Editing Nitric oxide synthase (section)

{{Short description|Class of enzymes}}
{{cleanup|reason=Has an ontology problem. Do we want to describe all NO synthases, or just the one with EC code 1.14.13.39?|date=March 2025}}
{{infobox enzyme
| Name       = Nitric-oxide synthase (NADPH)
| EC_number  = 1.14.13.39
| CAS_number = 125978-95-2
| GO_code    = 0051767
| image      = 1nsi.png
| width      =
| caption    = Human inducible nitric oxide synthase. PDB {{PDBe|1nsi}} 
}}
{{Infobox protein family
| Symbol = NO_synthase 
| Name = Nitric oxide synthase, oxygenase domain 
| image = Nitric_Oxide_Synthase.png
| width = 
| caption = Structure of endothelial nitric oxide synthase heme domain.<ref name="pmid21138269">{{PDB|3N5P}}; {{cite journal |vauthors=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 | pmc=3193998}}</ref>
| Pfam= PF02898
| InterPro= IPR004030
| SMART= 
| Prosite =          
| SCOP = 1nos
| TCDB = 
| OPM family= 
| OPM protein= 
}} 
'''Nitric oxide synthases''' ('''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).<ref>{{Cite journal |last1=Ahmad |first1=Nashrah |last2=Ansari |first2=Mohammad Y. |last3=Haqqi |first3=Tariq M. |date=October 2020 |title=Role of iNOS in osteoarthritis: Pathological and therapeutic aspects |journal=Journal of Cellular Physiology |language=en |volume=235 |issue=10 |pages=6366–6376 |doi=10.1002/jcp.29607 |issn=0021-9541 |pmc=8404685 |pmid=32017079}}</ref> 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 and ultimate causation|proximate cause]] of [[septic shock]] and may function in [[autoimmunity|autoimmune]] disease.

In the context of [[eukaryote]] biology, ''nitric oxide synthase'' refers to '''nitric-oxide synthase (NADPH)''' ({{EC number|1.14.13.39}}), which catalyzes the reaction:<ref name="pmid7510950" />
* 2 L-[[arginine]] + 3 [[nicotinamide adenine dinucleotide phosphate|NADPH]] +  3 H<sup>+</sup> + 4 O<sub>2</sub> <math>\rightleftharpoons</math> 2 [[citrulline]] +2  [[nitric oxide]] + 4 H<sub>2</sub>O + 3 NADP<sup>+</sup>

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.

Eukaryotic NOS isozymes are catalytically self-sufficient. The electron flow is: [[NADPH]] → [[flavin adenine dinucleotide|FAD]] → [[Flavin mononucleotide|FMN]] → [[heme]] → [[dioxygen|O<sub>2</sub>]]. [[Tetrahydrobiopterin]] provides an additional electron during the catalytic cycle which is replaced during turnover. [[Zinc]], though not a cofactor, also participates but as a structural element.<ref name="pmid25180171">{{cite journal|vauthors=Cortese-Krott M, Kulakov L, Opländer C, Kolb-Bachofen V, Kröncke K, Suschek C |title=Zinc regulates iNOS-derived nitric oxide formation in endothelial cells |journal=Redox Bio. J. |volume=2014 |issue=2 |pages=945–954 |date=July 2014 |doi=10.1016/j.redox.2014.06.011 |pmid=25180171 |pmc=4143817}}</ref> NOSs are unique in that they use five [[Cofactor (biochemistry)|cofactor]]s and are the only known [[enzyme]] that binds [[flavin adenine dinucleotide]] (FAD), [[flavin mononucleotide]] (FMN), [[heme]], [[tetrahydrobiopterin]] (BH<sub>4</sub>) and [[calmodulin]].{{citation needed|date=May 2016}}

The EC number 1.14.13.39 specifically refers to synthases with linked oxygenase and reductase domains, i.e. "catalytically self-sufficient" NO synthases. This kind of synthase is ound in eukaryotes and, through independent domain acquisition, ''[[Sorangium cellulosum]]''. Most bacteria and archaea have a version that only has an oxidase domain and depend on a partner protein; these are categorized as EC 1.14.14.47 "[[nitric-oxide synthase (flavodoxin)]]". All these enzymes' oxygenase domains share a common ancestor (see "oxygenase domain" infobox).<ref>{{cite journal |last1=Agapie |first1=Theodor |last2=Suseno |first2=Sandy |last3=Woodward |first3=Joshua J. |last4=Stoll |first4=Stefan |last5=Britt |first5=R. David |last6=Marletta |first6=Michael A. |title=NO formation by a catalytically self-sufficient bacterial nitric oxide synthase from Sorangium cellulosum |journal=Proceedings of the National Academy of Sciences |date=22 September 2009 |volume=106 |issue=38 |pages=16221–16226 |doi=10.1073/pnas.0908443106|doi-access=free |pmid=19805284 |pmc=2752531 |bibcode=2009PNAS..10616221A }}</ref><ref>{{cite web |title=ExplorEnz: EC 1.14.13.39 |url=https://www.enzyme-database.org/query.php?ec=1.14.13.39 |website=www.enzyme-database.org}}</ref>