Nitric Oxide Synthase: Difference between revisions

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<StructureSection load='2g6h' size='400' side='right' caption='Neuronal nitric oxide synthase dimer complex with cofactor tetrahydrobiopterin, acetate and Zn+2 (grey), (PDB entry [[2g6h]])' scene=''>
<StructureSection load='2g6h' size='350' side='right' caption='Neuronal nitric oxide synthase dimer complex with cofactor tetrahydrobiopterin, acetate and Zn+2 (grey), (PDB entry [[2g6h]])' scene=''>


'''Nitric Oxide Synthase''' (NOS) is an enzyme catalysing the formation of L-citrulline and [http://en.wikipedia.org/wiki/Nitric_Oxide/ nitric oxide] (NO) from L-arginine. NOS is a homodimeric protein with 125- to 160-kDa per monomer.  In mammals, NOS appears as 3 isozymes: neuronal NOS (nNOS) (for details see [[Nos1]]), cytokine-inducible NOS (iNOS) and endothelial NOS (eNOS).  The N-terminal domain of NOS is an oxygenase domain (OD).  NOS cofactors are: NADPH, FAD, FMN, heme and O2.  See also [[Nos1]].
'''Nitric Oxide Synthase''' (NOS) or '''Nitric Oxide Synthase oxygenase''' is an enzyme catalysing the formation of L-citrulline and [http://en.wikipedia.org/wiki/Nitric_Oxide/ nitric oxide] (NO) from L-arginine. NOS is a homodimeric protein with 125- to 160-kDa per monomer.  In mammals, NOS appears as 3 isozymes: neuronal NOS (nNOS) (for details see [[Nos1]]), cytokine-inducible NOS (iNOS) and endothelial NOS (eNOS).  The N-terminal domain of NOS is an '''oxygenase''' domain (OD).  NOS cofactors are: NADPH, FAD, FMN, heme and O2.  See also [[Nos1]].


=Introduction=
=Introduction=
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In mammals three isozymes of NOS have been identified: Neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS)<ref>Flemming, I., Chapter 3, Biology of Nitric Oxide Synthases, from Microcirculation, Editors Ronald F. Tuma, R. F., Durán, W. N., and Ley, K., 2nd edition, Academic Press, 2008</ref>. (The NOS enzymes are found in numeral organisms. Most facts used here are from the human NOS, but sites from different organisms are used). Neuronal NOS is producing NO in the nervous tissue in both the peripheral and the central nervous system. nNOS is functioning in cell signaling and communication - a vital part of the nervous tissue. Inducible NOS is connected with the immune system. Endothelial NOS is controlling the amount of NO signaling in the endothelial cells eg. blood vessel dilation.  An overview of the structural organization of the NOS homodimer is given below. All cofactors are included and the electron transfer pathway which takes place in NOS is indicated.  
In mammals three isozymes of NOS have been identified: Neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS)<ref>Flemming, I., Chapter 3, Biology of Nitric Oxide Synthases, from Microcirculation, Editors Ronald F. Tuma, R. F., Durán, W. N., and Ley, K., 2nd edition, Academic Press, 2008</ref>. (The NOS enzymes are found in numeral organisms. Most facts used here are from the human NOS, but sites from different organisms are used). Neuronal NOS is producing NO in the nervous tissue in both the peripheral and the central nervous system. nNOS is functioning in cell signaling and communication - a vital part of the nervous tissue. Inducible NOS is connected with the immune system. Endothelial NOS is controlling the amount of NO signaling in the endothelial cells eg. blood vessel dilation.  An overview of the structural organization of the NOS homodimer is given below. All cofactors are included and the electron transfer pathway which takes place in NOS is indicated.  
{{Clear}}
{{Clear}}
[[Image:schematic_NOS.png|500 px|left]]
[[Image:schematic_NOS.png|left|thumb|450px]]
{{Clear}}
{{Clear}}
Each NOS monomer is composed of two domains: an N-terminal oxygenase domain and a C-terminal reductase domain. Each subunit is held together by a zinc ion, which is bound by two cysteines from each oxygenase domain. Calmodulin binds to a linker region between the two domains and is necessary for activity. The reductase domain supplies electrons for the NOS reaction which takes place in the oxygenase domain. The reductase domain contains two redox-active prosthetic groups, flavin adenine dinucleotide (FAD) and Flavin mononucleotide (FMN). Nicotinamide adenine dinucleotide phosphate(NADPH) binds to the domain and passes on an electron to FAD which passes the electron on to FMN. FMN passes the electron on to the heme in the oxygenase domain on the opposite subunit. The oxygenase domain contains 5,6,7,8-tetrahydrobiopterin (H<sub>4</sub>B) and the already mentioned heme. These two are also redox active groups. Besides Heme and H<sub>4</sub>B, the oxygenase domain binds the substrate L-arginine which takes part in the NO synthase reaction (see below).
Each NOS monomer is composed of two domains: an N-terminal oxygenase domain and a C-terminal reductase domain. Each subunit is held together by a zinc ion, which is bound by two cysteines from each oxygenase domain. Calmodulin binds to a linker region between the two domains and is necessary for activity. The reductase domain supplies electrons for the NOS reaction which takes place in the oxygenase domain. The reductase domain contains two redox-active prosthetic groups, flavin adenine dinucleotide (FAD) and Flavin mononucleotide (FMN). Nicotinamide adenine dinucleotide phosphate(NADPH) binds to the domain and passes on an electron to FAD which passes the electron on to FMN. FMN passes the electron on to the heme in the oxygenase domain on the opposite subunit. The oxygenase domain contains 5,6,7,8-tetrahydrobiopterin (H<sub>4</sub>B) and the already mentioned heme. These two are also redox active groups. Besides Heme and H<sub>4</sub>B, the oxygenase domain binds the substrate L-arginine which takes part in the NO synthase reaction (see below).
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The NO production takes plase in the oxygenase domain, whereas the reductase domain provides the electrons necessary to drive the reaction in the oxygenase domain.
The NO production takes plase in the oxygenase domain, whereas the reductase domain provides the electrons necessary to drive the reaction in the oxygenase domain.
The reaction is:
The reaction is:
[[image:Makroprojekt-chemdraw-1-.gif|frame|left|thumb|450px]]
[[image:Makroprojekt-chemdraw-1-.gif|frame|left|thumb|400px]]
{{Clear}}
{{Clear}}
The reaction occurs in two steps. In the first step L-arginine is turned in to N-hydroxy-arginine. In the second step L-citrulline and NO are formed. The reaction utilizes 2O<sub>2</sub> and 3 electrons from 3/2 NADPH.<ref>PMID:17014963</ref>
The reaction occurs in two steps. In the first step L-arginine is turned in to N-hydroxy-arginine. In the second step L-citrulline and NO are formed. The reaction utilizes 2O<sub>2</sub> and 3 electrons from 3/2 NADPH.<ref>PMID:17014963</ref>
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Structures used in the section above: [[1tll]]
Structures used in the section above: [[1tll]]
</StructureSection>
== 3D Structures of Nitric Oxide Synthase ==


Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
= 3D Structures of Nitric Oxide Synthase =
{{#tree:id=OrganizedByTopic|openlevels=0|
[[Nitric Oxide Synthase 3D structures]]


*Endothelial NOS
</StructureSection>
 
**[[3nld]], [[3nle]], [[3nlf]], [[3nlg]], [[3jww]], [[3jwx]], [[3jwy]], [[3jwz]], [[3dqs]], [[3dqt]], [[3pnh]], [[4luw]] – b-eNOS OD+pyrrolidinomethyl pyridine derivative – bovine<br />
**[[1dm6]] – b-eNOS OD+guanidine derivative<br />
**[[3nlh]], [[3rqo]], [[3rqp]] – b-eNOS OD (mutant)+pyrrolidinomethyl aminopyridine derivative<br />
**[[1rs8]], [[1rs9]], [[1p6n]] – b-eNOS OD +dipeptide inhibitor<br />
**[[1nse]] – b-eNOS OD<br />
**[[1p6n]] – b-eNOS OD +dipeptide inhibitor<br />
**[[5nse]], [[1fol]], [[1foo]], [[1fop]], [[1dm7]], [[2nse]], [[3nse]], [[4nse]] – b-eNOS OD+arginine derivative<br />
**[[6nse]] – b-eNOS OD+canavanine<br />
**[[7nse]] – b-eNOS OD+ADMA<br />
**[[1i83]], [[1d1v]], [[1d1x]], [[1d1y]], [[1ed4]], [[9nse]] – b-eNOS OD+urea derivative<br />
**[[1dmj]], [[1dmk]] – b-eNOS OD+pterin derivative<br />
**[[1foi]], [[1dmi]], [[1i83]], [[3n5p]], [[3n5q]], [[3n5r]], [[3n5s]], [[3n5t]], [[3n5v]], [[3n5w]], [[3n5x]], [[3n5y]], [[3n5z]], [[3n60]], [[3n61]], [[3n62]], [[3n63]], [[3n64]], [[3n65]], [[3n66]], [[3n67]], [[3n68]], [[3n69]], [[3n6a]], [[3n6b]], [[3n6c]], [[3n6d]], [[3n6e]], [[3n6f]], [[3n6g]], [[3nlt]], [[3nlu]], [[3e7s]], [[5vv6]], [[5vv7]], [[5vv8]], [[5vv9]], [[4upq]], [[4upr]], [[4ups]], [[4upt]], [[5vva]], [[5vvb]], [[5vvc]], [[5vvd]], [[5vvg]], [[5vvn]], [[5uo8]], [[5uo9]], [[5uoa]], [[5uob]], [[5uoc]], [[5uod]], [[5fvy]], [[5fvz]], [[5fj2]], [[5fj3]], [[5adj]], [[5adk]], [[5adl]], [[5adm]], [[5adn]], [[4uh7]], [[4uh8]], [[4uh9]], [[4uha]], [[4d33]], [[4d34]], [[4d35]], [[4d36]], [[4d37]], [[4d38]], [[4d39]], [[4d3a]], [[4cul]], [[4cum]], [[4cun]], [[4cvg]], [[4cwv]], [[4cww]], [[4cwx]], [[4cty]], [[4ctz]], [[4cu0]], [[4cu1]] – b-eNOS OD+inhibitor<br />
**[[4cwz]], [[4cx0]], [[4cx1]], [[4cx2]]  – b-eNOS OD (mutant) +inhibitor<br />
**[[1d0c]], [[8nse]], [[1foj]], [[1ed5]], [[1d0o]], [[1d1w]] – b-eNOS OD+indazole derivative<br />
**[[1dm8]] – b-eNOS OD+triazole derivative<br />
**[[1ed6]] – b-eNOS OD+NO<br />
**[[1q2o]] – b-eNOS OD (mutant)+dipeptide inhibitor<br />
**[[1p6l]], [[1p6m]] – r-eNOS OD +dipeptide inhibitor - rat<br />
**[[3nli]] - r-eNOS OD (mutant)+pyrrolidinomethyl aminopyridine derivative<br />
**[[4jsk]], [[4jsl]], [[4jsm]], [[4imx]], [[4k5h]], [[4k5i]], [[4k5j]], [[4k5k]], [[4c3a]] – r-eNOS OD+ pyridine derivative<br />
**[[4kcp]], [[4kcq]], [[4kcr]], [[4kcs]] - r-eNOS OD heme domain +thiophene carboximidamide derivative<br />
**[[3eah]] – h-eNOS OD - human<br />
**[[3nos]] – h-eNOS OD+arginine<br />
**[[1m9j]] – h-eNOS OD+chlorzoxazone<br />
**[[1m9k]], [[1m9r]], [[4d1p]] – h-eNOS OD+ inhibitor<br />
**[[1nsi]] - h-eNOS OD+ Zn
 
*Neuronal NOS
 
**[[2hx2]] – b-nNOS OD+nitroguanidine derivative<br />
**[[3nlv]], [[3nlw]], [[3nlx]], [[3nly]], [[3nlz]], [[3nm0]], [[4uh7]], [[4uh8]], [[4uh9]], [[4uha]] - b-nNOS OD + inhibitor<br />
**[[3nli]], [[3nlj]], [[3nlk]], [[3nln]], [[3nlo]], [[3nlp]], [[3nlq]], [[3nlr]], [[3jws]], [[3jwt]], [[3jwu]], [[3jwv]], [[3jx0]], [[3jx1]], [[3jx2]], [[3jx3]], [[3jx4]], [[3jx5]], [[3jx6]], [[3pne]], [[3pnf]], [[3png]], [[3svp]], [[3svq]] - r-nNOS OD (mutant)+ pyridine derivative – rat<br />
**[[3nlm]], [[3nny]], [[3nnz]], [[3n2r]], [[3b3o]], [[3b3p]], [[3b3m]], [[3b3n]], [[3rqj]], [[3rqk]], [[3rql]], [[3rqm]], [[3rqn]], [[3tyl]], [[3tym]], [[3tyn]], [[3tyo]], [[4ims]], [[4imt]], [[4imu]], [[4imw]], [[4jse]], [[4jsf]], [[4jsg]], [[4jsh]], [[4jsi]], [[4jsj]], [[4k5d]], [[4k5e]], [[4k5f]], [[4k5g]], [[4lux]] - r-nNOS OD+ pyridine derivative<br />
**[[4gqe]]  – r-nNOS OD + norvaline derivative<br />
**[[1om4]], [[1k2r]], [[1k2s]], [[1lzx]], [[2hx4]], [[1zvl]], [[1qw6]], [[4fvw]], [[4fvx]], [[4fvy]], [[4fvz]], [[4fw0]] - r-nNOS OD+arginine derivative<br />
**[[4cam]], [[4can]], [[4cao]], [[4cap]], [[4caq]], [[4car]], [[4cdt]], [[4cft]]  – r-nNOS OD heme domain + quinoline derivative<br />
**[[1k2t]], [[1k2u]] – r-nNOS OD+thiourea derivative<br />
**[[1om5]] – r-nNOS OD+indazole derivative<br />
**[[1lzz]], [[1m00]], [[2hx3]]– r-nNOS OD+guanidine derivative<br />
**[[4kch]], [[4kci]], [[4kcj]], [[4kck]], [[4kcl]], [[4kcm]], [[4kcn]], [[4kco]] - r-nNOS OD heme domain +thiophene carboximidamide derivative<br />
**[[3fc5]], [[1zvi]] – r-nNOS OD<br />
**[[1qau]] - r-nNOS OD PDZ domain<br />
**[[1qav]], [[4hop]] - r-nNOS OD PDZ domain + α-1 syntrophin<br />
**[[1qwc]], [[3q99]], [[3q9a]], [[1mmv]], [[1mmw]], [[3dqr]], [[3ufo]], [[3ufp]], [[3ufq]], [[3ufr]], [[3ufs]], [[3uft]], [[3ufu]], [[3ufv]], [[3ufw]], [[4eux]], [[5vui]], [[4upm]], [[4upn]], [[4upo]], [[4upp]], [[5vuk]], [[5vul]], [[5vum]], [[5vun]], [[5vuo]], [[5vup]], [[5vuq]], [[5vur]], [[5vus]], [[5vut]], [[5vuu]], [[5unr]], [[5unt]], [[5unu]], [[5unv]], [[5unw]], [[5unx]], [[5uny]], [[5unz]], [[5uo0]], [[5fw0]], [[5fvo]], [[5fvp]], [[5fvq]], [[5fvr]], [[5fvs]], [[5fvt]], [[5agk]], [[5agl]], [[5agm]], [[5agn]], [[5ago]], [[5agp]], [[4v3v]], [[4v3w]], [[4v3x]], [[4v3y]], [[4v3z]], [[5ad4]], [[5ad5]], [[5ad6]], [[5ad7]], [[5ad8]], [[5ad9]], [[5ada]], [[5adb]], [[5adc]], [[4ugz]], [[4d33]], [[4d34]], [[4d35]], [[4d2y]], [[4d1z]], [[4d30]], [[4d31]], [[4uh4]], [[4d7o]], [[4d3b]], [[4d32]], [[4ctp]], [[4ctq]], [[4ctr]], [[4ctt]], [[4ctu]], [[4ctv]], [[4c39]] – r-nNOS OD+inhibitor<br />
**[[5vv0]], [[5vv3]], [[5vv5]], [[5uns]], [[5uo1]], [[5uo2]], [[5uo3]], [[5uo4]], [[5uo5]], [[5uo6]], [[5uo7]], [[5g0n]], [[5g0p]], [[5fvu]], [[5fvv]], [[5fvx]], [[5fvw]], [[5fvx]], [[4v3u]], [[5add]], [[5ade]], [[5adf]], [[5adg]], [[5adi]], [[4cx3]], [[4cx4]], [[4cx5]], [[4cx6]] – r-nNOS OD (mutant) +inhibitor<br />
**[[3jt3]], [[3jt4]], [[3jt5]], [[3jt6]], [[3jt7]], [[3jt8]], [[3jt9]], [[3jta]] – r-nNOS OD+ornithine derivative<br />
**[[3hsn]] – r-nNOS OD+NHA+CO<br />
**[[3hso]], [[3hsp]] -  r-nNOS OD+NHA+NO<br />
**[[2g6h]], [[2g6i]], [[2g6j]] – r-nNOS OD+pterin derivative<br />
**[[2g6k]], [[2g6l]] – r-nNOS OD+pterin derivative+NO<br />
**[[2g6m]], [[2g6n]], [[2g6o]] – r-nNOS OD+pterin derivative+CO<br />
**[[1zzq]], [[1zzr]], [[1zzs]], [[1zzt]], [[1zzu]], [[1p6k]] – r-nNOS OD (mutant)+dipeptide inhibitor<br />
**[[1rs6]], [[1rs7]], [[1p6h]], [[1p6i]], [[1p6j]] – r-nNOS OD +dipeptide inhibitor<br />
**[[1b8q]] – r-nNOS PDZ domain + heptapeptide<br />
**[[1f20]] - r-nNOS FAD/NADP domain<br />
**[[1vag]] – m-nNOS OD+inhibitor - mouse<br />
**[[4uh5]] - h-nNOS OD+inhibitor<br />
**[[4uh6]], [[4uch]] - h-nNOS OD (mutant) +inhibitor<br />
**[[4d1n]] - h-nNOS OD (mutant) + arginine<br />
 
*Inducible NOS
**[[3nqs]], [[3e65]], [[3eai]], [[3ebd]], [[3ebf]], [[1r35]], [[2nod]]  – m-iNOS OD + pterin derivative<br />
**[[1jwj]], [[1jwk]] – m-iNOS OD (mutant)+ pterin derivative<br />
**[[4ux6]] – m-iNOS OD + pterin derivative + inhibitor<br />
**[[2bhj]] – m-iNOS OD+coumarin<br />
**[[3nod]] – m-iNOS OD+product analog<br />
**[[1noc]] – m-iNOS OD+chloramphenicol acetyltransferase<br />
**[[3e67]] – m-iNOS OD+4-MAP<br />
**[[3e68]], [[3e6l]], [[3e6n]], [[3e6o]], [[3e6t]], [[3e7i]], [[3e7m]], [[3e7t]], [[1vaf]], [[1qw5]], [[1dd7]], [[2y37]] – m-iNOS OD+inhibitor <br />
**[[2orq]], [[2orr]], [[2ors]], [[2ort]], [[2oro]], [[2orp]], [[1nos]], [[3nw2]] – m-iNOS OD+imidazole derivative<br />
**[[1df1]] - m-iNOS OD+ urea derivative<br />
**[[3dwj]] – m-iNOS OD (mutant)<br />
**[[1qom]], [[4js9]] - m-iNOS OD<br />
**[[1qw4]], [[1dwv]], [[1dww]], [[1dwx]], [[1nod]] – m-iNOS OD+arginine derivative<br />
**[[2nos]] – m-iNOS OD+guanidine derivative<br />
**[[1n2n]] – m-iNOS OD+CN<br />
**[[1m9t]] – m-iNOS OD+indazole derivative<br />
**[[1m8d]] – m-iNOS OD+chlorzoxazone<br />
**[[1m8e]], [[1m8h]], [[1m8i]], [[1m9m]], [[1m9q]] – m-iNOS OD+ indazole derivative<br />
**[[1jwj]] – m-iNOS OD + inhibitor<br />
**[[1jwk]] - m-iNOS OD (mutant) + inhibitor<br />
**[[3hr4]] – h-iNOS residues 503-715+calmodulin – human<br />
**[[3e7g]] – h-iNOS residues 82-505+inhibitor<br />
**[[3ej8]] – h-iNOS OD+imidazole<br />
**[[4nos]], [[4cx7]] – h-iNOS OD+inhibitor<br />
**[[1nsi]] – h-iNOS OD+arginine<br />
**[[2nsi]] – h-iNOS OD+thiourea derivative<br />
**[[3gof]] - c-iNOS OD + calmodulin – chicken<br />
 
*Prokaryote NOS


**[[2amo]] – BsNOS – ''Bacillus subtilis''<br />
**[[2an0]], [[2an2]] – BsNOS (mutant)<br />
**[[2fbz]], [[2fc2]], [[2fc1]] – BsNOS+NO<br />
**[[1m7v]], [[1m7z]] – BsNOS+THF+arginine<br />
**[[5g67]], [[4ugl]] – BsNOS + inhibitor<br />
**[[2flq]] – NOS+arginine – ''Geobacillus stearothermophilus''<br />
}}
==References==
==References==
<references/>
<references/>


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