ID NOS3_CAVPO Reviewed; 1110 AA.
AC P97270; H0V303;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 08-NOV-2023, sequence version 2.
DT 27-MAR-2024, entry version 118.
DE RecName: Full=Nitric oxide synthase 3 {ECO:0000305};
DE EC=1.14.13.39 {ECO:0000250|UniProtKB:P29474};
DE AltName: Full=Constitutive NOS;
DE Short=cNOS;
DE AltName: Full=EC-NOS;
DE AltName: Full=NOS type III;
DE Short=NOSIII;
DE AltName: Full=Nitric oxide synthase, endothelial {ECO:0000305};
DE Short=Endothelial NOS {ECO:0000305};
DE Short=eNOS {ECO:0000305};
GN Name=NOS3; Synonyms=ENOS;
OS Cavia porcellus (Guinea pig).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Hystricomorpha; Caviidae;
OC Cavia.
OX NCBI_TaxID=10141;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=2N;
RX PubMed=21993624; DOI=10.1038/nature10530;
RA Lindblad-Toh K., Garber M., Zuk O., Lin M.F., Parker B.J., Washietl S.,
RA Kheradpour P., Ernst J., Jordan G., Mauceli E., Ward L.D., Lowe C.B.,
RA Holloway A.K., Clamp M., Gnerre S., Alfoldi J., Beal K., Chang J.,
RA Clawson H., Cuff J., Di Palma F., Fitzgerald S., Flicek P., Guttman M.,
RA Hubisz M.J., Jaffe D.B., Jungreis I., Kent W.J., Kostka D., Lara M.,
RA Martins A.L., Massingham T., Moltke I., Raney B.J., Rasmussen M.D.,
RA Robinson J., Stark A., Vilella A.J., Wen J., Xie X., Zody M.C., Baldwin J.,
RA Bloom T., Chin C.W., Heiman D., Nicol R., Nusbaum C., Young S.,
RA Wilkinson J., Worley K.C., Kovar C.L., Muzny D.M., Gibbs R.A., Cree A.,
RA Dihn H.H., Fowler G., Jhangiani S., Joshi V., Lee S., Lewis L.R.,
RA Nazareth L.V., Okwuonu G., Santibanez J., Warren W.C., Mardis E.R.,
RA Weinstock G.M., Wilson R.K., Delehaunty K., Dooling D., Fronik C.,
RA Fulton L., Fulton B., Graves T., Minx P., Sodergren E., Birney E.,
RA Margulies E.H., Herrero J., Green E.D., Haussler D., Siepel A., Goldman N.,
RA Pollard K.S., Pedersen J.S., Lander E.S., Kellis M.;
RT "A high-resolution map of human evolutionary constraint using 29 mammals.";
RL Nature 478:476-482(2011).
RN [2]
RP PARTIAL NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Endothelial cell;
RX PubMed=9838160; DOI=10.1016/s0165-3806(98)00145-x;
RA Aguan K., Murotsuki J., Gagnon R., Thompson L.P., Weiner C.P.;
RT "Effect of chronic hypoxemia on the regulation of nitric-oxide synthase in
RT the fetal sheep brain.";
RL Brain Res. Dev. Brain Res. 111:271-277(1998).
CC -!- FUNCTION: Produces nitric oxide (NO) which is implicated in vascular
CC smooth muscle relaxation through a cGMP-mediated signal transduction
CC pathway. NO mediates vascular endothelial growth factor (VEGF)-induced
CC angiogenesis in coronary vessels and promotes blood clotting through
CC the activation of platelets (By similarity).
CC {ECO:0000250|UniProtKB:P29474}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+) + 2 L-arginine + 3 NADPH + 4 O2 = 4 H2O + 2 L-citrulline
CC + 3 NADP(+) + 2 nitric oxide; Xref=Rhea:RHEA:19897,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:16480, ChEBI:CHEBI:32682, ChEBI:CHEBI:57743,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.14.13.39;
CC Evidence={ECO:0000250|UniProtKB:P29474};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19898;
CC Evidence={ECO:0000250|UniProtKB:P29474};
CC -!- COFACTOR:
CC Name=heme b; Xref=ChEBI:CHEBI:60344;
CC Evidence={ECO:0000250|UniProtKB:P29474};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000250|UniProtKB:P29476};
CC Note=Binds 1 FAD. {ECO:0000250|UniProtKB:P29476};
CC -!- COFACTOR:
CC Name=FMN; Xref=ChEBI:CHEBI:58210;
CC Evidence={ECO:0000250|UniProtKB:P35228};
CC Note=Binds 1 FMN. {ECO:0000250|UniProtKB:P35228};
CC -!- COFACTOR:
CC Name=(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin;
CC Xref=ChEBI:CHEBI:59560; Evidence={ECO:0000250|UniProtKB:P35228};
CC Note=Tetrahydrobiopterin (BH4). May stabilize the dimeric form of the
CC enzyme. {ECO:0000250|UniProtKB:P35228};
CC -!- ACTIVITY REGULATION: Stimulated by calcium/calmodulin. Inhibited by
CC NOSIP and NOSTRIN (By similarity). {ECO:0000250}.
CC -!- SUBUNIT: Homodimer. Interacts with NOSIP and NOSTRIN (By similarity).
CC Interacts with HSP90AB1 (By similarity). Forms a complex with ASL, ASS1
CC and SLC7A1; the complex regulates cell-autonomous L-arginine synthesis
CC and citrulline recycling while channeling extracellular L-arginine to
CC nitric oxide synthesis pathway (By similarity).
CC {ECO:0000250|UniProtKB:P29474, ECO:0000250|UniProtKB:P70313}.
CC -!- SUBCELLULAR LOCATION: Membrane, caveola {ECO:0000250}. Cytoplasm,
CC cytoskeleton {ECO:0000250}. Golgi apparatus {ECO:0000250}. Cell
CC membrane {ECO:0000250}. Note=Specifically associates with actin
CC cytoskeleton in the G2 phase of the cell cycle, which is favored by
CC interaction with NOSIP and results in a reduced enzymatic activity.
CC {ECO:0000250}.
CC -!- INDUCTION: Repressed by hypoxemia in fetal brain.
CC -!- SIMILARITY: Belongs to the NOS family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB40703.1; Type=Miscellaneous discrepancy; Evidence={ECO:0000305};
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DR EMBL; AAKN02032925; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; U76736; AAB40703.1; ALT_SEQ; mRNA.
DR AlphaFoldDB; P97270; -.
DR STRING; 10141.ENSCPOP00000003945; -.
DR Ensembl; ENSCPOT00000004421.3; ENSCPOP00000003946.3; ENSCPOG00000004373.4.
DR VEuPathDB; HostDB:ENSCPOG00000004373; -.
DR GeneTree; ENSGT00940000161389; -.
DR HOGENOM; CLU_001570_16_0_1; -.
DR InParanoid; P97270; -.
DR Proteomes; UP000005447; Unassembled WGS sequence.
DR Bgee; ENSCPOG00000004373; Expressed in zone of skin and 12 other cell types or tissues.
DR GO; GO:0005901; C:caveola; IEA:UniProtKB-SubCell.
DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell.
DR GO; GO:0005516; F:calmodulin binding; IEA:UniProtKB-KW.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; IEA:InterPro.
DR GO; GO:0010181; F:FMN binding; IEA:InterPro.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0050661; F:NADP binding; IEA:InterPro.
DR GO; GO:0004517; F:nitric-oxide synthase activity; IEA:UniProtKB-EC.
DR GO; GO:0006809; P:nitric oxide biosynthetic process; IEA:InterPro.
DR CDD; cd00795; NOS_oxygenase_euk; 1.
DR Gene3D; 3.40.50.360; -; 1.
DR Gene3D; 3.90.440.10; Nitric Oxide Synthase;Heme Domain;Chain A domain 2; 1.
DR Gene3D; 3.40.50.80; Nucleotide-binding domain of ferredoxin-NADP reductase (FNR) module; 1.
DR Gene3D; 2.40.30.10; Translation factors; 1.
DR InterPro; IPR003097; CysJ-like_FAD-binding.
DR InterPro; IPR017927; FAD-bd_FR_type.
DR InterPro; IPR001094; Flavdoxin-like.
DR InterPro; IPR008254; Flavodoxin/NO_synth.
DR InterPro; IPR001709; Flavoprot_Pyr_Nucl_cyt_Rdtase.
DR InterPro; IPR029039; Flavoprotein-like_sf.
DR InterPro; IPR039261; FNR_nucleotide-bd.
DR InterPro; IPR023173; NADPH_Cyt_P450_Rdtase_alpha.
DR InterPro; IPR044943; NOS_dom_1.
DR InterPro; IPR044940; NOS_dom_2.
DR InterPro; IPR044944; NOS_dom_3.
DR InterPro; IPR012144; NOS_euk.
DR InterPro; IPR004030; NOS_N.
DR InterPro; IPR036119; NOS_N_sf.
DR InterPro; IPR001433; OxRdtase_FAD/NAD-bd.
DR InterPro; IPR017938; Riboflavin_synthase-like_b-brl.
DR PANTHER; PTHR43410; NITRIC OXIDE SYNTHASE OXYGENASE; 1.
DR PANTHER; PTHR43410:SF1; NITRIC OXIDE SYNTHASE OXYGENASE; 1.
DR Pfam; PF00667; FAD_binding_1; 1.
DR Pfam; PF00258; Flavodoxin_1; 1.
DR Pfam; PF00175; NAD_binding_1; 1.
DR Pfam; PF02898; NO_synthase; 1.
DR PIRSF; PIRSF000333; NOS; 1.
DR PRINTS; PR00369; FLAVODOXIN.
DR PRINTS; PR00371; FPNCR.
DR SUPFAM; SSF52343; Ferredoxin reductase-like, C-terminal NADP-linked domain; 1.
DR SUPFAM; SSF52218; Flavoproteins; 1.
DR SUPFAM; SSF56512; Nitric oxide (NO) synthase oxygenase domain; 1.
DR SUPFAM; SSF63380; Riboflavin synthase domain-like; 1.
PE 2: Evidence at transcript level;
KW Calcium; Calmodulin-binding; Cell membrane; Cytoplasm; Cytoskeleton; FAD;
KW Flavoprotein; FMN; Golgi apparatus; Heme; Iron; Membrane; Metal-binding;
KW NADP; Oxidoreductase; Phosphoprotein; Reference proteome; Zinc.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:P29473"
FT CHAIN 2..1110
FT /note="Nitric oxide synthase 3"
FT /id="PRO_0000170942"
FT REGION 1..74
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 101..489
FT /note="Interaction with NOSIP"
FT /evidence="ECO:0000250|UniProtKB:P29474"
FT REGION 821..848
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 43..68
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 97
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="ligand shared between homodimeric partners"
FT /evidence="ECO:0000250|UniProtKB:P29474"
FT BINDING 102
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="ligand shared between homodimeric partners"
FT /evidence="ECO:0000250|UniProtKB:P29474"
FT BINDING 105
FT /ligand="(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin"
FT /ligand_id="ChEBI:CHEBI:59560"
FT /evidence="ECO:0000250|UniProtKB:P29474"
FT BINDING 187
FT /ligand="heme b"
FT /ligand_id="ChEBI:CHEBI:60344"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT /evidence="ECO:0000250|UniProtKB:P29474"
FT BINDING 250
FT /ligand="L-arginine"
FT /ligand_id="ChEBI:CHEBI:32682"
FT /evidence="ECO:0000250|UniProtKB:P29474"
FT BINDING 359
FT /ligand="L-arginine"
FT /ligand_id="ChEBI:CHEBI:32682"
FT /evidence="ECO:0000250|UniProtKB:P29474"
FT BINDING 360
FT /ligand="L-arginine"
FT /ligand_id="ChEBI:CHEBI:32682"
FT /evidence="ECO:0000250|UniProtKB:P29474"
FT BINDING 364
FT /ligand="L-arginine"
FT /ligand_id="ChEBI:CHEBI:32682"
FT /evidence="ECO:0000250|UniProtKB:P29474"
FT BINDING 368
FT /ligand="(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin"
FT /ligand_id="ChEBI:CHEBI:59560"
FT /evidence="ECO:0000250|UniProtKB:P29474"
FT BINDING 369
FT /ligand="L-arginine"
FT /ligand_id="ChEBI:CHEBI:32682"
FT /evidence="ECO:0000250|UniProtKB:P29474"
FT BINDING 449
FT /ligand="(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin"
FT /ligand_id="ChEBI:CHEBI:59560"
FT /evidence="ECO:0000250|UniProtKB:P29474"
FT BINDING 450
FT /ligand="(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin"
FT /ligand_id="ChEBI:CHEBI:59560"
FT /evidence="ECO:0000250|UniProtKB:P29474"
FT BINDING 463
FT /ligand="(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin"
FT /ligand_id="ChEBI:CHEBI:59560"
FT /evidence="ECO:0000250|UniProtKB:P29474"
FT BINDING 478
FT /ligand="heme b"
FT /ligand_id="ChEBI:CHEBI:60344"
FT /evidence="ECO:0000250|UniProtKB:P29474"
FT BINDING 529
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000250|UniProtKB:P35228"
FT BINDING 530
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000250|UniProtKB:P35228"
FT BINDING 531
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000250|UniProtKB:P35228"
FT BINDING 533
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000250|UniProtKB:P35228"
FT BINDING 575
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000250|UniProtKB:P35228"
FT BINDING 576
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000250|UniProtKB:P35228"
FT BINDING 657
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000250|UniProtKB:P35228"
FT BINDING 664
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000250|UniProtKB:P35228"
FT BINDING 690
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000250|UniProtKB:P35228"
FT BINDING 694
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000250|UniProtKB:P35228"
FT BINDING 779
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P29476"
FT BINDING 801
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P29476"
FT BINDING 941
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P29476"
FT BINDING 943
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P29476"
FT BINDING 944
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P29476"
FT BINDING 959
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P29476"
FT BINDING 961
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P29476"
FT BINDING 965
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P29476"
FT BINDING 978
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P29476"
FT BINDING 979
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P29476"
FT BINDING 980
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P29476"
FT BINDING 1019
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P29476"
FT BINDING 1052
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P29476"
FT BINDING 1081
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P29476"
FT BINDING 1082
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P29476"
FT BINDING 1088
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P29476"
FT MOD_RES 117
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P29474"
FT MOD_RES 498
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P29474"
FT MOD_RES 618
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P70313"
FT MOD_RES 636
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P29474"
FT MOD_RES 641
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P29474"
FT MOD_RES 839
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P29474"
SQ SEQUENCE 1110 AA; 122763 MW; 586488E7C3AEE6BC CRC64;
MGNFKSVGQE PGPPCGLGLG LGLGLCGKQG PASPAPVSAS EPTRAPSSPP LPLPAPEHSP
PLTRPPEGPK FPRVKNWEVG SIAYDTLSAQ AQQDGPCTPR RCLGSLVFPR KLQGRPSQSP
LPQEQLLGQA RDFINQYYSS IKRSGSQAHE LRLQEVEAEV VATGTYQLRE SELVFGAKQA
WRNAPRCVGR IQWGKLQVFD ARDCRSAQEM FTYICNHIKY ATNRGNLRSA ITVFPQRFPG
RGDFRIWNSQ LIRYAGYRQQ DGSVRGDPAN VEITELCVQH GWTPGNGRFD VLPLLLQAPD
EPPELFTLPP ELVLEVPLEH PTLEWFAALG LRWYALPAVS NMLLEIGGLE FPAVPFSGWY
MSSEIGMRNF CDPHRYNILE DVAVCMDLDT RTTSSLWKDK AAVEINVAVL HSYQLAKVTI
VDHHAATASF MKHLENEQKA RGGCPADWAW IVPPISGSLT PVFHQEMVNY FLSPAFRYQP
DPWKGSGTKG TGITRKKTFK EVANAVKISA SLMGTVMAKR VKATILYGSE TGRAQSYAQQ
LGRLFRKAFD PRVLCMDEYD VVSLEHETLV LVVTSTFGNG DPPENGESFA AALMEMSGPY
NSSPRPEQHK SYKIRFNSVS CSDPLVTSWR RKRKESSNTD SAGALGTLRF CVFGLGSRAY
PHFCAFARAV DTRLEELGGE RLLQLGQGDE LCGQEEAFRG WAQAAFQAAC ETFCVGEDAK
AAAKDIFSPK CSWKRQRYRL STQAQGLQLL PGLIHVHRRK MFQATILSVE NLQSSKSTRA
TILVRLDTGG QEGLQYQPGD HIGICPPNRP GLVEALLSRV EDPPPPAESV AVEQLEKGSP
GGPPPGWVRD PRLPPCTLRQ ALTFFLDITS PPSPRLLRLL STLAEEPSEQ QELETLSQDP
RRYEEWKWFR CPTLLEVLEQ FPSIALPAPL LLTQLPLLQP RYYSVSSAPS AHPGEIHLTV
AVLAYRTQDG LGPLHYGVCS TWLSQLKTGD QVPCFIRGAP SFRLPPDPSL PCILVGPGTG
IAPFRGFWQE RLHDIESKGL QPAPMTLVFG CRCSQLDHLY RDEVQDAQQR GVFGRVLTAF
SREPNSPKER HLRGAVPWAF DLPGPDTSSP
//
