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| {{Expert-subject|Molecular and Cellular Biology|date=May 2009}}
| | She is recognized by the name of Myrtle Shryock. What I adore doing is doing ceramics but I haven't made a dime with it. North Dakota is exactly where me and my husband reside. Hiring is her day occupation now but she's always wanted her personal business.<br><br>my page - meal delivery service - [http://P1N.me/weightlossfooddelivery24650 special info], |
| {{enzyme
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| | Name = Nitric-oxide synthase
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| | EC_number = 1.14.13.39
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| | CAS_number = 125978-95-2
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| | IUBMB_EC_number = 1/14/13/39
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| | GO_code = 0051767
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| | image = 1nsi.png
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| | width =
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| | caption = Human indicible nitric oxide synthase. PDB {{PDBe|1nsi}}
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| }}
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| {{Pfam_box
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| | Symbol = NO_synthase
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| | Name = Nitric oxide synthase, oxygenase domain
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| | image = Nitric_Oxide_Synthase.png
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| | width =
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| | caption = Structure of endothelial nitric oxide synthase heme domain.<ref name="pmid21138269">{{PDB|3N5P}}; {{cite journal | author = Delker SL, Xue F, Li H, Jamal J, Silverman RB, Poulos TL | title = Role of zinc in isoform-selective inhibitor binding to neuronal nitric oxide synthase | journal = Biochemistry | volume = 49 | issue = 51 | pages = 10803–10 |date=December 2010 | pmid = 21138269 | doi = 10.1021/bi1013479 }}</ref>
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| | Pfam= PF02898
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| | InterPro= IPR004030
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| | SMART=
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| | Prosite =
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| | SCOP = 1nos
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| | TCDB =
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| | OPM family=
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| | OPM protein=
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| }}
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| '''Nitric oxide synthases''' ({{EC number|1.14.13.39}}) ('''NOSs''') are a family of [[enzymes]] catalyzing the production of [[nitric oxide]] (NO) from [[L-arginine]]. NO is an important [[biological functions of nitric oxide|cellular signaling]] molecule. It helps modulate [[vascular tone]], [[insulin]] secretion, airway tone, and [[peristalsis]], and is involved in [[angiogenesis]] and neural development. It may function as a retrograde [[neurotransmitter]]. Nitric oxide is mediated in mammals by the [[calcium in biology|calcium]]-[[calmodulin]] controlled [[isozyme|isoenzyme]]s eNOS (endothelial NOS) and nNOS (neuronal NOS). The inducible isoform, iNOS, is 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 and ultimate causation|proximate cause]] of [[septic shock]] and may function in [[autoimmunity|autoimmune]] disease.
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| NOS catalyzes the reaction:
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| * L-[[arginine]] + 3/2 [[nicotinamide adenine dinucleotide phosphate|NADPH]] + H<sup>+</sup> + 2 O<sub>2</sub> <math>\rightleftharpoons</math> [[citrulline]] + [[nitric oxide]] + 3/2 NADP<sup>+</sup>
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| NOS isoforms catalyze other leak and side reactions, such as [[superoxide]] production at the expense of NADPH. As such, this stoichiometry is not generally observed, and reflects the three electrons supplied per NO by NADPH.
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| NOSs are unusual in that they require five [[Cofactor (biochemistry)|cofactor]]s. Eukaryotic NOS isozymes are catalytically self-sufficient. The electron flow in the NO synthase reaction is: [[NADPH]] → [[FAD]] → [[Flavin mononucleotide|FMN]] → [[heme]] → [[dioxygen|O<sub>2</sub>]]. 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]], [[tetrahydrobiopterin]] (BH<sub>4</sub>) and [[calmodulin]].
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| == Species distribution ==
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| Arginine-derived NO synthesis has been identified in mammals, fish, birds, invertebrates, and bacteria.<ref name="pmid8782597">{{cite journal | author = Liu Q, Gross SS | title = Binding sites of nitric oxide synthases | journal = Meth. Enzymol. | volume = 268 | issue = | pages = 311–24 | year = 1996 | pmid = 8782597 | doi = 10.1016/S0076-6879(96)68033-1 }}</ref> Best studied are mammals, where three distinct genes encode NOS [[isozyme]]s: [[neuronal]] (nNOS or NOS-1), [[cytokine]]-inducible (iNOS or NOS-2) and [[endothelial]] (eNOS or NOS-3).<ref name="pmid7510950">{{cite journal | author = Knowles RG, Moncada S | title = Nitric oxide synthases in mammals | journal = Biochem. J. | volume = 298 | issue = 2| pages = 249–58 |date=March 1994 | pmid = 7510950 | pmc = 1137932 }}</ref> iNOS and nNOS are soluble and found predominantly in the [[cytosol]], 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.
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| == Function ==
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| 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]], which induces smooth muscle relaxation by:
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| * Increased intracellular cGMP, which inhibits [[calcium]] entry into the cell, and decreases intracellular calcium concentrations
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| * Activation of K<sup>+</sup> channels, which leads to hyperpolarization and relaxation
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| * Stimulates a cGMP-dependent protein [[kinase]] that activates [[myosin]] light chain phosphatase, the enzyme that dephosphorylates [[myosin]] light chains, which leads to smooth muscle relaxation.
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| eNOS plays a critical role in embryonic heart development and morphogenesis of coronary arteries and cardiac valves.<ref name="pmid22579300">{{cite journal | author = Liu Y, Feng Q | title = NOing the heart: role of nitric oxide synthase-3 in heart development | journal = Differentiation | volume = 84 | issue = 1 | pages = 54–61 |date=July 2012 | pmid = 22579300 | doi = 10.1016/j.diff.2012.04.004 }}</ref>
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| 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.<ref name="pmid19770398">{{cite journal | author = Burger DE, Lu X, Lei M, Xiang FL, Hammoud L, Jiang M, Wang H, Jones DL, Sims SM, Feng Q | title = Neuronal nitric oxide synthase protects against myocardial infarction-induced ventricular arrhythmia and mortality in mice | journal = Circulation | volume = 120 | issue = 14 | pages = 1345–54 |date=October 2009 | pmid = 19770398 | doi = 10.1161/CIRCULATIONAHA.108.846402 }}</ref>
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| 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.
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| 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.
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| 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.
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| == Classification ==
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| Different members of the NOS family are encoded by separate genes.<ref name="pmid9366709">{{cite journal | author = Taylor BS, Kim YM, Wang Q, Shapiro RA, Billiar TR, Geller DA | title = Nitric oxide down-regulates hepatocyte-inducible nitric oxide synthase gene expression | journal = Arch Surg | volume = 132 | issue = 11 | pages = 1177–83 |date=November 1997 | pmid = 9366709 | doi = | url = }}</ref> NOS is one of the most regulated enzymes in biology. There are three known isoforms, two are constitutive (cNOS) and the third is inducible (iNOS).<ref name="pmid10320659">{{cite journal | author = Stuehr DJ | title = Mammalian nitric oxide synthases | journal = Biochim. Biophys. Acta | volume = 1411 | issue = 2–3 | pages = 217–30 |date=May 1999 | pmid = 10320659 | doi = 10.1016/S0005-2728(99)00016-X| url = }}</ref> Cloning of NOS enzymes indicates that cNOS include both brain constitutive ([[NOS1]]) and endothelial constitutive ([[endothelial NOS|NOS3]]); the third is the inducible ([[Nitric oxide synthase 2 (inducible)|NOS2]]) gene.<ref name="pmid10320659"/> Recently, NOS activity has been demonstrated in several bacterial species, including notorious pathogens Bacillus anthracis and Staphylococcus aureus.<ref name="pmid18316370">{{cite journal | author = Gusarov I, Starodubtseva M, Wang ZQ, McQuade L, Lippard SJ, Stuehr DJ, Nudler E | title = Bacterial Nitric-oxide Synthases Operate without a Dedicated Redox Partner | journal = J. Biol. Chem. | volume = 283 | issue = 19 | pages = 13140–7 |date=May 2008 | pmid = 18316370 | pmc = 2442334 | doi = 10.1074/jbc.M710178200 | url = }}</ref>
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| The different forms of NO synthase have been classified as follows:
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| {| class="wikitable"
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| | '''Name''' || '''Gene(s)''' || '''Location''' || '''Function'''
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| | '''[[Neuron]]al NOS''' (nNOS or NOS1) || [[NOS1]] (Chromosome 12) ||
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| *[[nervous tissue]]
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| *[[skeletal muscle]] type II
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| * cell communication
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| |-
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| | '''Inducible NOS''' (iNOS or NOS2) || [[Nitric oxide synthase 2 (inducible)|NOS2]] (Chromosome 17) ||
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| *[[immune system]]
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| *[[cardiovascular system]]
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| *[[immune]] defense against pathogens
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| |-
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| | '''[[Endothelial NOS]]''' (eNOS or NOS3 or cNOS) || [[Endothelial NOS|NOS3]] (Chromosome 7) ||
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| *[[endothelium]]
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| *[[vasodilation]]
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| |-
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| | '''Bacterial NOS''' (bNOS) || multiple ||
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| *various [[Gram-positive bacteria]]
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| *defense against [[oxidative stress]], [[antibiotic]]s, [[immune system|immune attack]]
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| |}
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| === nNOS ===
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| [[Neuron]]al NOS (nNOS) produces NO in [[nervous tissue]] in both the central and peripheral [[nervous system]]. The gene coding for nNOS is located on Chromosome 12.<ref name="Nitric oxide synthases in mammals">{{cite journal | author = Knowles RG, Moncada S | title = Nitric oxide synthases in mammals | journal = Biochem. J. | volume = 298 | issue = 2| pages = 249–58 |date=March 1994 | pmid = 7510950 | pmc = 1137932 | doi = }}</ref> 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]]). This form of the enzyme is specifically inhibited by [[7-Nitroindazole|7-nitroindazole]].<ref name="pmid8619882">{{cite journal | author = Southan GJ, Szabó C | title = Selective pharmacological inhibition of distinct nitric oxide synthase isoforms | journal = Biochem. Pharmacol. | volume = 51 | issue = 4 | pages = 383–94 |date=February 1996 | pmid = 8619882 | doi = 10.1016/0006-2952(95)02099-3 }}</ref>
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| 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]].<ref name="pmid7535955">{{cite journal | author = Ponting CP, Phillips C | title = DHR domains in syntrophins, neuronal NO synthases and other intracellular proteins | journal = Trends Biochem. Sci. | volume = 20 | issue = 3 | pages = 102–3 |date=March 1995 | pmid = 7535955 | doi = 10.1016/S0968-0004(00)88973-2 }}</ref>
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| === iNOS ===
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| 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 Ca<sup>2+</sup>. The gene coding for iNOS is located on Chromosome 17.<ref name="Nitric oxide synthases in mammals" /> While evidence for ‘baseline’ iNOS expression has been elusive, [[IRF1]] 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]]s (eg. [[Interleukin 1 family|Interleukin-1]], [[Tumor necrosis factor alpha]] and [[Interferon gamma]]).<ref name="pmid7537721">{{cite journal | author = Green SJ, Scheller LF, Marletta MA, Seguin MC, Klotz FW, Slayter M, Nelson BJ, Nacy CA | title = Nitric oxide: cytokine-regulation of nitric oxide in host resistance to intracellular pathogens | journal = Immunol. Lett. | volume = 43 | issue = 1-2 | pages = 87–94 |date=December 1994 | pmid = 7537721 | doi = }}</ref>
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| Induction of the high-output iNOS usually occurs in an oxidative environment, and thus high levels of NO have the opportunity to [[Reactive nitrogen species|react with superoxide]] leading to [[peroxynitrite]] 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.<ref name="pmid12379825">{{cite journal | author = Mungrue IN, Husain M, Stewart DJ | title = The role of NOS in heart failure: lessons from murine genetic models | journal = Heart Fail Rev | volume = 7 | issue = 4 | pages = 407–22 |date=October 2002 | pmid = 12379825 | doi = }}</ref>
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| It has been suggested that pathologic generation of [[nitric oxide]] through increased iNOS production may decrease [[fallopian tube|tubal]] [[cilia|ciliary]] beats and smooth muscle contractions and thus affect embryo transport, which may consequently result in [[ectopic pregnancy]].<ref name="pmid19482272">{{cite journal | author = Al-Azemi M, Refaat B, Amer S, Ola B, Chapman N, Ledger W | title = The expression of inducible nitric oxide synthase in the human fallopian tube during the menstrual cycle and in ectopic pregnancy | journal = Fertil. Steril. | volume = 94 | issue = 3 | pages = 833–40 |date=August 2010 | pmid = 19482272 | doi = 10.1016/j.fertnstert.2009.04.020 }}</ref>
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| === eNOS ===
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| {{Main|Endothelial NOS}}
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| Endothelial NOS (eNOS), also known as nitric oxide synthase 3 (NOS3), generates NO in [[blood vessel]]s and is involved with regulating vascular function. The gene coding for eNOS is located on Chromosome 7.<ref name="Nitric oxide synthases in mammals" /> A constitutive Ca<sup>2+</sup> dependent NOS provides a basal release of NO. eNOS is associated with "caveolae" a component of plasma membranes surrounding cells, and the membranes of Golgi bodies within cells. eNOS localisation to endothelial membranes is mediated by cotranslational N-terminal [[myristoylation]] and post-translational [[palmitoylation]].<ref name="pmid9199168">{{cite journal | author = Liu J, Hughes TE, Sessa WC | title = The First 35 Amino Acids and Fatty Acylation Sites Determine the Molecular Targeting of Endothelial Nitric Oxide Synthase into the Golgi Region of Cells: A Green Fluorescent Protein Study | journal = J. Cell Biol. | volume = 137 | issue = 7 | pages = 1525–35 |date=June 1997 | pmid = 9199168 | pmc = 2137822 | doi = 10.1083/jcb.137.7.1525 }}</ref>
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| === bNOS ===
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| 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.<ref name="pmid16172391">{{cite journal | author = Gusarov I, Nudler E | title = NO-mediated cytoprotection: Instant adaptation to oxidative stress in bacteria | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 102 | issue = 39 | pages = 13855–60 |date=September 2005 | pmid = 16172391 | pmc = 1236549 | doi = 10.1073/pnas.0504307102 | url = }}</ref><ref name="pmid19745150">{{cite journal | author = Gusarov I, Shatalin K, Starodubtseva M, Nudler E | title = Endogenous Nitric Oxide Protects Bacteria Against a Wide Spectrum of Antibiotics | journal = Science | volume = 325 | issue = 5946 | pages = 1380–4 |date=September 2009 | pmid = 19745150 | pmc = 2929644 | doi = 10.1126/science.1175439 }}</ref>
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| == Chemical reaction ==
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| [[Image:NOSreaction.svg]]
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| Nitric oxide synthases produce NO by catalysing a five-electron oxidation of a guanidino nitrogen of <small>L</small>-arginine (<small>L</small>-Arg). Oxidation of <small>L</small>-Arg to <small>L</small>-citrulline occurs via two successive monooxygenation reactions producing ''N''<sup>ω</sup>-hydroxy-<small>L</small>-arginine (NOHLA) as an intermediate. 2 mol of O<sub>2</sub> and 1.5 mol of NADPH are consumed per mole of NO formed.<ref name="pmid7510950"/>
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| == Structure ==
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| The enzymes exist as homodimers. In eukaryotes, each monomer consisting of two major regions: an N-terminal [[oxygenase]] domain, which belongs to the class of heme-thiolate proteins, and a multi-domain C-terminal [[reductase]], which is homologous to NADPH:[[cytochrome P450 reductase]] ({{EC number|1.6.2.4}}) 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]]-binding sequence. The oxygenase domain is a unique extended beta sheet cage with binding sites for heme and pterin.
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| NOSs can be [[protein dimer|dimeric]], calmodulin-dependent or calmodulin-containing [[cytochrome p450]]-like [[hemoprotein]] 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]] arginine with the aid of tetrahydrobiopterin.<ref name="pmid9493011">{{cite journal | author = Chinje EC, Stratford IJ | title = Role of nitric oxide in growth of solid tumours: a balancing act | journal = Essays Biochem. | volume = 32 | issue = | pages = 61–72 | year = 1997 | pmid = 9493011 | doi = | url = }}</ref>
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| All three [[isoform]]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]]. They also share an amino-terminal [[oxygenase domain]] containing a [[heme]] [[prosthetic group]], which is linked in the middle of the [[protein]] to a [[calmodulin]]-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 O<sub>2</sub> and <small>L</small>-arginine to [[nitric oxide|NO]] and <small>L</small>-citrulline. The oxygenase domain of each NOS isoform also contains an BH<sub>4</sub> prosthetic group, which is required for the efficient generation of NO. Unlike other enzymes where BH<sub>4</sub> is used as a source of reducing equivalents and is recycled by [[dihydrobiopterin reductase]] ({{EC number|1.5.1.33}}), BH<sub>4</sub> activates heme-bound O<sub>2</sub> by donating a single electron, which is then recaptured to enable nitric oxide release.
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| The first nitric oxide synthase to be identified was found in neuronal tissue (NOS1 or nNOS); the [[endothelial]] NOS (eNOS or NOS3) was the third to be identified. They were originally classified as "constitutively expressed" and "Ca<sup>2+</sup> sensitive" but it is now known that they are present in many different [[cell (biology)|cell]] types and that expression is regulated under specific physiological conditions.
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| In NOS1 and NOS3, physiological concentrations of Ca<sup>2+</sup> in cells regulate the binding of calmodulin to the "latch domains", thereby initiating electron transfer from the [[Flavin group|flavins]] to the [[heme]] moieties. In contrast, calmodulin remains tightly bound to the inducible and Ca<sup>2+</sup>-insensitive isoform (iNOS or NOS2) even at a low intracellular Ca<sup>2+</sup> activity, acting essentially as a subunit of this isoform.
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| Nitric oxide may itself regulate NOS expression and activity. Specifically, NO has been shown to play an important [[negative feedback]] 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 <small>L</small>-arginine in some cell types. This may be particularly important after the [[Enzyme induction and inhibition|induction]] of NOS2.
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| == See also ==
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| *[[Biological functions of nitric oxide]]
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| *[[Nitric-oxide synthase (NAD(P)H-dependent)]]
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| == References ==
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| {{Reflist|2}}
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| == External links ==
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| * {{MeshName|Nitric+oxide+synthase}}
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| * [http://nobelprize.org/nobel_prizes/medicine/laureates/1998/ The Nobel Prize in Physiology or Medicine 1998]
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| * University of Edinburgh, School of Chemistry - [http://homepages.ed.ac.uk/sd01/nospage.htm NO Synthase]
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| * [http://www.proteopedia.org/wiki/index.php/Nitric_oxide_synthase/ Nitric Oxide Synthase in Proteopedia]
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| {{Oxygenases}}
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| {{Neurotransmitter metabolism enzymes}}
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| {{DEFAULTSORT:Nitric Oxide Synthase}}
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| [[Category:EC 1.14.13]]
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| [[Category:Heme-thiolate proteins]]
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