Details of Host Protein-DME Interaction (HOSPPI)

General Information of Drug-Metabolizing Enzyme (DME ID: DME0123)
DME Name	Nitric oxide synthase endothelial (NOS3), Homo sapiens	DME Info
UniProt ID	NOS3_HUMAN
EC Number	EC: 1.14.13.39 (Click to Show/Hide the Complete EC Tree) Oxidoreductase Oxygen paired donor oxidoreductase NADH/NADPH donor oxidoreductase EC: 1.14.13.39
Lineage	Species: Homo sapiens (Click to Show/Hide the Complete Species Lineage) Kingdom: Metazoa Phylum: Chordata Class: Mammalia Order: Primates Family: Hominidae Genus: Homo Species: Homo sapiens
Interactome

Disease Specific Interactions between Host Protein and DME (HOSPPI)
ICD Disease Classification Healthy
ICD-11: Healthy		Click to Show/Hide the Full List of HOSPPI: 15 HOSPPI
Oligomerization
Cytoplasmic actin 1 (ACTB)		Health		Heterotrimer
Uniprot ID	ACTB_HUMAN
Interaction Name	ACTB, HSP90AA1 and NOS3 heterotrimerization				[3]
Studied Cell Lines	Endothelial cells
Description	Cytoplasmic actin 1 (ACTB) and Heat shock 90-alpha (HSP90AA1) are reported to heterotrimerize with the NOS3 protein, which leads to an altered activity of the drug-metabolizing enzyme Nitric oxide synthase endothelial. As a result, the interaction among ACTB, HSP90AA1 and NOS3 can modulate the drug-metabolizing process of Nitric oxide synthase endothelial.
Endothelial NOS (NOS3)		Health		Homodimer
Uniprot ID	NOS3_HUMAN
Interaction Name	NOS3-NOS3 homodimerization				[4]
Studied Cell Lines	Recombinant BL21(DE3)-pNTF cells
Description	Endothelial NOS (NOS3) is reported to homodimerize with the NOS3 protein, which leads to an increased activity of the drug-metabolizing enzyme Nitric oxide synthase endothelial. As a result, the interaction between NOS3 and NOS3 can facilitate the drug-metabolizing process of Nitric oxide synthase endothelial.
Heat shock 90-alpha (HSP90AA1)		Health		Heterotrimer
Uniprot ID	HS90A_HUMAN
Interaction Name	HSP90AA1, ACTB and NOS3 heterotrimerization				[3]
Studied Cell Lines	Endothelial cells
Description	Heat shock 90-alpha (HSP90AA1) and Cytoplasmic actin 1 (ACTB) are reported to heterotrimerize with the NOS3 protein, which leads to an altered activity of the drug-metabolizing enzyme Nitric oxide synthase endothelial. As a result, the interaction among HSP90AA1, ACTB and NOS3 can modulate the drug-metabolizing process of Nitric oxide synthase endothelial.
Transcription-factor regulation
Activating TF factor 2 (ATF2)		Health		Repression
Uniprot ID	ATF2_HUMAN
Interaction Name	ATF2-NOS3 interaction				[1]
Studied Cell Lines	Endothelial cell line
Ensembl ID	ENSG00000115966
Description	Activating TF factor 2 (ATF2) is reported to repress the transcription of NOS3 gene, which leads to a decreased expression of the drug-metabolizing enzyme Nitric oxide synthase endothelial. As a result, the interaction between ATF2 and NOS3 can repress the drug-metabolizing process of Nitric oxide synthase endothelial.
C/EBP-homologous protein (DDIT3)		Health		Repression
Uniprot ID	DDIT3_HUMAN
Interaction Name	DDIT3-NOS3 interaction				[2]
Studied Cell Lines	Human umbilical vein endothelial cell line
Ensembl ID	ENSG00000175197
Description	C/EBP-homologous protein (DDIT3) is reported to repress the transcription of NOS3 gene, which leads to a decreased expression of the drug-metabolizing enzyme Nitric oxide synthase endothelial. As a result, the interaction between DDIT3 and NOS3 can repress the drug-metabolizing process of Nitric oxide synthase endothelial.
GATA-binding factor 2 (GATA2)		Health		Activation
Uniprot ID	GATA2_HUMAN
Interaction Name	GATA2-NOS3 interaction				[5]
Studied Cell Lines	NCI-H441 cell line
Ensembl ID	ENSG00000179348
Description	GATA-binding factor 2 (GATA2) is reported to activate the transcription of NOS3 gene, which leads to an increased expression of the drug-metabolizing enzyme Nitric oxide synthase endothelial. As a result, the interaction between GATA2 and NOS3 can activate the drug-metabolizing process of Nitric oxide synthase endothelial.
Nuclear factor kappa-B p105 (NFKB1)		Health		Activation
Uniprot ID	NFKB1_HUMAN
Interaction Name	NFKB1-NOS3 interaction				[10], [11]
Studied Cell Lines	Human umbilical endothelial cell line
Ensembl ID	ENSG00000109320
Description	Nuclear factor kappa-B p105 (NFKB1) is reported to activate the transcription of NOS3 gene, which leads to an increased expression of the drug-metabolizing enzyme Nitric oxide synthase endothelial. As a result, the interaction between NFKB1 and NOS3 can activate the drug-metabolizing process of Nitric oxide synthase endothelial.
TF factor GATA-4 (GATA4)		Health		Activation
Uniprot ID	GATA4_HUMAN
Interaction Name	GATA4-NOS3 interaction				[12]
Studied Cell Lines	Bovine lung microvessel endothelial cell line
Ensembl ID	ENSG00000136574
Description	TF factor GATA-4 (GATA4) is reported to activate the transcription of NOS3 gene, which leads to an increased expression of the drug-metabolizing enzyme Nitric oxide synthase endothelial. As a result, the interaction between GATA4 and NOS3 can activate the drug-metabolizing process of Nitric oxide synthase endothelial.
Transcription factor p65 (RELA)		Health		Activation
Uniprot ID	TF65_HUMAN
Interaction Name	RELA-NOS3 interaction				[10]
Studied Cell Lines	Human umbilical endothelial cell line
Ensembl ID	ENSG00000173039
Description	Transcription factor p65 (RELA) is reported to activate the transcription of NOS3 gene, which leads to an increased expression of the drug-metabolizing enzyme Nitric oxide synthase endothelial. As a result, the interaction between RELA and NOS3 can activate the drug-metabolizing process of Nitric oxide synthase endothelial.
Transcription factor Sp1 (SP1)		Health		Activation
Uniprot ID	SP1_HUMAN
Interaction Name	SP1-NOS3 interaction				[5], [13], [14]
Studied Cell Lines	H441 cell line
Ensembl ID	ENSG00000185591
Description	Transcription factor Sp1 (SP1) is reported to activate the transcription of NOS3 gene, which leads to an increased expression of the drug-metabolizing enzyme Nitric oxide synthase endothelial. As a result, the interaction between SP1 and NOS3 can activate the drug-metabolizing process of Nitric oxide synthase endothelial.
Transcription factor Sp3 (SP3)		Health		Activation
Uniprot ID	SP3_HUMAN
Interaction Name	SP3-NOS3 interaction				[12]
Studied Cell Lines	Bovine lung microvessel endothelial cell line
Ensembl ID	ENSG00000172845
Description	Transcription factor Sp3 (SP3) is reported to activate the transcription of NOS3 gene, which leads to an increased expression of the drug-metabolizing enzyme Nitric oxide synthase endothelial. As a result, the interaction between SP3 and NOS3 can activate the drug-metabolizing process of Nitric oxide synthase endothelial.
Non-coding RNA regulation
hsa-miR-155-5p		Health		Suppression
miRBase ID	MIMAT0000646
Interaction Name	hsa-miR-155-5p--NOS3 regulation				[7]
Studied Cell Lines	Human umbilical vein endothelial cell line
Description	hsa-miR-155-5p is reported to suppress NOS3 mRNA translation by binding to the 3' untranslated region (3'UTR) of NOS3 mRNA, which leads to a decreased expression of the drug-metabolizing enzyme Nitric oxide synthase endothelial.
hsa-miR-200c-3p		Health		Suppression
miRBase ID	MIMAT0000617
Interaction Name	hsa-miR-200c-3p--NOS3 regulation				[8]
Studied Cell Lines	Human umbilical vein endothelial cell line
Description	hsa-miR-200c-3p is reported to suppress NOS3 mRNA translation by binding to the 3' untranslated region (3'UTR) of NOS3 mRNA, which leads to a decreased expression of the drug-metabolizing enzyme Nitric oxide synthase endothelial.
hsa-miR-24-3p		Health		Suppression
miRBase ID	MIMAT0000080
Interaction Name	hsa-miR-24-3p--NOS3 regulation				[9]
Studied Cell Lines	Human umbilical vein endothelial cell line
Description	hsa-miR-24-3p is reported to suppress NOS3 mRNA translation by binding to the 3' untranslated region (3'UTR) of NOS3 mRNA, which leads to a decreased expression of the drug-metabolizing enzyme Nitric oxide synthase endothelial.
Histone modification
Histone deacetylases (HDACs)		Health		Repression
Uniprot ID	HDAC1_HUMAN
Interaction Name	HDACs-NOS3 interaction				[6]
Studied Cell Lines	Cultured bovine aortic endothelial cells (BAECs)
Description	Histone deacetylases (HDACs) are reported to deacetylate the NOS3 gene and thereby repress the transcriptional activity of the drug-metabolizing enzyme Nitric oxide synthase endothelial. As a result, the interaction between HDACs and NOS3 can inhibit the drug-metabolizing process of Nitric oxide synthase endothelial.
ICD Disease Classification 02 Neoplasms
ICD-11: 2A00 Brain cancer		Click to Show/Hide the Full List of HOSPPI: 2 HOSPPI
DNA methylation
DNA methyltransferase (DNMT)		Multilayered rosettes embryonal tumour		Significant hypomethylation
Interaction Name	DNMT-NOS3 interaction
The Methylation Level of Disease Section Compare with the Healthy Individual Tissue	Significant hypomethylation p-value: 6.21E-06; delta-beta: -4.67E-01
Description	DNA methyltransferase (DNMT) is reported to significantly hypo-methylate the NOS3 gene, which leads to a significantly increased expression of the drug-metabolizing enzyme Nitric oxide synthase endothelial. As a result, the interaction between DNMT and NOS3 can significantly affect the drug-metabolizing process of Nitric oxide synthase endothelial.
DME methylation in the diseased tissue of patients DME methylation in the normal tissue of healthy individuals
Violin Diagram of DME Disease-specific Methylation Level			Click to View the Clearer Original Diagram
Download DME methylation barchart for all samples Download DME methylation data of patients in the disease section of the tissue Download DME methylation data in the tissue of healthy individual
DNA methyltransferase (DNMT)		Third ventricle chordoid glioma		Significant hypermethylation
Interaction Name	DNMT-NOS3 interaction
The Methylation Level of Disease Section Compare with the Healthy Individual Tissue	Significant hypermethylation p-value: 8.20E-03; delta-beta: 4.15E-01
Description	DNA methyltransferase (DNMT) is reported to significantly hyper-methylate the NOS3 gene, which leads to a significantly decreased expression of the drug-metabolizing enzyme Nitric oxide synthase endothelial. As a result, the interaction between DNMT and NOS3 can significantly affect the drug-metabolizing process of Nitric oxide synthase endothelial.
DME methylation in the diseased tissue of patients DME methylation in the normal tissue of healthy individuals
Violin Diagram of DME Disease-specific Methylation Level			Click to View the Clearer Original Diagram
Download DME methylation barchart for all samples Download DME methylation data of patients in the disease section of the tissue Download DME methylation data in the tissue of healthy individual
ICD-11: 2C82 Prostate cancer		Click to Show/Hide the Full List of HOSPPI: 2 HOSPPI
Non-coding RNA regulation
hsa-miR-335-3p		Prostate cancer		Suppression
miRBase ID	MIMAT0004703
Interaction Name	hsa-miR-335-3p--NOS3 regulation				[15]
Studied Cell Lines	PC3 cell line
Description	hsa-miR-335-3p is reported to suppress NOS3 mRNA translation by binding to the 3' untranslated region (3'UTR) of NOS3 mRNA, which leads to a decreased expression of the drug-metabolizing enzyme Nitric oxide synthase endothelial.
hsa-miR-543		Prostate cancer		Suppression
miRBase ID	MIMAT0004954
Interaction Name	hsa-miR-543--NOS3 regulation				[15]
Studied Cell Lines	PC3 cell line
Description	hsa-miR-543 is reported to suppress NOS3 mRNA translation by binding to the 3' untranslated region (3'UTR) of NOS3 mRNA, which leads to a decreased expression of the drug-metabolizing enzyme Nitric oxide synthase endothelial.
ICD Disease Classification 11 Circulatory system diseases
ICD-11: BA00 Hypertension		Click to Show/Hide the Full List of HOSPPI: 1 HOSPPI
Transcription-factor regulation
Krueppel-like factor 2 (KLF2)		Hypertension		Activation
Uniprot ID	KLF2_HUMAN
Interaction Name	KLF2-NOS3 interaction				[16]
Studied Cell Lines	Human umbilical vessel cell line
Ensembl ID	ENSG00000127528
Description	Krueppel-like factor 2 (KLF2) is reported to activate the transcription of NOS3 gene, which leads to an increased expression of the drug-metabolizing enzyme Nitric oxide synthase endothelial. As a result, the interaction between KLF2 and NOS3 can activate the drug-metabolizing process of Nitric oxide synthase endothelial.

References
1	Competitive binding of CREB and ATF2 to cAMP/ATF responsive element regulates eNOS gene expression in endothelial cells. Arterioscler Thromb Vasc Biol. 2006 May;26(5):1036-42.
2	C/EBP homologous protein-10 (CHOP-10) limits postnatal neovascularization through control of endothelial nitric oxide synthase gene expression. Circulation. 2012 Feb 28;125(8):1014-26.
3	beta-Actin regulates platelet nitric oxide synthase 3 activity through interaction with heat shock protein 90. Proc Natl Acad Sci U S A. 2007 May 22;104(21):8839-44.
4	Calmodulin promotes dimerization of the oxygenase domain of human endothelial nitric-oxide synthase. J Biol Chem. 1997 May 2;272(18):12030-4.
5	Molecular basis of cell-specific endothelial nitric-oxide synthase expression in airway epithelium. J Biol Chem. 2000 Mar 17;275(11):8183-9.
6	Histone deacetylase 1 reduces NO production in endothelial cells via lysine deacetylation of NO synthase 3. Am J Physiol Heart Circ Physiol. 2014 Sep 1;307(5):H803-9.
7	Essential role of microRNA-155 in regulating endothelium-dependent vasorelaxation by targeting endothelial nitric oxide synthase. Hypertension. 2012 Dec;60(6):1407-14.
8	eNOS expression and NO release during hypoxia is inhibited by miR-200b in human endothelial cells. Angiogenesis. 2018 Nov;21(4):711-724.
9	Roles of miRNA-24 in regulating endothelial nitric oxide synthase expression and vascular endothelial cell proliferation. Mol Cell Biochem. 2015 Jul;405(1-2):281-9.
10	Angiotensin II up-regulates expression of inducible nitric oxide synthase in human umbilical endothelial cells: roles of AT1 and AT2. Zhonghua Xin Xue Guan Bing Za Zhi. 2006 Jul;34(7):647-50.
11	NFKB1 promoter variation implicates shear-induced NOS3 gene expression and endothelial function in prehypertensives and stage I hypertensives. Am J Physiol Heart Circ Physiol. 2007 Oct;293(4):H2320-7.
12	TNF-alpha induces a decrease in eNOS promoter activity. Am J Physiol Lung Cell Mol Physiol. 2004 Feb;286(2):L452-9.
13	Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation. 2002 Sep 24;106(13):1652-8.
14	Lysophosphatidylcholine up-regulates human endothelial nitric oxide synthase gene transactivity by c-Jun N-terminal kinase signalling pathway. J Cell Mol Med. 2009 Jun;13(6):1136-48.
15	MicroRNA-335 and -543 suppress bone metastasis in prostate cancer via targeting endothelial nitric oxide synthase. Int J Mol Med. 2015 Nov;36(5):1417-25.
16	Grape seed proanthocyanidin extracts enhance endothelial nitric oxide synthase expression through 5'-AMP activated protein kinase/Surtuin 1-Krple like factor 2 pathway and modulate blood pressure in ouabain induced hypertensive rats. Biol Pharm Bull. 2012;35(12):2192-7.

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