DDAH1

Summary

DDAH1 (dimethylarginine dimethylaminohydrolase 1, HGNC:2715) is a protein-coding gene on chromosome 1p22.3, encoding N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (O94760). Hydrolyzes N(G),N(G)-dimethyl-L-arginine (ADMA) and N(G)-monomethyl-L-arginine (MMA) which act as inhibitors of NOS.

This gene belongs to the dimethylarginine dimethylaminohydrolase (DDAH) gene family. The encoded enzyme plays a role in nitric oxide generation by regulating cellular concentrations of methylarginines, which in turn inhibit nitric oxide synthase activity.

Source: NCBI Gene 23576 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 42 total
• Druggable target: yes — 5 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_012137

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2715
Approved symbol	DDAH1
Name	dimethylarginine dimethylaminohydrolase 1
Location	1p22.3
Locus type	gene with protein product
Status	Approved
Aliases	DDAH
Ensembl gene	ENSG00000153904
Ensembl biotype	protein_coding
OMIM	604743
Entrez	23576

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000284031, ENST00000426972, ENST00000633113, ENST00000866623, ENST00000866624

RefSeq mRNA: 3 — MANE Select: NM_012137 NM_001134445, NM_001330655, NM_012137

CCDS: CCDS44170, CCDS705, CCDS81348

Canonical transcript exons

ENST00000284031 — 6 exons

Exon	Start	End
ENSE00001013010	85464743	85465159
ENSE00003465385	85318485	85321568
ENSE00003476393	85324740	85324883
ENSE00003485260	85350415	85350534
ENSE00003640702	85351506	85351579
ENSE00003663670	85358748	85358847

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 50.1652 / max 3830.8522, expressed in 1475 samples.

FANTOM5 promoters (28 alternative TSS)

Promoter ID	TPM avg	Samples expressed
13047	17.4351	1441
13035	12.3985	1255
13064	9.8500	867
13067	1.1858	436
13030	1.1625	618
13066	1.0092	374
13068	0.9976	394
13048	0.7616	470
13044	0.6043	275
13072	0.5472	316

Top tissues by expression

303 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.87	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.63	gold quality
CA1 field of hippocampus	UBERON:0003881	99.56	gold quality
nephron tubule	UBERON:0001231	99.53	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.49	gold quality
medial globus pallidus	UBERON:0002477	99.38	gold quality
middle temporal gyrus	UBERON:0002771	99.38	gold quality
choroid plexus epithelium	UBERON:0003911	99.33	gold quality
lateral globus pallidus	UBERON:0002476	99.32	gold quality
ventricular zone	UBERON:0003053	99.31	gold quality
globus pallidus	UBERON:0001875	99.27	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.21	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.15	gold quality
renal medulla	UBERON:0000362	99.11	gold quality
entorhinal cortex	UBERON:0002728	99.06	gold quality
pancreatic ductal cell	CL:0002079	99.05	gold quality
substantia nigra pars compacta	UBERON:0001965	98.83	gold quality
corpus epididymis	UBERON:0004359	98.70	gold quality
parietal lobe	UBERON:0001872	98.64	gold quality
postcentral gyrus	UBERON:0002581	98.61	gold quality
adult organism	UBERON:0007023	98.55	gold quality
orbitofrontal cortex	UBERON:0004167	98.53	gold quality
caput epididymis	UBERON:0004358	98.52	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.52	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.52	gold quality
cranial nerve II	UBERON:0000941	98.45	gold quality
colonic mucosa	UBERON:0000317	98.39	gold quality
ventral tegmental area	UBERON:0002691	98.37	gold quality
superior vestibular nucleus	UBERON:0007227	98.25	gold quality
superior frontal gyrus	UBERON:0002661	98.13	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	18.91
E-GEOD-84465	yes	11.40
E-MTAB-7051	no	5290.94
E-GEOD-109979	no	903.11

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1H4, SREBF2, STAT3

miRNA regulators (miRDB)

161 targeting DDAH1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-219A-5P	99.91	73.36	735

Literature-anchored findings (GeneRIF, showing 40)

• hydrolyzes methylated inhibitors of nitric oxide synthase is present in circulating human red blood cells (PMID:11811522)
• The first evidence of the importance of DDAH1 polymorphisms in pre-eclampsia susceptibility was provided. (PMID:15501905)
• By increasing the synthesis of the proangiogenic factor nitric oxide, DDAH promotes postnatal angiogenesis and arteriogenesis. (PMID:15781754)
• DDAH-1 and DDAH-2 messenger RNA and protein were demonstrated in first trimester placental tissue, primary extravillous trophoblasts and extravillous trophoblast-derived cell lines. (PMID:16920729)
• it is concluded that L-arginine regulates asymmetric dimethylarginine (ADMA) metabolism dose-dependently by competing for DDAH thus maintaining the metabolic balance of L-arginine and ADMA, and endothelial NO homeostasis (PMID:17075694)
• DDAH-1 activity leads to accumulation of asymmetric dimethylarginine and reduction in nitric oxide signaling. (PMID:17273169)
• Demonstrate a critical role for DDAH-1 and endogenous methylarginines in the pathogenesis of endothelial dysfunction. (PMID:17881609)
• human dimethylarginine dimethylaminohydrolase-1 is inhibited by S-nitroso-L-homocysteine and hydrogen peroxide (PMID:17895252)
• maintenance of normoglycemia and not glycemia-independent actions of insulin maintained dimethylarginine tissue levels by preserving physiological DDAH activity. (PMID:18292189)
• Expression of hDDAH1 messenger RNA is found in all organs of DDAH1 transgenic mice investigated, whereas human DDAH1 is absent in wild-type littermates. (PMID:19666120)
• Recent studies in this review suggest that DDAH may regulate endothelial nitric oxide activity and endothelial function through both asymmetric dimethylarginine-dependent and -independent mechanisms. (PMID:19682581)
• Circulating methylarginine levels and the decline in renal function in patients with chronic kidney disease are modulated by DDAH1 polymorphisms. (PMID:20010544)
• Recombinant human DDAH1 overexpression protects transgenic mice from adverse structural and functional changes in cerebral arterioles in hyperhomocysteinemia but not from accelerated carotid artery thrombosis induced by the HM/LF diet. (PMID:20019334)
• Results suggest that the DDAH1 loss-of-function polymorphism is associated with both increased risk of thrombosis stroke and coronary artery disease in the Chinese Han population. (PMID:20167924)
• DDAH1 and DDAH2 polymorphisms are strongly and additively associated with serum ADMA concentrations in individuals with type 2 diabetes (PMID:20209122)
• This protein has been found differentially expressed in the anterior cingulate cortex from patients with schizophrenia (PMID:20381070)
• did not find evidence for association with pre-eclampsia (PMID:21174581)
• DDAH1 exerts a unique role in activating Akt that affects endothelial function independently of degrading endogenous nitirc oxide synthase inhibitors. (PMID:21212404)
• HDL significantly increased the attenuated endothelial cell NO production induced by ox-LDL, which was attributed to its effect on DDAH/ADMA pathway (PMID:21264497)
• Results provide evidence that SNP rs1241321 in DDAH1 is associated with type 2 diabetes and its long-term outcome. (PMID:21303562)
• A significant decrease in asymmetric dimethylarginine levels was found in ex-extremely low birth weight young adults compared to term birth weight young adults. (PMID:21420186)
• Indicate that DDAH1 is required for metabolizing asymmetrical dimethylarginine and N(omega)-monomethyl-L-arginine. (PMID:21493890)
• Data show that DDAH inhibition reduces fibroblast-induced collagen deposition in an ADMA-independent manner and reduces abnormal epithelial proliferation in an ADMA-dependent manner. (PMID:21677199)
• In acute congestive heart failure acute renal impairment function and the modulation of metabolism and extracellular transport by the DDAH-1/CAT-1 system determine high ADMA and SDMA levels after therapy for acute congestive heart failure. (PMID:21722652)
• Non-diabetic hypertensive subjects with a hypertensive response to exercise compared to those with normal response were characterized by augmented asymmetric dimethylarginine and osteoprotegerin levels. (PMID:21975354)
• High DDAH1 is associated with pediatric diffuse intrinsic pontine glioma. (PMID:22492959)
• Genetic polymorphisms in DDAH genes influence serum ADMA levels in individuals with T1 diabetes mellitus. (PMID:22521321)
• DDAH1 gene DNA methylation is impoetant in the pathogenesis of idiopathic pulmonary fibrosis. (PMID:22700861)
• Data suggest that estradiol alone has no effect on DDAH/asymmetric dimethylarginine/nitric oxide pathway in arterial endothelium, but rather counters oxidized LDL; estradiol restores DDAH activity and prevents loss of eNOS (nitric oxide synthase 3). (PMID:22982060)
• Elevated asymmetric dimethylaginine is not a part of the proatherogenic risk profile in the young adult offspring of patients with premature Coronary artery disease. (PMID:23022711)
• the advanced glycation end products-receptor for advanced glycation end products-mediated reactive oxygen species generation could be involved in endothelial dysfunction in diabetic end-stage renal disease patients (PMID:23766377)
• Only the DDAH1-V1 transcript is responsible for ADMA metabolism, and transcript specific primers are recommended to determine DDAH1 mRNA expression. (PMID:23864585)
• DDAH1 genotypes were closely related to asymmetric dimethylarginine levels, but not to measures of endothelium-dependent vasodilation in an elderly population. (PMID:23892448)
• DDAH1 deficiency attenuates endothelial cell cycle progression and angiogenesis. (PMID:24260221)
• increased ADMA levels in rheumatoid arthritis do not appear to relate to DDAH genetic polymorphisms (PMID:25194333)
• Genebased analyses revealed associations of the DDAH1 gene with longitudinal Blood Pressure phenotypes, associations with essential hypertension, Blood Pressure salt sensitivity, preeclampsia, or preclinical stages of atherosclerosis. (PMID:25424718)
• Inhibiting the expression of DDAH1, but not DDAH2, resulted in a significant increase in the sensitivity of the EVT cell line SGHPL-4 to tumour necrosis factor related apoptosis inducing ligand (TRAIL) induced apoptosis (PMID:26082478)
• FoxO1 regulates asymmetric dimethylarginine via downregulation of dimethylaminohydrolase 1 in HUVECs and subjects with carotid atherosclerosis. (PMID:26226438)
• results suggest that miR-21 may regulate renal fibrosis by the Wnt pathway via directly targeting DDAH1 (PMID:26455824)
• The most significant associations were detected for PECAM1*V/V + DDAH1*C (OR = 4.17 CI 1.56-11.15 Pperm = 0.005) (PMID:26662939)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ddah1	ENSDARG00000103042
mus_musculus	Ddah1	ENSMUSG00000028194
rattus_norvegicus	Ddah1	ENSRNOG00000014613
drosophila_melanogaster	CG1764	FBGN0030467
caenorhabditis_elegans		WBGENE00009549
caenorhabditis_elegans		WBGENE00020672

Paralogs (1): DDAH2 (ENSG00000213722)

Protein

Protein identifiers

N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 — O94760 (reviewed: O94760)

Alternative names: DDAHI, Dimethylargininase-1

All UniProt accessions (3): O94760, B2R644, B4DYP1

UniProt curated annotations — full annotation on UniProt →

Function. Hydrolyzes N(G),N(G)-dimethyl-L-arginine (ADMA) and N(G)-monomethyl-L-arginine (MMA) which act as inhibitors of NOS. Has therefore a role in the regulation of nitric oxide generation.

Subunit / interactions. Monomer.

Tissue specificity. Detected in brain, liver, kidney and pancreas, and at low levels in skeletal muscle.

Activity regulation. Inhibited by zinc ions. Enzyme purified in the absence of 1,10-phenanthroline contains on average 0.4 zinc atoms per subunit. Inhibited by 4-hydroxy-nonenal through the formation of a covalent adduct with His-173. Competitively inhibited by N(5)-iminopropyl-ornithine.

Similarity. Belongs to the DDAH family.

Isoforms (2)

UniProt ID	Names	Canonical?
O94760-1	1	yes
O94760-2	2

RefSeq proteins (3): NP_001127917, NP_001317584, NP_036269* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR033199	DDAH-like	Family

Pfam: PF19420

Enzyme classification (BRENDA):

• EC 3.5.3.18 — dimethylargininase (BRENDA: 12 organisms, 49 substrates, 190 inhibitors, 31 Km, 21 kcat entries)

Substrate kinetics (BRENDA)

14 substrates with measured Km, best-characterized 14. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
NG,NG-DIMETHYL-L-ARGININE	0.039–9.24	6
S-METHYL-L-THIOCITRULLINE	0.0014–0.143	6
NOMEGA,NOMEGA-DIMETHYL-L-ARGININE	0.11–13.7	4
NG-METHYL-L-ARGININE	0.044–0.67	3
NG-MONOMETHYL-L-ARGININE	0.36–1.6	3
ASYMMETRIC NOMEGA,NOMEGA-DIMETHYL-L-ARGININE	0.039	1
DIMETHYL-L-ARGININE	0.18	1
N,N-DIMETHYL-L-ARGININE	0.133	1
N5-(METHOXYCARBAMIMIDOYL)-L-ORNITHINE	0.13	1
N5-(METHYLCARBAMIMIDOYL)-L-ORNITHINE	0.106	1
N5-[2,5-DIHYDRO-1H-PYRROL-1-YL(IMINO)METHYL]-L-O	0.161	1
NG,NG-DIMETHYL-L-HOMOARGININE	33	1
NG-AMINO-L-ARGININE	1.11	1
NG-HYDROXY-L-ARGININE	2.3	1

Catalyzed reactions (Rhea), 2 shown:

• N(omega),N(omega)-dimethyl-L-arginine + H2O = dimethylamine + L-citrulline (RHEA:17305)
• N(omega)-methyl-L-arginine + H2O = L-citrulline + methylamine (RHEA:25173)

UniProt features (53 total): strand 16, helix 14, binding site 7, turn 5, modified residue 3, mutagenesis site 3, active site 2, initiator methionine 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
7USZ	X-RAY DIFFRACTION	1.65
7UT0	X-RAY DIFFRACTION	1.68
7ULX	X-RAY DIFFRACTION	1.71
6SZP	X-RAY DIFFRACTION	1.76
3I4A	X-RAY DIFFRACTION	1.9
6DGE	X-RAY DIFFRACTION	1.91
2JAJ	X-RAY DIFFRACTION	2
3I2E	X-RAY DIFFRACTION	2.03
7ULU	X-RAY DIFFRACTION	2.2
2JAI	X-RAY DIFFRACTION	2.3
7ULV	X-RAY DIFFRACTION	2.37
6SZQ	X-RAY DIFFRACTION	2.41
3P8E	X-RAY DIFFRACTION	2.49
3P8P	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94760-F1	95.94	0.94

Functional residue map

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

Catalytic / active sites (2): 173 (proton donor); 274 (nucleophile)

Ligand- & substrate-binding residues (7): 274; 30; 73; 78–79; 98; 145; 268

Post-translational modifications (3): 2, 222, 274

Mutagenesis-validated functional residues (3):

Position	Phenotype
30	reduces enzyme activity and affinity for asymmetric dimethylarginine about 12-fold.
78	reduces enzyme activity about 1000-fold, and affinity for asymmetric dimethylarginine about 100-fold.
271	reduces enzyme activity about 10-fold, and affinity for asymmetric dimethylarginine about 7-fold.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-203615	eNOS activation

MSigDB gene sets: 218 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, BENPORATH_ES_WITH_H3K27ME3, MYOGENIN_Q6, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, BROWNE_HCMV_INFECTION_8HR_UP, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, AREB6_03, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_METABOLIC_PROCESS, CHEN_LVAD_SUPPORT_OF_FAILING_HEART_UP

GO Biological Process (11): obsolete citrulline metabolic process (GO:0000052), regulation of systemic arterial blood pressure (GO:0003073), arginine metabolic process (GO:0006525), L-arginine catabolic process (GO:0006527), obsolete nitric oxide mediated signal transduction (GO:0007263), negative regulation of cell population proliferation (GO:0008285), negative regulation of vascular permeability (GO:0043116), positive regulation of nitric oxide biosynthetic process (GO:0045429), positive regulation of angiogenesis (GO:0045766), nitric oxide metabolic process (GO:0046209), negative regulation of cellular response to hypoxia (GO:1900038)

GO Molecular Function (5): catalytic activity (GO:0003824), dimethylargininase activity (GO:0016403), amino acid binding (GO:0016597), metal ion binding (GO:0046872), hydrolase activity (GO:0016787)

GO Cellular Component (2): cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of nitric oxide: NOS3 activation and regulation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of cellular process	2
regulation of blood pressure	1
amino acid metabolic process	1
carboxylic acid metabolic process	1
arginine metabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
cell population proliferation	1
regulation of cell population proliferation	1
regulation of vascular permeability	1
nitric oxide biosynthetic process	1
positive regulation of biosynthetic process	1
regulation of nitric oxide biosynthetic process	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
reactive nitrogen species metabolic process	1
negative regulation of response to stimulus	1
cellular response to hypoxia	1
regulation of cellular response to hypoxia	1
molecular_function	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amidines	1
binding	1
cation binding	1
catalytic activity	1
cytoplasm	1
cellular anatomical structure	1
extracellular vesicle	1

Protein interactions and networks

STRING

1064 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DDAH1	NOS3	P29474	865
DDAH1	AGXT2	Q9BYV1	846
DDAH1	PRMT1	Q99873	690
DDAH1	NOS1	P29475	607
DDAH1	ARG2	P78540	547
DDAH1	NF1	P21359	506
DDAH1	ZNF225	Q9UK10	480
DDAH1	ATP12A	P54707	461
DDAH1	ATP4A	P20648	458
DDAH1	UBE2J1	Q9Y385	453
DDAH1	EGR1	P18146	452
DDAH1	PRMT2	P55345	449
DDAH1	FGFBP3	Q8TAT2	444
DDAH1	TP73	O15350	443
DDAH1	ARG1	P05089	435

IntAct

29 interactions, top by confidence:

A	B	Type	Score
NME2	NME4	psi-mi:“MI:0914”(association)	0.660
PSMD10	CLIC1	psi-mi:“MI:0914”(association)	0.650
SDHAF3	NDUFAB1	psi-mi:“MI:0914”(association)	0.640
LYRM4	NDUFAB1	psi-mi:“MI:0914”(association)	0.640
FSD1	UBFD1	psi-mi:“MI:0914”(association)	0.530
DDAH2	OGT	psi-mi:“MI:0914”(association)	0.530
APOOL	MTX2	psi-mi:“MI:0914”(association)	0.530
PSMD10	DDAH1	psi-mi:“MI:0914”(association)	0.460
	FER1L5	psi-mi:“MI:0915”(physical association)	0.400
DDAH1	EPB41L2	psi-mi:“MI:0915”(physical association)	0.400
CD69	DDAH1	psi-mi:“MI:0915”(physical association)	0.400
RETREG1	DDAH1	psi-mi:“MI:0915”(physical association)	0.370
APBB1	SSPOP	psi-mi:“MI:0914”(association)	0.350
FGB	NME2	psi-mi:“MI:0914”(association)	0.350
ATP5F1A	ACOT7	psi-mi:“MI:0914”(association)	0.350
BOLA3	NDUFAB1	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350
IQCB1	PCP4L1	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
STING1	SMCHD1	psi-mi:“MI:0914”(association)	0.350
NDFIP2	DDAH1	psi-mi:“MI:0914”(association)	0.350
AFTPH	DDAH1	psi-mi:“MI:0914”(association)	0.350
MRPL49	UBA6	psi-mi:“MI:0914”(association)	0.350
DDAH1	der	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (52): DDAH1 (Affinity Capture-Western), DDAH1 (Affinity Capture-RNA), DDAH1 (Affinity Capture-RNA), DDAH1 (Affinity Capture-MS), DDAH1 (Affinity Capture-MS), DDAH1 (Affinity Capture-MS), DDAH1 (Affinity Capture-MS), DDAH1 (Affinity Capture-MS), DDAH1 (Affinity Capture-MS), DDAH1 (Affinity Capture-MS), DDAH1 (Affinity Capture-MS), DDAH1 (Affinity Capture-MS), DDAH1 (Affinity Capture-RNA), DDAH1 (Proximity Label-MS), DDAH1 (Co-fractionation)

ESM2 similar proteins: A1L1L6, B1H369, D3ZVR9, O00764, O08557, O35331, O35621, O46560, O94760, P50053, P56965, P81799, P82197, P97328, Q02974, Q0II59, Q15124, Q15126, Q2HJF8, Q3SZM9, Q3U129, Q3UFY7, Q4R4U1, Q5E982, Q5I0K3, Q5R5F8, Q5RD71, Q5ZKF6, Q5ZM73, Q5ZM83, Q6AYP7, Q6GV29, Q8BG51, Q8BZF8, Q8IXI2, Q8K183, Q8N0X4, Q8NHP1, Q8R4N0, Q923S8

Diamond homologs: O08557, O94760, O95865, P56965, Q3SX44, Q6MG60, Q99LD8, Q9CWS0, Q9I4E3, Q9X7M4, Q9Y8N2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	33
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1606 predictions. Top by Δscore:

Variant	Effect	Δscore
1:85321564:TAAAC:T	acceptor_gain	1.0000
1:85321565:AAAC:A	acceptor_gain	1.0000
1:85321566:AAC:A	acceptor_gain	1.0000
1:85321569:C:CC	acceptor_gain	1.0000
1:85321569:CTACA:C	acceptor_loss	1.0000
1:85321582:C:CT	acceptor_gain	1.0000
1:85321583:A:T	acceptor_gain	1.0000
1:85324735:TTTA:T	donor_loss	1.0000
1:85324737:TA:T	donor_loss	1.0000
1:85324739:CCTTT:C	donor_gain	1.0000
1:85324741:TTTGC:T	donor_gain	1.0000
1:85324879:ATGAT:A	acceptor_gain	1.0000
1:85324880:TGAT:T	acceptor_gain	1.0000
1:85324881:GAT:G	acceptor_gain	1.0000
1:85324882:AT:A	acceptor_gain	1.0000
1:85324884:C:CC	acceptor_gain	1.0000
1:85324885:T:C	acceptor_loss	1.0000
1:85350410:TTTA:T	donor_loss	1.0000
1:85350411:TTACC:T	donor_loss	1.0000
1:85350412:TA:T	donor_loss	1.0000
1:85350413:ACC:A	donor_loss	1.0000
1:85350418:AAGGG:A	donor_gain	1.0000
1:85350538:C:CT	acceptor_gain	1.0000
1:85350539:G:C	acceptor_gain	1.0000
1:85358744:ATAC:A	donor_loss	1.0000
1:85358745:TAC:T	donor_loss	1.0000
1:85358843:TCAAC:T	acceptor_gain	1.0000
1:85358844:CAAC:C	acceptor_gain	1.0000
1:85358844:CAACC:C	acceptor_gain	1.0000
1:85358845:AAC:A	acceptor_gain	1.0000

AlphaMissense

1871 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:85324815:A:C	C222W	0.999
1:85350446:C:T	G189E	0.999
1:85350447:C:A	G189W	0.999
1:85350524:A:T	V163D	0.999
1:85351546:G:A	T146I	0.999
1:85464783:G:T	A88D	0.999
1:85464810:T:A	D79V	0.999
1:85350475:G:C	S179R	0.998
1:85350475:G:T	S179R	0.998
1:85350477:T:G	S179R	0.998
1:85350480:A:G	C178R	0.998
1:85350491:A:G	L174S	0.998
1:85351509:A:C	F158L	0.998
1:85351509:A:T	F158L	0.998
1:85351510:A:G	F158S	0.998
1:85351511:A:G	F158L	0.998
1:85351534:C:T	G150D	0.998
1:85351561:C:T	G141D	0.998
1:85358759:A:T	V131D	0.998
1:85358762:T:A	D130V	0.998
1:85358763:C:G	D130H	0.998
1:85464780:A:G	L89P	0.998
1:85464804:G:T	A81D	0.998
1:85464810:T:G	D79A	0.998
1:85324746:A:C	S245R	0.997
1:85324746:A:T	S245R	0.997
1:85324748:T:G	S245R	0.997
1:85324780:A:G	L234S	0.997
1:85324846:A:G	L212P	0.997
1:85350447:C:G	G189R	0.997

dbSNP variants (sampled 300 via entrez): RS1000001960 (1:85333101 G>A), RS1000033910 (1:85350792 G>A), RS1000043425 (1:85382290 GC>G), RS1000054995 (1:85379746 C>A,T), RS1000057057 (1:85551394 G>A), RS1000060281 (1:85473461 A>G), RS1000062852 (1:85341568 C>A), RS1000066701 (1:85491296 A>C,G), RS1000105834 (1:85389659 C>T), RS1000111865 (1:85432447 T>G), RS1000141852 (1:85476046 A>T), RS1000146947 (1:85385450 A>G), RS1000167068 (1:85419517 A>G,T), RS1000177695 (1:85372946 T>C,G), RS1000234693 (1:85396370 T>C)

Disease associations

OMIM: gene MIM:604743 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST001198_16	Multiple sclerosis	1.000000e-06
GCST002239_14	Symmetrical dimethylarginine levels	1.000000e-18
GCST002241_13	Asymmetrical dimethylarginine levels	1.000000e-40
GCST002242_20	Serum dimethylarginine levels (asymmetric/symetric ratio)	1.000000e-20
GCST002620_1	Asymmetrical dimethylarginine levels	4.000000e-31
GCST004703_2	Obsessive-compulsive disorder or autism spectrum disorder	2.000000e-06
GCST005531_28	Multiple sclerosis	4.000000e-09
GCST006629_50	Pulse pressure	1.000000e-09
GCST008839_161	Height	2.000000e-11
GCST009733_217	Urinary metabolite levels in chronic kidney disease	6.000000e-16
GCST009733_78	Urinary metabolite levels in chronic kidney disease	2.000000e-32
GCST010146_5	Serum immune biomarker levels	5.000000e-10
GCST90020029_1256	Waist circumference adjusted for body mass index	4.000000e-08

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0006522	asymmetrical dimethylarginine measurement
EFO:0005763	pulse pressure measurement
EFO:0005116	urinary metabolite measurement
EFO:0004869	YKL40 measurement
EFO:0004872	inflammatory biomarker measurement
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6036 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

5 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 105,978 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1219	RABEPRAZOLE	4	12,441
CHEMBL1502	PANTOPRAZOLE	4	14,689
CHEMBL1503	OMEPRAZOLE	4	52,284
CHEMBL480	LANSOPRAZOLE	4	24,317
CHEMBL1475252	TENATOPRAZOLE	2	2,247

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Dimethylarginine dimethylaminohydrolases

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 2e [PMID: 19013076]	Inhibition	5.7	pKi

Binding affinities (BindingDB)

19 measured of 38 human assays (42 total across all organisms); most potent 19 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-(4,6-dimethyl-3-oxo-[1,2]thiazolo[5,4-b]pyridin-2-yl)-N-(2-methoxyethyl)acetamide	IC50	3300 nM	US-9011882: Dimethylarginine dimethylaminohydrolase inhibitors and methods of use thereof
N-butyl-2-(4,6-dimethyl-3-oxo-[1,2]thiazolo[5,4-b]pyridin-2-yl)acetamide	IC50	5100 nM	US-9011882: Dimethylarginine dimethylaminohydrolase inhibitors and methods of use thereof
2-(4,6-dimethyl-3-oxo-[1,2]thiazolo[5,4-b]pyridin-2-yl)-N-(3-ethoxypropyl)acetamide	IC50	7100 nM	US-9011882: Dimethylarginine dimethylaminohydrolase inhibitors and methods of use thereof
N-(2,3-dimethylcyclohexyl)-2-(4,6-dimethyl-3-oxo-[1,2]thiazolo[5,4-b]pyridin-2-yl)acetamide	IC50	8600 nM	US-9011882: Dimethylarginine dimethylaminohydrolase inhibitors and methods of use thereof
1,3-benzothiazol-2-yl(methyl)phosphinic acid	IC50	9900 nM	US-9011882: Dimethylarginine dimethylaminohydrolase inhibitors and methods of use thereof
2-(4,6-dimethyl-3-oxo-[1,2]thiazolo[5,4-b]pyridin-2-yl)-N-[2-(4-ethoxyphenyl)ethyl]acetamide	IC50	10500 nM	US-9011882: Dimethylarginine dimethylaminohydrolase inhibitors and methods of use thereof
N-(1,3-benzodioxol-5-ylmethyl)-2-(4,6-dimethyl-3-oxo-[1,2]thiazolo[5,4-b]pyridin-2-yl)acetamide	IC50	11000 nM	US-9011882: Dimethylarginine dimethylaminohydrolase inhibitors and methods of use thereof
N-[2-(cyclohexen-1-yl)ethyl]-2-(4,6-dimethyl-3-oxo-[1,2]thiazolo[5,4-b]pyridin-2-yl)acetamide	IC50	11800 nM	US-9011882: Dimethylarginine dimethylaminohydrolase inhibitors and methods of use thereof
N-(3-cyclohexylsulfanylpropyl)-2-(4,6-dimethyl-3-oxo-[1,2]thiazolo[5,4-b]pyridin-2-yl)acetamide	IC50	12800 nM	US-9011882: Dimethylarginine dimethylaminohydrolase inhibitors and methods of use thereof
3-(azepan-1-yl)-1-naphthalen-1-ylpyrrolidine-2,5-dione	IC50	13100 nM	US-9011882: Dimethylarginine dimethylaminohydrolase inhibitors and methods of use thereof
N-[2-(4-chlorophenyl)ethyl]-2-(4,6-dimethyl-3-oxo-[1,2]thiazolo[5,4-b]pyridin-2-yl)acetamide	IC50	13400 nM	US-9011882: Dimethylarginine dimethylaminohydrolase inhibitors and methods of use thereof
2-(4,6-dimethyl-3-oxo-[1,2]thiazolo[5,4-b]pyridin-2-yl)-N-(1-phenylethyl)acetamide	IC50	13700 nM	US-9011882: Dimethylarginine dimethylaminohydrolase inhibitors and methods of use thereof
2-(4,6-dimethyl-3-oxo-[1,2]thiazolo[5,4-b]pyridin-2-yl)-N-(4-phenylbutan-2-yl)acetamide	IC50	14100 nM	US-9011882: Dimethylarginine dimethylaminohydrolase inhibitors and methods of use thereof
US9011882, Table 1, Compound 5	IC50	17700 nM	US-9011882: Dimethylarginine dimethylaminohydrolase inhibitors and methods of use thereof
2-(4-aminobutyl)-1-(2-methoxyethyl)guanidine	KI	18000 nM	US-8921421: Inhibitors of dimethylarginine dimethylaminohydrolase
(E)-N’-(4-methylphenyl)but-2-enediamide	IC50	21200 nM	US-9011882: Dimethylarginine dimethylaminohydrolase inhibitors and methods of use thereof
4-(2,5-dioxopyrrol-1-yl)benzoic acid	IC50	23300 nM	US-9011882: Dimethylarginine dimethylaminohydrolase inhibitors and methods of use thereof
N-[(2-chlorophenyl)methyl]-2-(4,6-dimethyl-3-oxo-[1,2]thiazolo[5,4-b]pyridin-2-yl)acetamide	IC50	39900 nM	US-9011882: Dimethylarginine dimethylaminohydrolase inhibitors and methods of use thereof
3-[5-(4-methylphenyl)furan-2-yl]propanoic acid	IC50	45800 nM	US-9011882: Dimethylarginine dimethylaminohydrolase inhibitors and methods of use thereof

ChEMBL bioactivities

31 potent at pChembl≥5 of 110 total, top 20 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.72	Ki	190	nM	CHEMBL5423612
6.00	Ki	1000	nM	CHEMBL4444007
5.89	Ki	1300	nM	CHEMBL4461206
5.70	Ki	2000	nM	CHEMBL106820
5.52	IC50	3000	nM	CHEMBL4444007
5.48	IC50	3300	nM	CHEMBL3677847
5.29	IC50	5100	nM	CHEMBL2070857
5.26	IC50	5500	nM	CHEMBL3960681
5.16	Ki	7000	nM	CHEMBL5437726
5.15	IC50	7100	nM	CHEMBL3677841
5.12	Ki	7500	nM	CHEMBL1234051
5.11	IC50	7800	nM	TENATOPRAZOLE
5.07	IC50	8600	nM	CHEMBL3677839
5.06	IC50	8714	nM	CHEMBL595227
5.05	Ki	9000	nM	CHEMBL4449638
5.05	IC50	9000	nM	CHEMBL595227
5.05	Ki	9000	nM	CHEMBL5427675
5.04	IC50	9030	nM	CHEMBL3923351
5.00	IC50	9900	nM	CHEMBL3677835
5.00	IC50	9900	nM	CHEMBL1510394

PubChem BioAssay actives

17 with measured affinity, of 181 total; 9 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
(2S)-2-amino-6-[(1-amino-2-chloroethylidene)amino]hexanoic acid	2007214: Inhibition of N-terminal His6-tagged human DDAH1 expressed in Escherichia coli BL21 DE3 cells using L-Nva as substrate assessed as L-citrulline formation measured after 45 mins by colder assay	ki	0.1900	uM
(2S)-2-amino-5-[[amino-(2-methoxyethylamino)methylidene]amino]-N-methylsulfonylpentanamide	1581785: Inhibition of 6xHis-tagged recombinant human DDAH1 expressed in Escherichia coli BL21 cells using NMMA as substrate measured after 30 mins by colder reagent based microplate reader assay	ki	1.0000	uM
(2S)-2-amino-5-[(1-amino-2-chloroethylidene)amino]pentanoic acid	1581785: Inhibition of 6xHis-tagged recombinant human DDAH1 expressed in Escherichia coli BL21 cells using NMMA as substrate measured after 30 mins by colder reagent based microplate reader assay	ki	1.3000	uM
(2S)-2-amino-5-(1-aminobut-3-enylideneamino)pentanoic acid	1581785: Inhibition of 6xHis-tagged recombinant human DDAH1 expressed in Escherichia coli BL21 cells using NMMA as substrate measured after 30 mins by colder reagent based microplate reader assay	ki	2.0000	uM
2-[(4S)-4-amino-4-(5-oxo-4H-1,2,4-oxadiazol-3-yl)butyl]-1-(2-methoxyethyl)guanidine	2007209: Inhibition of recombinant human DDAH1 expressed in HEK293 cells using ADMA as substrate assessed as inhibition constant preincubated for 5 mins	ki	7.0000	uM
(2S)-2-amino-5-(1-aminopentylideneamino)pentanoic acid	1799854: Inhibition Assay from Article 10.1021/bi9007098: “Developing dual and specific inhibitors of dimethylarginine dimethylaminohydrolase-1 and nitric oxide synthase: toward a targeted polypharmacology to control nitric oxide.”	ki	7.5000	uM
3-amino-6-tert-butyl-N-(1,3-thiazol-2-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide	2007221: Inhibition of His-tagged human DDAH1 using SMTC as substrate assessed as inhibition constant	ki	9.0000	uM
(2S)-2-amino-5-[(1-amino-3-methoxypropylidene)amino]pentanoic acid	1581785: Inhibition of 6xHis-tagged recombinant human DDAH1 expressed in Escherichia coli BL21 cells using NMMA as substrate measured after 30 mins by colder reagent based microplate reader assay	ki	9.0000	uM
3,4-dihydro-2H-pyrimido[1,2-c][1,3]benzothiazin-6-imine	2007220: Inhibition of human DDAH1 using SMTC as substrate by fluorimetric assay	ic50	9.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	4
bisphenol A	increases methylation, decreases expression, increases expression	3
sodium arsenite	affects methylation, decreases expression, increases expression	3
Estradiol	affects expression, affects cotreatment, increases expression, decreases expression	3
Formaldehyde	decreases expression	3
Particulate Matter	increases expression, decreases expression, affects cotreatment, increases abundance	3
methylmercuric chloride	increases expression	2
trichostatin A	affects cotreatment, decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, decreases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Smoke	decreases expression, increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Tretinoin	decreases expression, increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
sodium arsenate	decreases expression	1
cobaltous chloride	decreases expression	1
zinc chromate	increases abundance, decreases expression	1
hydroquinone	decreases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
perfluorooctane sulfonic acid	decreases expression	1
ICG 001	decreases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
bisphenol S	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Temozolomide	increases expression	1
Zoledronic Acid	decreases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	1

ChEMBL screening assays

92 unique, capped per target: 92 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1020493	Binding	Inhibition of human DDAH1 at 1 mM by HPLC	Structure-activity relationship of novel and known inhibitors of human dimethylarginine dimethylaminohydrolase-1: alkenyl-amidines as new leads. — Bioorg Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1C0	Abcam A-431 DDAH1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.