NOS1

Summary

NOS1 (nitric oxide synthase 1, HGNC:7872) is a protein-coding gene on chromosome 12q24.22, encoding Nitric oxide synthase 1 (P29475). Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body.

The protein encoded by this gene belongs to the family of nitric oxide synthases, which synthesize nitric oxide from L-arginine. Nitric oxide is a reactive free radical, which acts as a biologic mediator in several processes, including neurotransmission, and antimicrobial and antitumoral activities. In the brain and peripheral nervous system, nitric oxide displays many properties of a neurotransmitter, and has been implicated in neurotoxicity associated with stroke and neurodegenerative diseases, neural regulation of smooth muscle, including peristalsis, and penile erection. This protein is ubiquitously expressed, with high level of expression in skeletal muscle. Multiple transcript variants that differ in the 5’ UTR have been described for this gene but the full-length nature of these transcripts is not known. Additionally, alternatively spliced transcript variants encoding different isoforms (some testis-specific) have been found for this gene.

Source: NCBI Gene 4842 — RefSeq curated summary.

At a glance

• Gene–disease (curated): idiopathic achalasia (Supportive, GenCC)
• Clinical variants (ClinVar): 261 total
• GTEx eGene: eQTL in 21 tissues, sQTL in 0 (q < 0.05)
• Drug target: yes — 1 via a complex or family; 10 molecules with ChEMBL bioactivity (top 3% of genes corpus-wide)
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.40 (moderately constrained)
• MANE Select transcript: NM_000620
• Interaction hub: 2,018 STRING partners (top 7% of genes corpus-wide)
• Notable: 261 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7872
Approved symbol	NOS1
Name	nitric oxide synthase 1
Location	12q24.22
Locus type	gene with protein product
Status	Approved
Aliases	nNOS
Ensembl gene	ENSG00000089250
Ensembl biotype	protein_coding
OMIM	163731
Entrez	4842

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 2 protein_coding_CDS_not_defined

MANE Select: ENST00000317775

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 1, TSL 3: 1, TSL 5: 2

ENST00000317775, ENST00000338101, ENST00000477584, ENST00000549189, ENST00000618760, ENST00001141950

RefSeq mRNA: 4 — MANE Select: NM_000620 NM_000620, NM_001204213, NM_001204214, NM_001204218

CCDS: CCDS41842, CCDS55890

Canonical transcript exons

ENST00000317775 — 29 exons

Exon	Start	End
ENSE00000835092	117311466	117311592
ENSE00000835093	117330345	117331489
ENSE00001358200	117361512	117361626
ENSE00001839331	117208142	117215324
ENSE00003714411	117253638	117253754
ENSE00003714713	117260465	117260609
ENSE00003714789	117222715	117222863
ENSE00003719994	117220075	117220269
ENSE00003721374	117263889	117263974
ENSE00003721564	117247348	117247522
ENSE00003721842	117280725	117280866
ENSE00003724744	117226683	117226770
ENSE00003727724	117225016	117225137
ENSE00003728985	117227431	117227641
ENSE00003732512	117268043	117268144
ENSE00003734603	117265316	117265510
ENSE00003737112	117234565	117234758
ENSE00003737876	117243297	117243435
ENSE00003739104	117231962	117232131
ENSE00003740930	117259026	117259130
ENSE00003741882	117242627	117242705
ENSE00003746038	117286104	117286266
ENSE00003746339	117218046	117218164
ENSE00003747561	117290298	117290426
ENSE00003747765	117277959	117278098
ENSE00003751599	117288074	117288219
ENSE00003751747	117272385	117272559
ENSE00003752983	117258397	117258455
ENSE00003753843	117285241	117285332

Expression profiles

Bgee: expression breadth ubiquitous, 167 present calls, max score 91.38.

FANTOM5 (CAGE): breadth broad, TPM avg 1.0274 / max 124.5772, expressed in 184 samples.

Highest expression (Bgee): body of tongue, biceps brachii, skeletal muscle tissue of biceps brachii, skeletal muscle tissue of rectus abdominis, hindlimb stylopod muscle.

Genetic regulation across tissues (GTEx eQTL / sQTL)

NOS1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 21 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 21 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Skin Sun Exposed Lower leg	eqtl	2.1e-92	-0.86	12:117349749:G:T
Skin Not Sun Exposed Suprapubic	eqtl	1.1e-67	-0.90	12:117349749:G:T
Muscle Skeletal	eqtl	1.1e-29	-0.28	12:117441519:T:C
Thyroid	eqtl	8.6e-21	+0.47	12:117567836:C:A
Brain Hippocampus	eqtl	7.6e-17	-0.63	12:117443669:T:G
Brain Frontal Cortex BA9	eqtl	1.4e-13	-0.39	12:117443459:G:A
Nerve Tibial	eqtl	4.0e-13	+0.21	12:117323735:A:G
Pancreas	eqtl	4.2e-13	-0.45	12:117408296:A:C
Brain Cortex	eqtl	5.6e-09	-0.39	12:117438669:A:G
Esophagus Mucosa	eqtl	7.8e-09	-0.31	12:117349749:G:T
Brain Spinal cord cervical c-1	eqtl	2.4e-08	-0.43	12:117451408:C:T
Brain Substantia nigra	eqtl	1.4e-05	-0.47	12:117438669:A:G
Brain Amygdala	eqtl	6.9e-05	-0.38	12:117441215:A:G
Brain Nucleus accumbens basal ganglia	eqtl	9.6e-05	+0.23	12:117358345:T:A
Heart Atrial Appendage	eqtl	3.7e-04	-0.32	12:117464353:T:C
Brain Anterior cingulate cortex BA24	eqtl	9.1e-04	-0.31	12:117464353:T:C
Brain Caudate basal ganglia	eqtl	1.2e-03	-0.20	12:117439202:A:G
Pituitary	eqtl	1.8e-03	-0.21	12:117299100:C:T
Lung	eqtl	1.7e-02	+0.16	12:117337773:T:C
Brain Putamen basal ganglia	eqtl	2.0e-02	-0.31	12:117443153:C:A

FANTOM5 promoters

9 alternative TSS:

Promoter ID	TPM avg	Samples expressed
133504	0.2486	73
133505	0.1982	78
133502	0.1377	59
133503	0.1373	52
133500	0.1268	54
133501	0.0599	29
206918	0.0540	28
133499	0.0358	16
133506	0.0290	15

Top tissues by expression

showing 100 of 272 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
body of tongue	UBERON:0011876	91.38	gold quality
biceps brachii	UBERON:0001507	88.72	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	88.66	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	87.91	gold quality
hindlimb stylopod muscle	UBERON:0004252	86.40	gold quality
pons	UBERON:0000988	83.20	gold quality
tongue	UBERON:0001723	82.31	gold quality
muscle of leg	UBERON:0001383	81.06	gold quality
gastrocnemius	UBERON:0001388	81.05	gold quality
skeletal muscle tissue	UBERON:0001134	80.59	gold quality
muscle organ	UBERON:0001630	80.29	gold quality
dorsal root ganglion	UBERON:0000044	80.09	gold quality
diaphragm	UBERON:0001103	77.77	gold quality
buccal mucosa cell	CL:0002336	76.90	gold quality
vastus lateralis	UBERON:0001379	76.85	gold quality
deltoid	UBERON:0001476	76.41	silver quality
muscle tissue	UBERON:0002385	76.24	gold quality
putamen	UBERON:0001874	76.00	gold quality
trigeminal ganglion	UBERON:0001675	75.91	gold quality
tibialis anterior	UBERON:0001385	75.88	silver quality
quadriceps femoris	UBERON:0001377	75.83	gold quality
lateral globus pallidus	UBERON:0002476	75.59	gold quality
superior vestibular nucleus	UBERON:0007227	75.20	gold quality
pancreatic ductal cell	CL:0002079	74.94	silver quality
ventral tegmental area	UBERON:0002691	74.68	gold quality
caudate nucleus	UBERON:0001873	74.12	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.81	gold quality
entorhinal cortex	UBERON:0002728	73.31	gold quality
superior surface of tongue	UBERON:0007371	72.48	gold quality
cerebellar vermis	UBERON:0004720	71.77	silver quality
temporal lobe	UBERON:0001871	71.30	gold quality
amygdala	UBERON:0001876	70.98	gold quality
nucleus accumbens	UBERON:0001882	70.57	gold quality
sural nerve	UBERON:0015488	70.09	gold quality
ileal mucosa	UBERON:0000331	69.97	silver quality
hair follicle	UBERON:0002073	69.48	gold quality
prefrontal cortex	UBERON:0000451	68.87	gold quality
hypothalamus	UBERON:0001898	67.76	gold quality
triceps brachii	UBERON:0001509	67.66	gold quality
telencephalon	UBERON:0001893	67.49	gold quality
Ammon’s horn	UBERON:0001954	67.19	gold quality
cingulate cortex	UBERON:0003027	67.03	gold quality
anterior cingulate cortex	UBERON:0009835	66.92	gold quality
medulla oblongata	UBERON:0001896	66.90	gold quality
cerebellum	UBERON:0002037	66.79	gold quality
parietal lobe	UBERON:0001872	66.50	gold quality
forebrain	UBERON:0001890	66.45	gold quality
gluteal muscle	UBERON:0002000	66.44	gold quality
postcentral gyrus	UBERON:0002581	66.28	gold quality
brain	UBERON:0000955	66.21	gold quality
inferior vagus X ganglion	UBERON:0005363	66.21	gold quality
frontal cortex	UBERON:0001870	66.05	gold quality
central nervous system	UBERON:0001017	66.03	gold quality
subthalamic nucleus	UBERON:0001906	65.93	silver quality
superior frontal gyrus	UBERON:0002661	65.89	gold quality
cerebellar cortex	UBERON:0002129	65.80	gold quality
neocortex	UBERON:0001950	65.60	gold quality
right hemisphere of cerebellum	UBERON:0014890	65.59	gold quality
pharyngeal mucosa	UBERON:0000355	65.54	silver quality
cerebellar hemisphere	UBERON:0002245	65.52	gold quality
epithelial cell of pancreas	CL:0000083	65.43	gold quality
endothelial cell	CL:0000115	65.43	gold quality
cerebral cortex	UBERON:0000956	65.17	gold quality
tibial nerve	UBERON:0001323	65.03	gold quality
midbrain	UBERON:0001891	65.03	gold quality
occipital lobe	UBERON:0002021	64.55	gold quality
jejunum	UBERON:0002115	64.06	gold quality
muscle layer of sigmoid colon	UBERON:0035805	63.92	gold quality
substantia nigra	UBERON:0002038	63.90	gold quality
gingival epithelium	UBERON:0001949	63.72	silver quality
dorsolateral prefrontal cortex	UBERON:0009834	63.62	gold quality
primary visual cortex	UBERON:0002436	63.38	gold quality
cartilage tissue	UBERON:0002418	63.13	gold quality
right frontal lobe	UBERON:0002810	63.10	gold quality
left ventricle myocardium	UBERON:0006566	63.01	gold quality
gingiva	UBERON:0001828	62.72	silver quality
myocardium	UBERON:0002349	62.29	gold quality
sigmoid colon	UBERON:0001159	62.19	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	62.03	silver quality
adult mammalian kidney	UBERON:0000082	61.86	gold quality
upper leg skin	UBERON:0004262	61.78	silver quality
skin of leg	UBERON:0001511	61.67	gold quality
substantia nigra pars compacta	UBERON:0001965	61.56	gold quality
mammalian vulva	UBERON:0000997	61.30	silver quality
zone of skin	UBERON:0000014	61.14	gold quality
parotid gland	UBERON:0001831	61.10	silver quality
dorsal plus ventral thalamus	UBERON:0001897	60.98	silver quality
Brodmann (1909) area 9	UBERON:0013540	60.97	gold quality
adult organism	UBERON:0007023	60.90	gold quality
nasal cavity epithelium	UBERON:0005384	60.84	gold quality
cardiac muscle of right atrium	UBERON:0003379	60.83	gold quality
tendon of biceps brachii	UBERON:0008188	60.75	gold quality
spinal cord	UBERON:0002240	60.66	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	60.65	gold quality
upper arm skin	UBERON:0004263	60.34	gold quality
frontal pole	UBERON:0002795	60.21	gold quality
middle frontal gyrus	UBERON:0002702	60.07	gold quality
corpus callosum	UBERON:0002336	59.81	gold quality
paraflocculus	UBERON:0005351	59.74	gold quality
tongue squamous epithelium	UBERON:0006919	59.71	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.45

HPA expression

RNA tissue specificity: Group enriched

showing 60 of 147 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Tongue	tissue	53.5
Skeletal muscle	tissue	36.2	medium
Skeletal muscle	tissue	34.5	low
Pons	tissue	30.2
Olfactory bulb	tissue	27.5
Locus coeruleus	tissue	27.4
Hippocampal formation	tissue	26.3
Caudate putamen	tissue	25.1
Nucleus accumbens	tissue	20.3
Amygdala	tissue	16.9
Frontal cortex	tissue	16.9
Cerebral cortex	tissue	16.2	medium
Motor cortex	tissue	16.2
Caudate putamen	tissue	15.3
Retrosplenial and cingulate cortex	tissue	15.2
Prefrontal cortex	tissue	15.0
Entorhinal cortex	tissue	14.7
Insular cortex	tissue	14.7
Somatosensory cortex	tissue	14.4
Retrosplenial cortex	tissue	14.0
Temporal cortex	tissue	14.0
Putamen	tissue	13.7
Midbrain	tissue	12.6
Occipital cortex	tissue	11.8
Locus coeruleus	tissue	11.7
Ventral forebrain	tissue	10.2
Hippocampus	tissue	9.8	medium
Basal ganglia	tissue	9.6	high
Hypothalamus	tissue	9.0
Superior colliculi	tissue	8.4
Cerebellum	tissue	8.2	high
Septum	tissue	8.2
Frontal cortex	tissue	8.0
Adrenal gland	tissue	7.6	high
Thalamus	tissue	7.3
Periaqueductal gray	tissue	7.0
Nucleus accumbens	tissue	7.0
Thyroid gland	tissue	6.6	medium
Postcentral gyrus	tissue	6.2
Placenta	tissue	5.9	high
Hippocampus	tissue	5.9	medium
Spinal cord	tissue	5.6
Medulla oblongata	tissue	5.5
Cerebral cortex	tissue	4.6	medium
Insular cortex	tissue	4.6
Hippocampal formation	tissue	4.5
Prefrontal cortex	tissue	4.3
Motor cortex	tissue	4.3
Postcentral gyrus	tissue	4.3
Entorhinal cortex	tissue	4.3
Temporal cortex	tissue	4.3
Substantia nigra	tissue	4.0
Choroid plexus	tissue	4.0
Retrosplenial cortex	tissue	4.0
Retrosplenial and cingulate cortex	tissue	3.9
Breast	tissue	3.8	medium
Retina	tissue	3.8
Amygdala	tissue	3.8
Septum	tissue	3.8
Heart muscle	tissue	3.4	medium

Brain sub-regions (HPA Brain Atlas): detected in 380; highest nTPM — Ventromedial nucleus (52.1), Arcuate nucleus (37.2), Subthalamic nucleus (32.0), Corticomedial amygdala (29.5), Ventral periolivary nuclei (28.0).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting NOS1 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 321 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4725-3P	99.96	69.53	2520

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.399, missense Z 4.73 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000317775 splits into 4 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
12:117,215,312–117,265,504	737 / 1030.3	0.72	no
12:117,265,505–117,285,284	134 / 267.3	0.50	no
12:117,285,285–117,290,368	129 / 186.0	0.69	no
12:117,290,369–117,331,069	362 / 402.0	0.90	no

Literature-anchored findings (GeneRIF, showing 40)

• fine mapping and single nucleotide polymorphism association results of candidate genes for asthma and related phenotypes (PMID:11668616)
• An alternative promoter of the human neuronal nitric oxide synthase gene is expressed specifically in Leydig cells. (PMID:11786430)
• quantitative expression of nNOS first exon variants in different human tissues and the characterization of the basal nNOS exon 1c promoter (PMID:11960979)
• ligand and protein vibrations at the substrate binding site. A study by FTIR. (PMID:12081486)
• allelic association of the gene with schizophrenia (PMID:12140778)
• assembly and activation of the heme-deficient neuronal enzyme with various porphyrins (PMID:12237228)
• Data report a 89-nucleotide alternatively spliced exon in human neuronal nitric oxide synthase located in the 5’-untranslated region between exon 1 variants and a common exon 2 that contains the translational initiation codon. (PMID:12403769)
• Association analysis of five polymorphic microsatellite markers in cluster headache (CH) patients reveals that genetic variations in the NOS1 gene do not contribute greatly to CH susceptibility. (PMID:12421162)
• nitric oxide synthases(inducible, brain and endothelial) were expressed in human pregnant term uterus and did not change in the myometrium during labor (PMID:12445599)
• expression in neurons of the Nuc. suprachiasmaticus (SCN) of depressed patients and matched controls (PMID:12485841)
• calmodulin activates electron transfer in the flavin domain of human neuronal nitric oxide synthase (PMID:12646269)
• Nitric oxide participates in the phosphorylation of eIF2alpha since nNOS processes are closely related to eIF2alpha(P) positive cells in temporal lobe epilepsy with hippocampal sclerosis (PMID:12686399)
• rate of intramolecular electron transfer between the two flavins in the iNOS flavin domain was faster than that of the nNOS flavin domain. (PMID:12777376)
• NOS1 is strongly expressed in most tubules of the human nephron. Epithelial cells may be major source of nitric oxide in human kidney under physiologic conditions. (PMID:12787407)
• nNOS staining was found in nerve fibers branching within seminal vesicle tissue (PMID:12802542)
• Results describe the expression of nitric oxide synthases 1, 2, and 3 in patients with chronic obstructive pulmonary disease, suggesting their involvement in muscle dysfunction in this disease. (PMID:12816735)
• There is no obvious association between ecNOS polymorphism and preeclampsia. (PMID:12908999)
• Variations in the NOS1 gene may contribute to atopy without this relationship being reflected by FENO. (PMID:12911502)
• Nitric oxide liberated from enteric neurons participates in the chloride secretory response to stroking in human jejunum in vitro. (PMID:12947326)
• nNOS can differentially regulate the ERK signal transduction pathway in a manner dependent on the presence of l-arginine and the production of NO*. (PMID:14602725)
• The increased NO production with increased expression of iNOS and ncNOS may contribute to the pathological and physiological features of UVB-induced erythema and skin inflammation. (PMID:14615895)
• Association analysis for the CA repeat polymorphism of the neuronal nitric oxide synthase (NOS1) gene and schizophrenia. (PMID:14623375)
• Cu,Zn superoxide dismutase and nitric oxide synthase in neurodegenerative processes (review) (PMID:14711010)
• MPP(+)-dependent aconitase inactivation, Tf-iron uptake, and oxidant generation result in the depletion of intracellular tetrahydrobiopterin, leading to the uncoupling of nNOS activity (PMID:14752097)
• IFN-gamma regulates NOS-1 expression through posttranscriptional and posttranslational mechanisms. (PMID:14980078)
• nitric noxide release by nitric oxide synthase 1 (neuronal) would significantly affect available smooth muscle nitric oxide (PMID:15033959)
• human mast cell lines produce NO in both cytoplasmic and nuclear compartments, and endogenously produced NO can regulate leukotriene production. (PMID:15044250)
• The nNOS gene polymorphism may not confer increased susceptibility to Tardive Dyskinesia, although more investigations on other populations are warranted. (PMID:15075442)
• NOS1 gene may participate in pathogenesis of high total serum IgE levels in allergic diseases. NOS1 may be candidate gene for IgE-mediated allergy. (PMID:15080837)
• Neuronal NOS expression in the prefrontal cortex was significantly higher in individuals with schizophrenia. (PMID:15094474)
• Intron4 polymorphism of the nitric oxide synthase gene is associated with the development of lupus nephritis. (PMID:15119548)
• Intracellular factors able to induce abnormalities in the nNOS monomer/dimer equilibrium could lead to pancreatic beta-cell dysfunction. (PMID:15161750)
• In trained vastus lateralis, NOS 1 protein and immunostaining at myofibers II were significantly increased at the end of head-down-tilt bed rest. (PMID:15180967)
• nNOS expression is regulated in the process of cutaneous wound repair. (PMID:15191553)
• increased activity of nNOS may be involved in the neuroprotection conferred by 17beta-estradiol. (PMID:15194886)
• Constitutive NOS activities are responsible for E2-induced NO production in neuroblastoma cells. Differential activation of NOS isoforms in these cells occurs in response to different treatments. (PMID:15242984)
• neuronal nitric-oxide synthase activity through serine 741 phosphorylation is inhibited by Calcium/calmodulin-dependent protein kinase I (PMID:15251453)
• NOS-1 mRNA and protein levels hint that not only NOS-3, but also NOS-1 may be involved in the regulation of systemic hyperdynamic circulation and portal hypertension. (PMID:15287858)
• CHIP is an E3 ligase for nNOS whose action is facilitated by (and possibly requires) its interaction with nNOS-bound hsp70 (PMID:15466472)
• The T/T genotype of the neuronal nitric oxide synthase C276T SNP seems to be associated wtith Alzheimer’s disease in Italy population, particularly with early onset. (PMID:15765269)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nos1	ENSDARG00000068910
mus_musculus	Nos1	ENSMUSG00000029361
rattus_norvegicus	Nos1	ENSRNOG00000001130

Paralogs (5): NOS2 (ENSG00000007171), MTRR (ENSG00000124275), POR (ENSG00000127948), NOS3 (ENSG00000164867), NDOR1 (ENSG00000188566)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:97360) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 113 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased body weight	3
increased aggression towards male mice	3
premature death	3
enlarged stomach	3
abnormal liver morphology	2
abnormal muscle physiology	2
pyloric stenosis	2
abnormal nervous system physiology	2
abnormal muscle relaxation	2
decreased cerebral infarct size	2
decreased susceptibility to neuronal excitotoxicity	2
decreased survivor rate	2
abnormal gastroesophageal sphincter physiology	2
pyloric sphincter hypertrophy	2
increased bone mineral density	1
abnormal trabecular bone morphology	1
abnormal hepatocyte morphology	1
abnormal motor neuron morphology	1
increased anxiety-related response	1
decreased male mating frequency	1
abnormal liquid preference	1
increased grooming behavior	1
abnormal spatial learning	1
abnormal sleep pattern	1
impaired balance	1

+88 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Escherichia coli APEC O1	A1AEV0	100.0%	Diamond
Escherichia coli O139:H28 str. E24377A	A7ZQK7	100.0%	Diamond
Escherichia coli ATCC 8739	B1IU77	100.0%	Diamond
Staphylococcus aureus	P0A004	100.0%	Diamond
Staphylococcus aureus subsp. aureus Mu50	P0A092	100.0%	Diamond
Staphylococcus aureus subsp. aureus N315	P0A093	100.0%	Diamond
Staphylococcus aureus subsp. aureus MW2	P0A094	100.0%	Diamond
Escherichia coli 536	Q0TEA2	100.0%	Diamond
Escherichia coli UTI89	Q1R7T4	100.0%	Diamond
Staphylococcus aureus subsp. aureus COL	Q5HEK7	100.0%	Diamond
Staphylococcus aureus subsp. aureus MSSA476	Q6G818	100.0%	Diamond
Shigella boydii Sb227	Q31XM4	99.8%	Diamond
Escherichia coli CFT073	Q8FEI7	99.8%	Diamond
Shigella sonnei Ss046	Q3YY94	99.7%	Diamond
Escherichia coli HS	A8A3P5	99.3%	Diamond
Nostoc sp. PCC 7119	P21890	99.3%	Diamond
Escherichia coli O157:H7	Q8X7U1	99.3%	Diamond
Shigella dysenteriae Sd197	Q32CG3	99.0%	Diamond
Staphylococcus aureus subsp. aureus MRSA252	Q6GFE2	98.6%	Diamond
Bos taurus	Q27995	97.0%	Diamond
Capra hircus	Q28314	97.0%	Diamond
Aspergillus niger	A0A100IM63	96.7%	Diamond
Lathyrus oleraceus	P10933	96.7%	Diamond
Sus scrofa	Q28969	95.6%	Diamond
Oryctolagus cuniculus	O19114	95.4%	Diamond
Cavia porcellus	P97270	94.6%	Diamond
Canis lupus familiaris	Q9TUX8	93.5%	Diamond
Sorghum bicolor	C5YJG8	92.8%	Diamond
Oryza sativa Japonica Group	Q0J705	92.8%	Diamond
Ovis aries	Q29498	91.9%	Diamond
Arabidopsis thaliana	Q8W493	89.5%	Diamond
Squalus acanthias	Q9I9M2	88.2%	Diamond
Penicillium expansum	A0A0A2J1Z6	86.5%	Diamond
Drosophila melanogaster	Q27597	85.8%	Diamond
Macaca mulatta	O46660	85.1%	Diamond
Serratia proteamaculans 568	A8G9X6	82.9%	Diamond
Artemisia annua	A0A2U1KZS6	79.4%	Diamond
Catharanthus roseus	Q05001	77.7%	Diamond
Synechocystis sp. PCC 6803 substr. Kazusa	Q55318	74.9%	Diamond
Vigna radiata var. radiata	P37116	74.2%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
FBXO21	protein-coding	23014
FBXW8	protein-coding	26259
TESC	protein-coding	54997
TESC-AS1	ncRNA	101928244
KSR2	protein-coding	283455
VSIG10	protein-coding	54621
WSB2	protein-coding	55884
RFC5	protein-coding	5985

Protein

Protein identifiers

Nitric oxide synthase 1 — P29475 (reviewed: P29475)

Alternative names: Constitutive NOS, NC-NOS, NOS type I, Neuronal NOS, Nitric oxide synthase, brain, Peptidyl-cysteine S-nitrosylase NOS1

All UniProt accessions (2): B3VK56, P29475

UniProt curated annotations — full annotation on UniProt →

Function. Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR.

Subunit / interactions. Homodimer. Interacts with DLG4; the interaction possibly being prevented by the association between NOS1 and CAPON. Forms a ternary complex with CAPON and RASD1. Forms a ternary complex with CAPON and SYN1. Interacts with ZDHHC23. Interacts with NOSIP; which may impair its synaptic location. Interacts with HTR4. Interacts with SLC6A4. Interacts with VAC14. Interacts (via N-terminal domain) with DLG4 (via N-terminal tandem pair of PDZ domains). Interacts with SLC6A4. Forms a complex with ASL, ASS1 and SLC7A1; the complex regulates cell-autonomous L-arginine synthesis and citrulline recycling while channeling extracellular L-arginine to nitric oxide synthesis pathway. Interacts with DMD; localizes NOS1 to sarcolemma in muscle cells. Interacts with DYNLL1; inhibits the nitric oxide synthase activity.

Subcellular location. Cell membrane. Sarcolemma. Cell projection. Dendritic spine.

Tissue specificity. Isoform 1 is ubiquitously expressed: detected in skeletal muscle and brain, also in testis, lung and kidney, and at low levels in heart, adrenal gland and retina. Not detected in the platelets. Isoform 3 is expressed only in testis. Isoform 4 is detected in testis, skeletal muscle, lung, and kidney, at low levels in the brain, but not in the heart and adrenal gland.

Post-translational modifications. Ubiquitinated; mediated by STUB1/CHIP in the presence of Hsp70 and Hsp40 (in vitro).

Activity regulation. Stimulated by calcium/calmodulin. Inhibited by DYNLL1 that prevents the dimerization of the protein. Inhibited by NOSIP.

Cofactor. Binds 1 FAD. Binds 1 FMN. Tetrahydrobiopterin (BH4). May stabilize the dimeric form of the enzyme.

Domain organisation. The PDZ domain participates in protein-protein interaction, and is responsible for targeting nNos to synaptic membranes. Mediates interaction with VAC14.

Similarity. Belongs to the NOS family.

Isoforms (5)

UniProt ID	Names	Canonical?
P29475-1	1, N-NOS-1	yes
P29475-2	2, N-NOS-2
P29475-3	3, TN-NOS, TN-NOSB
P29475-4	4, TEX2-insertion
P29475-5	5, nNOSmu

RefSeq proteins (4): NP_000611, NP_001191142, NP_001191143, NP_001191147 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001094	Flavdoxin-like	Domain
IPR001433	OxRdtase_FAD/NAD-bd	Domain
IPR001478	PDZ	Domain
IPR001709	Flavoprot_Pyr_Nucl_cyt_Rdtase	Domain
IPR003097	CysJ-like_FAD-binding	Domain
IPR004030	NOS_N	Domain
IPR008254	Flavodoxin/NO_synth	Domain
IPR012144	NOS_euk	Family
IPR017927	FAD-bd_FR_type	Domain
IPR017938	Riboflavin_synthase-like_b-brl	Homologous_superfamily
IPR023173	NADPH_Cyt_P450_Rdtase_alpha	Homologous_superfamily
IPR029039	Flavoprotein-like_sf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR036119	NOS_N_sf	Homologous_superfamily
IPR039261	FNR_nucleotide-bd	Homologous_superfamily
IPR044940	NOS_dom_2	Homologous_superfamily
IPR044943	NOS_dom_1	Homologous_superfamily
IPR044944	NOS_dom_3	Homologous_superfamily
IPR050607	NOS	Family

Pfam: PF00175, PF00258, PF00595, PF00667, PF02898

Enzyme classification (BRENDA)

• EC 1.14.13.39 — nitric-oxide synthase (NADPH) (BRENDA: 31 organisms, 140 substrates, 179 inhibitors, 88 Km, 25 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-ARGININE	0.0019–68.5	28
NADPH	0.0003–0.0041	9
TETRAHYDROBIOPTERIN	—	6
ADRIAMYCIN	0.012–0.078	5
MENADIONE	0.01–0.041	5
MITOMYCIN C	0.0073–0.055	5
NGAMMA-HYDROXY-L-ARGININE	0.019–0.129	5
2’,3’-DIALDEHYDE-NADPH	0.0008	1
CALMODULIN	—	1
NITROBLUE TETRAZOLIUM	0.016	1
NITRIC OXIDE	—	0

Catalyzed reactions (Rhea)

• 2 L-arginine + 3 NADPH + 4 O2 + H(+) = 2 L-citrulline + 2 nitric oxide + 3 NADP(+) + 4 H2O (RHEA:19897)

UniProt features (127 total): binding site 46, helix 27, strand 23, sequence conflict 6, region of interest 5, splice variant 5, sequence variant 5, domain 3, modified residue 3, turn 2, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

showing 30 of 122 structures by resolution:

PDB	Title	Method	Resolution (Å)
8BI9	Structure of a cyclic beta-hairpin peptide derived from neuronal nitric oxide synthase …	X-RAY DIFFRACTION	1.44
8BI8	Structure of a cyclic beta-hairpin peptide derived from neuronal nitric oxide synthase	X-RAY DIFFRACTION	1.59
6CID	Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in …	X-RAY DIFFRACTION	1.75
6CIC	Structure of the human nitric oxide synthase R354A/G357D mutant heme domain in complex …	X-RAY DIFFRACTION	1.75
6PNG	Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in …	X-RAY DIFFRACTION	1.77
6NG4	Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in …	X-RAY DIFFRACTION	1.78
5VV0	Structure of human neuronal nitric oxide synthase heme domain in complex with …	X-RAY DIFFRACTION	1.8
6NGD	Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in …	X-RAY DIFFRACTION	1.8
6NGI	Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in …	X-RAY DIFFRACTION	1.8
7TS6	Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in …	X-RAY DIFFRACTION	1.8
9CVS	Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain bound …	X-RAY DIFFRACTION	1.8
9CVX	Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain bound …	X-RAY DIFFRACTION	1.8
6PO9	Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in …	X-RAY DIFFRACTION	1.81
6POA	Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in …	X-RAY DIFFRACTION	1.81
6PO5	Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in …	X-RAY DIFFRACTION	1.82
7US8	Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in …	X-RAY DIFFRACTION	1.82
8FGF	Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in …	X-RAY DIFFRACTION	1.83
7UAM	Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in …	X-RAY DIFFRACTION	1.84
7TS5	Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in …	X-RAY DIFFRACTION	1.84
6PNH	Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in …	X-RAY DIFFRACTION	1.85
7TS4	Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in …	X-RAY DIFFRACTION	1.85
8FGG	Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in …	X-RAY DIFFRACTION	1.86
6AV4	Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in …	X-RAY DIFFRACTION	1.87
9CVW	Structure of human neuronal nitric oxide synthase R354A/G357D mutant bound with …	X-RAY DIFFRACTION	1.87
6PO8	Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in …	X-RAY DIFFRACTION	1.9
5UO1	Structure of human neuronal nitric oxide synthase heme domain in complex with …	X-RAY DIFFRACTION	1.9
6AV5	Structure of human neuronal nitric oxide synthase R354A/G356D mutant heme domain in …	X-RAY DIFFRACTION	1.9
6NG8	Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in …	X-RAY DIFFRACTION	1.9
6NGB	Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in …	X-RAY DIFFRACTION	1.9
7TS7	Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in …	X-RAY DIFFRACTION	1.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P29475-F1	80.12	0.52

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Oxidoreductases, Metabolic proteins, Transporters, Accessory Factors Involved in Transport, Predicted intracellular proteins, Plasma proteins, Cancer-related genes, Candidate cancer biomarkers, FDA approved drug targets, Small molecule drugs

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): plasma membrane; nucleoplasm

Antibody reliability (HPA): IH enhanced · IF supported

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (46)

Position	Role
339	(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin
420	heme b
483	L-arginine
592	L-arginine
593	L-arginine
597	L-arginine
682	(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin
683	(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin
696	(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin
711	heme b
766	FMN
767	FMN
768	FMN
770	FMN
771	FMN
812	FMN
813	FMN
817	FMN
891	FMN
896	FMN
898	FMN
924	FMN
928	FMN
1015	NADP(+)
1037	FAD
1178	FAD
1179	FAD
1180	FAD
1181	FAD
1196	FAD
1198	FAD
1201	NADP(+)
1202	FAD
1215	FAD
1216	FAD
1217	FAD
1256	NADP(+)
1289	NADP(+)
1318	NADP(+)
1319	NADP(+)
1325	NADP(+)
1327	NADP(+)
1329	NADP(+)
1362	NADP(+)
1403	NADP(+)
1405	NADP(+)

Post-translational modifications (3)

Type	Positions
Phosphoserine	852, 862, 863

Function

Pathways and Gene Ontology

Reactome pathways

3 curated (TAS) of 9; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

9 pathways:

ID	Pathway	Evidence
R-HSA-5578775	Ion homeostasis	curated
R-HSA-392154	Nitric oxide stimulates guanylate cyclase	curated
R-HSA-1222556	ROS and RNS production in phagocytes	curated
R-HSA-5576891	Cardiac conduction	—
R-HSA-109582	Hemostasis	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-397014	Muscle contraction	—
R-HSA-418346	Platelet homeostasis	—

MSigDB gene sets: 0 (showing top):

GO Biological Process (38): response to hypoxia (GO:0001666), regulation of sodium ion transport (GO:0002028), L-arginine catabolic process (GO:0006527), nitric oxide biosynthetic process (GO:0006809), striated muscle contraction (GO:0006941), myoblast fusion (GO:0007520), response to heat (GO:0009408), response to hormone (GO:0009725), negative regulation of calcium ion transport into cytosol (GO:0010523), regulation of cardiac muscle contraction by calcium ion signaling (GO:0010882), response to lipopolysaccharide (GO:0032496), multicellular organismal response to stress (GO:0033555), xenobiotic catabolic process (GO:0042178), vasodilation (GO:0042311), negative regulation of potassium ion transport (GO:0043267), positive regulation of neuron apoptotic process (GO:0043525), cell redox homeostasis (GO:0045454), negative regulation of blood pressure (GO:0045776), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of neurogenesis (GO:0050767), negative regulation of serotonin uptake (GO:0051612), negative regulation of calcium ion transport (GO:0051926), regulation of cardiac muscle contraction (GO:0055117), regulation of postsynaptic membrane potential (GO:0060078), cellular response to growth factor stimulus (GO:0071363), positive regulation of the force of heart contraction (GO:0098735), synaptic signaling by nitric oxide (GO:0099163), positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0106071), positive regulation of sodium ion transmembrane transport (GO:1902307), regulation of calcium ion transmembrane transport via high voltage-gated calcium channel (GO:1902514), positive regulation of membrane repolarization during ventricular cardiac muscle cell action potential (GO:1905026), cell communication (GO:0007154), blood circulation (GO:0008015), regulation of metal ion transport (GO:0010959), signaling (GO:0023052), negative regulation of monoatomic ion transport (GO:0043271), regulation of blood circulation (GO:1903522)

GO Molecular Function (18): nitric-oxide synthase activity (GO:0004517), calcium channel regulator activity (GO:0005246), calmodulin binding (GO:0005516), FMN binding (GO:0010181), sodium channel regulator activity (GO:0017080), heme binding (GO:0020037), tetrahydrobiopterin binding (GO:0034617), arginine binding (GO:0034618), peptidyl-cysteine S-nitrosylase activity (GO:0035605), transmembrane transporter binding (GO:0044325), cadmium ion binding (GO:0046870), calcium-dependent protein binding (GO:0048306), flavin adenine dinucleotide binding (GO:0050660), NADP binding (GO:0050661), scaffold protein binding (GO:0097110), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872)

GO Cellular Component (22): photoreceptor inner segment (GO:0001917), nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), caveola (GO:0005901), postsynaptic density (GO:0014069), sarcoplasmic reticulum (GO:0016529), Z disc (GO:0030018), T-tubule (GO:0030315), protein-containing complex (GO:0032991), sarcoplasmic reticulum membrane (GO:0033017), sarcolemma (GO:0042383), dendritic spine (GO:0043197), calyx of Held (GO:0044305), membrane raft (GO:0045121), synapse (GO:0045202), perinuclear region of cytoplasm (GO:0048471), cell periphery (GO:0071944), endomembrane system (GO:0012505)

Reactome top-level categories

6 top-level categories:

Category	Pathways
Innate Immune System	1
Platelet homeostasis	1
Cardiac conduction	1
Immune System	1
Hemostasis	1
Muscle contraction	1

GO top-level categories

showing 60 of 87 GO namespaces:

Category	Terms
cellular anatomical structure	6
protein binding	4
response to stress	3
cytoplasm	3
ion channel regulator activity	2
anion binding	2
binding	2
cation binding	2
intracellular membrane-bounded organelle	2
response to decreased oxygen levels	1
sodium ion transport	1
regulation of metal ion transport	1
arginine metabolic process	1
amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
biosynthetic process	1
nitric oxide metabolic process	1
muscle contraction	1
syncytium formation by cell-cell fusion	1
myotube differentiation	1
response to temperature stimulus	1
response to endogenous stimulus	1
response to chemical	1
regulation of calcium ion transport into cytosol	1
negative regulation of cytosolic calcium ion concentration	1
calcium ion transport into cytosol	1
negative regulation of calcium ion transmembrane transport	1
calcium-mediated signaling	1
regulation of cardiac muscle contraction	1
cardiac muscle contraction	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
multicellular organismal process	1
xenobiotic metabolic process	1
catabolic process	1
blood vessel diameter maintenance	1
potassium ion transport	1
regulation of potassium ion transport	1
negative regulation of monoatomic ion transport	1
positive regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
cellular homeostasis	1
regulation of blood pressure	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, NAD(P)H as one donor, and incorporation of one atom of oxygen	1
calcium channel activity	1
ribonucleotide binding	1
sodium channel activity	1
tetrapyrrole binding	1
amino acid binding	1
carboxylic acid binding	1
transferase activity, transferring nitrogenous groups	1
catalytic activity, acting on a protein	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 10 of 79 annotations. The rest are phylogenetic / computational / electronic (IEA).

10 experimentally-supported GO terms:

GO term	NS	Evidence
multicellular organismal response to stress	BP	mutant phenotype
positive regulation of neuron apoptotic process	BP	mutant phenotype
response to heat	BP	direct assay
response to hypoxia	BP	expression pattern
vasodilation	BP	direct assay
plasma membrane	CC	direct assay
sarcolemma	CC	direct assay
sarcoplasmic reticulum	CC	direct assay
nitric-oxide synthase activity	MF	direct assay
peptidyl-cysteine S-nitrosylase activity	MF	mutant phenotype

Protein interactions and networks

STRING

showing 15 of 2,018 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NOS1	XDH	P47989	809
NOS1	CALM1	P02593	734
NOS1	CALML3	P27482	734
NOS1	CALML5	Q9NZT1	734
NOS1	CALML4	Q96GE6	730
NOS1	NOS1AP	O75052	728
NOS1	CALML6	Q8TD86	727
NOS1	DLG4	P78352	711
NOS1	IL1B	P01584	699
NOS1	CAV3	P56539	689
NOS1	CYBB	P04839	673
NOS1	PVALB	P20472	670
NOS1	BDNF	P23560	670
NOS1	IL6	P05231	665
NOS1	TNF	P01375	665

IntAct

Human interaction partners of NOS1 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 269 partners by confidence:

Partner	Interaction type	MIscore	Records
VAC14	direct interaction	0.720	6
GRIN2A	physical association	0.610	2
E6	direct interaction	0.440	4
E	direct interaction	0.440	2
PDLIM4	direct interaction	0.440	2
ABCC4	direct interaction	0.440	1
ABCC6	direct interaction	0.440	1
ACE2	direct interaction	0.440	1
ACOT6	direct interaction	0.440	1
ACTN2	direct interaction	0.440	1
ACVR2A	direct interaction	0.440	1
ADAM17	direct interaction	0.440	1
ADAM22	direct interaction	0.440	1
ADGRA1	direct interaction	0.440	1
ADGRA3	direct interaction	0.440	1
ADGRE5	direct interaction	0.440	1
ADGRG1	direct interaction	0.440	1
ADRA1D	direct interaction	0.440	1
ADRB2	direct interaction	0.440	1
AKAP10	direct interaction	0.440	1
AKIP1	direct interaction	0.440	1
AMOTL1	direct interaction	0.440	1
APBA1	direct interaction	0.440	1
APPL1	direct interaction	0.440	1
AQP3	direct interaction	0.440	1
AQP6	direct interaction	0.440	1
ARHGAP17	direct interaction	0.440	1
ARHGAP6	direct interaction	0.440	1
ARHGEF16	direct interaction	0.440	1
ARHGEF7	direct interaction	0.440	1

BioGRID (64 interactions; top human partners by supporting records): DLG4 (Affinity Capture-Western; 6 records), NOS1AP (Two-hybrid; 5 records), STUB1 (Biochemical Activity; 5 records), PRKD1 (Affinity Capture-Western; 4 records), SOX2 (Reconstituted Complex; 3 records), BDKRB2 (Affinity Capture-Western; 2 records), SNTA1 (Reconstituted Complex; 2 records), ZDHHC23 (Affinity Capture-Western; 2 records), ADCY9 (Affinity Capture-MS), ANKRD62 (Cross-Linking-MS (XL-MS)), ARRDC1 (Affinity Capture-MS), C1orf226 (Affinity Capture-MS), CKAP4 (Cross-Linking-MS (XL-MS)), CSNK2B (Affinity Capture-MS), CUL9 (Affinity Capture-MS)

SIGNOR signaling

11 signaling interactions:

A	Effect	B	Mechanism
SNTA1	up-regulates	NOS1	relocalization
NOS1	“up-regulates quantity”	“nitric oxide”	“chemical modification”
NOS1	“form complex”	DGC	binding
DLG4	“up-regulates activity”	NOS1	binding
PRKD1	“up-regulates activity”	NOS1	phosphorylation
NOS1	“down-regulates activity”	HDAC2	s-nitrosylation
PRKCA	unknown	NOS1
PRKACA	unknown	NOS1	phosphorylation
CAMK1	“down-regulates activity”	NOS1	phosphorylation
CAMK2A	“down-regulates activity”	NOS1	phosphorylation
CAMK4	“down-regulates activity”	NOS1	phosphorylation

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
HSPA1A-NOS1-STUB1 complex	3	NOS1, STUB1, HSPA1A

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 269 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Tight junction interactions	9	17.0×	1e-06
Long-term potentiation	6	14.6×	4e-04
Unblocking of NMDA receptors, glutamate binding and activation	5	13.9×	2e-03
Negative regulation of NMDA receptor-mediated neuronal transmission	5	13.9×	2e-03
SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)	5	12.7×	3e-03
Assembly and cell surface presentation of NMDA receptors	8	10.4×	1e-04
EPHB-mediated forward signaling	6	8.2×	5e-03
Activation of NMDA receptors and postsynaptic events	8	7.6×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
calcium-independent cell-cell adhesion	8	25.3×	8e-07
glutamate receptor signaling pathway	6	22.1×	6e-05
positive regulation of synaptic transmission, glutamatergic	7	17.2×	5e-05
transmission of nerve impulse	5	12.8×	3e-03
focal adhesion assembly	6	12.4×	1e-03
monoatomic cation transmembrane transport	5	12.3×	4e-03
positive regulation of Rho protein signal transduction	5	11.4×	5e-03
maintenance of blood-brain barrier	6	11.4×	2e-03

Disease & clinical

Genetic variants

Variant evidence for NOS1: 261 ClinVar records (0 pathogenic / likely pathogenic).

ClinVar

261 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	167
Likely benign	49
Benign	23

AlphaMissense

4,389 missense substitutions predicted likely pathogenic (of 9,451 scored), across 990 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M1359	9	0.966	0.997
M750	9	0.965	0.997
M594	9	0.938	0.998
M700	9	0.888	0.998
M443	9	0.885	0.998
H1037	8	0.999	1.000
D1398	8	0.999	1.000
D632	8	0.998	0.999
D655	8	0.998	1.000
H656	8	0.998	1.000
H657	8	0.998	1.000
H697	8	0.997	1.000
F814	8	0.997	1.000
F736	8	0.996	1.000
F786	8	0.996	1.000
D923	8	0.995	0.999
D319	8	0.993	0.999
D500	8	0.993	0.999
F589	8	0.993	0.999
H666	8	0.992	1.000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Breast Invasive Carcinoma (TCGA)	unfavorable	8.36e-06

Disease associations

OMIM: gene MIM:163731 | disease phenotypes:

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
idiopathic achalasia	Supportive	Autosomal recessive

Mondo (1): idiopathic achalasia (MONDO:0019635)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL2096621 (SELECTIVITY GROUP), CHEMBL2111405 (SELECTIVITY GROUP), CHEMBL3568 (SINGLE PROTEIN), CHEMBL4630725 (PROTEIN FAMILY)

Drugs acting on a complex or family that includes this protein

Curated ChEMBL mechanism-of-action drugs whose target is a protein complex or family of ≤10 members that includes NOS1 — the drug acts on the assembly or class, not necessarily on this subunit alone.

1 drugs via a complex or family:

Drug	Target (ChEMBL)	Members	Max phase
TILARGININE	Nitric oxide synthase	3	3

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 72,587 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

10 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL1371	CHLORZOXAZONE	4	16,875
CHEMBL1201774	SAPROPTERIN	4	2,617
CHEMBL256147	TILARGININE	3	2,046
CHEMBL344760	AMINOTHIAZOLE	2	19,994
CHEMBL114551	GW-274150	2	1,071
CHEMBL1911882	KD7040	2	8
CHEMBL7890	L-NAME	2	1,196
CHEMBL225304	PIMAGEDINE	2	24,594
CHEMBL503356	PRAXADINE	2	1,714
CHEMBL227744	NITROARGININE	1	2,472

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Nitric oxide synthases

Most potent curated ligand interactions (7 total), top 7:

Ligand	Action	Affinity	Parameter
compound 14j [PMID: 27050842]	Inhibition	7.89	pKi
L-NNA	Inhibition	7.82	pKi
Nωpropyl-L-arginine	Inhibition	7.2	pKi
3-bromo-7NI	Inhibition	6.5	pIC50
tilarginine	Inhibition	6.08	pKi
7NI	Inhibition	5.3	pIC50
GW274150	Inhibition	4.74	pIC50

Binding affinities (BindingDB)

1054 measured of 1202 human assays (1253 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
CHEMBL2046871	KI	0.43 nM
CHEMBL106871	IC50	1 nM
6-{4-[2-(4-Quinolin-8-yl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine	KI	3 nM
N-(3-Aminomethyl-phenyl)-furan-2-carboxamidine	KI	6 nM
N-(3-Aminomethyl-phenyl)-furan-2-carboxamidine	KI	6.3 nM
N-(3-Aminomethyl-phenyl)-thiophene-2-carboxamidine	KI	8.7 nM
4-Methyl-6-propylpyridin-2-amine, 7	IC50	10 nM
6-[[(2R,4S)-4-[(6-amino-4-methyl-2-pyridinyl)methoxy]pyrrolidin-2-yl]methoxymethyl]-4-methylpyridin-2-amine	KI	10 nM	US-9732037: 2-aminopyridine-based selective neuronal nitric oxide synthase inhibitors
N-(3-Aminomethyl-phenyl)-2-fluoro-acetamidine	KI	11 nM
N-(3-Aminomethyl-phenyl)-2-methylsulfanyl-acetamidine	KI	11 nM
CHEMBL1944717	IC50	12 nM
CHEMBL2046877	KI	12 nM
CHEMBL4856400	IC50	12 nM
CHEMBL4878434	IC50	12 nM
N’-[4-[3-(dimethylamino)propyl]-2,3-dihydro-1,4-benzothiazin-7-yl]thiophene-2-carboximidamide	IC50	14 nM	US-8618286: Benzoxazines, benzothiazines, and related compounds having NOS inhibitory activity
4-Methyl-piperidin-(2Z)-ylideneamine	IC50	16 nM
2-{2-[4-(2-CARBAMIMIDOYLSULFANYL-ETHYL)-PHENYL]-ETHYL}-ISOTHIOUREA	KI	16 nM
N1-((3R,4S)-4-((6-aminopyridin-2-yl)methyl)pyrrolidin-3-yl)-N2-(4-fluorobenzyl)ethane-1,2-diamine tetrahydrochloride	KI	17.7 nM	US-9090589: Specific nNOS inhibitors for the therapy and prevention of human melanoma
7-[[5-(methylaminomethyl)-3-pyridinyl]oxymethyl]quinolin-2-amine	KI	19 nM	US-9783500: 2-aminoquinoline-based compounds for potent and selective neuronal nitric oxide synthase inhibition
CHEMBL5420690	KI	19 nM
CHEMBL4068062	KI	20 nM
CHEMBL1825174	IC50	20 nM
7-[[3-[(dimethylamino)methyl]phenoxy]methyl]quinolin-2-amine	KI	21 nM	US-9783500: 2-aminoquinoline-based compounds for potent and selective neuronal nitric oxide synthase inhibition
7-(pyridin-3-yloxymethyl)quinolin-2-amine	KI	21 nM	US-9783500: 2-aminoquinoline-based compounds for potent and selective neuronal nitric oxide synthase inhibition
CHEMBL4089246	KI	21 nM
CHEMBL4532683	KI	21 nM
CHEMBL5191295	KI	21 nM
CHEMBL4590333	KI	23 nM
CHEMBL4874244	IC50	23 nM
6-[2-[5-[(2R)-1-amino-3-(6-amino-4-methyl-2-pyridinyl)propan-2-yl]-3-pyridinyl]ethyl]-4-methylpyridin-2-amine	KI	24 nM	US-9951014: Mammalian and bacterial nitric oxide synthase inhibitors
N1-{(+/-)-4’-[(6’’-amino-4’’-methylpyridin-2’’-yl)methyl]pyrrolidin-3’-yl}-N2-phenethylethane-1,2-diamine tetrahydrochloride	KI	24 nM	US-9090589: Specific nNOS inhibitors for the therapy and prevention of human melanoma
6-[[(2S,4R)-4-[(6-amino-4-methyl-2-pyridinyl)methoxy]pyrrolidin-2-yl]methoxymethyl]-4-methylpyridin-2-amine	KI	26 nM	US-9732037: 2-aminopyridine-based selective neuronal nitric oxide synthase inhibitors
N’-[4-[3-(methylamino)propyl]-2,3-dihydro-1,4-benzothiazin-7-yl]thiophene-2-carboximidamide	IC50	28 nM	US-8618286: Benzoxazines, benzothiazines, and related compounds having NOS inhibitory activity
2-Ethyl-isothiourea	KI	29 nM
2-Propyl-isothiourea	KI	29 nM
CHEMBL4440481	KI	29 nM
CHEMBL5189279	KI	29 nM
(+/-)-N-{2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-benzothiazol-5-yl}-thiophene-2-carboxamidine	IC50	30 nM
CHEMBL4094689	KI	30 nM
CHEMBL4092027	KI	30 nM
7-[[3-(dimethylamino)phenoxy]methyl]quinolin-2-amine	KI	31 nM	US-9783500: 2-aminoquinoline-based compounds for potent and selective neuronal nitric oxide synthase inhibition
(4R,7R)-4-Methyl-octahydro-[1]pyrindin-(2E)-ylideneamine	IC50	31 nM
CHEMBL4079543	KI	31 nM
6-[[(2S,4S)-4-[(6-amino-4-methyl-2-pyridinyl)methoxy]pyrrolidin-2-yl]methoxymethyl]-4-methylpyridin-2-amine	KI	31 nM	US-9732037: 2-aminopyridine-based selective neuronal nitric oxide synthase inhibitors
CHEMBL4465991	KI	31 nM
CHEMBL4062164	KI	32 nM
6-[[(2R)-3-amino-2-[(6-amino-4-methyl-2-pyridinyl)methoxy]propoxy]methyl]-4-methylpyridin-2-amine	KI	32 nM	US-9732037: 2-aminopyridine-based selective neuronal nitric oxide synthase inhibitors

ChEMBL bioactivities

1127 potent at pChembl≥5 of 1372 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.07	Ki	0.085	nM	CHEMBL474637
9.82	Ki	0.15	nM	CHEMBL227937
9.60	Ki	0.25	nM	CHEMBL526688
9.52	Ki	0.3	nM	CHEMBL44833
9.41	Ki	0.388	nM	CHEMBL510760
9.00	Kd	1	nM	CHEMBL106871
9.00	IC50	1	nM	CHEMBL106871
8.28	Ki	5.3	nM	CHEMBL594682
8.22	Ki	6	nM	CHEMBL96680
8.20	Ki	6.3	nM	CHEMBL96680
8.20	Ki	6.3	nM	CHEMBL552825
8.06	Ki	8.7	nM	CHEMBL262040
8.06	Ki	8.7	nM	CHEMBL555715
8.03	Ki	9.4	nM	CHEMBL475797
8.00	Ki	10	nM	CHEMBL3109188
8.00	IC50	10	nM	CHEMBL302657
7.96	Ki	11	nM	CHEMBL455310
7.96	Ki	11	nM	CHEMBL476988
7.96	Ki	11	nM	CHEMBL555794
7.96	Ki	11	nM	CHEMBL555584
7.92	IC50	12	nM	CHEMBL1944717
7.89	Ki	13	nM	CHEMBL3818373
7.85	Ki	14	nM	CHEMBL594682
7.85	IC50	14	nM	CHEMBL3675250
7.82	Ki	15	nM	NITROARGININE
7.80	IC50	16	nM	CHEMBL6808
7.80	Ki	16	nM	CHEMBL444422
7.75	Ki	17.7	nM	CHEMBL1233715
7.72	Ki	19	nM	CHEMBL5420690
7.72	Ki	19	nM	CHEMBL3736598
7.70	Ki	20	nM	CHEMBL4068062
7.70	IC50	20	nM	CHEMBL3216307
7.68	IC50	21	nM	CHEMBL191242
7.68	Ki	21	nM	CHEMBL4089246
7.68	Ki	21	nM	CHEMBL4532683
7.68	Ki	21	nM	CHEMBL5191295
7.68	Ki	21	nM	CHEMBL3736585
7.68	Ki	21	nM	CHEMBL3736588
7.64	Ki	23	nM	CHEMBL4590333
7.64	IC50	23	nM	CHEMBL302657
7.62	Ki	24	nM	CHEMBL1187747
7.62	Ki	24	nM	CHEMBL3262026
7.60	Ki	25	nM	CHEMBL3736587
7.60	Ki	25	nM	CHEMBL1615288
7.58	Ki	26	nM	CHEMBL3109186
7.55	IC50	28	nM	CHEMBL3639741
7.54	Ki	29	nM	CHEMBL4440481
7.54	Ki	29	nM	ETHYLISOTHIOUREA
7.54	Ki	29	nM	CHEMBL5189279
7.54	Ki	29	nM	CHEMBL483092

PubChem BioAssay actives

947 with measured affinity, of 1698 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N’-[(3S,4S)-4-[(6-amino-4-methyl-2-pyridinyl)methyl]pyrrolidin-3-yl]-N-[(4-chlorophenyl)methyl]ethane-1,2-diamine	414629: Inhibition of nNOS	ki	0.0001	uM
2-[(4S)-4-amino-5-(2-aminoethylamino)pentyl]-1-nitroguanidine	414629: Inhibition of nNOS	ki	0.0001	uM
(2S,4R)-4-[[(2S)-2-amino-5-[[amino(nitramido)methylidene]amino]pentanoyl]amino]pyrrolidine-2-carboxamide	414629: Inhibition of nNOS	ki	0.0001	uM
N’-[(3R,4S)-4-[(6-amino-4-methyl-2-pyridinyl)methyl]pyrrolidin-3-yl]-N-[(3-chlorophenyl)methyl]ethane-1,2-diamine	414629: Inhibition of nNOS	ki	0.0003	uM
(2S)-2-amino-5-[[amino(nitramido)methylidene]amino]-N-[(2S)-1,4-diamino-1-oxobutan-2-yl]pentanamide	414629: Inhibition of nNOS	ki	0.0003	uM
N’-[(3S,4S)-4-[(6-amino-2-pyridinyl)methyl]pyrrolidin-3-yl]ethane-1,2-diamine	414629: Inhibition of nNOS	ki	0.0004	uM
(2S)-2-amino-5-[[amino(ethylsulfanyl)methylidene]amino]pentanoic acid	2007148: Inhibition of human nNOS assessed as dissociation constant	kd	0.0010	uM
N’-[(3R,4R)-4-[(6-amino-4-methyl-2-pyridinyl)methyl]pyrrolidin-3-yl]-N-[2-(3-fluorophenyl)ethyl]ethane-1,2-diamine	593172: Inhibition of nNOS	ki	0.0053	uM
N’-[3-(aminomethyl)phenyl]furan-2-carboximidamide	2007182: Inhibition of human nNOS assessed as reduction of L-[14C]arginine to L-[14C]-citrulline conversion	ki	0.0060	uM
N’-[3-(aminomethyl)phenyl]furan-2-carboximidamide;dihydrobromide	146133: Inhibitory activity against human neuronal nitric oxide synthase (nNOS) isoenzyme.	ki	0.0063	uM
N’-[3-(aminomethyl)phenyl]thiophene-2-carboximidamide	404423: Inhibition of nNOS assessed as conversion of L-[3H]arginine to L-[3H]citrulline	ki	0.0087	uM
N’-[3-(aminomethyl)phenyl]thiophene-2-carboximidamide;dihydrobromide	146133: Inhibitory activity against human neuronal nitric oxide synthase (nNOS) isoenzyme.	ki	0.0087	uM
3-[[(3S,4S)-4-[(6-amino-2-pyridinyl)methyl]pyrrolidin-3-yl]amino]propan-1-ol	414629: Inhibition of nNOS	ki	0.0094	uM
4-methyl-6-propylpyridin-2-amine	146120: In vitro inhibition of human neuronal nitric oxide synthase.	ic50	0.0100	uM
N’-[3-(aminomethyl)phenyl]-2-fluoroethanimidamide	404423: Inhibition of nNOS assessed as conversion of L-[3H]arginine to L-[3H]citrulline	ki	0.0110	uM
N’-[3-(aminomethyl)phenyl]-2-fluoroethanimidamide;dihydrobromide	146133: Inhibitory activity against human neuronal nitric oxide synthase (nNOS) isoenzyme.	ki	0.0110	uM
N’-[3-(aminomethyl)phenyl]-2-methylsulfanylethanimidamide	404423: Inhibition of nNOS assessed as conversion of L-[3H]arginine to L-[3H]citrulline	ki	0.0110	uM
N’-[3-(aminomethyl)phenyl]-2-methylsulfanylethanimidamide;dihydrobromide	146133: Inhibitory activity against human neuronal nitric oxide synthase (nNOS) isoenzyme.	ki	0.0110	uM
4-[(3-chloro-N-pyrazin-2-ylanilino)methyl]-7,8-difluoro-1H-quinolin-2-one	643399: Inhibition of human nNOS expressed in HEK293 cells assessed as NO production by 2,3-diaminonapthalene-based fluorescence assay	ic50	0.0120	uM
4-methyl-6-[2-[5-[3-(methylamino)propyl]-3-pyridinyl]ethyl]pyridin-2-amine	1308021: Inhibition of human recombinant nNOS expressed in Escherichia coli using L-arginine as substrate assessed as reduction in NO production measured for 6 mins in presence of tetrahydrobiopterin by hemoglobin capture assay	ki	0.0130	uM
(2S)-2-amino-5-[[amino(nitramido)methylidene]amino]pentanoic acid	146133: Inhibitory activity against human neuronal nitric oxide synthase (nNOS) isoenzyme.	ki	0.0150	uM
2-[4-(2-carbamimidoylsulfanylethyl)phenyl]ethyl carbamimidothioate	404423: Inhibition of nNOS assessed as conversion of L-[3H]arginine to L-[3H]citrulline	ki	0.0160	uM
4-methyl-2,3,4,5-tetrahydropyridin-6-amine	241314: Inhibitory activity against human Neuronal nitric oxide synthase (nNOS)	ic50	0.0160	uM
6-[2-[5-[2-(dimethylamino)ethyl]-2,3-difluorophenyl]ethyl]-4-methylpyridin-2-amine;dihydrochloride	1982703: Inhibition of human nNOS expressed in Escherichia coli using human oxyhemoglobin by hemoglobin (Hb) NO capture assay	ki	0.0190	uM
4-[2-[(2-aminoquinolin-7-yl)methylamino]ethyl]-2-methylbenzonitrile	1458728: Inhibition of recombinant human nNOS expressed in Escherichia coli using L-arginine as substrate after 30 secs by hemoglobin capture assay	ki	0.0200	uM
N’-[1-[2-[(2S)-1-methylpyrrolidin-2-yl]ethyl]indol-5-yl]thiophene-2-carboximidamide;dihydrochloride	617462: Inhibition of human recombinant nNOS expressed in Sf9 cells assessed as conversion of [3H]-L-arginine to [3H]-L-citrulline by radiometric method	ic50	0.0200	uM
(4R,4aR,7aR)-4-methyl-4,4a,5,6,7,7a-hexahydro-3H-cyclopenta[b]pyridin-2-amine	241314: Inhibitory activity against human Neuronal nitric oxide synthase (nNOS)	ic50	0.0210	uM
4-[2-[(2-aminoquinolin-7-yl)methylamino]ethyl]-2-chlorobenzonitrile	1458728: Inhibition of recombinant human nNOS expressed in Escherichia coli using L-arginine as substrate after 30 secs by hemoglobin capture assay	ki	0.0210	uM
6-[2-[2,3-difluoro-5-[2-[(2S)-1-methylpyrrolidin-2-yl]ethyl]phenyl]ethyl]-4-methylpyridin-2-amine	1602916: Inhibition of human neuronal NOS expressed in Escherichia coli using L-arginine as substrate in presence of human oxyhemoglobin after 6 mins by hemoglobin NO capture assay	ki	0.0210	uM
4-methyl-6-[3-(methylamino)propyl]pyridin-2-amine	1862037: Inhibition of human nNOS using L-arginine as substrate assessed as reduction in NO production in the presence of NADPH by NO-hemoglobin capture assay	ki	0.0210	uM
6-[2-[2,3-difluoro-5-[2-[(2S)-1-methylazetidin-2-yl]ethyl]phenyl]ethyl]-4-methylpyridin-2-amine	1602916: Inhibition of human neuronal NOS expressed in Escherichia coli using L-arginine as substrate in presence of human oxyhemoglobin after 6 mins by hemoglobin NO capture assay	ki	0.0230	uM
6-[2-[5-[2-(6-amino-4-methyl-2-pyridinyl)ethyl]-3-pyridinyl]ethyl]-4-methylpyridin-2-amine	1799843: Inhibitory Assay from Article 10.1021/bi1013479: “Role of zinc in isoform-selective inhibitor binding to neuronal nitric oxide synthase .”	ki	0.0250	uM
propyl carbamimidothioate	2007165: Inhibition of nNOS in human DLD-1 cells assessed as reduction of L-[14C]arginine to L-[14C]citrulline conversion	ki	0.0290	uM
6-[2-[5-[3-(dimethylamino)propyl]-2,3-difluorophenyl]ethyl]-4-methylpyridin-2-amine	1602916: Inhibition of human neuronal NOS expressed in Escherichia coli using L-arginine as substrate in presence of human oxyhemoglobin after 6 mins by hemoglobin NO capture assay	ki	0.0290	uM
6-[3-(dimethylamino)propyl]-4-methylpyridin-2-amine	1862037: Inhibition of human nNOS using L-arginine as substrate assessed as reduction in NO production in the presence of NADPH by NO-hemoglobin capture assay	ki	0.0290	uM
ethyl carbamimidothioate	404423: Inhibition of nNOS assessed as conversion of L-[3H]arginine to L-[3H]citrulline	ki	0.0290	uM
4-[2-[(2-amino-4-methylquinolin-7-yl)methylamino]ethyl]-2-methylbenzonitrile	1458728: Inhibition of recombinant human nNOS expressed in Escherichia coli using L-arginine as substrate after 30 secs by hemoglobin capture assay	ki	0.0300	uM
6-[2-[3-[3-(dimethylamino)propyl]-5-fluorophenyl]ethyl]-4-methylpyridin-2-amine	1476978: Inhibition of human neuronal NOS expressed in Escherichia coli using L-arginine as substrate assessed as reduction in NO production by measuring oxidation of oxyHb to metHb measured for 6 mins by hemoglobin- NO capture assay	ki	0.0300	uM
N’-[2-[2-(1-methylpyrrolidin-2-yl)ethylamino]-1,3-benzothiazol-5-yl]thiophene-2-carboximidamide	294488: Inhibition of human neuronal NOS activity	ic50	0.0300	uM
3-[(2-amino-4-methylquinolin-7-yl)methoxy]-5-(methylaminomethyl)benzonitrile	1482931: Inhibition of recombinant human full-length nNOS expressed in Escherichia coli BL21(DE3) assessed as reduction in nitric oxide production using L-arginine as substrate measured for 5 mins in presence of calmodulin/10 uM H4B by hemoglobin capture assay	ki	0.0310	uM
7-[3-(aminomethyl)-4-(1,3-thiazol-4-ylmethoxy)phenyl]-4-methylquinolin-2-amine	1548626: Inhibition of human nNOS expressed in Escherichia coli expression system assessed as reduction in NO production in presence of L-arginine measured for 30 sec by hemoglobin capture assay	ki	0.0310	uM
4-[2-[(2-aminoquinolin-7-yl)methylamino]ethyl]benzonitrile	1458728: Inhibition of recombinant human nNOS expressed in Escherichia coli using L-arginine as substrate after 30 secs by hemoglobin capture assay	ki	0.0320	uM
4-methyl-7-[[3-(methylaminomethyl)phenoxy]methyl]quinolin-2-amine	1482931: Inhibition of recombinant human full-length nNOS expressed in Escherichia coli BL21(DE3) assessed as reduction in nitric oxide production using L-arginine as substrate measured for 5 mins in presence of calmodulin/10 uM H4B by hemoglobin capture assay	ki	0.0330	uM
N’-[4-[2-[(3-chlorophenyl)methylamino]ethyl]phenyl]thiophene-2-carboximidamide	225704: Inhibitory concentration against recombinant human (neuronal nitric oxide synthase) n-NOS	ic50	0.0350	uM
N’-[4-[2-[2-(3-chlorophenyl)ethylamino]ethyl]phenyl]thiophene-2-carboximidamide	730389: Inhibition of human nNOS	ic50	0.0350	uM
(4S,4aS,7aS)-4-methyl-4,4a,5,6,7,7a-hexahydro-3H-cyclopenta[b]pyridin-2-amine	241314: Inhibitory activity against human Neuronal nitric oxide synthase (nNOS)	ic50	0.0360	uM
3-[(2-aminoquinolin-7-yl)methoxy]-5-(methylaminomethyl)benzonitrile;dihydrochloride	1482931: Inhibition of recombinant human full-length nNOS expressed in Escherichia coli BL21(DE3) assessed as reduction in nitric oxide production using L-arginine as substrate measured for 5 mins in presence of calmodulin/10 uM H4B by hemoglobin capture assay	ki	0.0360	uM
6-[2-[3-[3-(dimethylamino)propyl]-2,6-difluorophenyl]ethyl]-4-methylpyridin-2-amine	1602916: Inhibition of human neuronal NOS expressed in Escherichia coli using L-arginine as substrate in presence of human oxyhemoglobin after 6 mins by hemoglobin NO capture assay	ki	0.0360	uM
6-[2-[5-[3-(dimethylamino)propyl]-3-pyridinyl]ethyl]-4-methylpyridin-2-amine	1308021: Inhibition of human recombinant nNOS expressed in Escherichia coli using L-arginine as substrate assessed as reduction in NO production measured for 6 mins in presence of tetrahydrobiopterin by hemoglobin capture assay	ki	0.0370	uM
2-[3-(2-carbamimidoylsulfanylethyl)phenyl]ethyl carbamimidothioate	2007165: Inhibition of nNOS in human DLD-1 cells assessed as reduction of L-[14C]arginine to L-[14C]citrulline conversion	ki	0.0370	uM

CTD chemical–gene interactions

59 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, decreases expression, increases expression	4
bisphenol A	affects cotreatment, increases methylation, increases expression	3
entinostat	increases expression, affects cotreatment	2
Pesticides	affects response to substance, decreases methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Silicon Dioxide	decreases expression	2
beta-N-methylamino-L-alanine	increases expression	1
apocarotenal	increases expression	1
propionaldehyde	increases expression	1
palytoxin	increases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
cypermethrin	decreases expression	1
5,5-dimethyl-1-pyrroline-1-oxide	affects cotreatment, increases oxidation	1
sodium sulfite	affects cotreatment, increases oxidation	1
aflatoxin B2	decreases methylation	1
lead chloride	decreases expression	1
N-(4-O-glycerol-3-methoxybenzyl)nonivamide	decreases reaction, increases expression	1
CGP 52608	affects binding, increases reaction	1
goniothalamin	decreases expression	1
7,8-diacetoxy-4-methylcoumarin	increases acetylation, increases reaction	1
2-palmitoylglycerol	increases expression	1
rofecoxib	affects expression	1
KMUP 1	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	1
abrine	increases expression	1
dorsomorphin	decreases expression, affects cotreatment, increases expression	1
3-(4-dimethylaminobenzylidene)-1,3-dihydroindol-2-one	affects binding	1
Bortezomib	decreases reaction, increases expression	1
Resveratrol	increases expression, affects reaction	1
Fulvestrant	affects cotreatment, increases methylation	1

ChEMBL screening assays

238 unique, capped per target: 234 binding, 2 functional, 1 unclassified, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1003684	Binding	Selectivity ratio, EC50 for human iNOS over EC50 for human nNOS	Discovery of inducible nitric oxide synthase (iNOS) inhibitor development candidate KD7332, part 1: Identification of a novel, potent, and selective series of quinolinone iNOS dimerization inhibitors that are orally active in rodent pain models. — *J Med Chem*
CHEMBL4346022	Unclassified	Selectivity index, ratio of Ki for human iNOS expressed in Escherichia coli expression system to Ki for human nNOS expressed in Escherichia coli expression system	First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate. — *J Med Chem*
CHEMBL4810222	ADMET	Inhibition of NOS (unknown origin) at 0.1 to 1 uM	Discovery of Pemigatinib: A Potent and Selective Fibroblast Growth Factor Receptor (FGFR) Inhibitor. — *J Med Chem*

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D1XS	Abcam A-549 NOS1 KO	Cancer cell line	Male
CVCL_D2C2	Abcam HCT 116 NOS1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

16 trials:

NCT	Phase	Status	Title
NCT01560559	Phase 3	COMPLETED	Peroral Endoscopic Myotomy for Primary Esophageal Achalasia
NCT03784365	Phase 3	UNKNOWN	Single-Versus Multiple-dose Antimicrobial Prophylaxis for Peroral Endoscopic Myotomy in Achalasia
NCT06189859	Phase 3	RECRUITING	Electrosurgical Modes for Endoscopic Submucosal Dissection in Peroral Endoscopic Esophageal Myotomy
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02025790	Not specified	UNKNOWN	POEM Versus Pneumatic Dilatation in Achalasia Cardia
NCT03186248	Not specified	COMPLETED	Randomized Clinical Trial Comparing Short Versus Long Oesophageal Myotomy in POEM for Achalasia Cardia.
NCT03438838	Not specified	UNKNOWN	Randomised Trial Between LHM Alone Vs LHM With Anterior Fundoplication In Achalasia Cardia
NCT04951739	Not specified	COMPLETED	To Investigate the Incidence of Reflux in Patients After Per-oral Endoscopic Myotomy in Achalasia Cardia Patients
NCT05729971	Not specified	COMPLETED	Nasogastric Tube After Laparoscopic Heller-Dor Myotomy
NCT06290882	Not specified	ACTIVE_NOT_RECRUITING	Endoscopic Versus Robotic Myotomy for Treatment of Achalasia
NCT07022886	Not specified	ACTIVE_NOT_RECRUITING	INCIDENCE, PREVALENCE AND OVERALL RISK OF ESOPHAGEAL CANCER IN ACHALASIA: A PROPENSITY-MATCHED POPULATION-BASED STUDY FROM A LARGE MULTICENTER DATABASE
NCT07167355	Not specified	NOT_YET_RECRUITING	Comparison of Balloon Dilatation and Per Oral Endoscopic Myotomy in Children With Achalasia Cardia
NCT07177222	Not specified	COMPLETED	Compare the Quality of Life of Patients With Achalasia Cardia (AC) After Laparoscopic and Open Esophagocardiomyotomy.
NCT07399652	Not specified	COMPLETED	Artificial Intelligence-Guided Detection of Blood Vessels to Enhance Safety in Third-Space Endoscopic Procedures
NCT07451301	Not specified	COMPLETED	Serum Anti-enteric Neuronal Antibodies in Patients With Achalasia and Their Association With Clinical Profiles
NCT07620899	Not specified	ACTIVE_NOT_RECRUITING	Biological Optimization Versus Standard Care in Post-POEM Achalasia Patients (BIO-POEM)

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for NOS1 across ~30M SureChEMBL compounds — explore on Sugi Predict.