P29474 (NOS3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Nitric oxide synthase, endothelial
EC=1.14.13.39

Alternative name(s):
Constitutive NOS
Short name=cNOS
EC-NOS
Endothelial NOS
Short name=eNOS
NOS type III
Short name=NOSIII

Gene names

Name:

NOS3

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	1203 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. NO mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets. Ref.7 Isoform eNOS13C: Lacks eNOS activity, dominant-negative form that may down-regulate eNOS activity by forming heterodimers with isoform 1. Ref.7
Catalytic activity	2 L-arginine + 3 NADPH + 4 O2 = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O.
Cofactor	Heme group. Binds 1 FAD. Binds 1 FMN. Tetrahydrobiopterin (BH4). May stabilize the dimeric form of the enzyme.
Enzyme regulation	Stimulated by calcium/calmodulin. Inhibited by NOSIP and NOSTRIN. Ref.20 Ref.21
Subunit structure	Homodimer. Interacts with NOSIP and NOSTRIN. Ref.20 Ref.21
Subcellular location	Cell membrane. Membrane › caveola. Cytoplasm › cytoskeleton. Golgi apparatus. Note: Specifically associates with actin cytoskeleton in the G2 phase of the cell cycle; which is favored by interaction with NOSIP and results in a reduced enzymatic activity. Ref.20 Ref.21 Ref.23 Ref.24
Tissue specificity	Platelets, placenta, liver and kidney. Ref.19
Post-translational modification	Phosphorylation by AMPK at Ser-1177 in the presence of Ca2+-calmodulin (CaM) activates activity. In absence of Ca2+-calmodulin, AMPK also phosphorylates Thr-495, resulting in inhibition of activity By similarity. Phosphorylation of Ser-114 by CDK5 reduces activity.
Polymorphism	Variation in NOS3 seem to be associated with susceptibility to coronary spasm.
Sequence similarities	Belongs to the NOS family. Contains 1 FAD-binding FR-type domain. Contains 1 flavodoxin-like domain.

Ontologies

Keywords
Cellular component	Cell membrane Cytoplasm Cytoskeleton Golgi apparatus Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Ligand	Calcium Calmodulin-binding FAD FMN Heme Iron Metal-binding NADP Zinc
Molecular function	Oxidoreductase
PTM	Lipoprotein Myristate Palmitate Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	angiogenesis Inferred from electronic annotation. Source: Compara arginine catabolic process Inferred from direct assay Ref.1PubMed 7488039. Source: BHF-UCL blood coagulation Traceable author statement. Source: Reactome blood vessel remodeling Inferred from sequence or structural similarity. Source: BHF-UCL endothelial cell migration Inferred from mutant phenotype PubMed 8999856. Source: BHF-UCL in utero embryonic development Inferred from electronic annotation. Source: Compara interaction with host Traceable author statement. Source: Reactome lipopolysaccharide-mediated signaling pathway Inferred from electronic annotation. Source: Compara lung development Inferred from electronic annotation. Source: Compara mitochondrion organization Inferred from sequence or structural similarity. Source: BHF-UCL negative regulation of apoptotic process Inferred from sequence or structural similarity. Source: BHF-UCL negative regulation of blood pressure Inferred from Biological aspect of Ancestor. Source: RefGenome negative regulation of calcium ion transport Inferred from electronic annotation. Source: Compara negative regulation of cell proliferation Inferred from sequence or structural similarity. Source: BHF-UCL negative regulation of hydrolase activity Inferred from electronic annotation. Source: Compara negative regulation of muscle hyperplasia Inferred from sequence or structural similarity. Source: BHF-UCL negative regulation of platelet activation Non-traceable author statement PubMed 7504210. Source: BHF-UCL negative regulation of potassium ion transport Inferred from electronic annotation. Source: Compara nitric oxide biosynthetic process Inferred from direct assay Ref.1PubMed 7488039. Source: BHF-UCL nitric oxide mediated signal transduction Inferred from Biological aspect of Ancestor. Source: RefGenome ovulation from ovarian follicle Inferred from electronic annotation. Source: Compara phagosome maturation Traceable author statement. Source: Reactome positive regulation of angiogenesis Inferred from sequence or structural similarity. Source: BHF-UCL positive regulation of guanylate cyclase activity Inferred from mutant phenotype PubMed 17502619. Source: BHF-UCL positive regulation of vasodilation Non-traceable author statement PubMed 18048451. Source: BHF-UCL regulation of blood vessel size Inferred from sequence or structural similarity. Source: BHF-UCL regulation of nitric-oxide synthase activity Traceable author statement. Source: Reactome regulation of sodium ion transport Inferred from electronic annotation. Source: Compara regulation of systemic arterial blood pressure by endothelin Inferred from mutant phenotype PubMed 8999856. Source: BHF-UCL regulation of the force of heart contraction by chemical signal Inferred from electronic annotation. Source: Compara response to fluid shear stress Inferred from expression pattern PubMed 10376603. Source: BHF-UCL response to heat Non-traceable author statement PubMed 18048451. Source: BHF-UCL smooth muscle hyperplasia Inferred from sequence or structural similarity. Source: BHF-UCL
Cellular_component	Golgi membrane Traceable author statement. Source: Reactome caveola Inferred from direct assay PubMed 17502619PubMed 17848177. Source: BHF-UCL cytoskeleton Inferred from electronic annotation. Source: UniProtKB-SubCell cytosol Traceable author statement. Source: Reactome endocytic vesicle membrane Traceable author statement. Source: Reactome nucleus Inferred from sequence or structural similarity. Source: BHF-UCL
Molecular_function	FMN binding Non-traceable author statement PubMed 7488039. Source: BHF-UCL NADP binding Non-traceable author statement PubMed 7488039. Source: BHF-UCL NADPH-hemoprotein reductase activity Inferred from Biological aspect of Ancestor. Source: RefGenome arginine binding Inferred from direct assay PubMed 7488039. Source: BHF-UCL cadmium ion binding Non-traceable author statement PubMed 7488039. Source: BHF-UCL flavin adenine dinucleotide binding Non-traceable author statement PubMed 7488039. Source: BHF-UCL heme binding Inferred from direct assay PubMed 7488039. Source: BHF-UCL iron ion binding Inferred from electronic annotation. Source: InterPro nitric-oxide synthase activity Inferred from direct assay Ref.1PubMed 7488039. Source: BHF-UCL tetrahydrobiopterin binding Inferred from direct assay PubMed 7488039. Source: BHF-UCL
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CDC37	Q16543	4	EBI-1391623,EBI-295634
NOSTRIN	Q8IVI9	7	EBI-1391623,EBI-1391643
ST13	P50502	3	EBI-1391623,EBI-357285

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P29474-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform eNOS13C (identifier: P29474-2)

The sequence of this isoform differs from the canonical sequence as follows:
     584-625: ESFAAALMEM...ISCSDPLVSS → EGLTLWPRLE...VGTTGACHDA
     626-1203: Missing.

Note: Lacks eNOS activity.

Isoform eNOS13B (identifier: P29474-3)

The sequence of this isoform differs from the canonical sequence as follows:
     585-614: SFAAALMEMSGPYNSSPRPEQHKSYKIRFN → RWGFAMLPRLVSNSWVQAIHLPRPPKVLRL
     615-1203: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 1203

1203

Nitric oxide synthase, endothelial

PRO_0000170943

Regions

Domain

520 – 703

184

Flavodoxin-like

Domain

756 – 1002

247

FAD-binding FR-type

Nucleotide binding

649 – 680

32

FMN By similarity

Nucleotide binding

793 – 804

12

FAD By similarity

Nucleotide binding

935 – 945

11

FAD By similarity

Nucleotide binding

1010 – 1028

19

NADP By similarity

Nucleotide binding

1108 – 1123

16

NADP By similarity

Region

98 – 486

389

Interaction with NOSIP

Region

491 – 510

20

Calmodulin-binding Potential

Sites

Metal binding

94

1

Zinc

Metal binding

99

1

Zinc

Metal binding

184

1

Iron (heme axial ligand)

Amino acid modifications

Modified residue

114

1

Phosphoserine; by CDK5 Ref.25

Modified residue

141

1

Phosphoserine By similarity

Modified residue

495

1

Phosphothreonine; by AMPK Ref.22

Modified residue

633

1

Phosphoserine By similarity

Modified residue

1175

1

Phosphothreonine By similarity

Modified residue

1177

1

Phosphoserine; by AMPK Ref.22

Lipidation

2

1

N-myristoyl glycine By similarity

Lipidation

15

1

S-palmitoyl cysteine By similarity

Lipidation

26

1

S-palmitoyl cysteine By similarity

Natural variations

Alternative sequence

584 – 625

42

ESFAA…PLVSS → EGLTLWPRLECSSTITAHCS LNLLDSSNPPTSTSQVVGTT GACHDA in isoform eNOS13C.

VSP_042625

Alternative sequence

585 – 614

30

SFAAA…KIRFN → RWGFAMLPRLVSNSWVQAIH LPRPPKVLRL in isoform eNOS13B.

VSP_045495

Alternative sequence

615 – 1203

589

Missing in isoform eNOS13B.

VSP_045496

Alternative sequence

626 – 1203

578

Missing in isoform eNOS13C.

VSP_042626

Natural variant

112

1

R → Q. Ref.12
Corresponds to variant rs3918166 [ dbSNP | Ensembl ].

VAR_031218

Natural variant

298

1

E → D in susceptibility to coronary spasm. Ref.7 Ref.10 Ref.12 Ref.16 Ref.29 Ref.30
Corresponds to variant rs1799983 [ dbSNP | Ensembl ].

VAR_008037

Natural variant

474

1

R → C in a colorectal cancer sample; somatic mutation. Ref.31

VAR_036303

Natural variant

602

1

R → Q in a colorectal cancer sample; somatic mutation. Ref.31

VAR_036304

Natural variant

665

1

R → H.
Corresponds to variant rs7792133 [ dbSNP | Ensembl ].

VAR_061377

Natural variant

827

1

V → M. Ref.12
Corresponds to variant rs3918232 [ dbSNP | Ensembl ].

VAR_031219

Natural variant

885

1

R → M. Ref.12
Corresponds to variant rs3918201 [ dbSNP | Ensembl ].

VAR_031220

Natural variant

982

1

Q → L. Ref.12
Corresponds to variant rs3918234 [ dbSNP | Ensembl ].

VAR_031221

Experimental info

Mutagenesis

114

1

S → A: Reduced nitrite (NO) production. Ref.25

Sequence conflict

53

1

S → R in AAA36373. Ref.17

Sequence conflict

168

1

S → G in BAG37648. Ref.10

Sequence conflict

414

1

K → R in BAF85617. Ref.10

Sequence conflict

489

1

G → S in AAD14336. Ref.18

Sequence conflict

567

1

V → W in CAA53950. Ref.5

Sequence conflict

1150

1

R → RQ in BAA05652. Ref.6

Sequence conflict

1194

1

D → E in CAA53950. Ref.5

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

1203

Helix Strand Turn

Details...

Beta strand

70 – 73

4

Turn

74 – 76

3

Beta strand

79 – 81

3

Helix

85 – 87

3

Beta strand

88 – 90

3

Helix

121 – 137

17

Helix

144 – 160

17

Helix

167 – 180

14

Helix

187 – 189

3

Beta strand

194 – 197

4

Helix

204 – 219

16

Helix

220 – 222

3

Beta strand

227 – 230

4

Beta strand

236 – 238

3

Beta strand

245 – 249

5

Beta strand

253 – 255

3

Beta strand

261 – 263

3

Helix

265 – 267

3

Helix

268 – 276

9

Beta strand

284 – 286

3

Beta strand

291 – 294

4

Beta strand

301 – 303

3

Helix

307 – 309

3

Beta strand

312 – 314

3

Helix

321 – 326

6

Beta strand

329 – 332

4

Beta strand

340 – 343

4

Beta strand

346 – 349

4

Helix

359 – 363

5

Helix

365 – 368

4

Turn

370 – 373

4

Helix

376 – 382

7

Helix

390 – 392

3

Helix

394 – 413

20

Helix

420 – 438

19

Helix

445 – 448

4

Beta strand

451 – 453

3

Helix

454 – 456

3

Helix

458 – 461

4

Beta strand

470 – 474

5

Helix

497 – 505

9

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified January 23, 2007. Version 3. Checksum: CD9E60FA277B22C6	FASTA	1,203	133,289
	10 20 30 40 50 60 MGNLKSVAQE PGPPCGLGLG LGLGLCGKQG PATPAPEPSR APASLLPPAP EHSPPSSPLT 70 80 90 100 110 120 QPPEGPKFPR VKNWEVGSIT YDTLSAQAQQ DGPCTPRRCL GSLVFPRKLQ GRPSPGPPAP 130 140 150 160 170 180 EQLLSQARDF INQYYSSIKR SGSQAHEQRL QEVEAEVAAT GTYQLRESEL VFGAKQAWRN 190 200 210 220 230 240 APRCVGRIQW GKLQVFDARD CRSAQEMFTY ICNHIKYATN RGNLRSAITV FPQRCPGRGD 250 260 270 280 290 300 FRIWNSQLVR YAGYRQQDGS VRGDPANVEI TELCIQHGWT PGNGRFDVLP LLLQAPDEPP 310 320 330 340 350 360 ELFLLPPELV LEVPLEHPTL EWFAALGLRW YALPAVSNML LEIGGLEFPA APFSGWYMST 370 380 390 400 410 420 EIGTRNLCDP HRYNILEDVA VCMDLDTRTT SSLWKDKAAV EINVAVLHSY QLAKVTIVDH 430 440 450 460 470 480 HAATASFMKH LENEQKARGG CPADWAWIVP PISGSLTPVF HQEMVNYFLS PAFRYQPDPW 490 500 510 520 530 540 KGSAAKGTGI TRKKTFKEVA NAVKISASLM GTVMAKRVKA TILYGSETGR AQSYAQQLGR 550 560 570 580 590 600 LFRKAFDPRV LCMDEYDVVS LEHETLVLVV TSTFGNGDPP ENGESFAAAL MEMSGPYNSS 610 620 630 640 650 660 PRPEQHKSYK IRFNSISCSD PLVSSWRRKR KESSNTDSAG ALGTLRFCVF GLGSRAYPHF 670 680 690 700 710 720 CAFARAVDTR LEELGGERLL QLGQGDELCG QEEAFRGWAQ AAFQAACETF CVGEDAKAAA 730 740 750 760 770 780 RDIFSPKRSW KRQRYRLSAQ AEGLQLLPGL IHVHRRKMFQ ATIRSVENLQ SSKSTRATIL 790 800 810 820 830 840 VRLDTGGQEG LQYQPGDHIG VCPPNRPGLV EALLSRVEDP PAPTEPVAVE QLEKGSPGGP 850 860 870 880 890 900 PPGWVRDPRL PPCTLRQALT FFLDITSPPS PQLLRLLSTL AEEPREQQEL EALSQDPRRY 910 920 930 940 950 960 EEWKWFRCPT LLEVLEQFPS VALPAPLLLT QLPLLQPRYY SVSSAPSTHP GEIHLTVAVL 970 980 990 1000 1010 1020 AYRTQDGLGP LHYGVCSTWL SQLKPGDPVP CFIRGAPSFR LPPDPSLPCI LVGPGTGIAP 1030 1040 1050 1060 1070 1080 FRGFWQERLH DIESKGLQPT PMTLVFGCRC SQLDHLYRDE VQNAQQRGVF GRVLTAFSRE 1090 1100 1110 1120 1130 1140 PDNPKTYVQD ILRTELAAEV HRVLCLERGH MFVCGDVTMA TNVLQTVQRI LATEGDMELD 1150 1160 1170 1180 1190 1200 EAGDVIGVLR DQQRYHEDIF GLTLRTQEVT SRIRTQSFSL QERQLRGAVP WAFDPPGSDT NSP
	Isoform eNOS13C [UniParc]. Checksum: 057DDC37143265B6	FASTA	629	68,980
	10 20 30 40 50 60 MGNLKSVAQE PGPPCGLGLG LGLGLCGKQG PATPAPEPSR APASLLPPAP EHSPPSSPLT 70 80 90 100 110 120 QPPEGPKFPR VKNWEVGSIT YDTLSAQAQQ DGPCTPRRCL GSLVFPRKLQ GRPSPGPPAP 130 140 150 160 170 180 EQLLSQARDF INQYYSSIKR SGSQAHEQRL QEVEAEVAAT GTYQLRESEL VFGAKQAWRN 190 200 210 220 230 240 APRCVGRIQW GKLQVFDARD CRSAQEMFTY ICNHIKYATN RGNLRSAITV FPQRCPGRGD 250 260 270 280 290 300 FRIWNSQLVR YAGYRQQDGS VRGDPANVEI TELCIQHGWT PGNGRFDVLP LLLQAPDEPP 310 320 330 340 350 360 ELFLLPPELV LEVPLEHPTL EWFAALGLRW YALPAVSNML LEIGGLEFPA APFSGWYMST 370 380 390 400 410 420 EIGTRNLCDP HRYNILEDVA VCMDLDTRTT SSLWKDKAAV EINVAVLHSY QLAKVTIVDH 430 440 450 460 470 480 HAATASFMKH LENEQKARGG CPADWAWIVP PISGSLTPVF HQEMVNYFLS PAFRYQPDPW 490 500 510 520 530 540 KGSAAKGTGI TRKKTFKEVA NAVKISASLM GTVMAKRVKA TILYGSETGR AQSYAQQLGR 550 560 570 580 590 600 LFRKAFDPRV LCMDEYDVVS LEHETLVLVV TSTFGNGDPP ENGEGLTLWP RLECSSTITA 610 620 HCSLNLLDSS NPPTSTSQVV GTTGACHDA
	Isoform eNOS13B [UniParc]. Checksum: A567DB899BD1372E	FASTA	614	67,876
	10 20 30 40 50 60 MGNLKSVAQE PGPPCGLGLG LGLGLCGKQG PATPAPEPSR APASLLPPAP EHSPPSSPLT 70 80 90 100 110 120 QPPEGPKFPR VKNWEVGSIT YDTLSAQAQQ DGPCTPRRCL GSLVFPRKLQ GRPSPGPPAP 130 140 150 160 170 180 EQLLSQARDF INQYYSSIKR SGSQAHEQRL QEVEAEVAAT GTYQLRESEL VFGAKQAWRN 190 200 210 220 230 240 APRCVGRIQW GKLQVFDARD CRSAQEMFTY ICNHIKYATN RGNLRSAITV FPQRCPGRGD 250 260 270 280 290 300 FRIWNSQLVR YAGYRQQDGS VRGDPANVEI TELCIQHGWT PGNGRFDVLP LLLQAPDEPP 310 320 330 340 350 360 ELFLLPPELV LEVPLEHPTL EWFAALGLRW YALPAVSNML LEIGGLEFPA APFSGWYMST 370 380 390 400 410 420 EIGTRNLCDP HRYNILEDVA VCMDLDTRTT SSLWKDKAAV EINVAVLHSY QLAKVTIVDH 430 440 450 460 470 480 HAATASFMKH LENEQKARGG CPADWAWIVP PISGSLTPVF HQEMVNYFLS PAFRYQPDPW 490 500 510 520 530 540 KGSAAKGTGI TRKKTFKEVA NAVKISASLM GTVMAKRVKA TILYGSETGR AQSYAQQLGR 550 560 570 580 590 600 LFRKAFDPRV LCMDEYDVVS LEHETLVLVV TSTFGNGDPP ENGERWGFAM LPRLVSNSWV 610 QAIHLPRPPK VLRL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and expression of a cDNA encoding human endothelium-derived relaxing factor/nitric oxide synthase." Janssens S.P., Shimouchi A., Quertermous T., Bloch D.B., Bloch K.D. J. Biol. Chem. 267:14519-14522(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	Erratum Janssens S.P., Shimouchi A., Quertermous T., Bloch D.B., Bloch K.D. J. Biol. Chem. 267:22694-22694(1992)
[3]	"Molecular cloning and characterization of human endothelial nitric oxide synthase." Marsden P.A., Schappert K.T., Chen H.S., Flowers M., Sundell C.L., Wilcox J.N., Lamas S., Michel T. FEBS Lett. 307:287-293(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[4]	"Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene." Marsden P.A., Heng H.H.Q., Scherer S.W., Stewart R.J., Hall A.V., Shi X.-M., Tsui L.-C., Schappert K.T. J. Biol. Chem. 268:17478-17488(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	"Gene structure, polymorphism and mapping of the human endothelial nitric oxide synthase gene." Nadaud S.A., Bonnardeaux A., Lathrop M., Soubrier F. Biochem. Biophys. Res. Commun. 198:1027-1033(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Placenta.
[6]	"Cloning and structural characterization of the human endothelial nitric-oxide-synthase gene." Miyahara K., Kawamoto T., Sase K., Yui Y., Toda K., Yang L.X., Hattori R., Aoyama T., Yamamoto Y., Doi Y., Ogoshi S., Hashimoto K., Kawai C., Sasayama S., Shizuta Y. Eur. J. Biochem. 223:719-726(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[7]	"Alternative splicing in intron 13 of the human eNOS gene: a potential mechanism for regulating eNOS activity." Lorenz M., Hewing B., Hui J., Zepp A., Baumann G., Bindereif A., Stangl V., Stangl K. FASEB J. 21:1556-1564(2007) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS ENOS13B AND ENOS13C), ALTERNATIVE SPLICING, FUNCTION (ISOFORM ENOS13C), VARIANT ASP-298.
[8]	Liao J.K. Submitted (DEC-1993) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Umbilical vein.
[9]	"The role of phosphatidylinositol-3-oh kinase in platelet-derived nitric oxide release and platelet disaggregation." Zhang Y., Freedman J.E. Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Platelet.
[10]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANT ASP-298. Tissue: Hippocampus and Trachea.
[11]	Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S. Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Spleen.
[12]	SeattleSNPs variation discovery resource Submitted (JUN-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS GLN-112; ASP-298; MET-827; MET-885 AND LEU-982.
[13]	NHLBI resequencing and genotyping service (RS&G) Submitted (DEC-2007) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[14]	"The DNA sequence of human chromosome 7." Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., Delehaunty K.D., Miner T.L. , Nash W.E., Cordes M., Du H., Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., Wilson R.K. Nature 424:157-164(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[15]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[16]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANT ASP-298. Tissue: Placenta.
[17]	"Isolation and chromosomal localization of the human endothelial nitric oxide synthase (NOS3) gene." Robinson L.J., Weremowicz S., Morton C.C., Michel T. Genomics 19:350-357(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-53. Tissue: Placenta.
[18]	"Expression of constitutive endothelial nitric oxide synthase in human blood platelets." Sase K., Michel T. Life Sci. 57:2049-2055(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 411-528 (ISOFORM 1/ENOS13C). Tissue: Platelet.
[19]	"Purification and characterization of the constitutive nitric oxide synthase from human placenta." Garvey E.P., Tuttle J.V., Covington K., Merrill B.M., Wood E.R., Baylis S.A., Charles I.G. Arch. Biochem. Biophys. 311:235-241(1994) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 167-175; 531-540; 835-845; 876-881; 886-898; 1001-1005 AND 1068-1080, TISSUE SPECIFICITY. Tissue: Placenta.
[20]	"NOSIP, a novel modulator of endothelial nitric oxide synthase activity." Dedio J., Koenig P., Wohlfart P., Schroeder C., Kummer W., Mueller-Esterl W. FASEB J. 15:79-89(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH NOSIP, ENZYME REGULATION, SUBCELLULAR LOCATION.
[21]	"NOSTRIN: a protein modulating nitric oxide release and subcellular distribution of endothelial nitric oxide synthase." Zimmermann K., Opitz N., Dedio J., Renne C., Mueller-Esterl W., Oess S. Proc. Natl. Acad. Sci. U.S.A. 99:17167-17172(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH NOSTRIN, ENZYME REGULATION, SUBCELLULAR LOCATION.
[22]	"Endothelial thrombomodulin induces Ca2+ signals and nitric oxide synthesis through epidermal growth factor receptor kinase and calmodulin kinase II." David-Dufilho M., Millanvoye-Van Brussel E., Topal G., Walch L., Brunet A., Rendu F. J. Biol. Chem. 280:35999-36006(2005) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT THR-495 AND SER-1177.
[23]	"NOSTRIN functions as a homotrimeric adaptor protein facilitating internalization of eNOS." Icking A., Matt S., Opitz N., Wiesenthal A., Mueller-Esterl W., Schilling K. J. Cell Sci. 118:5059-5069(2005) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION.
[24]	"Cell cycle-regulated inactivation of endothelial NO synthase through NOSIP-dependent targeting to the cytoskeleton." Schleicher M., Brundin F., Gross S., Mueller-Esterl W., Oess S. Mol. Cell. Biol. 25:8251-8258(2005) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION.
[25]	"CDK5 phosphorylates eNOS at Ser-113 and regulates NO production." Lee C.-H., Wei Y.-W., Huang Y.-T., Lin Y.-T., Lee Y.-C., Lee K.-H., Lu P.-J. J. Cell. Biochem. 110:112-117(2010) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-114, MUTAGENESIS OF SER-114.
[26]	"Structural characterization of nitric oxide synthase isoforms reveals striking active-site conservation." Fischmann T.O., Hruza A., Niu X.D., Fossetta J.D., Lunn C.A., Dolphin E., Prongay A.J., Reichert P., Lundell D.J., Narula S.K., Weber P.C. Nat. Struct. Biol. 6:233-242(1999) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS).
[27]	"Conformational changes in nitric oxide synthases induced by chlorzoxazone and nitroindazoles: crystallographic and computational analyses of inhibitor potency." Rosenfeld R.J., Garcin E.D., Panda K., Andersson G., Aberg A., Wallace A.V., Morris G.M., Olson A.J., Stuehr D.J., Tainer J.A., Getzoff E.D. Biochemistry 41:13915-13925(2002) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.96 ANGSTROMS) OF 67-480.
[28]	"Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase." Garcin E.D., Arvai A.S., Rosenfeld R.J., Kroeger M.D., Crane B.R., Andersson G., Andrews G., Hamley P.J., Mallinder P.R., Nicholls D.J., St-Gallay S.A., Tinker A.C., Gensmantel N.P., Mete A., Cheshire D.R., Connolly S., Stuehr D.J., Aberg A. , Wallace A.V., Tainer J.A., Getzoff E.D. Nat. Chem. Biol. 4:700-707(2008) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.44 ANGSTROMS) OF 66-492.
[29]	"A missense Glu298Asp variant in the endothelial nitric oxide synthase gene is associated with coronary spasm in the Japanese." Yoshimura M., Yasue H., Nakayama M., Shimasaki Y., Sumida H., Sugiyama S., Kugiyama K., Ogawa H., Ogawa Y., Saito Y., Miyamoto Y., Nakao K. Hum. Genet. 103:65-69(1998) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT SUSCEPTIBILITY TO CORONARY SPASM ASP-298.
[30]	"In-vivo effects of Glu298Asp endothelial nitric oxide synthase polymorphism." Sofowora G., Dishy V., Xie H.G., Imamura H., Nishimi Y., Morales C.R., Morrow J.D., Kim R.B., Stein C.M., Wood A.J. Pharmacogenetics 11:809-814(2001) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT SUSCEPTIBILITY TO CORONARY SPASM ASP-298.
[31]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] CYS-474 AND GLN-602.
+	Additional computationally mapped references.

Web resources

Wikipedia

Nitric oxide synthase entry

GeneReviews

SeattleSNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M93718 mRNA. Translation: AAA36364.1.
M95296 mRNA. Translation: AAA36372.1.
L10709 , L10693, L10694, L10695, L10696, L10697, L10698, L10699, L10700, L10701, L10702, L10703, L10704, L10705, L10706, L10707, L10708 Genomic DNA. Translation: AAA36365.1.
X76303 , X76304, X76305, X76306, X76307, X76308, X76309, X76310, X76311, X76312, X76313, X76314, X76315, X76316 Genomic DNA. Translation: CAA53950.1.
D26607 Genomic DNA. Translation: BAA05652.1.
DQ256130 mRNA. Translation: ABB79839.1.
DQ256131 mRNA. Translation: ABB79840.1.
L26914 Genomic DNA. Translation: AAA36374.1.
AF400594 mRNA. Translation: AAK83389.1.
AK292928 mRNA. Translation: BAF85617.1.
AK315213 mRNA. Translation: BAG37648.1.
AK223636 mRNA. Translation: BAD97356.1.
AF519768 Genomic DNA. Translation: AAM74944.1.
EU332855 Genomic DNA. Translation: ABY87544.1.
AC010973 Genomic DNA. No translation available.
CH471173 Genomic DNA. Translation: EAW54069.1.
BC063294 mRNA. Translation: AAH63294.1.
BC069465 mRNA. Translation: AAH69465.1.
L23210 Genomic DNA. Translation: AAA36373.1.
S80791 mRNA. Translation: AAD14336.1.

IPI

IPI00218845.
IPI00930257.
IPI00930307.

PIR

A47501.

RefSeq

NP_000594.2. NM_000603.4.
NP_001153581.1. NM_001160109.1.
NP_001153582.1. NM_001160110.1.
NP_001153583.1. NM_001160111.1.

UniGene

Hs.647092.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1M9J	X-ray	2.43	A/B	67-481	[»]
1M9K	X-ray	2.01	A/B	67-481	[»]
1M9M	X-ray	1.96	A/B	67-481	[»]
1M9Q	X-ray	2.01	A/B	67-481	[»]
1M9R	X-ray	2.56	A/B	67-481	[»]
2LL7	NMR	-	B	493-509	[»]
3EAH	X-ray	2.44	A/B	66-492	[»]
3NOS	X-ray	2.40	A/B	66-492	[»]

ProteinModelPortal

P29474.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-38479N.

IntAct

P29474. 27 interactions.

MINT

MINT-106980.

PTM databases

PhosphoSite

P29474.

Polymorphism databases

DMDM

266648.

Proteomic databases

PaxDb

P29474.

PRIDE

P29474.

Protocols and materials databases

DNASU

4846.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000297494; ENSP00000297494; ENSG00000164867.
ENST00000484524; ENSP00000420215; ENSG00000164867.

GeneID

4846.

KEGG

hsa:4846.

UCSC

uc003wif.3. human.
uc011kuz.2. human.
uc011kva.2. human.

Organism-specific databases

CTD

4846.

GeneCards

GC07P150688.

H-InvDB

HIX0033558.

HGNC

HGNC:7876. NOS3.

HPA

CAB002168.

MIM

163729. gene+phenotype.

neXtProt

NX_P29474.

PharmGKB

PA254.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG4362.

HOGENOM

HOG000111088.

HOVERGEN

HBG000159.

InParanoid

P29474.

KO

K13242.

OrthoDB

EOG4ZS92B.

Enzyme and pathway databases

BioCyc

MetaCyc:HS09149-MONOMER.

Pathway_Interaction_DB

angiopoietinreceptor_pathway. Angiopoietin receptor Tie2-mediated signaling.
er_nongenomic_pathway. Plasma membrane estrogen receptor signaling.
vegfr1_2_pathway. Signaling events mediated by VEGFR1 and VEGFR2.
txa2pathway. Thromboxane A2 receptor signaling.
vegfr1_pathway. VEGFR1 specific signals.

Reactome

REACT_111217. Metabolism.
REACT_116125. Disease.
REACT_604. Hemostasis.

SignaLink

P29474.

Gene expression databases

ArrayExpress

P29474.

Bgee

P29474.

CleanEx

HS_NOS3.

Genevestigator

P29474.

GermOnline

ENSG00000164867. Homo sapiens.

Family and domain databases

Gene3D

1.20.990.10. 1 hit.
3.90.340.10. 1 hit.

InterPro

IPR003097. FAD-binding_1.
IPR017927. Fd_Rdtase_FAD-bd.
IPR001094. Flavdoxin.
IPR008254. Flavodoxin/NO_synth.
IPR001709. Flavoprot_Pyr_Nucl_cyt_Rdtase.
IPR023173. NADPH_Cyt_P450_Rdtase_dom3.
IPR004030. NO_synthase_oxygenase_dom.
IPR026009. NOS.
IPR012144. NOS_met.
IPR001433. OxRdtase_FAD/NAD-bd.
IPR017938. Riboflavin_synthase-like_b-brl.
[Graphical view]

PANTHER

PTHR19384:SF5. PTHR19384:SF5. 1 hit.

Pfam

PF00667. FAD_binding_1. 1 hit.
PF00258. Flavodoxin_1. 1 hit.
PF00175. NAD_binding_1. 1 hit.
PF02898. NO_synthase. 1 hit.
[Graphical view]

PIRSF

PIRSF000333. NOS. 1 hit.

PRINTS

PR00369. FLAVODOXIN.
PR00371. FPNCR.

SUPFAM

SSF56512. NO_synthase_oxygenase_reg. 1 hit.
SSF63380. Riboflavin_synthase_like_b-brl. 1 hit.

PROSITE

PS51384. FAD_FR. 1 hit.
PS50902. FLAVODOXIN_LIKE. 1 hit.
PS60001. NOS. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P29474.

ChEMBL

CHEMBL4803.

ChiTaRS

NOS3. human.

DrugBank

DB00125. L-Arginine.
DB00155. L-Citrulline.
DB01098. Rosuvastatin.
DB00360. Tetrahydrobiopterin.

EvolutionaryTrace

P29474.

GenomeRNAi

4846.

NextBio

18666.

SOURCE

Search...

Entry information

Entry name

NOS3_HUMAN

Accession

Primary (citable) accession number: P29474
Secondary accession number(s): A0S0A7 , A0S0A8, A8KA63, B2RCQ1, E9PFR2, Q13662, Q14251, Q14434, Q548C1, Q6GSL5, Q9UDC6

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 1, 1993
Last sequence update:	January 23, 2007
Last modified:	May 29, 2013
This is version 164 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.