BHMT2

gene
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Summary

BHMT2 (betaine–homocysteine S-methyltransferase 2, HGNC:1048) is a protein-coding gene on chromosome 5q14.1, encoding S-methylmethionine–homocysteine S-methyltransferase BHMT2 (Q9H2M3). Involved in the regulation of homocysteine metabolism.

Homocysteine is a sulfur-containing amino acid that plays a crucial role in methylation reactions. Transfer of the methyl group from betaine to homocysteine creates methionine, which donates the methyl group to methylate DNA, proteins, lipids, and other intracellular metabolites. The protein encoded by this gene is one of two methyl transferases that can catalyze the transfer of the methyl group from betaine to homocysteine. Anomalies in homocysteine metabolism have been implicated in disorders ranging from vascular disease to neural tube birth defects such as spina bifida. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 23743 — RefSeq curated summary.

At a glance

  • GWAS associations: 17
  • Clinical variants (ClinVar): 69 total
  • Druggable target: yes
  • MANE Select transcript: NM_017614

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:1048
Approved symbolBHMT2
Namebetaine–homocysteine S-methyltransferase 2
Location5q14.1
Locus typegene with protein product
StatusApproved
Ensembl geneENSG00000132840
Ensembl biotypeprotein_coding
OMIM605932
Entrez23743

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 13 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000255192, ENST00000518666, ENST00000518758, ENST00000519743, ENST00000521567, ENST00000523046, ENST00000523472, ENST00000896177, ENST00000896178, ENST00000896179, ENST00000896180, ENST00000896181, ENST00000896182, ENST00000896183, ENST00000896184, ENST00000896185, ENST00000896186

RefSeq mRNA: 2 — MANE Select: NM_017614 NM_001178005, NM_017614

CCDS: CCDS4045, CCDS54871

Canonical transcript exons

ENST00000255192 — 8 exons

ExonStartEnd
ENSE000009716537908319279083374
ENSE000021157517908849379090069
ENSE000025053697908362879083856
ENSE000035617407907748079077612
ENSE000035619897906976779069815
ENSE000036406097908068779080878
ENSE000036841277908280979082956
ENSE000036946847907936979079460

Expression profiles

Bgee: expression breadth ubiquitous, 237 present calls, max score 99.16.

FANTOM5 (CAGE): breadth broad, TPM avg 4.6244 / max 515.7169, expressed in 596 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter IDTPM avgSamples expressed
572303.1159417
572290.7740321
572270.6726336
572280.061932

Top tissues by expression

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

TissueAnatomy IDExpression scoreQuality
renal medullaUBERON:000036299.16gold quality
right lobe of liverUBERON:000111499.11gold quality
liverUBERON:000210798.67gold quality
adult mammalian kidneyUBERON:000008298.63gold quality
metanephros cortexUBERON:001053397.95gold quality
nephron tubuleUBERON:000123197.50gold quality
kidney epitheliumUBERON:000481996.52gold quality
adult organismUBERON:000702396.32gold quality
kidneyUBERON:000211396.11gold quality
lower esophagus muscularis layerUBERON:003583395.58gold quality
lower esophagusUBERON:001347395.52gold quality
caput epididymisUBERON:000435895.23gold quality
renal glomerulusUBERON:000007493.98gold quality
mucosa of stomachUBERON:000119993.51gold quality
right lobe of thyroid glandUBERON:000111993.48gold quality
esophagogastric junction muscularis propriaUBERON:003584193.47gold quality
metanephric glomerulusUBERON:000473693.45gold quality
descending thoracic aortaUBERON:000234593.43gold quality
cortex of kidneyUBERON:000122592.85gold quality
left lobe of thyroid glandUBERON:000112092.71gold quality
corpus epididymisUBERON:000435992.28gold quality
tibial nerveUBERON:000132391.60gold quality
right adrenal gland cortexUBERON:003582791.54gold quality
thyroid glandUBERON:000204691.48gold quality
subcutaneous adipose tissueUBERON:000219091.38gold quality
metanephrosUBERON:000008191.15gold quality
stromal cell of endometriumCL:000225590.76gold quality
adipose tissueUBERON:000101390.75gold quality
thoracic aortaUBERON:000151590.70gold quality
left adrenal glandUBERON:000123490.58gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

ExperimentMarker?Max mean expression
E-CURD-119yes46.15
E-CURD-135no1573.07
E-ANND-3no0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

55 targeting BHMT2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-3064-3P100.0070.091254
HSA-MIR-548C-3P99.9974.017587
HSA-MIR-453199.9969.703181
HSA-MIR-56899.9869.862084
HSA-MIR-6778-3P99.9667.292693
HSA-MIR-3605-5P99.9667.12932
HSA-MIR-205-3P99.9269.923165
HSA-MIR-627-3P99.9071.423316
HSA-MIR-153-5P99.8973.866317
HSA-MIR-449299.8768.253611
HSA-MIR-5582-3P99.8672.484221
HSA-MIR-3121-3P99.8271.963630
HSA-MIR-548M99.7068.871749
HSA-MIR-548BA99.6969.141514
HSA-MIR-320299.6667.702737
HSA-MIR-613299.6065.831554
HSA-MIR-6836-5P99.6065.621538
HSA-MIR-7152-5P99.6069.332094
HSA-MIR-76299.5866.611994
HSA-MIR-449899.4767.422360
HSA-MIR-616599.4467.121389
HSA-MIR-501-3P99.3366.12651
HSA-MIR-502-3P99.3366.12651
HSA-MIR-519099.1567.761234
HSA-MIR-6510-5P99.1466.591081
HSA-MIR-125399.1267.081688
HSA-MIR-5001-5P99.0566.761972
HSA-MIR-6506-5P99.0465.661386
HSA-MIR-7151-3P99.0469.722370
HSA-MIR-511-5P98.9770.942268

Literature-anchored findings (GeneRIF, showing 10)

  • Hyperhomocysteinemia, a risk factor for coronary diseases, can be caused by genetic mutations in BHMT2 metabolism. (PMID:12818402)
  • Betaine-homocysteine S-methyltransferase-2 is an S-methylmethionine-homocysteine methyltransferase. (PMID:18230605)
  • Common genetic variation in BHMT and BHMT2 and functionally characterized BHMT SNPs. (PMID:18457970)
  • gene-gene interaction analysis revealed a significant epistatic interaction of BHMT2 (rs673752), PEMT (rs12325817), and PCYT1A (rs712012) with maternal NCL/P susceptibility. (PMID:20662904)
  • No significant level of association was found with cleft lip with or without cleft palate and BHMT2 variants. (PMID:21564312)
  • Multiple SNPs in BHMT and BHMT2 were identified to be associated with the occurrence of infant obstructive heart defects and interaction effects with maternal use of folic acid supplements. (PMID:25846410)
  • The faster evolutionary rate of BHMT2 overall suggests that selective constraints were reduced relative to BHMT. (PMID:26213999)
  • A three-way interaction among maternal and fetal variants in BHMT2, GSTP1 and GPX3 contribute to congenital heart defects (PMID:26612412)
  • Our study suggested markers in BHMT/BHMT2 and DMGDH might affect the risk of NSCL/P through pairwise interaction. (PMID:29356306)
  • Association of Maternal Betaine-Homocysteine Methyltransferase (BHMT) and BHMT2 Genes Polymorphisms with Congenital Heart Disease in Offspring. (PMID:35835902)

Cross-species orthologs

3 orthologs

OrganismSymbolGene ID
danio_reriobhmtENSDARG00000013430
mus_musculusBhmt2ENSMUSG00000042118
rattus_norvegicusBhmt2ENSRNOG00000040120

Paralogs (4): MTR (ENSG00000116984), UROD (ENSG00000126088), BHMT (ENSG00000145692), MTHFR (ENSG00000177000)

Protein

Protein identifiers

S-methylmethionine–homocysteine S-methyltransferase BHMT2Q9H2M3 (reviewed: Q9H2M3)

Alternative names: Betaine–homocysteine S-methyltransferase 2

All UniProt accessions (3): E5RGH5, E5RH96, Q9H2M3

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the regulation of homocysteine metabolism. Converts homocysteine to methionine using S-methylmethionine (SMM) as a methyl donor.

Subunit / interactions. Homotetramer. May interact with PRNP.

Tissue specificity. Expressed in liver and kidney and at reduced levels in the brain, heart, and skeletal muscle.

Cofactor. Binds 1 zinc ion per subunit.

Pathway. Amino-acid biosynthesis; L-methionine biosynthesis via de novo pathway; L-methionine from L-homocysteine (BhmT route): step 1/1.

Isoforms (2)

UniProt IDNamesCanonical?
Q9H2M3-11yes
Q9H2M3-22

RefSeq proteins (2): NP_001171476, NP_060084* (*=MANE)

Domains & families (InterPro)

IDNameType
IPR003726HCY_domDomain
IPR017226BHMT-likeFamily
IPR036589HCY_dom_sfHomologous_superfamily
IPR051524BHMTFamily

Pfam: PF02574

Catalyzed reactions (Rhea), 1 shown:

  • S-methyl-L-methionine + L-homocysteine = 2 L-methionine + H(+) (RHEA:26337)

UniProt features (7 total): binding site 3, chain 1, domain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-Q9H2M3-F195.820.92

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 (3): 208; 290; 291

Post-translational modifications (1): 321

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

IDPathway
R-HSA-1614635Sulfur amino acid metabolism
R-HSA-1430728Metabolism
R-HSA-71291Metabolism of amino acids and derivatives

MSigDB gene sets: 106 (showing top): GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_ASPARTATE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_SULFUR_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_S_ADENOSYLMETHIONINE_METABOLIC_PROCESS, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_METHIONINE_BIOSYNTHETIC_PROCESS, GOBP_METHIONINE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_AMINO_ACID_BETAINE_METABOLIC_PROCESS, GOBP_SULFUR_AMINO_ACID_METABOLIC_PROCESS, GOBP_METHYLATION

GO Biological Process (6): methylation (GO:0032259), S-methylmethionine metabolic process (GO:0033477), S-adenosylmethionine metabolic process (GO:0046500), L-methionine salvage (GO:0071267), modified amino acid metabolic process (GO:0006575), obsolete methionine biosynthetic process (GO:0009086)

GO Molecular Function (6): zinc ion binding (GO:0008270), S-methylmethionine-homocysteine S-methyltransferase activity (GO:0061627), methyltransferase activity (GO:0008168), S-methyltransferase activity (GO:0008172), transferase activity (GO:0016740), metal ion binding (GO:0046872)

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

Reactome top-level categories

Rollup of top-2 pathways:

CategoryPathways
Metabolism of amino acids and derivatives1
Metabolism1

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
metabolic process2
sulfur compound metabolic process2
modified amino acid metabolic process1
amino acid salvage1
L-methionine biosynthetic process1
transition metal ion binding1
S-methyltransferase activity1
transferase activity, transferring one-carbon groups1
methyltransferase activity1
catalytic activity1
cation binding1
cytoplasm1
cellular anatomical structure1
extracellular vesicle1

Protein interactions and networks

STRING

1274 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
BHMT2DMGDHQ9UI17814
BHMT2MTRRQ9UBK8795
BHMT2MTHFRP42898672
BHMT2AHCYP23526661
BHMT2P0DN79P0DN79659
BHMT2H7C2H4H7C2H4658
BHMT2MAT1AQ00266636
BHMT2SHMT1P34896625
BHMT2MTHFD1P11586622
BHMT2AHCYL2Q96HN2559
BHMT2GNMTQ14749542
BHMT2CTHP32929534
BHMT2TCN2P20062527
BHMT2MTRQ99707525
BHMT2ENOPH1Q9UHY7524

IntAct

6 interactions, top by confidence:

ABTypeScore
BHMT2INPPL1psi-mi:“MI:0914”(association)0.530
BHMTBHMT2psi-mi:“MI:0914”(association)0.530
BHMT2GAPDHSpsi-mi:“MI:0915”(physical association)0.400

BioGRID (13): BHMT (Affinity Capture-MS), INPPL1 (Affinity Capture-MS), TBCE (Affinity Capture-MS), BHMT2 (Affinity Capture-MS), TBCE (Affinity Capture-MS), INPPL1 (Affinity Capture-MS), BHMT2 (Affinity Capture-MS), INPPL1 (Affinity Capture-MS), BHMT2 (Affinity Capture-MS), BIRC7 (Affinity Capture-MS), TBCE (Affinity Capture-MS), GAPDHS (Affinity Capture-MS), APP (Reconstituted Complex)

ESM2 similar proteins: A0A1S4BZI5, A7M6E7, A7M6E8, B4G0F3, B8BKI7, B9SQI7, C6JS30, F4JGR5, F4JP46, F4JVN6, O04015, O04226, O65361, O80574, O95394, P11172, P31754, P32296, P69060, Q10P67, Q10S55, Q28EN2, Q2R483, Q32LQ4, Q3SZM5, Q53JY8, Q5R514, Q5R6R5, Q5RAK7, Q5RF32, Q5XGM3, Q6P6M7, Q6STH5, Q8GSJ1, Q8LAX0, Q8LB01, Q8NFW8, Q90WG6, Q91WS4, Q94A08

Diamond homologs: O06745, O09171, O33259, O33465, P13009, P37586, Q49775, Q55786, Q5M8Z0, Q5RF32, Q95332, Q9AJQ8, Q9H2M3, O35490, Q32LQ4, Q5I597, Q5RFG2, Q5XGM3, Q68FT5, Q91WS4, Q93088

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance59
Likely benign3
Benign1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1120 predictions. Top by Δscore:

VariantEffectΔscore
5:79069813:AAGGT:Adonor_loss1.0000
5:79069814:AGGTG:Adonor_loss1.0000
5:79069815:GGTG:Gdonor_loss1.0000
5:79069816:GTG:Gdonor_loss1.0000
5:79079342:A:AGacceptor_gain1.0000
5:79083188:ACAG:Aacceptor_gain1.0000
5:79083188:ACAGG:Aacceptor_gain1.0000
5:79069812:GAAG:Gdonor_gain0.9900
5:79069817:T:Gdonor_loss0.9900
5:79079342:AAT:Aacceptor_gain0.9900
5:79079343:A:Gacceptor_gain0.9900
5:79079344:T:Gacceptor_gain0.9900
5:79079349:A:AGacceptor_gain0.9900
5:79079350:A:Gacceptor_gain0.9900
5:79083186:GCACA:Gacceptor_loss0.9900
5:79083187:CACAG:Cacceptor_loss0.9900
5:79083189:C:Gacceptor_gain0.9900
5:79083189:CA:Cacceptor_loss0.9900
5:79083190:A:ACacceptor_loss0.9900
5:79083190:A:AGacceptor_gain0.9900
5:79083190:AG:Aacceptor_gain0.9900
5:79083190:AGG:Aacceptor_gain0.9900
5:79083190:AGGG:Aacceptor_gain0.9900
5:79083191:G:GGacceptor_gain0.9900
5:79083191:GG:Gacceptor_gain0.9900
5:79083191:GGG:Gacceptor_gain0.9900
5:79083191:GGGG:Gacceptor_gain0.9900
5:79083263:G:GTdonor_gain0.9900
5:79083266:GGTCT:Gdonor_gain0.9900
5:79069816:G:GGdonor_gain0.9800

AlphaMissense

2378 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
5:79077528:A:CS28R0.985
5:79077530:C:AS28R0.985
5:79077530:C:GS28R0.985
5:79079369:T:AV56D0.978
5:79079428:T:CF76L0.974
5:79079430:T:AF76L0.974
5:79079430:T:GF76L0.974
5:79079398:G:CA66P0.967
5:79079411:T:AV70D0.966
5:79079389:T:CF63L0.965
5:79079391:C:AF63L0.965
5:79079391:C:GF63L0.965
5:79080709:C:AA94D0.965
5:79083712:G:AG289E0.961
5:79083743:G:CR299S0.961
5:79083743:G:TR299S0.961
5:79083744:G:CA300P0.961
5:79080757:C:AA110E0.960
5:79079378:T:CL59P0.959
5:79083214:C:AN207K0.958
5:79083214:C:GN207K0.958
5:79077520:G:AG25E0.955
5:79083236:A:CS215R0.955
5:79083238:C:AS215R0.955
5:79083238:C:GS215R0.955
5:79083653:A:CR269S0.955
5:79083653:A:TR269S0.955
5:79088511:G:CW343C0.955
5:79088511:G:TW343C0.955
5:79083760:T:CL305P0.954

dbSNP variants (sampled 300 via entrez): RS1000004663 (5:79071837 A>C,T), RS1000092160 (5:79076776 C>T), RS1000144343 (5:79076453 G>C,T), RS1000241362 (5:79071343 A>G), RS1000287640 (5:79084025 A>G), RS1000303490 (5:79083492 T>G), RS1000581075 (5:79082060 G>A), RS1000888109 (5:79082563 G>A), RS1001057054 (5:79076048 G>A), RS1001657569 (5:79087730 G>A), RS1001757983 (5:79075092 G>A), RS1001810317 (5:79074729 C>A,T), RS1002090090 (5:79073533 G>A), RS1002141602 (5:79087943 G>C), RS1002270042 (5:79068974 T>C)

Disease associations

OMIM: gene MIM:605932 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

17 associations (top):

StudyTraitp-value
GCST001852_5Metabolite levels2.000000e-09
GCST002039_10Blood trace element (Se levels)8.000000e-12
GCST002039_2Blood trace element (Se levels)9.000000e-28
GCST002670_1Blood and toenail selenium levels2.000000e-39
GCST002670_10Blood and toenail selenium levels8.000000e-20
GCST002670_2Blood and toenail selenium levels6.000000e-11
GCST002670_7Blood and toenail selenium levels2.000000e-15
GCST002670_8Blood and toenail selenium levels2.000000e-11
GCST002670_9Blood and toenail selenium levels1.000000e-36
GCST002671_15Toenail selenium levels3.000000e-13
GCST002671_16Toenail selenium levels5.000000e-06
GCST002671_5Toenail selenium levels1.000000e-16
GCST002671_6Toenail selenium levels2.000000e-11
GCST003358_1Betaine levels in individuals undergoing cardiac evaluation7.000000e-13
GCST006997_1Cerebrospinal fluid t-tau levels in mild cognitive impairment2.000000e-07
GCST009391_144Metabolite levels7.000000e-33
GCST012020_108Serum metabolite levels2.000000e-19

EFO canonical traits (4, from GWAS)

EFO IDTrait name
EFO:0004471insulin sensitivity measurement
EFO:0007787plasma betaine measurement
EFO:0004760t-tau measurement
EFO:0010476dimethylglycine measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2163167 (SINGLE PROTEIN), CHEMBL3391661 (PROTEIN FAMILY)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChemblTypeValueUnitMolecule
7.11Ki77nMCHEMBL2164724
5.44IC503600nMCHEMBL2164724

PubChem BioAssay actives

2 with measured affinity, of 11 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

CompoundAssayTypeValueUnit
2-amino-7-[(3S)-3-amino-3-carboxypropyl]sulfanyl-5-methylheptanoic acid697235: Competitive inhibition of recombinant human BHMT2 expressed in Escherichia coli BL31(DE3) by Dixon plot method in presence of D,L-homocysteineki0.0770uM

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

ChemicalActions (top 5)PubMed papers
Benzo(a)pyrenedecreases expression, decreases methylation, increases expression, increases methylation5
sodium arseniteincreases expression2
Acetaminophendecreases expression, increases expression2
Silicon Dioxidedecreases expression2
Cyclosporineincreases expression, decreases expression2
Aflatoxin B1affects expression, decreases methylation2
testosterone enanthateaffects expression1
pirinixic acidaffects binding, increases activity, increases expression1
bisphenol Aincreases expression1
ethyl-p-hydroxybenzoateincreases expression1
bisphenol Saffects cotreatment, decreases expression1
Dexamethasoneaffects cotreatment, decreases expression1
Diethylhexyl Phthalatedecreases expression1
Indomethacindecreases expression, affects cotreatment1
Methioninedecreases reaction, increases metabolic processing1
Quercetindecreases expression1
S-Adenosylmethioninedecreases reaction, increases metabolic processing1
Valproic Aciddecreases expression1
Vitamin Uincreases metabolic processing, decreases reaction1
1-Methyl-3-isobutylxanthineaffects cotreatment, decreases expression1
Okadaic Aciddecreases expression1
Copper Sulfateincreases expression1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL2166486BindingInhibition of recombinant human BHMT2 expressed in Escherichia coli BL31(DE3) at 20 uMDouble-headed sulfur-linked amino acids as first inhibitors for betaine-homocysteine S-methyltransferase 2. — J Med Chem

Clinical trials (associated diseases)

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

No linked Atlas pages yet — the cross-entity mesh grows as the corpus expands.