Editing Nitric oxide synthase (section)

== Mammalian isoforms ==

Different members of the NOS family are encoded by separate genes.<ref name="pmid9366709">{{cite journal |vauthors=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 = 10.1001/archsurg.1997.01430350027005}}</ref> There are three known isoforms in mammals, 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| doi-access =  }}</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 the notorious pathogens Bacillus anthracis and Staphylococcus aureus.<ref name="pmid18316370">{{cite journal |vauthors=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 | doi-access = free }}</ref>

The different forms of NO synthase have been classified as follows:

{| class="wikitable"
! Name || Gene(s) || Location || width=30% | Function
 |-
 | '''[[Neuron]]al NOS''' (nNOS or NOS1)  || [[NOS1]] (Chromosome 12) ||
*[[nervous tissue]]
*[[skeletal muscle]] type II
||
* multiple functions (see below)
 |-
 | '''Inducible NOS''' (iNOS or NOS2) 
Calcium insensitive 
|| [[Nitric oxide synthase 2 (inducible)|NOS2]] (Chromosome 17) ||
*[[immune system]]
*[[cardiovascular system]]
||
*[[immune]] defense against pathogens
 |-
 | '''[[Endothelial NOS]]''' (eNOS or NOS3 or cNOS)  || [[Endothelial NOS|NOS3]] (Chromosome 7) ||
*[[endothelium]]
||
*[[vasodilation]]
|}

=== nNOS ===

[[Neuron]]al NOS (nNOS) produces NO in [[nervous tissue]] in both the central and peripheral [[nervous systems]]. Its functions include:<ref>{{cite journal|last1=Förstermann|first1=Ulrich|last2=Sessa|first2=William|title=Nitric oxide synthases: regulation and function|journal=European Heart Journal|date=Apr 2012|volume=33|issue=7|pages=829–837|pmc=3345541|doi=10.1093/eurheartj/ehr304|pmid=21890489}}</ref>

* 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]]). This form of the enzyme is specifically inhibited by [[7-Nitroindazole|7-nitroindazole]].<ref name="pmid8619882">{{cite journal |vauthors=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>

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 |vauthors=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>

The gene coding for nNOS is located on Chromosome 12.<ref name="Nitric oxide synthases in mammals">{{cite journal |vauthors=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 =  10.1042/bj2980249}}</ref>

=== 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 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 (e.g. [[Interleukin 1 family|Interleukin-1]], [[Tumor necrosis factor alpha]] and [[Interferon gamma]]).<ref name="pmid7537721">{{cite journal |vauthors=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 = 10.1016/0165-2478(94)00158-8| hdl = 2027.42/31140 | url = https://deepblue.lib.umich.edu/bitstream/2027.42/31140/1/0000037.pdf | hdl-access = free }}</ref>

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]] 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 |vauthors=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 = 10.1023/a:1020762401408| s2cid = 26600958 }}</ref>

It has been suggested that pathologic generation of [[nitric oxide]] through increased iNOS production may decrease [[fallopian tube|tubal]] [[cilia]]ry beats and smooth muscle contractions and thus affect embryo transport, which may consequently result in [[ectopic pregnancy]].<ref name="pmid19482272">{{cite journal |vauthors=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>

=== eNOS ===
{{Main|Endothelial NOS}}
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 localizes to caveolae, a plasma membrane domain primarily composed of the protein [[caveolin 1]], and to the Golgi apparatus. These two eNOS populations are distinct, but are both necessary for proper NO production and cell health.<ref name ="pmid32152543">{{cite journal |vauthors = Maulik SJ, Junyi Z, Aneesh TV, Yamuna K | title = A DNA-based fluorescent probe maps NOS3 activity with subcellular spatial resolution
| journal = Nat. Chem. Biol. | issue = 6 | pages = 660–6 | date=March 2020 | volume = 16
| pmid = 32152543 | doi = 10.1038/s41589-020-0491-3| s2cid = 212642840
}}</ref> eNOS localization to endothelial membranes is mediated by cotranslational N-terminal [[myristoylation]] and post-translational [[palmitoylation]].<ref name="pmid9199168">{{cite journal |vauthors=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> As an essential co-factor for nitric oxide synthase, [[tetrahydrobiopterin]] (BH4) supplementation has shown beneficial results for the treatment of [[endothelial dysfunction]] in animal experiments and clinical trials, although the tendency of BH4 to become oxidized to BH2 remains a problem.<ref name="pmid29596860">{{cite journal | vauthors = Yuyun MF, Ng LL, Ng GA | title=Endothelial dysfunction, endothelial nitric oxide bioavailability, tetrahydrobiopterin, and 5-methyltetrahydrofolate in cardiovascular disease. Where are we with therapy? | journal= Microvascular Research | volume=119 | pages=7–12 | year=2018 | doi= 10.1016/j.mvr.2018.03.012 | pmid=29596860}}</ref>