AHCY

Summary

AHCY (adenosylhomocysteinase, HGNC:343) is a protein-coding gene on chromosome 20q11.22, encoding Adenosylhomocysteinase (P23526). Catalyzes the hydrolysis of S-adenosyl-L-homocysteine to form adenosine and homocysteine. It is a selective cancer dependency (DepMap: 83.2% of cell lines).

S-adenosylhomocysteine hydrolase belongs to the adenosylhomocysteinase family. It catalyzes the reversible hydrolysis of S-adenosylhomocysteine (AdoHcy) to adenosine (Ado) and L-homocysteine (Hcy). Thus, it regulates the intracellular S-adenosylhomocysteine (SAH) concentration thought to be important for transmethylation reactions. Deficiency in this protein is one of the different causes of hypermethioninemia. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 191 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase (Definitive, ClinGen)
• GWAS associations: 9
• Clinical variants (ClinVar): 385 total — 6 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 56
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 83.2% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000687

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:343
Approved symbol	AHCY
Name	adenosylhomocysteinase
Location	20q11.22
Locus type	gene with protein product
Status	Approved
Aliases	SAHH, AdoHcyase
Ensembl gene	ENSG00000101444
Ensembl biotype	protein_coding
OMIM	180960
Entrez	191

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 2 protein_coding, 2 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000217426, ENST00000468908, ENST00000473516, ENST00000480653, ENST00000538132, ENST00000606061

RefSeq mRNA: 6 — MANE Select: NM_000687 NM_000687, NM_001161766, NM_001322084, NM_001322085, NM_001322086, NM_001362750

CCDS: CCDS13233, CCDS54457

Canonical transcript exons

ENST00000217426 — 10 exons

Exon	Start	End
ENSE00000661386	34290551	34290638
ENSE00001048932	34290332	34290449
ENSE00001152081	34303243	34303355
ENSE00001820276	34280268	34281165
ENSE00003483013	34294081	34294156
ENSE00003638433	34290731	34290938
ENSE00003640815	34295395	34295585
ENSE00003663748	34285440	34285634
ENSE00003680454	34291419	34291531
ENSE00003682179	34292358	34292507

Expression profiles

Bgee: expression breadth ubiquitous, 145 present calls, max score 98.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 122.3440 / max 1199.1351, expressed in 1819 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
186986	120.9405	1819
186985	1.1867	748
186984	0.2167	91

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	98.22	gold quality
body of pancreas	UBERON:0001150	98.06	gold quality
right lobe of liver	UBERON:0001114	97.83	gold quality
right testis	UBERON:0004534	97.69	gold quality
left ovary	UBERON:0002119	97.58	gold quality
left testis	UBERON:0004533	97.54	gold quality
esophagus mucosa	UBERON:0002469	97.52	gold quality
ovary	UBERON:0000992	97.37	gold quality
right ovary	UBERON:0002118	97.28	gold quality
pancreas	UBERON:0001264	97.15	gold quality
adult mammalian kidney	UBERON:0000082	97.10	gold quality
liver	UBERON:0002107	96.96	gold quality
testis	UBERON:0000473	96.69	gold quality
mucosa of transverse colon	UBERON:0004991	96.67	gold quality
prostate gland	UBERON:0002367	96.58	gold quality
fallopian tube	UBERON:0003889	96.51	gold quality
ventricular zone	UBERON:0003053	96.34	gold quality
duodenum	UBERON:0002114	96.27	gold quality
body of stomach	UBERON:0001161	96.22	gold quality
gastrocnemius	UBERON:0001388	96.17	gold quality
right lobe of thyroid gland	UBERON:0001119	96.12	gold quality
right uterine tube	UBERON:0001302	96.03	gold quality
islet of Langerhans	UBERON:0000006	95.88	gold quality
left lobe of thyroid gland	UBERON:0001120	95.84	gold quality
endocervix	UBERON:0000458	95.83	gold quality
esophagus	UBERON:0001043	95.83	gold quality
thyroid gland	UBERON:0002046	95.82	gold quality
kidney	UBERON:0002113	95.82	gold quality
fundus of stomach	UBERON:0001160	95.81	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	95.77	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	68.57
E-GEOD-125970	yes	21.52
E-MTAB-10042	yes	14.58
E-CURD-112	yes	8.56
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

31 targeting AHCY, 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-4673	100.00	66.64	1490
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-9851-3P	99.63	69.68	1110
HSA-MIR-593-5P	99.34	69.50	965
HSA-MIR-3160-5P	99.28	69.07	1938
HSA-MIR-4796-3P	99.08	68.38	1681
HSA-MIR-1207-3P	98.99	66.22	1532
HSA-MIR-3926	98.95	69.26	1438
HSA-MIR-6760-5P	98.87	66.73	1515
HSA-MIR-29B-1-5P	98.86	68.35	1364
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-758-3P	98.42	68.60	1122
HSA-MIR-6773-3P	98.17	65.51	1213
HSA-MIR-211-3P	98.14	66.77	1052
HSA-MIR-3664-3P	97.85	67.62	1452
HSA-MIR-3085-5P	97.72	65.43	544
HSA-MIR-6886-3P	96.96	66.36	844
HSA-MIR-1295B-3P	96.68	66.11	276
HSA-MIR-3162-5P	95.67	67.53	794
HSA-MIR-4513	95.04	67.06	727
HSA-MIR-6855-3P	95.04	66.57	725
HSA-MIR-3914	94.91	65.77	643
HSA-MIR-5704	94.82	67.46	448

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 83.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 38)

• Five active site residues (E156, N181, K186, D190, N191) of AdoHcy hydrolase have been individually mutated to alanine and each engineered enzyme characterized with respect to its redox partial reaction and elimination/addition partial reaction. (PMID:12069606)
• a discussion of its hydrolytic activity (review) (PMID:12369977)
• Maintenance of ionizable active-site residues in catalytically suitable protonation states in closed forms of placental AHCY may be assisted by a water chain, stabilized by Asp182, that can import and export protons from and to the environment. (PMID:12590576)
• AdoHcy is involved in adenosine-induced apoptosis by altering gene expression. (PMID:17097637)
• R38W and G123R amino-acid exchanges did not bring about major changes to the catalytic rates. However, circular dichroism analysis showed that both polymorphisms effect the thermal stability. (PMID:17164794)
• SAHH, which is diffuse in the cytoplasm of nonmotile Dictyostelium amoebae and human neutrophils, concentrates with F-actin in pseudopods at the front of motile, chemotaxing cells (PMID:17172447)
• In the case of Hs-SAHH, the slow-binding phase terminates in micromolar affinity, but over a period of hours, the dissociation rate constant decreases until the final equilibrium affinity is in the nanomolar range. (PMID:17447732)
• We found clinically relevant levels of Hcy (0-500 microM) induced elevation of SAH, declination of SAM and SAM/SAH ratio and reduced expression of SAHH and MBD2, but increased activity of DNMT3a and DNMT3b affecting DNA methylation (PMID:17688412)
• The mechanism of action of copper on this enzyme sugges a regulative role for copper on the intracellular activity. (PMID:17892301)
• consider changes in charge and the sterical incompatibility in mutant p.A89V protein as main reason for enzyme malfunction with AdoHcyase deficiency as consequence (PMID:18211827)
• SAHH from Homo sapiens (Hs-SAHH) and from the parasite Trypanosoma cruzi (Tc-SAHH) are very similar in structure and catalytic properties but differ in the kinetics and thermodynamics of association and dissociation of the cofactor NAD (+) (PMID:18393535)
• Streptococcal pyrogenic exotoxin B (SPE B) potentially causes immunosuppression by cleaving human S-adenosylhomocysteine hydrolase (AdoHcyase). (PMID:18522500)
• increased plasma concentration in patients with idiopathic thrombocytopenic purpura (PMID:18683034)
• SAHH mRNA was lost in 50% of tumor tissues from 206 patients with different kinds of tumors in comparison with normal tissue counterparts. Moreover, SAHH protein was also affected in some colon cancers (PMID:18713839)
• These data show that 2-5-fold enhanced AdoHcyase activity is well tolerated by the cell, while greatly enhanced AdoHcyase activity results in adenosine-induced apoptosis. (PMID:18769049)
• S-adenosylhomocysteine hydrolase (PMID:19619139)
• The simulations of ligand-induced transition revealed that the signal of intrasubunit closure dynamics is transmitted to form intersubunit contacts, which in turn invoke a precise alignment of active site. (PMID:22023331)
• A fluorescence-based assay for the measurement of S-adenosylhomocysteine hydrolase activity in biological samples. (PMID:23079506)
• SAHH can promote apoptosis, inhibit migration and adhesion of ESCC cells suggesting that it may be involved in carcinogenesis of the esophagus. (PMID:24430301)
• S-adenosylhomocysteine hydrolase is regulated by lysine acetylation (PMID:25248746)
• SAH hydrolase deficiency can remain asymptomatic in childhood, and the disorder can be associated with early onset hepatocellular carcinoma. (PMID:26527160)
• H19 knockdown activates SAHH, leading to increased DNMT3B-mediated methylation of an lncRNA-encoding gene Nctc1 within the Igf2-H19-Nctc1 locus. (PMID:26687445)
• We have validated the vectors and confirmed self-association of AHCY, AHCYL1, and galectin-3. In a high-throughput BiFC screen, we identified new AHCY interaction partners: galectin-3 and PUS7L. We also describe additional steps in protein interaction analysis, applied for AHCY-galectin-3 interaction (PMID:27455993)
• In order to enable the development of small molecule AHCY inhibitors as targeted cancer therapeutics we developed an assay based on a RapidFire high-throughput mass spectrometry detection system, which allows the direct measurement of AHCY enzymatic activity. (PMID:28533090)
• We investigated previously assumed interaction with AHCY-like-1 protein (AHCYL1), a paralog of AHCY. Indeed, significant interaction between both proteins exists. Additionally, silencing AHCYL1 leads to moderate inhibition of nuclear export of endogenous AHCY. (PMID:28647132)
• Data report that SAHH binds to DNMT1 during DNA replication. SAHH enhances DNMT1 activity, and its overexpression led to hypermethylation of the genome, whereas its inhibition resulted in hypomethylation of the genome. Hypermethylation leads to aberrant gene regulation. Results suggest that alteration of SAHH level affects global DNA methylation levels and gene expression. (PMID:29758262)
• Results uncover a H19/SAHH circuit involving gene-methylation alterations by carcinogen BaP. (PMID:29772428)
• DNA methylation of AHCY may increase the risk of ischemic stroke. (PMID:32020847)
• Inhibition of DJ-1 potently enhances the sensitivity of tumor cells to ferroptosis inducers both in vitro and in vivo. Metabolic analysis and metabolite rescue assay reveal that DJ-1 depletion inhibits the transsulfuration pathway by disrupting the formation of the S-adenosyl homocysteine hydrolase tetramer and impairing its activity. Study findings show that DJ-1 determines the response of cancer cells to ferroptosis. (PMID:32144268)
• Genetic variants in S-adenosyl-methionine synthesis pathway and nonsyndromic cleft lip with or without cleft palate in Chile. (PMID:32492698)
• CRB1-related retinopathy overlapping the ocular phenotype of S-adenosylhomocysteine hydrolase deficiency. (PMID:32689861)
• The values of AHCY and CBS promoter methylation on the diagnosis of cerebral infarction in Chinese Han population. (PMID:33138824)
• Novel candidate factors predicting the effect of S-1 adjuvant chemotherapy of pancreatic cancer. (PMID:33753854)
• Proteomics study of colorectal cancer and adenomatous polyps identifies TFR1, SAHH, and HV307 as potential biomarkers for screening. (PMID:33915303)
• Genomic and transcriptomic profiling of hepatoid adenocarcinoma of the stomach. (PMID:34326469)
• Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target. (PMID:37580540)
• Effects of S-Adenosylhomocysteine Hydrolase Downregulation on Wnt Signaling Pathway in SW480 Cells. (PMID:38003292)
• Inhibition of AHCY impedes proliferation and differentiation of mouse and human adipocyte progenitor cells. (PMID:38064408)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ahcy	ENSDARG00000005191
mus_musculus	Ahcy	ENSMUSG00000027597
mus_musculus	Ahcyl	ENSMUSG00000048087
rattus_norvegicus		ENSRNOG00000063861
drosophila_melanogaster	Ahcy	FBGN0014455
caenorhabditis_elegans	ahcy-1	WBGENE00019322

Paralogs (2): AHCYL2 (ENSG00000158467), AHCYL1 (ENSG00000168710)

Protein

Protein identifiers

Adenosylhomocysteinase — P23526 (reviewed: P23526)

Alternative names: S-adenosyl-L-homocysteine hydrolase

All UniProt accessions (2): P23526, A0A384MTQ3

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the hydrolysis of S-adenosyl-L-homocysteine to form adenosine and homocysteine. Binds copper ions.

Subunit / interactions. Homotetramer. Interaction with AHCYL1.

Subcellular location. Cytoplasm. Melanosome. Nucleus. Endoplasmic reticulum.

Disease relevance. Hypermethioninemia with S-adenosylhomocysteine hydrolase deficiency (HMAHCHD) [MIM:613752] A metabolic disorder characterized by hypermethioninemia associated with failure to thrive, mental and motor retardation, facial dysmorphism with abnormal hair and teeth, and myocardiopathy. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 NAD(+) per subunit.

Pathway. Amino-acid biosynthesis; L-homocysteine biosynthesis; L-homocysteine from S-adenosyl-L-homocysteine: step 1/1.

Similarity. Belongs to the adenosylhomocysteinase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P23526-1	1	yes
P23526-2	2

RefSeq proteins (6): NP_000678, NP_001155238, NP_001309013, NP_001309014, NP_001309015, NP_001349679 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000043	Adenosylhomocysteinase-like	Family
IPR015878	Ado_hCys_hydrolase_NAD-bd	Domain
IPR020082	S-Ado-L-homoCys_hydrolase_CS	Conserved_site
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily
IPR042172	Adenosylhomocyst_ase-like_sf	Homologous_superfamily

Pfam: PF00670, PF05221

Enzyme classification (BRENDA):

• EC 3.3.1.1 — adenosylhomocysteinase (BRENDA: 0 organisms, 0 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• S-adenosyl-L-homocysteine + H2O = L-homocysteine + adenosine (RHEA:21708)

UniProt features (84 total): helix 22, strand 21, binding site 12, sequence variant 9, mutagenesis site 8, modified residue 4, turn 4, initiator methionine 1, chain 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
9QYI	X-RAY DIFFRACTION	1.59
9QYJ	X-RAY DIFFRACTION	1.93
1LI4	X-RAY DIFFRACTION	2.01
4PFJ	X-RAY DIFFRACTION	2.3
5W49	X-RAY DIFFRACTION	2.4
3NJ4	X-RAY DIFFRACTION	2.5
4PGF	X-RAY DIFFRACTION	2.59
5W4B	X-RAY DIFFRACTION	2.65
4YVF	X-RAY DIFFRACTION	2.7
1A7A	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P23526-F1	98.21	0.99

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 (12): 248; 299–301; 346; 353; 57; 131; 156; 157–159; 186; 190; 222–227; 243

Post-translational modifications (4): 2, 183, 186, 193

Mutagenesis-validated functional residues (8):

Position	Phenotype
1–127	affects nuclear-cytoplasmic protein distribution resulting in increased protein amount in the nucleus.
7	does not affect nuclear-cytoplasmic protein distribution resulting in subcellular localization similar to the wild-type
84	severely decreased adenosylhomocysteinase activity.
84	decreased adenosylhomocysteinase activity; when associated with v-89.
84	no effect on adenosylhomocysteinase activity.
89	decreased adenosylhomocysteinase activity; when associated with s-84.
115	slightly reduced adenosylhomocysteinase activity.
365–432	affects nuclear-cytoplasmic protein distribution resulting in increased protein amount in the nucleus.

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-156581	Methylation
R-HSA-1614635	Sulfur amino acid metabolism
R-HSA-2408508	Metabolism of ingested SeMet, Sec, MeSec into H2Se
R-HSA-5578997	Defective AHCY causes HMAHCHD
R-HSA-1430728	Metabolism
R-HSA-156580	Phase II - Conjugation of compounds
R-HSA-1643685	Disease
R-HSA-211859	Biological oxidations
R-HSA-2408522	Selenoamino acid metabolism
R-HSA-5579029	Metabolic disorders of biological oxidation enzymes
R-HSA-5668914	Diseases of metabolism
R-HSA-71291	Metabolism of amino acids and derivatives

MSigDB gene sets: 330 (showing top): BORCZUK_MALIGNANT_MESOTHELIOMA_UP, REACTOME_BIOLOGICAL_OXIDATIONS, PAL_PRMT5_TARGETS_UP, KEGG_CYSTEINE_AND_METHIONINE_METABOLISM, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, SHAFFER_IRF4_TARGETS_IN_ACTIVATED_B_LYMPHOCYTE, MITSIADES_RESPONSE_TO_APLIDIN_DN, SMITH_TERT_TARGETS_DN, SCHUHMACHER_MYC_TARGETS_UP, GOBP_S_ADENOSYLMETHIONINE_METABOLIC_PROCESS, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, GOBP_ONE_CARBON_METABOLIC_PROCESS, RHODES_CANCER_META_SIGNATURE, GOTZMANN_EPITHELIAL_TO_MESENCHYMAL_TRANSITION_DN, BYSTRYKH_HEMATOPOIESIS_STEM_CELL_AND_BRAIN_QTL_TRANS

GO Biological Process (2): one-carbon metabolic process (GO:0006730), L-methionine cycle (GO:0033353)

GO Molecular Function (3): adenosylhomocysteinase activity (GO:0004013), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (6): nucleus (GO:0005634), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), melanosome (GO:0042470), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	2
Metabolism	2
Phase II - Conjugation of compounds	1
Selenoamino acid metabolism	1
Metabolic disorders of biological oxidation enzymes	1
Biological oxidations	1
Diseases of metabolism	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	2
cytoplasm	2
cellular anatomical structure	2
small molecule metabolic process	1
L-methionine metabolic process	1
modified amino acid metabolic process	1
purine ribonucleoside metabolic process	1
S-adenosylmethionine metabolic process	1
homocysteine metabolic process	1
hydrolase activity, acting on carbon-sulfur bonds	1
binding	1
catalytic activity	1
endomembrane system	1
pigment granule	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

3615 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AHCY	MTR	Q99707	882
AHCY	BHMT	Q93088	816
AHCY	ADA	P00813	806
AHCY	MAT1A	Q00266	778
AHCY	H7C2H4	H7C2H4	758
AHCY	P0DN79	P0DN79	758
AHCY	MTHFR	P42898	758
AHCY	ASIP	P42127	756
AHCY	GNMT	Q14749	752
AHCY	CTH	P32929	729
AHCY	MAT2A	P31153	720
AHCY	ADK	P55263	713
AHCY	ITPA	Q9BY32	704
AHCY	SHMT1	P34896	677
AHCY	BHMT2	Q9H2M3	661

IntAct

155 interactions, top by confidence:

A	B	Type	Score
AHCY	C1orf50	psi-mi:“MI:0915”(physical association)	0.920
C1orf50	AHCY	psi-mi:“MI:0915”(physical association)	0.920
ANKRD40	AHCY	psi-mi:“MI:0915”(physical association)	0.900
AHCY	ANKRD40	psi-mi:“MI:0915”(physical association)	0.900
ANKRD40	AHCY	psi-mi:“MI:0914”(association)	0.900
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
APPBP2	AHCY	psi-mi:“MI:0915”(physical association)	0.560
AHCY	APPBP2	psi-mi:“MI:0915”(physical association)	0.560
ORF	EIF3F	psi-mi:“MI:0914”(association)	0.560
HSCB	AHCY	psi-mi:“MI:0915”(physical association)	0.550

BioGRID (368): AHCY (Affinity Capture-MS), AHCY (Affinity Capture-MS), AHCY (Two-hybrid), APPBP2 (Two-hybrid), C1orf50 (Two-hybrid), ANKRD40 (Two-hybrid), AHCY (Affinity Capture-MS), AHCYL1 (Affinity Capture-MS), C1orf50 (Affinity Capture-MS), ANKRD40 (Affinity Capture-MS), AHCY (Affinity Capture-MS), AHCY (Co-fractionation), AHCY (Co-fractionation), AHCY (Co-fractionation), AHCY (Co-fractionation)

ESM2 similar proteins: A0M5W6, A1BEZ2, A1WXM7, A4SF77, A5FJK3, A5GI30, A6GW32, A6UEJ1, A6WX40, B0CJJ7, B2S994, B3EDY3, B3QJT3, B3QMF5, B4SD43, O13639, O50562, O76757, O93477, P10760, P10819, P23526, P27604, P28183, P36889, P50247, P51893, P83783, Q01VU1, Q04NN6, Q04WX0, Q0ALW1, Q13AQ5, Q27580, Q2IZR1, Q2KE72, Q3AQC2, Q3B532, Q3MHL4, Q4R596

Diamond homologs: A0M5W6, A0PRF5, A1BEZ2, A1KNQ0, A1UCK8, A1WXM7, A2C620, A3PW97, A4SF77, A4ZHR8, A5FJK3, A5GI30, A5U7S2, A5VT52, A6GW32, A6UEJ1, A6WX40, A9IL83, A9KD88, A9M9T1, B0CJJ7, B0U232, B2HEP6, B2I7N4, B2S994, B2SPN6, B3EDY3, B3QJT3, B3QMF5, B4SD43, B6J3R0, B6J6H1, B8ZQE9, B9JG53, C0RFY3, C1AH22, O13639, O50562, O76757, O93477

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 147 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
Dengue Virus Genome Translation and Replication	6	17.5×	8e-04

GO biological processes:

GO term	Partners	Fold	FDR
cytoplasmic pattern recognition receptor signaling pathway	5	33.9×	3e-04
intrinsic apoptotic signaling pathway	6	16.4×	4e-04
autophagosome maturation	6	16.1×	4e-04
mitophagy	6	14.6×	5e-04
positive regulation of miRNA transcription	6	13.3×	8e-04
macroautophagy	7	12.9×	4e-04
JNK cascade	5	10.4×	8e-03
transforming growth factor beta receptor signaling pathway	8	9.7×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	10
Uncertain significance	153
Likely benign	151
Benign	16

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
12952	NM_000687.4(AHCY):c.336G>A (p.Trp112Ter)	Pathogenic
2011118	NM_000687.4(AHCY):c.882del (p.Ile295fs)	Pathogenic
2692384	NM_000687.4(AHCY):c.170C>T (p.Thr57Ile)	Pathogenic
2692385	NM_000687.4(AHCY):c.649G>A (p.Val217Met)	Pathogenic
2893172	NM_000687.4(AHCY):c.145del (p.Arg49fs)	Pathogenic
3248564	NC_000020.11:g.34210141_34393539dup	Pathogenic
2584488	NM_000687.4(AHCY):c.106C>T (p.Arg36Trp)	Likely pathogenic
2912157	NM_000687.4(AHCY):c.558+1_558+2delinsCG	Likely pathogenic
3587194	NM_000687.4(AHCY):c.972+1G>A	Likely pathogenic
3587195	NM_000687.4(AHCY):c.763del (p.Glu255fs)	Likely pathogenic
3587196	NM_000687.4(AHCY):c.373del (p.Leu125fs)	Likely pathogenic
3587197	NM_000687.4(AHCY):c.322G>A (p.Glu108Lys)	Likely pathogenic
3587198	NM_000687.4(AHCY):c.28+2T>G	Likely pathogenic
3587199	NM_000687.4(AHCY):c.6del (p.Asp3fs)	Likely pathogenic
4746907	NM_000687.4(AHCY):c.266C>G (p.Ala89Gly)	Likely pathogenic
986179	NM_000687.4(AHCY):c.473C>T (p.Thr158Met)	Likely pathogenic

SpliceAI

1381 predictions. Top by Δscore:

Variant	Effect	Δscore
20:34281161:TCCAG:T	acceptor_gain	1.0000
20:34281162:CCAG:C	acceptor_gain	1.0000
20:34281162:CCAGC:C	acceptor_gain	1.0000
20:34281163:CAG:C	acceptor_gain	1.0000
20:34281163:CAGC:C	acceptor_gain	1.0000
20:34281164:AG:A	acceptor_gain	1.0000
20:34281165:GCTGG:G	acceptor_loss	1.0000
20:34281166:C:CA	acceptor_loss	1.0000
20:34281166:C:CC	acceptor_gain	1.0000
20:34281167:T:A	acceptor_loss	1.0000
20:34285633:ACC:A	acceptor_loss	1.0000
20:34285634:CCTA:C	acceptor_loss	1.0000
20:34285636:T:A	acceptor_loss	1.0000
20:34290329:CACCT:C	donor_loss	1.0000
20:34290330:A:AG	donor_loss	1.0000
20:34290331:CCT:C	donor_loss	1.0000
20:34290331:CCTG:C	donor_gain	1.0000
20:34290446:GTGC:G	acceptor_gain	1.0000
20:34290455:A:T	acceptor_gain	1.0000
20:34290459:A:T	acceptor_gain	1.0000
20:34290463:C:CT	acceptor_gain	1.0000
20:34290463:C:T	acceptor_gain	1.0000
20:34290464:A:T	acceptor_gain	1.0000
20:34290469:C:CT	acceptor_gain	1.0000
20:34290547:CTAC:C	donor_loss	1.0000
20:34290548:TAC:T	donor_loss	1.0000
20:34290549:A:AC	donor_gain	1.0000
20:34290549:ACCG:A	donor_loss	1.0000
20:34290549:ACCGG:A	donor_gain	1.0000
20:34290550:C:CC	donor_gain	1.0000

AlphaMissense

2853 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:34290924:G:C	N191K	1.000
20:34290924:G:T	N191K	1.000
20:34290928:T:A	D190V	1.000
20:34291419:C:A	K186N	1.000
20:34291419:C:G	K186N	1.000
20:34285569:G:C	N346K	0.999
20:34285569:G:T	N346K	0.999
20:34290832:C:T	G222D	0.999
20:34290910:C:G	R196P	0.999
20:34290912:G:C	C195W	0.999
20:34290916:C:T	G194D	0.999
20:34290917:C:G	G194R	0.999
20:34290927:G:C	D190E	0.999
20:34290927:G:T	D190E	0.999
20:34290928:T:G	D190A	0.999
20:34290929:C:G	D190H	0.999
20:34291421:T:C	K186E	0.999
20:34291421:T:G	K186Q	0.999
20:34294136:G:C	N80K	0.999
20:34294136:G:T	N80K	0.999
20:34294139:G:C	C79W	0.999
20:34294150:A:G	W76R	0.999
20:34294150:A:T	W76R	0.999
20:34285530:A:C	S359R	0.998
20:34285530:A:T	S359R	0.998
20:34285532:T:G	S359R	0.998
20:34285567:A:G	L347P	0.998
20:34290405:C:T	G300E	0.998
20:34290410:G:C	N298K	0.998
20:34290410:G:T	N298K	0.998

dbSNP variants (sampled 300 via entrez): RS1000034183 (20:34296480 T>A), RS1000123331 (20:34269080 A>C,G), RS1000134319 (20:34305044 C>T), RS1000184697 (20:34244051 T>C), RS1000244685 (20:34298819 T>C,G), RS1000256337 (20:34249417 G>A), RS1000333681 (20:34255025 T>C), RS1000351471 (20:34262378 T>A,C), RS1000381916 (20:34294263 A>G), RS1000390386 (20:34299368 C>T), RS1000391036 (20:34255500 C>T), RS1000434076 (20:34293974 C>T), RS1000448811 (20:34293091 G>T), RS1000519702 (20:34303488 A>C,G,T), RS1000563000 (20:34288327 T>C)

Disease associations

OMIM: gene MIM:180960 | disease phenotypes: MIM:613752, MIM:613385, MIM:620195

GenCC curated gene-disease

Disease	Classification	Inheritance
hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase	Definitive	AR

Mondo (4): hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase (MONDO:0013404), syndromic multisystem autoimmune disease due to ITCH deficiency (MONDO:0013245), obesity and hypopigmentation (MONDO:0859351), intellectual disability (MONDO:0001071)

Orphanet (3): S-adenosylhomocysteine hydrolase deficiency (Orphanet:88618), Syndromic multisystem autoimmune disease due to Itch deficiency (Orphanet:228426), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

56 total (30 of 56 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000164	Abnormality of the dentition
HP:0000252	Microcephaly
HP:0000486	Strabismus
HP:0000565	Esotropia
HP:0000708	Atypical behavior
HP:0000736	Short attention span
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001321	Cerebellar hypoplasia
HP:0001324	Muscle weakness
HP:0001392	Abnormality of the liver
HP:0001402	Hepatocellular carcinoma
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001638	Cardiomyopathy
HP:0001763	Pes planus
HP:0001789	Hydrops fetalis
HP:0001928	Abnormality of coagulation
HP:0001976	Reduced antithrombin III activity
HP:0001999	Abnormal facial shape
HP:0002079	Hypoplasia of the corpus callosum
HP:0002119	Ventriculomegaly
HP:0002160	Hyperhomocystinemia
HP:0002376	Developmental regression
HP:0002421	Poor head control
HP:0002878	Respiratory failure
HP:0002910	Elevated circulating hepatic transaminase concentration

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST004785_56	Vitiligo	1.000000e-19
GCST006979_539	Heel bone mineral density	2.000000e-11
GCST008163_481	Height	1.000000e-06
GCST010135_33	Oily fish consumption	7.000000e-09
GCST010140_23	Pork consumption	7.000000e-09
GCST010142_10	Fish- and plant-related diet	8.000000e-12
GCST011122_18	Walking pace	2.000000e-09
GCST012227_1084	Hip circumference adjusted for BMI	2.000000e-14
GCST90013405_117	Liver enzyme levels (alanine transaminase)	2.000000e-19

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0008111	diet measurement
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2664 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (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
CHEMBL1232461	MOLIBRESIB	2	1,538

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Adenosine turnover

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
DZNep	Inhibition	12.3	pKi
3-deazaadenosine	Inhibition	8.5	pIC50

ChEMBL bioactivities

228 potent at pChembl≥5 of 267 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	Ki	0.01	nM	CHEMBL154745
9.30	Ki	0.5	nM	CHEMBL280595
8.89	IC50	1.3	nM	CHEMBL3290657
8.82	IC50	1.5	nM	NEOPLANOCIN A
8.82	IC50	1.5	nM	CHEMBL301499
8.82	IC50	1.5	nM	CHEMBL3290650
8.82	Ki	1.5	nM	CHEMBL3322562
8.66	IC50	2.2	nM	CHEMBL3290658
8.57	IC50	2.7	nM	CHEMBL3290668
8.48	Ki	3.3	nM	CHEMBL281476
8.42	Ki	3.8	nM	NEOPLANOCIN A
8.40	Ki	4	nM	3-DEAZAARISTEROMYCIN A
8.30	IC50	5	nM	CHEMBL3322562
8.14	IC50	7.2	nM	NEOPLANOCIN A
8.10	IC50	8	nM	CHEMBL2115462
8.07	IC50	8.5	nM	CHEMBL3597832
8.03	IC50	9.4	nM	CHEMBL3290663
8.00	IC50	10	nM	NEOPLANOCIN A
7.92	Ki	12	nM	CHEMBL301499
7.89	IC50	13	nM	CHEMBL3322547
7.80	IC50	16	nM	CHEMBL3290658
7.75	IC50	18	nM	CHEMBL281337
7.66	Ki	22	nM	CHEMBL50728
7.62	IC50	24	nM	CHEMBL3290663
7.57	Ki	27	nM	CHEMBL50306
7.55	IC50	28	nM	CHEMBL3290665
7.51	IC50	31	nM	3-DEAZANEPLANOCIN A
7.46	Ki	35	nM	CHEMBL147260
7.44	IC50	36	nM	CHEMBL3290659
7.41	Ki	39	nM	CHEMBL308037
7.41	Ki	39	nM	CHEMBL77518
7.40	IC50	40	nM	CHEMBL3290657
7.40	IC50	40	nM	CHEMBL2374428
7.39	Ki	41	nM	CHEMBL299961
7.39	IC50	41	nM	CHEMBL3290662
7.37	Ki	43	nM	CHEMBL77518
7.37	Ki	43	nM	CHEMBL308037
7.36	IC50	44	nM	CHEMBL3322550
7.31	IC50	49	nM	CHEMBL3322556
7.31	IC50	49	nM	CHEMBL3322549
7.31	IC50	49	nM	CHEMBL3597818
7.31	Ki	49	nM	CHEMBL299961
7.28	IC50	52	nM	CHEMBL3322540
7.27	Kd	53.28	nM	CHEMBL5653589
7.27	ED50	53.28	nM	CHEMBL5653589
7.26	IC50	55	nM	CHEMBL301499
7.22	IC50	60	nM	CHEMBL3322555
7.22	IC50	60	nM	CHEMBL3597817
7.16	IC50	70	nM	CHEMBL3322554
7.16	IC50	70	nM	CHEMBL3597816

PubChem BioAssay actives

219 with measured affinity, of 901 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
(1S,2R,5R)-5-(4-aminoimidazo[4,5-c]pyridin-1-yl)-3-(hydroxymethyl)cyclopent-3-ene-1,2-diol	1868663: Inhibition of SAH hydrolase (unknown origin) assessed as inhibition constant	ki	<0.0001	uM
(1R,2S,3R)-3-(4-amino-7-fluoroimidazo[4,5-c]pyridin-1-yl)cyclopentane-1,2-diol	1152850: Inhibition of AHCY in human SH-SY5Y cells assessed as formation of homocysteine after 48 hrs by HPLC analysis	ic50	0.0013	uM
(1R,2S,3S)-3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)cyclopentane-1,2-diol	1152850: Inhibition of AHCY in human SH-SY5Y cells assessed as formation of homocysteine after 48 hrs by HPLC analysis	ic50	0.0015	uM
(1S,2R,5R)-5-(6-aminopurin-9-yl)-3-(hydroxymethyl)cyclopent-3-ene-1,2-diol	1152849: Inhibition of recombinant human AHCY using SAH as substrate assessed as formation of homocysteine after 10 mins	ic50	0.0015	uM
(1R,2S,3R)-3-(6-aminopurin-9-yl)cyclopentane-1,2-diol	1152850: Inhibition of AHCY in human SH-SY5Y cells assessed as formation of homocysteine after 48 hrs by HPLC analysis	ic50	0.0015	uM
2-[5-chloro-2-(4-chlorophenoxy)-N-[2-[1,3-dihydroisoindol-2-yl(methyl)amino]-2-oxoethyl]anilino]-N-[2-(methylamino)ethyl]acetamide;hydrochloride	1183596: Inhibition of human recombinant S-adenosyl-L-homocysteine hydrolase assessed as AdoHcy hydrolysis activity by Lineweaver-Burk plot	ki	0.0015	uM
(1R,2S,3R)-3-(4-amino-7-chloroimidazo[4,5-c]pyridin-1-yl)cyclopentane-1,2-diol	1152850: Inhibition of AHCY in human SH-SY5Y cells assessed as formation of homocysteine after 48 hrs by HPLC analysis	ic50	0.0022	uM
(1R,2S,3S)-3-(4-amino-7-fluoroimidazo[4,5-c]pyridin-1-yl)-4-fluorocyclopentane-1,2-diol	1152850: Inhibition of AHCY in human SH-SY5Y cells assessed as formation of homocysteine after 48 hrs by HPLC analysis	ic50	0.0027	uM
(1R,2S,3R,5R)-3-(4-aminoimidazo[4,5-c]pyridin-1-yl)-5-(hydroxymethyl)cyclopentane-1,2-diol	199940: Binding affinity against S-adenosyl-homocysteine hydrolase	ki	0.0040	uM
(1R,2S,3S,4R,5R)-3-(6-aminopurin-9-yl)-4-fluoro-5-(hydroxymethyl)cyclopentane-1,2-diol	200094: Inhibition of S-adenosyl-homocysteine (AdoHcy)hydrolase from rabbit erythrocytes	ic50	0.0080	uM
2-[5-chloro-2-(4-chlorophenoxy)-N-[2-[1,3-dihydroisoindol-2-yl(methyl)amino]-2-oxoethyl]anilino]-N-[2-(ethylamino)ethyl]acetamide;hydrochloride	1236982: Inhibition of recombinant human S-adenosyl-L-homocysteine hydrolase assessed as hydrolysis of AdoHcy after 8 mins by HPLC analysis	ic50	0.0085	uM
(1S,2R,3S,4R)-4-(4-amino-7-fluoroimidazo[4,5-c]pyridin-1-yl)cyclopentane-1,2,3-triol	1152850: Inhibition of AHCY in human SH-SY5Y cells assessed as formation of homocysteine after 48 hrs by HPLC analysis	ic50	0.0094	uM
2-[5-chloro-2-(4-chlorophenoxy)-N-[2-[1,3-dihydroisoindol-2-yl(methyl)amino]-2-oxoethyl]anilino]-N-(2-pyrrolidin-1-ylethyl)acetamide	1183595: Inhibition of human recombinant S-adenosyl-L-homocysteine hydrolase assessed as AdoHcy hydrolysis activity by HPLC analysis	ic50	0.0130	uM
(1R,2S,3R,5R)-3-(6-aminopurin-9-yl)-5-ethenylcyclopentane-1,2-diol	199453: Inhibitory activity against bovine liver S-adenosyl-L-homocysteine hydrolase (AdoHcy).	ki	0.0220	uM
(1R,2S,3R,5S)-3-(6-aminopurin-9-yl)-5-methylcyclopentane-1,2-diol	199453: Inhibitory activity against bovine liver S-adenosyl-L-homocysteine hydrolase (AdoHcy).	ki	0.0270	uM
(1S,2R,5R)-5-(4-amino-7-fluoroimidazo[4,5-c]pyridin-1-yl)cyclopent-3-ene-1,2-diol	1152850: Inhibition of AHCY in human SH-SY5Y cells assessed as formation of homocysteine after 48 hrs by HPLC analysis	ic50	0.0280	uM
(1S,2R)-5-(4-aminoimidazo[4,5-c]pyridin-1-yl)cyclopent-3-ene-1,2-diol	199928: Time course of inactivation of bovine liver S-adenosyl-homocysteine hydrolase	ki	0.0350	uM
(1R,2S,3R)-3-(4-amino-7-methylimidazo[4,5-c]pyridin-1-yl)cyclopentane-1,2-diol	1152850: Inhibition of AHCY in human SH-SY5Y cells assessed as formation of homocysteine after 48 hrs by HPLC analysis	ic50	0.0360	uM
(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolane-2-carbaldehyde	199471: Binding affinity towards purified recombinant human placental S-adenosyl-L-homocysteine hydrolase	ki	0.0390	uM
(2S,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolane-2-carbaldehyde	199279: concentration dependent inhibition of S-Adenosyl-homocysteine hydrolase was determined by Kitz and Wilson method	ki	0.0390	uM
(2R)-2-[(1R)-1-(6-aminopurin-9-yl)-2-oxoethoxy]-3-hydroxypropanal	200095: Inhibition of S-adenosyl-homocysteine (AdoHcy)hydrolase from rabbit erythrocytes	ic50	0.0400	uM
(1S,2S,3R,5S)-3-(4-amino-7-fluoroimidazo[4,5-c]pyridin-1-yl)-5-fluorocyclopentane-1,2-diol	1152850: Inhibition of AHCY in human SH-SY5Y cells assessed as formation of homocysteine after 48 hrs by HPLC analysis	ic50	0.0410	uM
(1S,2R,5R)-5-(6-aminopurin-9-yl)cyclopent-3-ene-1,2-diol	199928: Time course of inactivation of bovine liver S-adenosyl-homocysteine hydrolase	ki	0.0410	uM
methyl 4-[[2-[5-chloro-2-(4-chlorophenoxy)-N-[2-oxo-2-(2-pyrrolidin-1-ylethylamino)ethyl]anilino]acetyl]-methylamino]piperazine-1-carboxylate	1183595: Inhibition of human recombinant S-adenosyl-L-homocysteine hydrolase assessed as AdoHcy hydrolysis activity by HPLC analysis	ic50	0.0440	uM
2-[5-chloro-2-(4-chlorophenoxy)-N-[2-[methyl-(4-methylsulfonylpiperazin-1-yl)amino]-2-oxoethyl]anilino]-N-(2-pyrrolidin-1-ylethyl)acetamide	1183595: Inhibition of human recombinant S-adenosyl-L-homocysteine hydrolase assessed as AdoHcy hydrolysis activity by HPLC analysis	ic50	0.0490	uM
2-[5-chloro-2-(4-chlorophenoxy)-N-[2-[2,3-dihydro-1H-inden-2-yl(methyl)amino]-2-oxoethyl]anilino]-N-[2-(propan-2-ylamino)ethyl]acetamide	1183595: Inhibition of human recombinant S-adenosyl-L-homocysteine hydrolase assessed as AdoHcy hydrolysis activity by HPLC analysis	ic50	0.0490	uM
tert-butyl N-[2-[[2-[5-chloro-2-(4-chlorophenoxy)-N-[2-[2,3-dihydro-1H-inden-2-yl(methyl)amino]-2-oxoethyl]anilino]acetyl]amino]ethyl]-N-propan-2-ylcarbamate	1236982: Inhibition of recombinant human S-adenosyl-L-homocysteine hydrolase assessed as hydrolysis of AdoHcy after 8 mins by HPLC analysis	ic50	0.0490	uM
2-[5-chloro-2-(4-chlorophenoxy)-N-[2-[2,3-dihydro-1H-inden-2-yl(methyl)amino]-2-oxoethyl]anilino]-N-(2-pyrrolidin-1-ylethyl)acetamide	1183595: Inhibition of human recombinant S-adenosyl-L-homocysteine hydrolase assessed as AdoHcy hydrolysis activity by HPLC analysis	ic50	0.0520	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147820: Binding affinity to human AHCY incubated for 45 mins by Kinobead based pull down assay	kd	0.0533	uM
2-[5-chloro-2-(4-chlorophenoxy)-N-[2-[2,3-dihydro-1H-inden-2-yl(methyl)amino]-2-oxoethyl]anilino]-N-[2-(ethylamino)ethyl]acetamide	1183595: Inhibition of human recombinant S-adenosyl-L-homocysteine hydrolase assessed as AdoHcy hydrolysis activity by HPLC analysis	ic50	0.0600	uM
tert-butyl N-[2-[[2-[5-chloro-2-(4-chlorophenoxy)-N-[2-[2,3-dihydro-1H-inden-2-yl(methyl)amino]-2-oxoethyl]anilino]acetyl]amino]ethyl]-N-ethylcarbamate	1236982: Inhibition of recombinant human S-adenosyl-L-homocysteine hydrolase assessed as hydrolysis of AdoHcy after 8 mins by HPLC analysis	ic50	0.0600	uM
2-[5-chloro-2-(4-chlorophenoxy)-N-[2-[2,3-dihydro-1H-inden-2-yl(methyl)amino]-2-oxoethyl]anilino]-N-[2-(methylamino)ethyl]acetamide	1183595: Inhibition of human recombinant S-adenosyl-L-homocysteine hydrolase assessed as AdoHcy hydrolysis activity by HPLC analysis	ic50	0.0700	uM
tert-butyl N-[2-[[2-[5-chloro-2-(4-chlorophenoxy)-N-[2-[2,3-dihydro-1H-inden-2-yl(methyl)amino]-2-oxoethyl]anilino]acetyl]amino]ethyl]-N-methylcarbamate	1236982: Inhibition of recombinant human S-adenosyl-L-homocysteine hydrolase assessed as hydrolysis of AdoHcy after 8 mins by HPLC analysis	ic50	0.0700	uM
3-(6-aminopurin-9-yl)-5-(hydroxymethyl)-4-methylidenecyclopentane-1,2-diol	200094: Inhibition of S-adenosyl-homocysteine (AdoHcy)hydrolase from rabbit erythrocytes	ic50	0.0800	uM
2-[5-chloro-2-(4-chlorophenoxy)-N-[2-[methyl(1,2,3,4-tetrahydronaphthalen-2-yl)amino]-2-oxoethyl]anilino]-N-(2-pyrrolidin-1-ylethyl)acetamide	1183595: Inhibition of human recombinant S-adenosyl-L-homocysteine hydrolase assessed as AdoHcy hydrolysis activity by HPLC analysis	ic50	0.0810	uM
(Z,2R)-5-(4-aminoimidazo[4,5-c]pyridin-1-yl)pent-3-ene-1,2-diol	200065: Inhibition against bovine-liver S-Adenosyl-homocysteine (AdoHcy) hydrolase	ki	0.0900	uM
(3R,4S,5R)-2-(6-aminopurin-9-yl)-5-[(E)-methoxyiminomethyl]oxolane-3,4-diol	199279: concentration dependent inhibition of S-Adenosyl-homocysteine hydrolase was determined by Kitz and Wilson method	ki	0.0946	uM
(3R,4S,5R)-2-(6-aminopurin-9-yl)-5-[(E)-2-iodoethenyl]oxolane-3,4-diol	199277: Tested for kinetic constant for the inhibition of recombinant human placental S-Adenosyl-L-homocysteine Hydrolase	ki	0.0960	uM
(1R,2S,3R)-3-(6-amino-2-fluoropurin-9-yl)cyclopentane-1,2-diol	1152850: Inhibition of AHCY in human SH-SY5Y cells assessed as formation of homocysteine after 48 hrs by HPLC analysis	ic50	0.0980	uM
(3R,4S,5R)-2-(6-aminopurin-9-yl)-5-[(E)-phenylmethoxyiminomethyl]oxolane-3,4-diol	199279: concentration dependent inhibition of S-Adenosyl-homocysteine hydrolase was determined by Kitz and Wilson method	ki	0.1010	uM
(2R,3R,4S,5R)-2-(6-aminopurin-9-yl)-5-[(E)-2-chloroethenyl]oxolane-3,4-diol	199277: Tested for kinetic constant for the inhibition of recombinant human placental S-Adenosyl-L-homocysteine Hydrolase	ki	0.1100	uM
2-[5-chloro-2-(4-chlorophenoxy)-N-[2-[2,3-dihydro-1H-inden-2-yl(methyl)amino]-2-oxoethyl]anilino]-N-[[(2S)-pyrrolidin-2-yl]methyl]acetamide	1183595: Inhibition of human recombinant S-adenosyl-L-homocysteine hydrolase assessed as AdoHcy hydrolysis activity by HPLC analysis	ic50	0.1100	uM
tert-butyl (2S)-2-[[[2-[5-chloro-2-(4-chlorophenoxy)-N-[2-[2,3-dihydro-1H-inden-2-yl(methyl)amino]-2-oxoethyl]anilino]acetyl]amino]methyl]pyrrolidine-1-carboxylate	1236982: Inhibition of recombinant human S-adenosyl-L-homocysteine hydrolase assessed as hydrolysis of AdoHcy after 8 mins by HPLC analysis	ic50	0.1100	uM
2-[2-(6-aminopurin-9-yl)ethylidene]propane-1,3-diol	200065: Inhibition against bovine-liver S-Adenosyl-homocysteine (AdoHcy) hydrolase	ki	0.1100	uM
(1R,2S,3R,5R)-3-(6-aminopurin-9-yl)-5-(hydroxymethyl)cyclopentane-1,2-diol	199940: Binding affinity against S-adenosyl-homocysteine hydrolase	ki	0.1100	uM
(3R,4S,5R)-2-(6-aminopurin-9-yl)-5-[(E)-ethoxyiminomethyl]oxolane-3,4-diol	199279: concentration dependent inhibition of S-Adenosyl-homocysteine hydrolase was determined by Kitz and Wilson method	ki	0.1110	uM
(Z)-4-(6-aminopurin-9-yl)but-2-en-1-ol	200065: Inhibition against bovine-liver S-Adenosyl-homocysteine (AdoHcy) hydrolase	ki	0.1250	uM
2-[5-chloro-2-(4-chlorophenoxy)-N-[2-[2,3-dihydro-1H-inden-2-yl(methyl)amino]-2-oxoethyl]anilino]-N-[2-(dimethylamino)ethyl]acetamide	1183595: Inhibition of human recombinant S-adenosyl-L-homocysteine hydrolase assessed as AdoHcy hydrolysis activity by HPLC analysis	ic50	0.1300	uM
(2R,3R,4S,5R)-2-(6-aminopurin-9-yl)-5-[(E)-2-bromoethenyl]oxolane-3,4-diol	199277: Tested for kinetic constant for the inhibition of recombinant human placental S-Adenosyl-L-homocysteine Hydrolase	ki	0.1340	uM
2-[5-chloro-2-(4-chlorophenoxy)-N-[2-[2,3-dihydro-1H-inden-2-yl(methyl)amino]-2-oxoethyl]anilino]-N-(piperidin-2-ylmethyl)acetamide	1183595: Inhibition of human recombinant S-adenosyl-L-homocysteine hydrolase assessed as AdoHcy hydrolysis activity by HPLC analysis	ic50	0.1500	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, decreases expression, increases expression	4
methylmercuric chloride	decreases expression	2
bisphenol A	affects expression, decreases expression	2
epigallocatechin gallate	decreases expression, affects cotreatment, increases expression	2
chloropicrin	decreases expression	2
Cisplatin	affects cotreatment, increases expression	2
Doxorubicin	decreases expression, increases expression	2
Smoke	decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Valproic Acid	decreases expression	2
Cadmium Chloride	increases abundance, increases expression	2
aristolochic acid I	increases expression	1
TAK-243	increases sumoylation	1
bismuth tripotassium dicitrate	increases expression	1
pyrogallol 1,3-dimethyl ether	decreases expression, affects cotreatment, affects localization, increases expression	1
arsenite	affects binding, increases reaction	1
ochratoxin A	increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
cupric oxide	decreases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
azoxystrobin	increases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
fluoroneplanocin A	affects binding, decreases activity	1
pyrimidifen	increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	decreases expression	1
bisphenol S	increases expression	1
jinfukang	increases expression, affects cotreatment	1
LDN 193189	affects cotreatment, decreases expression	1

ChEMBL screening assays

211 unique, capped per target: 197 binding, 14 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1005162	Binding	Inhibition of human S-adenosyl-L-homocysteine hydrolase at 281 uM after 0.5 hrs	Synthesis of 5’-functionalized nucleosides: S-Adenosylhomocysteine analogues with the carbon-5’ and sulfur atoms replaced by a vinyl or halovinyl unit. — Bioorg Med Chem
CHEMBL664127	Functional	NAD+ content of the enzyme tetramer was measured by HPLC on a C 18 reverse-phase column	9-(trans-2’,trans-3’-dihydroxycyclopent-4’-enyl) derivatives of adenine and 3-deazaadenine: potent inhibitors of bovine liver S-adenosylhomocysteine hydrolase. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D2HY	Abcam Raji AHCY KO	Cancer cell line	Male
CVCL_UQ09	Abcam Jurkat AHCY KO	Cancer cell line	Male
CVCL_WQ93	Abcam K-562 AHCY KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders