOME

TheInfoList



OR:

Nitric oxide synthases () (NOSs) are a family of
enzymes Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. ...
catalyzing the production of
nitric oxide Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its ch ...
(NO) from
L-arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...
. NO is an important
cellular signaling In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellular ...
molecule. It helps modulate
vascular tone Vascular resistance is the resistance that must be overcome to push blood through the circulatory system and create flow. The resistance offered by the systemic circulation is known as the systemic vascular resistance (SVR) or may sometimes be ...
, insulin secretion, airway tone, and
peristalsis Peristalsis ( , ) is a radially symmetrical contraction and relaxation of muscles that propagate in a wave down a tube, in an anterograde direction. Peristalsis is progression of coordinated contraction of involuntary circular muscles, which ...
, and is involved in
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splittin ...
and neural development. It may function as a retrograde neurotransmitter. Nitric oxide is mediated in mammals by the
calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...
-
calmodulin Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca2+, and the bind ...
controlled
isoenzyme In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. dif ...
s eNOS ( endothelial NOS) and nNOS (neuronal NOS). The inducible isoform, iNOS, involved in immune response, binds calmodulin at physiologically relevant concentrations, and produces NO as an immune defense mechanism, as NO is a free radical with an unpaired electron. It is the
proximate cause In law and insurance, a proximate cause is an event sufficiently related to an injury that the courts deem the event to be the cause of that injury. There are two types of causation in the law: cause-in-fact, and proximate (or legal) cause. C ...
of septic shock and may function in
autoimmune In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...
disease. NOS catalyzes the reaction: * 2 L-
arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the a ...
+ 3
NADPH Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NAD ...
+ 3 H+ + 4 O2 \rightleftharpoons 2
citrulline The organic compound citrulline is an α-amino acid. Its name is derived from '' citrullus'', the Latin word for watermelon. Although named and described by gastroenterologists since the late 19th century, it was first isolated from watermelon in ...
+2
nitric oxide Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its ch ...
+ 4 H2O + 3 NADP+ NOS isoforms catalyze other leak and side reactions, such as
superoxide In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of th ...
production at the expense of NADPH. As such, this stoichiometry is not generally observed, and reflects the three electrons supplied per NO by NADPH. NOSs are unusual in that they require five cofactors. Eukaryotic NOS isozymes are catalytically self-sufficient. The electron flow in the NO synthase reaction is:
NADPH Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NAD ...
FAD A fad or trend is any form of collective behavior that develops within a culture, a generation or social group in which a group of people enthusiastically follow an impulse for a short period. Fads are objects or behaviors that achieve short- ...
FMN
heme Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver. In biochemical terms, heme is a coordination complex "consist ...
O2. Tetrahydrobiopterin provides an additional electron during the catalytic cycle which is replaced during turnover. NOS is the only known enzyme that binds flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN),
heme Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver. In biochemical terms, heme is a coordination complex "consist ...
,
tetrahydrobiopterin Tetrahydrobiopterin (BH4, THB), also known as sapropterin (INN), is a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotoni ...
(BH4) and
calmodulin Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca2+, and the bind ...
.


Species distribution

Arginine-derived NO synthesis has been identified in mammals, fish, birds, invertebrates, and bacteria. Best studied are mammals, where three distinct genes encode NOS isozymes:
neuronal A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. No ...
(nNOS or NOS-1),
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autoc ...
-inducible (iNOS or NOS-2) and
endothelial The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the ve ...
(eNOS or NOS-3). iNOS and nNOS are soluble and found predominantly in the
cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrio ...
, while eNOS is membrane associated. Evidence has been found for NO signaling in plants, but plant genomes are devoid of homologs to the superfamily which generates NO in other kingdoms.


Function

In mammals, the endothelial isoform is the primary signal generator in the control of vascular tone, insulin secretion, and airway tone, is involved in regulation of cardiac function and angiogenesis (growth of new blood vessels). NO produced by eNOS has been shown to be a vasodilator identical to the endothelium-derived relaxing factor produced in response to shear from increased blood flow in arteries. This dilates blood vessels by relaxing smooth muscle in their linings. eNOS is the primary controller of smooth muscle tone. NO activates
guanylate cyclase Guanylate cyclase (EC 4.6.1.2, also known as guanyl cyclase, guanylyl cyclase, or GC; systematic name GTP diphosphate-lyase (cyclizing; 3′,5′-cyclic-GMP-forming)) is a lyase enzyme that converts guanosine triphosphate (GTP) to cyclic guanos ...
, which induces smooth muscle relaxation by: * Increased intracellular cGMP, which inhibits
calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...
entry into the cell, and decreases intracellular calcium concentrations * Activation of K+ channels, which leads to hyperpolarization and relaxation * Stimulates a cGMP-dependent protein kinase that activates
myosin Myosins () are a superfamily of motor proteins best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are ATP-dependent and responsible for actin-based motility. The first myosin (M ...
light chain phosphatase, the enzyme that dephosphorylates
myosin Myosins () are a superfamily of motor proteins best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are ATP-dependent and responsible for actin-based motility. The first myosin (M ...
light chains, which leads to smooth muscle relaxation. eNOS plays a critical role in embryonic heart development and morphogenesis of coronary arteries and cardiac valves. The neuronal isoform is involved in the development of nervous system. It functions as a retrograde neurotransmitter important in long term potentiation and hence is likely to be important in memory and learning. nNOS has many other physiological functions, including regulation of cardiac function and peristalsis and sexual arousal in males and females. An alternatively spliced form of nNOS is a major muscle protein that produces signals in response to calcium release from the SR. nNOS in the heart protects against cardiac arrhythmia induced by myocardial infarction. The primary receiver for NO produced by eNOS and nNOS is soluble guanylate cyclase, but many secondary targets have been identified. S-nitrosylation appears to be an important mode of action. The inducible isoform iNOS produces large amounts of NO as a defense mechanism. It is synthesized by many cell types in response to cytokines and is an important factor in the response of the body to attack by parasites, bacterial infection, and tumor growth. It is also the cause of septic shock and may play a role in many diseases with an autoimmune etiology. NOS signaling is involved in development and in fertilization in vertebrates. It has been implicated in transitions between vegetative and reproductive states in invertebrates, and in differentiation leading to spore formation in slime molds. NO produced by bacterial NOS is protective against oxidative damage. NOS activity has also been correlated with major depressive episodes (MDEs) in the context of major depressive disorder, in a large case-control treatment study published in mid-2021. 460 patients with a current major depressive episode were compared to 895 healthy patients, and by measuring L-citrulline/L-arginine ratio before and after 3–6 months of antidepressant treatment, results indicate that patients in a major depressive episode have significantly lower NOS activity compared to healthy patients, whilst treatment with antidepressants significantly elevated NOS activity levels in patients in a major depressive episode.


Classification

Different members of the NOS family are encoded by separate genes. There are three known isoforms in mammals, two are constitutive (cNOS) and the third is inducible (iNOS). Cloning of NOS enzymes indicates that cNOS include both brain constitutive (
NOS1 Nitric oxide synthase 1 (neuronal), also known as NOS1, is an enzyme that in humans is encoded by the ''NOS1'' gene. Function Nitric oxide synthases () (NOSs) are a family of synthases that catalyze the production of nitric oxide (NO) from L-a ...
) and endothelial constitutive ( NOS3); the third is the inducible ( NOS2) gene. Recently, NOS activity has been demonstrated in several bacterial species, including notorious pathogens Bacillus anthracis and Staphylococcus aureus. The different forms of NO synthase have been classified as follows:


nNOS

Neuronal NOS (nNOS) produces NO in
nervous tissue Nervous tissue, also called neural tissue, is the main tissue component of the nervous system. The nervous system regulates and controls body functions and activity. It consists of two parts: the central nervous system (CNS) comprising the bra ...
in both the central and peripheral
nervous systems In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes t ...
. Its functions include: * Synaptic plasticity in the central nervous system (CNS) * Smooth muscle relaxation * Central regulation of blood pressure * Vasodilatation via peripheral nitrergic nerves Neuronal NOS also performs a role in cell communication and is associated with plasma membranes. nNOS action can be inhibited by NPA (
N-propyl-L-arginine ''N''-Propyl--arginine, or more properly NG-propyl--arginine (NPA), is a selective inhibitor of neuronal nitric oxide synthase Nitric oxide synthases () (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-ar ...
). This form of the enzyme is specifically inhibited by
7-nitroindazole 7-Nitroindazole, or 7-NI, is a heterocyclic small molecule containing an indazole ring that has been nitrated at the 7 position. Nitroindazole acts as a selective inhibitor for neuronal nitric oxide synthase, a hemoprotein enzyme that, in neuron ...
. The subcellular localisation of nNOS in skeletal muscle is mediated by anchoring of nNOS to dystrophin. nNOS contains an additional N-terminal domain, the
PDZ domain The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, viruses and animals. Proteins containing PDZ domains play a key role in anchoring receptor proteins in the membrane to c ...
. The gene coding for nNOS is located on Chromosome 12.


iNOS

As opposed to the critical calcium-dependent regulation of constitutive NOS enzymes (nNOS and eNOS), iNOS has been described as calcium-insensitive, likely due to its tight non-covalent interaction with calmodulin (CaM) and Ca2+. The gene coding for iNOS is located on Chromosome 17. While evidence for ‘baseline’ iNOS expression has been elusive,
IRF1 Interferon regulatory factor 1 is a protein that in humans is encoded by the ''IRF1'' gene. Function Interferon regulatory factor 1 was the first member of the interferon regulatory transcription factor (IRF) family identified. Initially desc ...
and NF-κB-dependent activation of the inducible NOS promoter supports an inflammation mediated stimulation of this transcript. iNOS produces large quantities of NO upon stimulation, such as by
proinflammatory cytokine An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule (a cytokine) that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include inte ...
s (e.g.
Interleukin-1 The Interleukin-1 family (IL-1 family) is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults. Discovery Discovery of these cytokines began with studies on t ...
, Tumor necrosis factor alpha and
Interferon gamma Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...
). Induction of the high-output iNOS usually occurs in an oxidative environment, and thus high levels of NO have the opportunity to react with superoxide leading to
peroxynitrite Peroxynitrite (sometimes called peroxonitrite) is an ion with the formula ONOO−. It is a structural isomer of nitrate, Preparation Peroxynitrite can be prepared by the reaction of superoxide with nitric oxide: : It is prepared by the reacti ...
formation and cell toxicity. These properties may define the roles of iNOS in host immunity, enabling its participation in anti-microbial and anti-tumor activities as part of the oxidative burst of macrophages. It has been suggested that pathologic generation of
nitric oxide Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its ch ...
through increased iNOS production may decrease
tubal Tubal ( he, תֻבָל, ''Ṯuḇāl'', ), in Genesis 10 (the " Table of Nations"), was the name of a son of Japheth, son of Noah. He is known to be the father of the Caucasian Iberians (ancestors of the Georgians) according to primary sources. ...
ciliary beats and smooth muscle contractions and thus affect embryo transport, which may consequently result in
ectopic pregnancy Ectopic pregnancy is a complication of pregnancy in which the embryo attaches outside the uterus. Signs and symptoms classically include abdominal pain and vaginal bleeding, but fewer than 50 percent of affected women have both of these symptoms. ...
.


eNOS

Endothelial NOS (eNOS), also known as nitric oxide synthase 3 (NOS3), generates NO in blood vessels and is involved with regulating vascular function. The gene coding for eNOS is located on Chromosome 7. A constitutive Ca2+ dependent NOS provides a basal release of NO. eNOS localizes to caveolae, a plasma membrane domain primarily composed of the protein
caveolin 1 Caveolin-1 is a protein that in humans is encoded by the ''CAV1'' gene. Function The scaffolding protein encoded by this gene is the main component of the caveolae plasma membranes found in most cell types. The protein links integrin subunits ...
, and to the Golgi apparatus. These two eNOS populations are distinct, but are both necessary for proper NO production and cell health. eNOS localization to endothelial membranes is mediated by cotranslational N-terminal myristoylation and post-translational palmitoylation.


bNOS

Bacterial NOS (bNOS) has been shown to protect bacteria against oxidative stress, diverse antibiotics, and host immune response. bNOS plays a key role in the transcription of superoxide dismutase (SodA). Bacteria late in the log phase who do not possess bNOS fail to upregulate SodA, which disables the defenses against harmful oxidative stress. Initially, bNOS may have been present to prepare the cell for stressful conditions but now seems to help shield the bacteria against conventional antimicrobials. As a clinical application, a bNOS inhibitor could be produced to decrease the load of Gram positive bacteria.


Chemical reaction

Nitric oxide synthases produce NO by catalysing a five-electron oxidation of a guanidino nitrogen of L-arginine (L-Arg). Oxidation of L-Arg to L-citrulline occurs via two successive monooxygenation reactions producing ''N''ω-hydroxy-L-arginine (NOHLA) as an intermediate. 2 mol of O2 and 1.5 mol of NADPH are consumed per mole of NO formed.


Structure

The enzymes exist as homodimers. In eukaryotes, each monomer consisting of two major regions: an N-terminal
oxygenase An oxygenase is any enzyme that oxidizes a substrate by transferring the oxygen from molecular oxygen O2 (as in air) to it. The oxygenases form a class of oxidoreductases; their EC number is EC 1.13 or EC 1.14. Discoverers Oxygenases were discov ...
domain, which belongs to the class of heme-thiolate proteins, and a multi-domain C-terminal
reductase A reductase is an enzyme that catalyzes a reduction reaction. Examples * 5α-Reductase * 5β-Reductase * Dihydrofolate reductase * HMG-CoA reductase * Methemoglobin reductase * Ribonucleotide reductase * Thioredoxin reductase * ''E. coli'' ni ...
, which is homologous to NADPH:
cytochrome P450 reductase Cytochrome P450 reductase (; also known as NADPH:ferrihemoprotein oxidoreductase, NADPH:hemoprotein oxidoreductase, NADPH:P450 oxidoreductase, P450 reductase, POR, CPR, CYPOR) is a membrane-bound enzyme required for electron transfer from NADP ...
() and other flavoproteins. The FMN binding domain is homologous to flavodoxins, and the two domain fragment containing the FAD and NADPH binding sites is homologous to flavodoxin-NADPH reductases. The interdomain linker between the oxygenase and reductase domains contains a
calmodulin Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca2+, and the bind ...
-binding sequence. The oxygenase domain is a unique extended beta sheet cage with binding sites for heme and pterin. NOSs can be dimeric, calmodulin-dependent or calmodulin-containing
cytochrome p450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various comp ...
-like
hemoprotein A hemeprotein (or haemprotein; also hemoprotein or haemoprotein), or heme protein, is a protein that contains a heme prosthetic group. They are a very large class of metalloproteins. The heme group confers functionality, which can include oxyge ...
that combines reductase and oxygenase catalytic domains in one dimer, bear both flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), and carry out a 5`-electron oxidation of non-aromatic
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
arginine with the aid of tetrahydrobiopterin. All three
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some is ...
s (each of which is presumed to function as a homodimer during activation) share a carboxyl-terminal reductase domain homologous to the
cytochrome P450 reductase Cytochrome P450 reductase (; also known as NADPH:ferrihemoprotein oxidoreductase, NADPH:hemoprotein oxidoreductase, NADPH:P450 oxidoreductase, P450 reductase, POR, CPR, CYPOR) is a membrane-bound enzyme required for electron transfer from NADP ...
. They also share an amino-terminal oxygenase domain containing a
heme Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver. In biochemical terms, heme is a coordination complex "consist ...
prosthetic group A prosthetic group is the non-amino acid component that is part of the structure of the heteroproteins or conjugated proteins, being tightly linked to the apoprotein. Not to be confused with the cofactor that binds to the enzyme apoenzyme (eith ...
, which is linked in the middle of the protein to a
calmodulin Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca2+, and the bind ...
-binding domain. Binding of calmodulin appears to act as a "molecular switch" to enable electron flow from flavin prosthetic groups in the reductase domain to heme. This facilitates the conversion of O2 and L-arginine to NO and L-citrulline. The oxygenase domain of each NOS isoform also contains an BH4 prosthetic group, which is required for the efficient generation of NO. Unlike other enzymes where BH4 is used as a source of reducing equivalents and is recycled by
dihydrobiopterin reductase In enzymology, 6,7-dihydropteridine reductase (, also Dihydrobiopterin reductase) is an enzyme that catalyzes the chemical reaction : 5,6,7,8-tetrahydropteridine + NAD(P)+ \rightleftharpoons 6,7-dihydropteridine + NAD(P)H + H+ The four substrate ...
(), BH4 activates heme-bound O2 by donating a single electron, which is then recaptured to enable nitric oxide release. The first nitric oxide synthase to be identified was found in neuronal tissue (NOS1 or nNOS); the
endothelial The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the ve ...
NOS (eNOS or NOS3) was the third to be identified. They were originally classified as "constitutively expressed" and "Ca2+ sensitive" but it is now known that they are present in many different
cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...
types and that expression is regulated under specific physiological conditions. In NOS1 and NOS3, physiological concentrations of Ca2+ in cells regulate the binding of calmodulin to the "latch domains", thereby initiating electron transfer from the
flavins Flavins (from Latin ''flavus'', "yellow") are organic compounds, like their base, pteridine. They are formed by the tricyclic heterocycle isoalloxazine. The biochemical source is the vitamin riboflavin. The flavin moiety is often attached with ...
to the
heme Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver. In biochemical terms, heme is a coordination complex "consist ...
moieties. In contrast, calmodulin remains tightly bound to the inducible and Ca2+-insensitive isoform (iNOS or NOS2) even at a low intracellular Ca2+ activity, acting essentially as a subunit of this isoform. Nitric oxide may itself regulate NOS expression and activity. Specifically, NO has been shown to play an important
negative feedback Negative feedback (or balancing feedback) occurs when some function of the output of a system, process, or mechanism is fed back in a manner that tends to reduce the fluctuations in the output, whether caused by changes in the input or by othe ...
regulatory role on NOS3, and therefore vascular endothelial cell function. This process, known formally as ''S''-nitrosation (and referred to by many in the field as ''S''-nitrosylation), has been shown to reversibly inhibit NOS3 activity in vascular endothelial cells. This process may be important because it is regulated by cellular redox conditions and may thereby provide a mechanism for the association between "oxidative stress" and endothelial dysfunction. In addition to NOS3, both NOS1 and NOS2 have been found to be ''S''-nitrosated, but the evidence for dynamic regulation of those NOS isoforms by this process is less complete. In addition, both NOS1 and NOS2 have been shown to form ferrous-nitrosyl complexes in their heme prosthetic groups that may act partially to self-inactivate these enzymes under certain conditions. The rate-limiting step for the production of nitric oxide may well be the availability of L-arginine in some cell types. This may be particularly important after the induction of NOS2.


Inhibitors

Ronopterin (VAS-203), also known as 4-amino-tetrahydrobiopterin (4-ABH4), an analogue of BH4 (a cofactor of NOS), is an NOS inhibitor that is under development as a neuroprotective agent for the treatment of traumatic brain injurybr>
Other NOS inhibitors that have been or are being researched for possible clinical use include cindunistat, A-84643, ONO-1714, L-NOARG, NCX-456, VAS-2381, GW-273629, NXN-462, CKD-712, KD-7040, and guanidinoethyldisulfide, among others.


See also

*
Biological functions of nitric oxide Nitric oxide (nitrogen monoxide) is a molecule and chemical compound with chemical formula of N O. In mammals including humans, nitric oxide is a signaling molecule involved in several physiological and pathological processes. It is a powerful ...
* Nitric-oxide synthase (NAD(P)H-dependent) *
Nitric oxide synthase 2 (inducible) Nitric oxide synthase, inducible is an enzyme which is encoded by the ''NOS2'' gene in humans and mice. Genetics Three related pseudogenes are located within the Smith-Magenis syndrome region on chromosome 17. Alternative splicing of this gene r ...


References


External links

*
The Nobel Prize in Physiology or Medicine 1998
* University of Edinburgh, School of Chemistry


Nitric Oxide Synthase in Proteopedia
{{DEFAULTSORT:Nitric Oxide Synthase EC 1.14.13 Heme-thiolate proteins