AHCYL1

Summary

AHCYL1 (adenosylhomocysteinase like 1, HGNC:344) is a protein-coding gene on chromosome 1p13.3, encoding S-adenosylhomocysteine hydrolase-like protein 1 (O43865). Multifaceted cellular regulator which coordinates several essential cellular functions including regulation of epithelial HCO3(-) and fluid secretion, mRNA processing and DNA replication. It is a selective cancer dependency (DepMap: 33.4% of cell lines).

The protein encoded by this gene interacts with inositol 1,4,5-trisphosphate receptor, type 1 and may be involved in the conversion of S-adenosyl-L-homocysteine to L-homocysteine and adenosine. Several transcript variants encoding two different isoforms have been found for this gene.

Source: NCBI Gene 10768 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 39 total — 1 pathogenic, 1 likely-pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 33.4% of screened cell lines
• MANE Select transcript: NM_006621

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:344
Approved symbol	AHCYL1
Name	adenosylhomocysteinase like 1
Location	1p13.3
Locus type	gene with protein product
Status	Approved
Aliases	XPVKONA, IRBIT, PPP1R78
Ensembl gene	ENSG00000168710
Ensembl biotype	protein_coding
OMIM	607826
Entrez	10768

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 10 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000359172, ENST00000369799, ENST00000393614, ENST00000469401, ENST00000475081, ENST00000481423, ENST00000853520, ENST00000853521, ENST00000853522, ENST00000972196, ENST00000972197, ENST00000972198, ENST00000972199

RefSeq mRNA: 5 — MANE Select: NM_006621 NM_001242673, NM_001242674, NM_001242675, NM_001242676, NM_006621

CCDS: CCDS55620, CCDS818

Canonical transcript exons

ENST00000369799 — 17 exons

Exon	Start	End
ENSE00001151934	110018552	110018650
ENSE00001151941	110018373	110018467
ENSE00001151954	110016667	110016730
ENSE00001151984	110012362	110012462
ENSE00001450935	110021674	110023742
ENSE00001450937	109984765	109985172
ENSE00001657443	110019051	110019119
ENSE00001737286	110016344	110016460
ENSE00003539501	110009034	110009145
ENSE00003559317	110019548	110019626
ENSE00003560164	110011214	110011357
ENSE00003591825	110017946	110018016
ENSE00003600565	110017495	110017583
ENSE00003604683	110015425	110015531
ENSE00003682428	110014763	110014857
ENSE00003683565	110020731	110020851
ENSE00003685075	110012897	110012999

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 61.4961 / max 699.3804, expressed in 1827 samples.

FANTOM5 promoters (18 alternative TSS)

Promoter ID	TPM avg	Samples expressed
4482	55.7388	1827
4491	1.2126	321
4481	0.9678	309
4483	0.7451	355
4495	0.7102	296
4490	0.6184	193
4497	0.3704	195
4486	0.3599	118
4496	0.2520	105
4489	0.1083	55

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral globus pallidus	UBERON:0002476	99.85	gold quality
ventral tegmental area	UBERON:0002691	99.61	gold quality
superior vestibular nucleus	UBERON:0007227	99.57	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.55	gold quality
medulla oblongata	UBERON:0001896	99.54	gold quality
globus pallidus	UBERON:0001875	99.52	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.51	gold quality
medial globus pallidus	UBERON:0002477	99.46	gold quality
subthalamic nucleus	UBERON:0001906	99.42	gold quality
substantia nigra pars compacta	UBERON:0001965	99.37	gold quality
inferior olivary complex	UBERON:0002127	99.36	gold quality
dorsal plus ventral thalamus	UBERON:0001897	99.33	gold quality
inferior vagus X ganglion	UBERON:0005363	99.25	gold quality
middle frontal gyrus	UBERON:0002702	99.17	gold quality
paraflocculus	UBERON:0005351	99.14	gold quality
CA1 field of hippocampus	UBERON:0003881	99.09	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.04	gold quality
parietal lobe	UBERON:0001872	98.91	gold quality
midbrain	UBERON:0001891	98.90	gold quality
postcentral gyrus	UBERON:0002581	98.89	gold quality
nucleus accumbens	UBERON:0001882	98.87	gold quality
cerebellar vermis	UBERON:0004720	98.87	gold quality
substantia nigra	UBERON:0002038	98.85	gold quality
caudate nucleus	UBERON:0001873	98.80	gold quality
hypothalamus	UBERON:0001898	98.80	gold quality
olfactory bulb	UBERON:0002264	98.79	gold quality
jejunal mucosa	UBERON:0000399	98.76	gold quality
pons	UBERON:0000988	98.74	gold quality
adult organism	UBERON:0007023	98.73	gold quality
cranial nerve II	UBERON:0000941	98.69	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	72.28
E-HCAD-25	yes	24.40
E-GEOD-84465	yes	11.24
E-CURD-10	no	437.43
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTCF, TP63

miRNA regulators (miRDB)

172 targeting AHCYL1, 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-4668-3P	100.00	68.74	2635
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-137-3P	99.87	74.74	2401

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 33.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 22)

• regulation through IRBIT enables NBC1 variants to have different physiological roles (PMID:16769890)
• An IRBIT homologue, Long-IRBIT, demonstrates only weak binding ability to inositol 1,4,5-trisphosphate receptor because of an inhibitory effect of its LISN domain, a Long-IRBIT specific N-terminal appendage. (PMID:19220705)
• IRBIT is critically involved in mediating activation of NHE3 by ANG II via a Ca(2+)/calmodulin-dependent protein kinases II-dependent pathway. (PMID:20584908)
• Both IRBIT (inositol 1,4,5-trisphosphate receptor-binding protein) and WNK [with no lysine (K)] kinase have been implicated as additional HCO(3)(-) secretory controllers. (PMID:21242704)
• IRBIT opposes the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, in addition to stimulating their activities (PMID:21317537)
• A NBCe1-B construct that lacks amino acid residues 2-16 of the amino-terminus is fully autoinhibited, but cannot be stimulated by IRBIT, indicating that autoinhibitory and IRBIT-binding determinants within the cytosolic amino-terminus are not identical. (PMID:22012331)
• conclude that AHCYL1 expression is associated with ovarian carcinogenesis as an oncogene in chickens, whereas it plays the role of tumor suppressor in human EOC, suggesting a paradoxical function of AHCYL1 in ovarian carcinogenesis (PMID:22826361)
• relationships between the WNK/SPAK and IRBIT/PP1 sites in the regulation of Na+-HCO3- cotransporters (PMID:23431199)
• IRBIT plays an important role in intracellular pH regulation, mediated by NHE3, and further regulated by SPAK. (PMID:23769829)
• IRBIT is a master regulator of ion channels and ion transporters. (Review) (PMID:24518248)
• Formation of the Ribonucleotide reductase-IRBIT complex is regulated through phosphorylation of IRBIT, and ablation of IRBIT expression in HeLa cells causes imbalanced dNTP pools and altered cell cycle progression. (PMID:25237103)
• IRBIT forms signaling complexes with PIPKIalpha and NBCe1-B, whose activity is regulated by PI(4,5)P2. (PMID:26509711)
• 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)
• These results suggest that by inhibiting Bcl2l10 activity and promoting contact between endoplasmic reticulum and mitochondria, IRBIT facilitates massive Ca(2+) transfer to mitochondria and promotes apoptosis. (PMID:27995898)
• 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)
• IRBIT controlled five phosphorylation sites in NBCe1-B that determined both the active conformation of the transporter and its regulation by Cl(-) (PMID:30377224)
• in the group receiving postoperative adjuvant chemotherapy, a significant association was found between IRBIT expression and both overall and disease-free survival. IRBIT may be used as a useful predictive marker for chemotherapy. (PMID:31366495)
• Adenosylhomocysteinase like 1 interacts with nonstructural 5A and regulates hepatitis C virus propagation. (PMID:33355889)
• Both IRBIT and long-IRBIT bind to and coordinately regulate Cl(-)/HCO3(-) exchanger AE2 activity through modulating the lysosomal degradation of AE2. (PMID:33727633)
• Unbiased proteomic profiling reveals the IP3R modulator AHCYL1/IRBIT as a novel interactor of microtubule-associated protein tau. (PMID:35218773)
• NRAS Mutant Dictates AHCYL1-Governed ER Calcium Homeostasis for Melanoma Tumor Growth. (PMID:38294692)
• The role of S-adenosylhomocysteine hydrolase-like 1 in cancer. (PMID:39154900)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ahcyl1	ENSDARG00000056331
mus_musculus	Ahcyl1	ENSMUSG00000027893
rattus_norvegicus	Ahcyl1	ENSRNOG00000018569
drosophila_melanogaster	AhcyL2	FBGN0015011
drosophila_melanogaster	AhcyL1	FBGN0035371

Paralogs (2): AHCY (ENSG00000101444), AHCYL2 (ENSG00000158467)

Protein

Protein identifiers

S-adenosylhomocysteine hydrolase-like protein 1 — O43865 (reviewed: O43865)

Alternative names: DC-expressed AHCY-like molecule, IP(3)Rs binding protein released with IP(3), Putative adenosylhomocysteinase 2, S-adenosyl-L-homocysteine hydrolase 2

All UniProt accessions (2): O43865, A0A024R0A8

UniProt curated annotations — full annotation on UniProt →

Function. Multifaceted cellular regulator which coordinates several essential cellular functions including regulation of epithelial HCO3(-) and fluid secretion, mRNA processing and DNA replication. Regulates ITPR1 sensitivity to inositol 1,4,5-trisphosphate, competing for the common binding site and acting as endogenous ‘pseudoligand’ whose inhibitory activity can be modulated by its phosphorylation status. Promotes the formation of contact points between the endoplasmic reticulum (ER) and mitochondria, facilitating transfer of Ca(2+) from the ER to mitochondria. Under normal cellular conditions, functions cooperatively with BCL2L10 to limit ITPR1-mediated Ca(2+) release but, under apoptotic stress conditions, dephosphorylated which promotes dissociation of both AHCYL1 and BCL2L10 from mitochondria-associated endoplasmic reticulum membranes, inhibits BCL2L10 interaction with ITPR1 and leads to increased Ca(2+) transfer to mitochondria which promotes apoptosis. In the pancreatic and salivary ducts, at resting state, attenuates inositol 1,4,5-trisphosphate-induced calcium release by interacting with ITPR1. When extracellular stimuli induce ITPR1 phosphorylation or inositol 1,4,5-trisphosphate production, dissociates from ITPR1 to interact with CFTR and SLC26A6, mediating their synergistic activation by calcium and cAMP that stimulates the epithelial secretion of electrolytes and fluid. Also activates basolateral SLC4A4 isoform 1 to coordinate fluid and HCO3(-) secretion. Inhibits the effect of STK39 on SLC4A4 and CFTR by recruiting PP1 phosphatase which activates SLC4A4, SLC26A6 and CFTR through dephosphorylation. Mediates the induction of SLC9A3 surface expression produced by Angiotensin-2. Depending on the cell type, activates SLC9A3 in response to calcium or reverses SLC9A3R2-dependent calcium inhibition. May modulate the polyadenylation state of specific mRNAs, both by controlling the subcellular location of FIP1L1 and by inhibiting PAPOLA activity, in response to a stimulus that alters its phosphorylation state. Acts as a (dATP)-dependent inhibitor of ribonucleotide reductase large subunit RRM1, controlling the endogenous dNTP pool and ensuring normal cell cycle progression. In vitro does not exhibit any S-adenosyl-L-homocysteine hydrolase activity.

Subunit / interactions. Forms multimers. Forms heteromultimers with AHCYL2 (via the C-terminal region). Interacts (when phosphorylated) with ITPR1 (when not phosphorylated); the interaction suppresses inositol 1,4,5-trisphosphate binding to ITPR1. Interacts with BCL2L10; this strengthens the interaction of AHCYL1 with ITPR1. Interacts with CFTR and SLC26A6; the interactions take place once AHCYL1 is released from ITPR1 and increase CFTR and SLC26A6 activities. Interacts with RRM1; in a phosphorylation- and (dATP)-dependent manner. Interacts (via PEST domain when phosphorylated) with SLC4A4 isoform 1 but not isoform 2; the interaction increases SLC4A4 isoform 1 activity. Interacts (when phosphorylated) with SLC9A3; the interaction is required for SLC9A3 apical location and activity. Interacts (when phosphorylated) with FIP1L1; the interaction is direct and associates AHCYL1 with the CPSF complex and RNA. Interacts with PAPOLA. Interacts with ZCCHC4. Interacts with AHCY.

Subcellular location. Endoplasmic reticulum. Cytoplasm. Cytosol. Apical cell membrane. Microsome.

Tissue specificity. Expressed in dendritic cells.

Post-translational modifications. Phosphorylated at Ser/Thr residues between Ser-68 and Thr-72 in the PEST region: required for interaction with dATP-bound RRM1 and ITPR1. Phosphorylation at Ser-68 by PRKD1 and CAMK4 is required for further phosphorylations by CSNK1A1. Phosphorylation is induced by oxidative stress. Probably phosphorylated by CAMK2A; phosphorylation at Ser-68 may be required for interaction with SLC9A3. Dephosphorylated in response to apoptotic stress conditions which causes translocation of both AHCYL1 and BCL2L10 from mitochondria-associated endoplasmic reticulum membranes and promotes apoptosis.

Cofactor. Binds 1 NAD(+) per subunit.

Domain organisation. The PEST region is essential for the interaction with ITPR1, and, when phosphorylated, is also the RRM1-binding region. The PDZ-binding region is required for maximal interaction with ITPR1 and is also responsible for the IP3-insensitive interaction with ITPR1.

Miscellaneous. Ablation of expression in HeLa cells causes imbalanced dNTP pools and altered cell cycle progression.

Similarity. Belongs to the adenosylhomocysteinase family.

Isoforms (2)

UniProt ID	Names	Canonical?
O43865-1	1	yes
O43865-2	2

RefSeq proteins (5): NP_001229602, NP_001229603, NP_001229604, NP_001229605, NP_006612* (*=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

UniProt features (89 total): helix 21, mutagenesis site 18, strand 16, modified residue 10, binding site 9, region of interest 5, turn 4, sequence conflict 2, initiator methionine 1, chain 1, splice variant 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3MTG	X-RAY DIFFRACTION	2.64

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43865-F1	85.35	0.78

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 (9): 254; 284; 288; 318–322; 341; 376; 397–399; 155; 229

Post-translational modifications (10): 2, 2, 40, 68, 71, 74, 77, 84, 391, 1

Mutagenesis-validated functional residues (18):

Position	Phenotype
52	no effect on interaction with slc4a4.
58	no effect on interaction with slc4a4.
62	no effect on interaction with slc4a4. no effect on interaction with fip1l1.
64	no effect on interaction with itpr1. no effect on phosphorylation. no effect on interaction with slc4a4. no effect on in
66	slightly decreases interaction with itpr1. slightly decreases phosphorylation. no effect on interaction with slc4a4. abo
68	highly decreases phosphorylation. abolishes interaction with itpr1. no effect on interaction with bcl2l10. marked decrea
70	highly decreases interaction with itpr1. no effect on phosphorylation. no effect on interaction with slc4a4. abolishes i
71	abolishes interaction with itpr1. highly decreases phosphorylation. abolishes interaction with slc4a4. abolishes interac
72	highly decreases interaction with itpr1. slightly increases phosphorylation. no effect on interaction with slc4a4. highl
74	abolishes interaction with itpr1. slightly decreases phosphorylation. strongly decreases interaction with slc4a4. abolis
76	no effect on interaction with itpr1. no effect on phosphorylation. no effect on interaction with slc4a4. no effect on in
77	highly decreases interaction with itpr1. slightly decreases phosphorylation. strongly decreases interaction with slc4a4.
80	no effect on interaction with slc4a4. highly decreases interaction with fip1l1.
82	no effect on interaction with itpr1. no effect on phosphorylation. no effect on interaction with slc4a4. decreases inter
84	slightly decreases interaction with itpr1. no effect on phosphorylation. no effect on interaction with slc4a4. decreases
85	slightly decreases interaction with itpr1. no effect on phosphorylation. no effect on interaction with slc4a4. decreases
90	no effect on interaction with itpr1. no effect on phosphorylation. no effect on interaction with slc4a4. no effect on in
97	no effect on interaction with itpr1. no effect on interaction with slc4a4. no effect on interaction with fip1l1.

Function

Pathways and Gene Ontology

Reactome pathways

38 pathways

ID	Pathway
R-HSA-112043	PLC beta mediated events
R-HSA-1489509	DAG and IP3 signaling
R-HSA-2029485	Role of phospholipids in phagocytosis
R-HSA-2871809	FCERI mediated Ca+2 mobilization
R-HSA-422356	Regulation of insulin secretion
R-HSA-5218921	VEGFR2 mediated cell proliferation
R-HSA-5578775	Ion homeostasis
R-HSA-5607763	CLEC7A (Dectin-1) induces NFAT activation
R-HSA-9664323	FCGR3A-mediated IL10 synthesis
R-HSA-983695	Antigen activates B Cell Receptor (BCR) leading to generation of second messengers
R-HSA-111885	Opioid Signalling
R-HSA-112040	G-protein mediated events
R-HSA-1280218	Adaptive Immune System
R-HSA-1430728	Metabolism
R-HSA-162582	Signal Transduction
R-HSA-163685	Integration of energy metabolism
R-HSA-1643685	Disease
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-194138	Signaling by VEGF
R-HSA-2029480	Fcgamma receptor (FCGR) dependent phagocytosis
R-HSA-2454202	Fc epsilon receptor (FCERI) signaling
R-HSA-372790	Signaling by GPCR
R-HSA-388396	GPCR downstream signalling
R-HSA-397014	Muscle contraction
R-HSA-418594	G alpha (i) signalling events
R-HSA-4420097	VEGFA-VEGFR2 Pathway
R-HSA-5576891	Cardiac conduction
R-HSA-5607764	CLEC7A (Dectin-1) signaling
R-HSA-5621481	C-type lectin receptors (CLRs)

MSigDB gene sets: 321 (showing top): GCM_MAP4K4, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, REACTOME_INNATE_IMMUNE_SYSTEM, DORSAM_HOXA9_TARGETS_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, KEGG_CYSTEINE_AND_METHIONINE_METABOLISM, GOBP_RESPONSE_TO_ANGIOTENSIN, TGACCTY_ERR1_Q2, GOBP_POSITIVE_REGULATION_OF_SODIUM_ION_TRANSPORT, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_MEMBRANE_DOCKING, GOBP_REGULATION_OF_SODIUM_ION_TRANSPORT

GO Biological Process (12): protein export from nucleus (GO:0006611), one-carbon metabolic process (GO:0006730), apoptotic process (GO:0006915), positive regulation of sodium ion transport (GO:0010765), regulation of mRNA 3’-end processing (GO:0031440), obsolete regulation of monoatomic ion transmembrane transporter activity (GO:0032412), L-methionine cycle (GO:0033353), angiotensin-activated signaling pathway (GO:0038166), epithelial fluid transport (GO:0042045), regulation of monoatomic anion transport (GO:0044070), response to calcium ion (GO:0051592), obsolete mitochondrion-endoplasmic reticulum membrane tethering (GO:1990456)

GO Molecular Function (5): RNA binding (GO:0003723), enzyme regulator activity (GO:0030234), identical protein binding (GO:0042802), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (9): cytoplasm (GO:0005737), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), apical plasma membrane (GO:0016324), mitochondria-associated endoplasmic reticulum membrane contact site (GO:0044233), extracellular exosome (GO:0070062), endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Immune System	2
G-protein mediated events	1
Intracellular signaling by second messengers	1
Fcgamma receptor (FCGR) dependent phagocytosis	1
Fc epsilon receptor (FCERI) signaling	1
Integration of energy metabolism	1
VEGFA-VEGFR2 Pathway	1
Cardiac conduction	1
CLEC7A (Dectin-1) signaling	1
Anti-inflammatory response favouring Leishmania parasite infection	1
Signaling by the B Cell Receptor (BCR)	1
G alpha (i) signalling events	1
Opioid Signalling	1
Metabolism	1
Signaling by Receptor Tyrosine Kinases	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
catalytic activity	2
cytoplasm	2
intracellular protein transport	1
nuclear export	1
small molecule metabolic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
regulation of sodium ion transport	1
sodium ion transport	1
positive regulation of monoatomic ion transport	1
mRNA 3’-end processing	1
regulation of mRNA processing	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
G protein-coupled receptor signaling pathway	1
cellular response to angiotensin	1
fluid transport	1
transepithelial transport	1
monoatomic anion transport	1
regulation of monoatomic ion transport	1
response to metal ion	1
nucleic acid binding	1
molecular function regulator activity	1
protein binding	1
binding	1
intracellular anatomical structure	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
apical part of cell	1
plasma membrane region	1
organelle membrane contact site	1
extracellular vesicle	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2779 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AHCYL1	SLC4A4	Q9Y6R1	962
AHCYL1	ITPR1	Q14643	870
AHCYL1	ITPR3	Q14573	768
AHCYL1	SLC26A6	Q9BXS9	742
AHCYL1	BICC1	Q9H694	661
AHCYL1	SLC4A10	Q6U841	636
AHCYL1	CA8	P35219	634
AHCYL1	BCL2L10	Q9HD36	603
AHCYL1	BHMT	Q93088	568
AHCYL1	STK39	Q9UEW8	565
AHCYL1	SLC4A3	P48751	548
AHCYL1	PPHLN1	Q8NEY8	541
AHCYL1	MTR	Q99707	516
AHCYL1	CTH	P32929	516
AHCYL1	TACC3	Q9Y6A5	507

IntAct

337 interactions, top by confidence:

A	B	Type	Score
AHCYL1	CDKN2C	psi-mi:“MI:0915”(physical association)	0.850
CDKN2C	AHCYL1	psi-mi:“MI:0915”(physical association)	0.850
HEXIM2	AHCYL1	psi-mi:“MI:0914”(association)	0.740
AHCYL1	HEXIM2	psi-mi:“MI:0915”(physical association)	0.740
AHCYL1	JOSD2	psi-mi:“MI:0915”(physical association)	0.740
DACH1	AHCYL1	psi-mi:“MI:0915”(physical association)	0.720
GEM	AHCYL1	psi-mi:“MI:0915”(physical association)	0.720
AHCYL1	DACH1	psi-mi:“MI:0915”(physical association)	0.720
AHCYL1	GEM	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
AHCYL1	AHCYL1	psi-mi:“MI:0915”(physical association)	0.670
TGIF2LY	PGP	psi-mi:“MI:0914”(association)	0.640

BioGRID (483): AHCYL1 (Two-hybrid), AHCYL1 (Two-hybrid), AHCYL1 (Two-hybrid), AHCYL1 (Two-hybrid), AHCYL1 (Two-hybrid), AHCYL1 (Two-hybrid), AHCYL1 (Two-hybrid), AHCYL1 (Two-hybrid), AHCYL1 (Two-hybrid), AHCYL1 (Two-hybrid), SOX30 (Two-hybrid), AHCYL1 (Affinity Capture-RNA), AHCYL1 (Affinity Capture-RNA), AHCYL1 (Affinity Capture-MS), AHCYL1 (Affinity Capture-MS)

ESM2 similar proteins: A0A067XMV2, A0A075D5I4, A0A075D654, A0A075D657, A0A075D6M1, A0A0A2IBN3, A0A482NB13, A0A8X8M4T9, A0A8X8M4W6, A0A8X8M501, A0A8X8M505, B0S6C5, C3SBU4, C3SBU5, C8YTM5, H2E7T5, H2E7T6, H2E7T7, H2E7T8, H2E7T9, H2E7U0, L0E172, M1W268, O42898, O43865, P0DO33, P0DXV1, P0DXV2, P34254, P50245, P74388, P9WEU0, Q108P1, Q54EW2, Q57195, Q5R889, Q7YTB0, Q80SW1, Q8CIG3, Q8KGE0

Diamond homologs: A0M5W6, A1V8Z2, A1WXM7, A2C620, A2S6W2, A3MQW7, A3NER1, A3P0L8, A3PFB5, A4G975, A5ENA7, A5FJK3, A5GI30, A6GW32, A6QLP2, A6T2Y9, A8G7D1, A9BD69, A9IGY5, A9KD88, B1Y647, B2AGG2, B2JIP4, B2S994, B2T6X2, B2U774, B3EDY3, B3QJT3, B3QMF5, B5DFN2, B6J3R0, B6J6H1, B9MD45, C0RFY3, O13639, O43865, O93477, P10760, P10819, P23526

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
AHCYL1	“up-regulates activity”	SLC4A4	binding
AHCYL1	“down-regulates activity”	PAPOLA	binding
AHCYL1	“down-regulates activity”	PAPOLB	binding
PPP1CC	unknown	AHCYL1	dephosphorylation
PPP1CA	unknown	AHCYL1	dephosphorylation
PPP1CB	unknown	AHCYL1	dephosphorylation
AHCYL1	“up-regulates activity”	PP1	relocalization
PP1	unknown	AHCYL1	dephosphorylation
PDPK1	“down-regulates activity”	AHCYL1	phosphorylation
CSNK1A1	unknown	AHCYL1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	24
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
60009	GRCh38/hg38 1p21.1-13.3(chr1:106074587-110144290)x1	Pathogenic
635280	Single allele	Likely pathogenic

SpliceAI

2401 predictions. Top by Δscore:

Variant	Effect	Δscore
1:109985169:GAAG:G	donor_gain	1.0000
1:109985170:A:T	donor_gain	1.0000
1:109985171:AGGTG:A	donor_loss	1.0000
1:109985172:GGTG:G	donor_loss	1.0000
1:109985173:G:C	donor_loss	1.0000
1:109985174:T:G	donor_loss	1.0000
1:110009027:T:TA	acceptor_gain	1.0000
1:110009030:A:AG	acceptor_gain	1.0000
1:110009031:T:G	acceptor_gain	1.0000
1:110009032:A:AG	acceptor_gain	1.0000
1:110009033:G:GT	acceptor_gain	1.0000
1:110009033:GC:G	acceptor_gain	1.0000
1:110009033:GCA:G	acceptor_gain	1.0000
1:110009033:GCAA:G	acceptor_gain	1.0000
1:110009033:GCAAA:G	acceptor_gain	1.0000
1:110009142:TCAG:T	donor_loss	1.0000
1:110009143:CAG:C	donor_loss	1.0000
1:110009144:AG:A	donor_loss	1.0000
1:110009145:GGTA:G	donor_loss	1.0000
1:110011205:T:TA	acceptor_gain	1.0000
1:110011206:G:A	acceptor_gain	1.0000
1:110011211:TAGCT:T	acceptor_loss	1.0000
1:110011212:A:AG	acceptor_gain	1.0000
1:110011212:AGCT:A	acceptor_gain	1.0000
1:110011213:G:GG	acceptor_gain	1.0000
1:110011213:GC:G	acceptor_gain	1.0000
1:110011213:GCT:G	acceptor_gain	1.0000
1:110011213:GCTG:G	acceptor_gain	1.0000
1:110011213:GCTGC:G	acceptor_gain	1.0000
1:110011353:GCAAG:G	donor_gain	1.0000

AlphaMissense

3483 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:110011328:G:A	G116E	1.000
1:110012939:T:A	W174R	1.000
1:110012939:T:C	W174R	1.000
1:110012953:C:A	N178K	1.000
1:110012953:C:G	N178K	1.000
1:110014780:T:A	W200R	1.000
1:110014780:T:C	W200R	1.000
1:110014804:T:C	F208L	1.000
1:110014806:C:A	F208L	1.000
1:110014806:C:G	F208L	1.000
1:110014815:T:G	C211W	1.000
1:110015431:G:C	D228H	1.000
1:110015438:G:A	G230E	1.000
1:110015497:G:C	G250R	1.000
1:110015498:G:A	G250D	1.000
1:110015512:A:C	S255R	1.000
1:110015514:C:A	S255R	1.000
1:110015514:C:G	S255R	1.000
1:110015521:G:C	G258R	1.000
1:110015522:G:A	G258D	1.000
1:110016346:T:C	L262P	1.000
1:110016355:T:C	L265P	1.000
1:110016385:C:A	A275D	1.000
1:110016392:C:A	N277K	1.000
1:110016392:C:G	N277K	1.000
1:110016394:T:A	V278D	1.000
1:110018012:C:G	C373W	1.000
1:110019555:C:A	A465E	1.000
1:110019558:T:C	L466P	1.000
1:110019567:T:C	L469P	1.000

dbSNP variants (sampled 300 via entrez): RS1000016253 (1:110023208 A>G), RS1000053370 (1:109984433 C>G,T), RS1000084728 (1:110008167 AC>A), RS1000114489 (1:110018938 C>G,T), RS1000133359 (1:109985062 C>T), RS1000225293 (1:110017349 T>G), RS1000312477 (1:109984288 A>C), RS1000396236 (1:110019408 T>C), RS1000531147 (1:109992903 C>A,G,T), RS1000551710 (1:110004114 A>G), RS1000831307 (1:110003618 A>G), RS1000882889 (1:109989985 A>C), RS1000912036 (1:109990308 GTTAGCAT>G), RS1001092678 (1:109985381 C>A,T), RS1001092949 (1:110020026 C>T)

Disease associations

OMIM: gene MIM:607826 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008839_337	Height	1.000000e-10

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3751646 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.57	IC50	2.7	nM	CHEMBL2059155
8.49	IC50	3.2	nM	CHEMBL3753637
7.89	IC50	13	nM	CHEMBL3753746
5.00	IC50	1e+04	nM	CHEMBL3754027

PubChem BioAssay actives

4 with measured affinity, of 5 total; 4 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-amino-7-bromoimidazo[4,5-c]pyridin-1-yl)-3-(hydroxymethyl)cyclopent-3-ene-1,2-diol	1272472: Inhibition of S-adenosylhomocysteine hydrolase (unknown origin)	ic50	0.0027	uM
(1R,2S,5R)-3-(4-aminoimidazo[4,5-c]pyridin-1-yl)-5-(hydroxymethyl)cyclopent-3-ene-1,2-diol	1272472: Inhibition of S-adenosylhomocysteine hydrolase (unknown origin)	ic50	0.0032	uM
(1R,2S,5R)-3-(4-amino-7-bromoimidazo[4,5-c]pyridin-1-yl)-5-(hydroxymethyl)cyclopent-3-ene-1,2-diol	1272472: Inhibition of S-adenosylhomocysteine hydrolase (unknown origin)	ic50	0.0130	uM
(1S,2R,5S)-3-(4-amino-7-bromoimidazo[4,5-c]pyridin-1-yl)-5-(hydroxymethyl)cyclopent-3-ene-1,2-diol	1272472: Inhibition of S-adenosylhomocysteine hydrolase (unknown origin)	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, decreases expression, affects cotreatment	3
bisphenol S	affects expression, increases expression	2
Smoke	decreases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
bisphenol F	affects cotreatment, increases expression	1
2,4,6-tribromophenol	decreases expression	1
sodium arsenate	decreases expression	1
decabromobiphenyl ether	decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	decreases expression	1
nickel sulfate	affects expression	1
pentabromodiphenyl ether	increases expression	1
CGP 52608	affects binding, increases reaction	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	decreases expression	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	affects response to substance	1
Coumestrol	decreases expression	1
Dexamethasone	increases expression, affects cotreatment	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3757541	Binding	Inhibition of S-adenosylhomocysteine hydrolase (unknown origin)	Enantiomeric 3-deaza-1’,6’-isoneplanocin and its 3-bromo analogue: Synthesis by the Ullmann reaction and their antiviral properties. — Bioorg Med Chem Lett

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9XE	Ubigene HeLa AHCYL1 KO	Cancer cell line	Female
CVCL_E4KV	ICC25	Cancer cell line	Female

Clinical trials (associated diseases)

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