内皮型一酸化窒素合成酵素、血管内皮型一酸化窒素合成酵素、内皮型NO合成酵素、血管内皮型NO合成酵素

関: endothelial NO synthase、endothelial NOS、eNOS、nitric oxide synthase type III

WordNet

any compound of oxygen with another element or a radical
of or relating to or located in the endothelium

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酸化物
窒素の,窒素を含む

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/02/14 05:10:54」(JST)

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Endothelial NOS (eNOS), also known as nitric oxide synthase 3 (NOS3) or constitutive NOS (cNOS), is an enzyme that in humans is encoded by the NOS3 gene located in the 7q35-7q36 region of chromosome 7.^[4] This enzyme is one of three isoforms that synthesize nitric oxide (NO), a small gaseous and lipophilic molecule that participates in several biological processes.^[5]^[6] The other isoforms include neuronal nitric oxide synthase (nNOS), which is constitutively expressed in specific neurons of the brain^[7] and inducible nitric oxide synthase (iNOS), whose expression is typically induced in inflammatory diseases.^[8] eNOS is primarily responsible for the generation of NO in the vascular endothelium,^[9] a monolayer of flat cells lining the interior surface of blood vessels, at the interface between circulating blood in the lumen and the remainder of the vessel wall.^[10] NO produced by eNOS in the vascular endothelium plays crucial roles in regulating vascular tone, cellular proliferation, leukocyte adhesion, and platelet aggregation.^[11] Therefore, a functional eNOS is essential for a healthy cardiovascular system.

Structure and catalytic activities

eNOS is a dimer containing two identical monomers of 134 kD constituted by a reductase domain, which displays binding sites for nicotinamide adenine dinucleotide phosphate (NADPH), flavin mononucleotide (FMN), and flavin adenine dinucleotide (FAD), and an oxidase domain, which displays binding sites for heme group, zinc, the cofactor tetrahydrobiopterin (BH4), and the substrate L-arginine.^[12] The reductase domain is linked to the oxidase domain by a calmodulin-binding sequence.^[13] In the vascular endothelium, NO is synthesized by eNOS from L-arginine and molecular oxygen, which binds to the heme group of eNOS, is reduced and finally incorporated into L- arginine to form NO and L-citrulline.^[14]^[15] The binding of the cofactor BH4 is essential for eNOS to efficiently generate NO.^[16] In the absence of this cofactor, eNOS shifts from a dimeric to a monomeric form, thus becoming uncoupled.^[17] In this conformation, instead of synthesizing NO, eNOS produces superoxide anion, a highly reactive free radical with deleterious consequences to the cardiovascular system.^[18]^[19]

Function

eNOS has a protective function in the cardiovascular system, which is attributed to NO production. Regulation of the vascular tone is one of the best known roles of NO in the cardiovascular system. Once produced in endothelial cells, NO diffuses across the vascular smooth muscle cell membranes and activates the enzyme soluble guanylate cyclase (sGC), which catalyzes the conversion of guanosine triphosphate into cyclic guanosine monophosphate (cGMP).^[20] cGMP, in turn, activates protein kinase G (PKG), which promotes multiple phosphorylation of cellular targets lowering cellular Ca²⁺ concentrations and promoting vascular relaxation.^[21] NO exerts antiproliferative effects by cGMP-dependent inhibiting Ca²⁺ influx or by directly inhibiting the activity of arginase and ornithine decarboxylase, decreasing the generation of polyamides required for DNA synthesis.^[22]^[23] NO also has antithrombotic effects that result of its diffusion across platelet membrane and sGC activation, resulting in inhibition of platelet aggregation.^[24] Moreover, NO affects leukocyte adhesion to the vascular endothelium by inhibiting the nuclear factor kappa B (NF-κB), which induces vascular endothelial expression of chemokines and adhesion molecules.^[25] In addition to these functions, NO produced by eNOS has antioxidant properties as it reduces superoxide anion formation as a result of NO-induced increases in the expression of superoxide dismutase, an antioxidant enzyme that catalyzes the conversion of superoxide anion to hydrogen peroxide.^[26] Furthermore, part of antioxidants properties of NO is attributable to up-regulation of heme-oxygenase-I and ferritin expression, which reduce superoxide anion concentrations in blood vessels.^[27]

Regulation

eNOS expression and activity are carefully controlled by multiple interconnected mechanisms of regulation present at the transcriptional, posttranscriptional, and posttranslational levels. Binding of transcription factors such as Sp1, Sp3, Ets-1, Elf-1, and YY1 to the NOS3 promoter and DNA methylation represents an important mechanism of transcriptional regulation.^[28] Posttranscriptionally, eNOS is regulated by modifications of the primary transcript, mRNA stability, subcellular localization, and nucleocytoplasmatic transport.^[29] Posttranslational modifications of eNOS include fatty acid acylation, protein-protein interactions, substrate, and co-factor availability, and degree of phosphorylation. Importantly, eNOS is attached by myristoylation and palmitoylation to caveolae, a pocket-like invagination on the membrane rich in cholesterol and sphingolipids.^[30] With the binding of eNOS to caveolae, the enzyme is inactivated due to the strong and direct interaction of eNOS with caveolin-1.^[31] The binding of calcium-activated calmodulin to eNOS displaces caveolin-1 and activates eNOS. Moreover, eNOS activation is dynamically regulated by multiple phosphorylation sites at tyrosine, serine, and threonine residues.^[12]

Clinical significance

Impaired NO production is involved in the pathogenesis of several diseases such as hypertension, preeclampsia, diabetes mellitus, obesity, erectile dysfunction, and migraine. In this regard, a large number of studies showed that polymorphisms in NOS3 gene affect the susceptibility to these diseases. Although NOS3 is a highly polymorphic gene, three genetic polymorphisms in this gene have been widely studied: the single nucleotide polymorphisms (SNPs) g.-786T>C (where "g." denotes genomic change which results in a Glu298Asp change in the coded protein), located in NOS3 promoter and in exon 7, respectively, and the variable number of tandem repeats (VNTR) characterized by 27 bp repeat in intron 4.^[32] The C allele for the g.-786T>C polymorphism, which results in reduced eNOS expression and NO production,^[33] was associated with increased risk for hypertension,^[34] preeclampsia,^[35] diabetic nephropathy,^[36] and retinopathy,^[37] migraine,^[38] and erectile dysfunction,^[39] The presence of ‘Asp’ allele for the Glu298Asp polymorphism reduces eNOS activity,^[40] and was associated with higher susceptibility to hypertension,^[41]^[42] preeclampsia,^[43] diabetes mellitus,^[44] migraine,^[38] and erectile dysfunction.^[45]^[46] The VNTR in intron 4 affects eNOS expression,^[47] and the susceptibility to hypertension,^[34] preeclampsia,^[35] obesity,^[48] and diabetes mellitus.^[44] Growing evidence supports the association of diseases with NOS3 haplotypes (combination of alleles in close proximity, within a DNA block). This approach may be more informative than the analysis of genetic polymorphisms one by one.^[49] Haplotypes including the SNPs g.-786T>C and Glu298Asp and the VNTR in intron 4 affected the susceptibility to hypertension,^[50]^[51]^[52]^[53] preeclampsia,^[54] and hypertension in diabetic subjects,^[55] NOS3 variants may also affect the responses to drugs that affect NO signaling, such as statins, angiotensin-converting enzyme inhibitors (ACEi) and phosphodiesterase type 5 (PDE-5) inhibitors (PDE5i). Statin treatment was more effective in increasing NO bioavailability in subjects carrying the CC genotype for the g.-786T>C polymorphism than in TT carriers.^[56]^[57] Hypertensive patients carrying the TC/CC genotypes and the C allele for the g.-786T>C polymorphism showed better antihypertensive responses to ACEi enalapril.^[58] Likewise, patients with erectile dysfunction carrying the C allele for g.-786T>C polymorphism showed better responses to PDE-5 inhibitor sildenafil.^[59]^[60] Together, these studies suggest that statins, ACEi and PDE-5 inhibitors may restore an impaired NO production in subjects carrying the variant allele/genotype for g.-786T>C NOS3 polymorphism, thus attenuating the cardiovascular risk. In addition to analysis of genetic polymorphisms individually, haplotypes including the SNPs g.-786T>C and Glu298Asp and the VNTR in intron 4 were showen to affect the responses to sildenafil in patients with erectile dysfunction.^[59]

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Sun Yueliu,Hu Xiaorong,Hu Gangying [他],Xu Changwu,Jiang Hong
Biological and Pharmaceutical Bulletin 38(8), 1134-1141, 2015
… Endothelial senescence has been proposed to be involved in endothelial dysfunction and atherogenesis. … However, the effect of curcumin on endothelial senescence is unclear. … This study explores the effect of curcumin on hydrogen peroxide (H2O2)-induced endothelial premature senescence and the mechanisms involved. … Human umbilical vein endothelial cells (HUVECs) were cultured, and premature senescence was induced with 100 µM H2O2. …
NAID 130005090660

L-Arginine Exacerbates Experimental Cerebral Malaria by Enhancing Pro-Inflammatory Responses

Xu Hongbin,Feng Yonghui,Chen Guang,Zhu Xiaotong,Pang Wei,Du Yunting,Wang Qinghui,Qi Zanmei,Cao Yaming
The Tohoku Journal of Experimental Medicine 236(1), 21-31, 2015
… L-Arginine (L-Arg), the substrate for nitric oxide (NO) synthase, has been used to treat malaria to reverse endothelial dysfunction in adults. … Therefore, the prophylactic use of L-Arg to treat CM, based on the assumption that restoring the bioavailability of endothelial NO improves the outcome of CM, may need to be reconsidered especially for children. …
NAID 130005067322

Related Pictures

★リンクテーブル★

リンク元	「内皮型一酸化窒素合成酵素」「endothelial NOS」「内皮型NO合成酵素」「血管内皮型NO合成酵素」「endothelial NO synthase」
関連記事	「synthase」「endothelial」「endothelia」「oxide」「nitric」

「内皮型一酸化窒素合成酵素」

NOS3
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	1M9J, 1M9K, 1M9M, 1M9Q, 1M9R, 1NIW, 2LL7, 3EAH, 3NOS, 2MG5, 4D1O, 4D1P
Identifiers
Aliases	NOS3, ECNOS, eNOS, nitric oxide synthase 3
External IDs	OMIM: 163729 MGI: 97362 HomoloGene: 504 GeneCards: NOS3
Targeted by Drug
	nitroarginine
Gene ontology
Molecular function	• iron ion binding; • FMN binding; • actin monomer binding; • flavin adenine dinucleotide binding; • scaffold protein binding; • arginine binding; • tetrahydrobiopterin binding; • metal ion binding; • calmodulin binding; • protein binding; • heme binding; • NADP binding; • oxidoreductase activity; • cadmium ion binding; • nitric-oxide synthase activity;
Cellular component	• cytoplasm; • endocytic vesicle membrane; • cytosol; • Golgi apparatus; • membrane; • Golgi membrane; • plasma membrane; • caveola; • cytoskeleton; • nucleus;
Biological process	• negative regulation of muscle hyperplasia; • ovulation from ovarian follicle; • positive regulation of guanylate cyclase activity; • nitric oxide biosynthetic process; • regulation of blood vessel size; • regulation of systemic arterial blood pressure by endothelin; • regulation of sodium ion transport; • lung development; • negative regulation of blood pressure; • removal of superoxide radicals; • positive regulation of vasodilation; • regulation of nitric-oxide synthase activity; • mitochondrion organization; • response to heat; • in utero embryonic development; • negative regulation of hydrolase activity; • cell redox homeostasis; • arginine catabolic process; • positive regulation of angiogenesis; • response to fluid shear stress; • regulation of blood pressure; • negative regulation of platelet activation; • blood vessel remodeling; • negative regulation of extrinsic apoptotic signaling pathway via death domain receptors; • angiogenesis; • negative regulation of potassium ion transport; • nitric oxide mediated signal transduction; • negative regulation of calcium ion transport; • smooth muscle hyperplasia; • regulation of the force of heart contraction by chemical signal; • oxidation-reduction process; • endothelial cell migration; • lipopolysaccharide-mediated signaling pathway; • negative regulation of cell proliferation;
	Sources:Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	4846
	18127
	ENSG00000164867
	ENSMUSG00000028978
	P29474
	P70313
	NM_000603; NM_001160109; NM_001160110; NM_001160111
	NM_008713
	NP_000594; NP_001153581; NP_001153582; NP_001153583
	NP_032739.3; NP_032739
	Wikidata
View/Edit Human	View/Edit Mouse

　　[★]

英: endothelial nitric oxide synthase、endothelial NO synthase、endothelial NOS、eNOS、endothelial isoform of nitric oxide synthase
関: 内皮型NO合成酵素、内皮型NOS、血管内皮型一酸化窒素合成酵素、血管内皮型NO合成酵素、一酸化窒素合成酵素III型

「endothelial NOS」

　　[★]

内皮型NOS、内皮型NO合成酵素、内皮型一酸化窒素合成酵素、血管内皮型NO合成酵素、血管内皮型一酸化窒素合成酵素

関: endothelial nitric oxide synthase、endothelial NO synthase、eNOS

「内皮型NO合成酵素」

　　[★]

英: endothelial NO synthase、endothelial nitric oxide synthase、endothelial NOS、eNOS
関: 内皮型一酸化窒素合成酵素、内皮型NOS、血管内皮型一酸化窒素合成酵素、血管内皮型NO合成酵素

「血管内皮型NO合成酵素」

　　[★]

英: endothelial NO synthase、endothelial nitric oxide synthase、endothelial NOS
関: 内皮型一酸化窒素合成酵素、内皮型NO合成酵素、内皮型NOS、血管内皮型一酸化窒素合成酵素

「endothelial NO synthase」

　　[★]

内皮型NO合成酵素、血管内皮型NO合成酵素、内皮型一酸化窒素合成酵素、血管内皮型一酸化窒素合成酵素

関: endothelial nitric oxide synthase、endothelial NOS、eNOS

「synthase」

　　[★]

n.

(脱離酵素リアーゼの逆反応である合成方向の反応を指す) シンターゼ, 合成酵素, 付加酵素

関: lyase、synthetase、transferase

「endothelial」

　　[★]

adj.

内皮の

関: endodermis、endothelia、endothelium

「endothelia」

　　[★]

np.

内皮

関: endodermis、endothelial、endothelium

「oxide」

　　[★]

酸化物、オキシド、オキサイド　　

「nitric」

　　[★]

adj.

窒素の

関: N、N2、nitrogen

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[2] "Human PubMed Reference:".

[3] "Mouse PubMed Reference:".

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[29] Searles CD (Nov 2006). "Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression". American Journal of Physiology. Cell Physiology. 291 (5): C803–16. doi:10.1152/ajpcell.00457.2005. PMID 16738003.

[30] Lisanti MP, Scherer PE, Tang Z, Sargiacomo M (Jul 1994). "Caveolae, caveolin and caveolin-rich membrane domains: a signalling hypothesis". Trends in Cell Biology. 4 (7): 231–5. doi:10.1016/0962-8924(94)90114-7. PMID 14731661.

[31] Ju H, Zou R, Venema VJ, Venema RC (Jul 1997). "Direct interaction of endothelial nitric-oxide synthase and caveolin-1 inhibits synthase activity". The Journal of Biological Chemistry. 272 (30): 18522–5. doi:10.1074/jbc.272.30.18522. PMID 9228013.

[32] Lacchini R, Silva PS, Tanus-Santos JE (May 2010). "A pharmacogenetics-based approach to reduce cardiovascular mortality with the prophylactic use of statins". Basic & Clinical Pharmacology & Toxicology. 106 (5): 357–61. doi:10.1111/j.1742-7843.2010.00551.x. PMID 20210789.

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[Dai_B_2013-35] Dai B, Liu T, Zhang B, Zhang X, Wang Z (Apr 2013). "The polymorphism for endothelial nitric oxide synthase gene, the level of nitric oxide and the risk for pre-eclampsia: a meta-analysis". Gene. 519 (1): 187–93. doi:10.1016/j.gene.2013.01.004. PMID 23375994.

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[37] Taverna MJ, Elgrably F, Selmi H, Selam JL, Slama G (Aug 2005). "The T-786C and C774T endothelial nitric oxide synthase gene polymorphisms independently affect the onset pattern of severe diabetic retinopathy". Nitric Oxide. 13 (1): 88–92. doi:10.1016/j.niox.2005.04.004. PMID 15890549.

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[40] Joshi MS, Mineo C, Shaul PW, Bauer JA (Sep 2007). "Biochemical consequences of the NOS3 Glu298Asp variation in human endothelium: altered caveolar localization and impaired response to shear". FASEB Journal. 21 (11): 2655–63. doi:10.1096/fj.06-7088com. PMID 17449720.

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[46] Hermans MP, Ahn SA, Rousseau MF (Jul 2012). "eNOS [Glu298Asp] polymorphism, erectile function and ocular pressure in type 2 diabetes". European Journal of Clinical Investigation. 42 (7): 729–37. doi:10.1111/j.1365-2362.2011.02638.x. PMID 22224829.

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[48] Souza-Costa DC, Belo VA, Silva PS, Sertorio JT, Metzger IF, Lanna CM, Machado MA, Tanus-Santos JE (Mar 2011). "eNOS haplotype associated with hypertension in obese children and adolescents". International Journal of Obesity. 35 (3): 387–92. doi:10.1038/ijo.2010.146. PMID 20661250.

[49] Crawford DC, Nickerson DA (2005). "Definition and clinical importance of haplotypes". Annual Review of Medicine. 56: 303–20. doi:10.1146/annurev.med.56.082103.104540. PMID 15660514.

[50] Sandrim VC, Coelho EB, Nobre F, Arado GM, Lanchote VL, Tanus-Santos JE (Jun 2006). "Susceptible and protective eNOS haplotypes in hypertensive black and white subjects". Atherosclerosis. 186 (2): 428–32. doi:10.1016/j.atherosclerosis.2005.08.003. PMID 16168996.

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v t e Oxidoreductases: dioxygenases, including steroid hydroxylases (EC 1.14)

1.14.11: 2-oxoglutarate	Prolyl hydroxylase Lysyl hydroxylase

1.14.13: NADH or NADPH	Flavin-containing monooxygenase FMO1 FMO2 FMO3 FMO4 FMO5 Nitric oxide synthase NOS1 NOS2 NOS3 Cholesterol 7 alpha-hydroxylase Methane monooxygenase 3A4 Lanosterol 14 alpha-demethylase 24-hydroxycholesterol 7α-hydroxylase

1.14.14: reduced flavin or flavoprotein	19A1 2D6 2E1

1.14.15: reduced iron-sulfur protein	11B1 11B2 11A1

1.14.16: reduced pteridine (BH4 dependent)	Phenylalanine hydroxylase Tyrosine hydroxylase Tryptophan hydroxylase

1.14.17: reduced ascorbate	Dopamine beta-hydroxylase

1.14.18-19: other	Tyrosinase Stearoyl-CoA desaturase-1

1.14.99 - miscellaneous	Cyclooxygenase Heme oxygenase (HMOX1) Squalene monooxygenase 17A1 21A2

v t e Enzymes

Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics

Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list)

匿名

検索

案内

案内

endothelial nitric oxide synthase