ASMT

Summary

ASMT (acetylserotonin O-methyltransferase, HGNC:750) is a protein-coding gene on chromosome Xp22.3 and Yp11.3, encoding Acetylserotonin O-methyltransferase (P46597). Catalyzes the transfer of a methyl group onto N-acetylserotonin, producing melatonin (N-acetyl-5-methoxytryptamine).

This gene belongs to the methyltransferase superfamily, and is located in the pseudoautosomal region (PAR) at the end of the short arms of the X and Y chromosomes. The encoded enzyme catalyzes the final reaction in the synthesis of melatonin, and is abundant in the pineal gland. Alternatively spliced transcript variants have been noted for this gene.

Source: NCBI Gene 438 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 116 total
• MANE Select transcript: NM_001171038

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:750
Approved symbol	ASMT
Name	acetylserotonin O-methyltransferase
Location	Xp22.3 and Yp11.3
Locus type	gene with protein product
Status	Approved
Aliases	HIOMT, ASMTY, HIOMTY
Ensembl gene	ENSG00000196433
Ensembl biotype	protein_coding
OMIM	300015, 402500
Entrez	438

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000381229, ENST00000381233, ENST00000381241, ENST00000432523, ENST00000509780

RefSeq mRNA: 3 — MANE Select: NM_001171038 NM_001171038, NM_001171039, NM_001416525

CCDS: CCDS14117, CCDS55364

Canonical transcript exons

ENST00000381241 — 9 exons

Exon	Start	End
ENSE00001122491	1636438	1636560
ENSE00001153223	1623139	1623313
ENSE00001203617	1633150	1633290
ENSE00001203622	1629821	1629939
ENSE00001303750	1627703	1627771
ENSE00001328959	1624269	1624398
ENSE00001598652	1632704	1632787
ENSE00001700403	1642803	1643081
ENSE00001927792	1615059	1615268

Expression profiles

Bgee: expression breadth ubiquitous, 148 present calls, max score 80.60.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.0188 / max 2377.5713, expressed in 18 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
195346	0.7613	4
195347	0.5251	7
195345	0.3404	4
195348	0.1865	6
195351	0.1092	6
195350	0.0708	4
195349	0.0255	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.60	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	67.07	gold quality
secondary oocyte	CL:0000655	63.70	gold quality
vena cava	UBERON:0004087	62.83	gold quality
colonic epithelium	UBERON:0000397	60.64	gold quality
superficial temporal artery	UBERON:0001614	60.50	gold quality
vastus lateralis	UBERON:0001379	60.12	gold quality
adenohypophysis	UBERON:0002196	59.73	gold quality
quadriceps femoris	UBERON:0001377	59.69	gold quality
pituitary gland	UBERON:0000007	58.94	gold quality
oocyte	CL:0000023	58.06	silver quality
cerebellar vermis	UBERON:0004720	56.81	gold quality
bone marrow	UBERON:0002371	56.67	gold quality
sural nerve	UBERON:0015488	56.45	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	56.24	gold quality
endocervix	UBERON:0000458	55.82	gold quality
ectocervix	UBERON:0012249	55.73	gold quality
nasal cavity epithelium	UBERON:0005384	55.63	gold quality
mammary duct	UBERON:0001765	55.39	gold quality
epithelium of mammary gland	UBERON:0003244	55.32	gold quality
left uterine tube	UBERON:0001303	55.16	gold quality
germinal epithelium of ovary	UBERON:0001304	54.78	gold quality
decidua	UBERON:0002450	54.69	gold quality
body of uterus	UBERON:0009853	54.69	gold quality
adrenal tissue	UBERON:0018303	54.59	gold quality
endothelial cell	CL:0000115	54.42	gold quality
right adrenal gland	UBERON:0001233	54.33	gold quality
choroid plexus epithelium	UBERON:0003911	54.25	silver quality
mucosa of paranasal sinus	UBERON:0005030	54.15	gold quality
esophagus squamous epithelium	UBERON:0006920	54.13	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CRX, OTX2

Literature-anchored findings (GeneRIF, showing 21)

• Two polymorphisms located in the acetylserotonin methyltransferase (ASMT)promoter were more frequent in autism spectrum disorders (ASD); analyses revealed a highly significant decrease in ASMT activity and melatonin level in individuals with ASD. (PMID:17505466)
• The data of this study does not support a correleation between asmt gene and autism. (PMID:17957233)
• The results of this study indicated that HIOMT immunohistochemistry may be useful for the diagnosis of PPTs and be a prognostic factor in pineal parenchymal cell tumors. (PMID:20418777)
• Results show the AA genotype and the GG genotype of ASMT were associated with lower risk for having recurrent depressive disorder. In turn, patients with depression were characterised by reduced mRNA expression for ASMT. (PMID:20433639)
• study of genetic variability of ASMT in a cohort of patients with intellectual disability (ID)and controls; identifed patients with deleterious ASMT mutations and decreased ASMT activity; however, study does not support ASMT as a causative gene for ID (PMID:21251267)
• The expression of HIOMT in epithelial cells of striated ducts in human submandibular glands. (PMID:21437622)
• Data found a splice site mutation in ASMT (IVS5+2T>C) and one stop mutation in MTNR1A (Y170X) - detected exclusively in patients with ADHD - for which biochemical analyses indicated that they abolish the activity of ASMT and MTNR1A. (PMID:21615493)
• There is dysregulation of the AANAT/ASMT/melatonin –> melatonin receptor axis in cholangiocarcinoma, which inhibited melatonin secretion and subsequently enhanced CCA growth. (PMID:21778461)
• Rare and common variations in ASMT might play a role in bipolar disorder vulnerability. (PMID:22694957)
• study presents the X-ray crystal structure of ASMT; analysis of nonsynonymous variants found that the majority of these mutations reduced or abolished ASMT activity; estimate the allelic frequency of ASMT deleterious mutations ranges from 0.66% in Europe to 2.97% in Asia (PMID:22775292)
• ASMT might be a susceptibility gene for autism (PMID:23349736)
• results support the possible involvement of the ASMT gene in autism spectrum disorders (PMID:23995775)
• Bipolar disorder-associated SNP influences sleep and circadian rhythms in bipolar patients in remission and controls. (PMID:24308489)
• These data suggest a relationship between decreased mRNA and protein expression levels of ASMT gene and cognitive impairment. (PMID:24881886)
• results indicate that expression of sleep onset delay relates to melatonin pathway genes. (PMID:25059483)
• two single nucleotide polymorphisms (rs4446909 and rs5989681)in the promoter of ASMT do not contribute to the pathogenesis of schizophrenia in Chinese-Han subjects (PMID:26154813)
• The pseudoautosomal region of human X and Y chromosome encoded ASMT protein was predicted to interact with many small molecules than that of interacting proteins. (PMID:26279084)
• Even when considering only high-grade glioma patients, a low ASMT:CYP1B1 value, which suggests decreased melatonin and enhanced aggressiveness, was strongly associated with poor survival. Overall, our data reveal the prognostic value of the melatonergic system of gliomas and provide insights into the therapeutic role of melatonin. (PMID:26510398)
• Low HIOMT expression is associated with lung cancer. (PMID:29794137)
• A novel signature predicts recurrence risk and therapeutic response in breast cancer patients. (PMID:33586202)
• [Association of polymorphic variants of DDC (AADC), AANAT and ASMT genes encoding enzymes for melatonin synthesis with the higher risk of neuropsychiatric disorders].", trans “Assotsiatsiya polimorfizmov genov DDC (AADC), AANAT i ASMT, kodiruyushchikh fermenty sinteza melatonina, s riskom razvitiya psikhonevrologicheskikh rasstroistv. (PMID:34184492)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	asmt	ENSDARG00000098249
mus_musculus	Asmt	ENSMUSG00000093806
rattus_norvegicus	Asmt	ENSRNOG00000001324

Paralogs (1): ASMTL (ENSG00000169093)

Protein

Protein identifiers

Acetylserotonin O-methyltransferase — P46597 (reviewed: P46597)

Alternative names: Hydroxyindole O-methyltransferase

All UniProt accessions (4): P46597, I7HFW6, X5D2A4, X5D784

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the transfer of a methyl group onto N-acetylserotonin, producing melatonin (N-acetyl-5-methoxytryptamine). Does not show Acetylserotonin O-methyltransferase activity. Does not show Acetylserotonin O-methyltransferase activity.

Subunit / interactions. Homodimer.

Tissue specificity. Expressed in the pineal gland (at protein level). In the retina, very low expression is found at the mRNA level, and not at the protein level.

Induction. By all-trans-, 9-cis- and 13-cis-retinoic acid and by serum treatment, following starvation, in the retinoblastoma cell line Y79.

Pathway. Aromatic compound metabolism; melatonin biosynthesis; melatonin from serotonin: step 1/2.

Miscellaneous. The gene coding for this protein is located in the pseudoautosomal region 1 (PAR1) of X and Y chromosomes. Includes part of a LINE-1 element.

Similarity. Belongs to the class I-like SAM-binding methyltransferase superfamily. Cation-independent O-methyltransferase family.

Isoforms (3)

UniProt ID	Names	Canonical?
P46597-1	1	yes
P46597-2	2
P46597-3	3

RefSeq proteins (3): NP_001164509, NP_001164510, NP_001403454 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001077	COMT_C	Domain
IPR012967	COMT-like_dimerisation	Domain
IPR016461	COMT-like	Family
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily

Pfam: PF00891, PF08100

Enzyme classification (BRENDA):

• EC 2.1.1.4 — acetylserotonin O-methyltransferase (BRENDA: 29 organisms, 33 substrates, 33 inhibitors, 22 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

3 substrates with measured Km, best-characterized 3. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
N-ACETYLSEROTONIN	0.005–0.864	13
S-ADENOSYL-L-METHIONINE	0.005–0.11	7
SEROTONIN	1.036	1

Catalyzed reactions (Rhea), 1 shown:

• N-acetylserotonin + S-adenosyl-L-methionine = melatonin + S-adenosyl-L-homocysteine + H(+) (RHEA:15573)

UniProt features (73 total): sequence variant 21, helix 19, strand 12, binding site 8, mutagenesis site 6, splice variant 2, sequence conflict 2, chain 1, active site 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4A6D	X-RAY DIFFRACTION	2.4
4A6E	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P46597-F1	95.55	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 (1): 255 (proton donor/acceptor)

Ligand- & substrate-binding residues (8): 147; 164; 210; 235–237; 252; 256; 302; 306

Mutagenesis-validated functional residues (6):

Position	Phenotype
11	reduced enzyme activity.
31	no effect on enzyme activity.
111	no effect on enzyme activity.
248	nearly abolishes enzyme activity.
296	nearly abolishes enzyme activity.
318	reduced enzyme activity.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-209931	Serotonin and melatonin biosynthesis
R-HSA-1430728	Metabolism
R-HSA-209776	Metabolism of amine-derived hormones
R-HSA-71291	Metabolism of amino acids and derivatives

MSigDB gene sets: 51 (showing top): GOBP_REGULATION_OF_HORMONE_LEVELS, GCM_MYCL1, GOBP_TRANSLATION, GCM_RING1, GOBP_AMIDE_METABOLIC_PROCESS, GCM_DPF2, GOBP_AMIDE_BIOSYNTHETIC_PROCESS, GOBP_HORMONE_BIOSYNTHETIC_PROCESS, GOBP_INDOLE_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, GOBP_METHYLATION, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, GOMF_PROTEIN_DIMERIZATION_ACTIVITY, GOMF_PROTEIN_HOMODIMERIZATION_ACTIVITY, GOMF_O_METHYLTRANSFERASE_ACTIVITY

GO Biological Process (5): translation (GO:0006412), lipid metabolic process (GO:0006629), melatonin biosynthetic process (GO:0030187), methylation (GO:0032259), indolalkylamine biosynthetic process (GO:0046219)

GO Molecular Function (8): O-methyltransferase activity (GO:0008171), S-methyltransferase activity (GO:0008172), acetylserotonin O-methyltransferase activity (GO:0017096), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), methyltransferase activity (GO:0008168), transferase activity (GO:0016740), protein dimerization activity (GO:0046983)

GO Cellular Component (1): cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Metabolism of amine-derived hormones	1
Metabolism of amino acids and derivatives	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
indole-containing compound biosynthetic process	2
methyltransferase activity	2
protein binding	2
peptidyltransferase activity	1
translational initiation	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
primary metabolic process	1
melatonin metabolic process	1
hormone biosynthetic process	1
metabolic process	1
biogenic amine biosynthetic process	1
O-methyltransferase activity	1
S-adenosylmethionine-dependent methyltransferase activity	1
identical protein binding	1
protein dimerization activity	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
cytoplasm	1
cellular anatomical structure	1

Protein interactions and networks

STRING

972 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ASMT	AANAT	Q16613	940
ASMT	SLC25A6	P12236	849
ASMT	AKAP17A	Q02040	784
ASMT	ESCO1	Q5FWF5	742
ASMT	TPH1	P17752	741
ASMT	ESCO2	Q56NI9	735
ASMT	EPRS1	P07814	700
ASMT	CSF2RA	P15509	692
ASMT	DDC	P20711	688
ASMT	AMELX	Q99217	677
ASMT	CLCN4	P51793	649
ASMT	MTNR1A	P48039	648
ASMT	SHOX	O15266	646
ASMT	STS	P08842	645
ASMT	MTNR1B	P49286	624

IntAct

3 interactions, top by confidence:

A	B	Type	Score
ASMT	ASMT	psi-mi:“MI:0407”(direct interaction)	0.540
ASMT	ASMT	psi-mi:“MI:0915”(physical association)	0.540

BioGRID (1): ASMT (Positive Genetic)

ESM2 similar proteins: A0A6N3IN21, A3KCL7, A4IFH5, A7MBC0, A7MBI7, D3ZDK7, D3ZDM7, E1BNQ4, P09367, P10950, P11172, P13439, P17256, P20132, P24298, P25409, P31754, P46597, P50053, P97328, Q02974, Q03426, Q0VCW4, Q1JPD3, Q3B8E3, Q3TY86, Q3ZKN0, Q5BJJ5, Q5E9T8, Q5M7T9, Q5R514, Q5R824, Q5RD71, Q5RFE6, Q6PCB7, Q6SKR2, Q80W22, Q8CHP8, Q8CIM3, Q8HZJ0

Diamond homologs: A0A0K2JL91, A0A166U5H3, A0A172J1V3, A8J6X1, A8QW51, A9X7L0, B0CN39, C7SDN9, D3KU66, D3KU67, I3V6A7, K4RFM2, O82054, P0DXJ8, P10950, P16559, P28002, P42712, P46597, P55790, Q06509, Q06528, Q0IP69, Q12120, Q39522, Q41086, Q43047, Q54527, Q6T1F6, Q6VMV9, Q7XB11, Q8HZJ0, Q92056, Q9HWH2, Q9X5T6, A0A088MF62, A0A0E3VJW8, A0A0N9HTA1, A0A1B2CTC1, A0A1L9UR19

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
ASMT	“up-regulates quantity”	melatonin	“chemical modification”
N-acetylserotonin	“up-regulates activity”	ASMT	“chemical activation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	12
Likely benign	5
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1180 predictions. Top by Δscore:

Variant	Effect	Δscore
X:1615264:CCCAG:C	donor_loss	1.0000
X:1615265:CCAG:C	donor_loss	1.0000
X:1615269:GT:G	donor_loss	1.0000
X:1615270:T:G	donor_loss	1.0000
X:1623130:T:TA	acceptor_gain	1.0000
X:1623137:A:G	acceptor_gain	1.0000
X:1623309:AAAAG:A	donor_loss	1.0000
X:1623312:AGGTG:A	donor_loss	1.0000
X:1623313:GGT:G	donor_loss	1.0000
X:1623314:G:GA	donor_loss	1.0000
X:1623315:T:A	donor_loss	1.0000
X:1624257:T:TA	acceptor_gain	1.0000
X:1624259:T:TA	acceptor_gain	1.0000
X:1624261:T:TA	acceptor_gain	1.0000
X:1624266:CAGCT:C	acceptor_loss	1.0000
X:1624267:A:AG	acceptor_gain	1.0000
X:1624267:AGCTT:A	acceptor_loss	1.0000
X:1624268:G:GA	acceptor_gain	1.0000
X:1624268:GC:G	acceptor_gain	1.0000
X:1624268:GCT:G	acceptor_gain	1.0000
X:1624268:GCTT:G	acceptor_gain	1.0000
X:1624268:GCTTT:G	acceptor_gain	1.0000
X:1624342:G:GT	donor_gain	1.0000
X:1624345:G:GG	donor_gain	1.0000
X:1624391:GCC:G	donor_gain	1.0000
X:1624394:GTGAG:G	donor_loss	1.0000
X:1624395:TGAG:T	donor_loss	1.0000
X:1624396:GAGG:G	donor_loss	1.0000
X:1624398:GGT:G	donor_loss	1.0000
X:1627701:A:AG	acceptor_gain	1.0000

AlphaMissense

2424 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
Y:1629843:T:C	F156L	0.994
Y:1629845:C:A	F156L	0.994
Y:1629845:C:G	F156L	0.994
Y:1615254:T:C	F19L	0.993
Y:1615256:C:A	F19L	0.993
Y:1615256:C:G	F19L	0.993
Y:1627755:T:C	F143L	0.993
Y:1627757:T:A	F143L	0.993
Y:1627757:T:G	F143L	0.993
Y:1642953:T:C	F326S	0.992
Y:1642824:A:T	E283V	0.991
Y:1623169:T:C	F34L	0.990
Y:1623171:T:A	F34L	0.990
Y:1623171:T:G	F34L	0.990
Y:1642952:T:C	F326L	0.989
Y:1642954:C:A	F326L	0.989
Y:1642954:C:G	F326L	0.989
Y:1636497:C:G	H255D	0.988
Y:1642815:T:C	L280P	0.988
Y:1624373:T:A	W117R	0.987
Y:1624373:T:C	W117R	0.987
Y:1624391:G:C	A123P	0.987
Y:1642885:G:A	M303I	0.987
Y:1642885:G:C	M303I	0.987
Y:1642885:G:T	M303I	0.987
Y:1623270:T:G	C67W	0.986
Y:1642912:G:C	R312S	0.986
Y:1642912:G:T	R312S	0.986
Y:1623268:T:C	C67R	0.985
Y:1629867:T:A	W164R	0.985

dbSNP variants (sampled 300 via entrez): RS10534149 (X:1607472 ATAAT>A), RS10582998 (X:1629082 TTATA>T,TTA,TTATATA,TTATATATA), RS111161782 (X:1596662 T>C), RS111161783 (X:1596666 T>A,C), RS111162435 (X:1596680 C>A,T), RS111236391 (X:1613428 G>C), RS111268194 (X:1618318 C>A,T), RS111286854 (X:1624661 C>G), RS111318906 (X:1636024 C>G,T), RS111322391 (X:1616098 G>A,T), RS111323053 (X:1614683 G>A,C), RS111332569 (X:1599780 T>C), RS111361922 (X:1615756 C>A,G,T), RS111387616 (X:1605447 G>A,T), RS111402127 (X:1596934 A>C,G,T)

Disease associations

OMIM: gene MIM:300015, MIM:402500 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST004904_25	Body mass index	5.000000e-11
GCST007705_26	Pulse pressure	2.000000e-11
GCST007707_64	Hypertension	4.000000e-10
GCST012354_36	Anxiety	4.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0005763	pulse pressure measurement
EFO:0009863	anxiety measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

7 total (human), top 7 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
propionaldehyde	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
CGP 52608	affects binding, increases reaction	1
Urethane	increases expression	1
Valproic Acid	increases methylation	1
Cyclosporine	decreases methylation	1

Clinical trials (associated diseases)

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