HEMK1

Summary

HEMK1 (HemK methyltransferase 1, mitochondrial release factors N(5)-glutamine, HGNC:24923) is a protein-coding gene on chromosome 3p21.31, encoding MTRF1L release factor glutamine methyltransferase (Q9Y5R4). N5-glutamine methyltransferase responsible for the methylation of the glutamine residue in the universally conserved GGQ motif of the mitochondrial translation release factors MTRF1, MTRF1L, MRPL58/ICT1 and MTRFR.

Enables peptide chain release factor N(5)-glutamine methyltransferase activity. Predicted to be involved in translational termination. Located in mitochondrion.

Source: NCBI Gene 51409 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 39 total
• MANE Select transcript: NM_016173

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24923
Approved symbol	HEMK1
Name	HemK methyltransferase 1, mitochondrial release factors N(5)-glutamine
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	MTQ1
Ensembl gene	ENSG00000114735
Ensembl biotype	protein_coding
OMIM	618609
Entrez	51409

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 28 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000232854, ENST00000424388, ENST00000434410, ENST00000443894, ENST00000448997, ENST00000455834, ENST00000482974, ENST00000904245, ENST00000904246, ENST00000904247, ENST00000904248, ENST00000904249, ENST00000904250, ENST00000904251, ENST00000904252, ENST00000904253, ENST00000904254, ENST00000904255, ENST00000904256, ENST00000928436, ENST00000928437, ENST00000928438, ENST00000960467, ENST00000960468, ENST00000960469, ENST00000960470, ENST00000960471, ENST00000960472, ENST00000960473, ENST00000960474, ENST00000960475

RefSeq mRNA: 12 — MANE Select: NM_016173 NM_001317851, NM_001377420, NM_001377421, NM_001377422, NM_001377423, NM_001377424, NM_001377425, NM_001377426, NM_001377427, NM_001377428, NM_001377429, NM_016173

CCDS: CCDS2830

Canonical transcript exons

ENST00000232854 — 11 exons

Exon	Start	End
ENSE00000769816	50579844	50579939
ENSE00000769817	50580116	50580229
ENSE00000769818	50580381	50596166
ENSE00000860772	50570931	50571332
ENSE00001852106	50569522	50569574
ENSE00003462320	50572115	50572208
ENSE00003541995	50577826	50577875
ENSE00003546350	50577052	50577186
ENSE00003565420	50577509	50577573
ENSE00003613219	50578821	50578926
ENSE00003690947	50571710	50571801

Expression profiles

Bgee: expression breadth ubiquitous, 264 present calls, max score 92.24.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.4652 / max 96.6072, expressed in 1748 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36740	7.2070	1727
36739	1.2485	728
36741	0.0097	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	92.24	gold quality
right lobe of thyroid gland	UBERON:0001119	91.02	gold quality
right lobe of liver	UBERON:0001114	89.71	gold quality
left lobe of thyroid gland	UBERON:0001120	89.42	gold quality
mucosa of transverse colon	UBERON:0004991	89.37	gold quality
thyroid gland	UBERON:0002046	89.06	gold quality
right testis	UBERON:0004534	88.87	gold quality
granulocyte	CL:0000094	88.81	gold quality
apex of heart	UBERON:0002098	88.79	gold quality
right adrenal gland	UBERON:0001233	88.37	gold quality
left testis	UBERON:0004533	88.20	gold quality
body of pancreas	UBERON:0001150	88.17	gold quality
left ovary	UBERON:0002119	88.07	gold quality
right adrenal gland cortex	UBERON:0035827	87.93	gold quality
lower esophagus mucosa	UBERON:0035834	87.74	gold quality
body of stomach	UBERON:0001161	87.57	gold quality
right ovary	UBERON:0002118	87.38	gold quality
adenohypophysis	UBERON:0002196	87.12	gold quality
left adrenal gland cortex	UBERON:0035825	86.87	gold quality
endocervix	UBERON:0000458	86.75	gold quality
left adrenal gland	UBERON:0001234	86.62	gold quality
stromal cell of endometrium	CL:0002255	86.35	gold quality
tendon of biceps brachii	UBERON:0008188	86.35	gold quality
pituitary gland	UBERON:0000007	86.11	gold quality
adrenal cortex	UBERON:0001235	85.87	gold quality
sperm	CL:0000019	85.81	gold quality
body of uterus	UBERON:0009853	85.76	gold quality
transverse colon	UBERON:0001157	85.75	gold quality
testis	UBERON:0000473	85.69	gold quality
stomach	UBERON:0000945	85.37	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.58

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

121 targeting HEMK1, 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-6798-5P	100.00	65.77	699
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-370-5P	99.78	66.81	706
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-4690-5P	99.65	66.24	813
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-26A-1-3P	99.64	66.81	788

Literature-anchored findings (GeneRIF, showing 2)

• Human mitochondrial methyltransferase, HMPrmC, which methylates the glutamine residue in the GGQ tripeptide motif of HMRF1L, was identified. (PMID:18541145)
• Mammalian HEMK1 methylates glutamine residue of the GGQ motif of mitochondrial release factors. (PMID:35260756)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	hemk1	ENSDARG00000078894
mus_musculus	Hemk1	ENSMUSG00000032579
rattus_norvegicus	Hemk1	ENSRNOG00000015458
drosophila_melanogaster	HemK1	FBGN0031817

Paralogs (2): ETFBKMT (ENSG00000139160), HEMK2 (ENSG00000156239)

Protein

Protein identifiers

MTRF1L release factor glutamine methyltransferase — Q9Y5R4 (reviewed: Q9Y5R4)

Alternative names: HemK methyltransferase family member 1, M.HsaHemKP

All UniProt accessions (4): A0A140VK98, Q9Y5R4, F2Z2F0, H7C258

UniProt curated annotations — full annotation on UniProt →

Function. N5-glutamine methyltransferase responsible for the methylation of the glutamine residue in the universally conserved GGQ motif of the mitochondrial translation release factors MTRF1, MTRF1L, MRPL58/ICT1 and MTRFR.

Subcellular location. Mitochondrion.

Similarity. Belongs to the protein N5-glutamine methyltransferase family.

RefSeq proteins (12): NP_001304780, NP_001364349, NP_001364350, NP_001364351, NP_001364352, NP_001364353, NP_001364354, NP_001364355, NP_001364356, NP_001364357, NP_001364358, NP_057257* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002052	DNA_methylase_N6_adenine_CS	Conserved_site
IPR002295	N4/N6-MTase_EcoPI_Mod-like	Family
IPR004556	HemK-like	Family
IPR007848	Small_mtfrase_dom	Domain
IPR019874	RF_methyltr_PrmC	Family
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily
IPR040758	PrmC_N	Domain
IPR050320	N5-glutamine_MTase	Family

Pfam: PF05175, PF17827

Enzyme classification (BRENDA):

• EC 2.1.1.297 — peptide chain release factor N5-glutamine methyltransferase (BRENDA: 6 organisms, 23 substrates, 0 inhibitors, 1 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• L-glutaminyl-[peptide chain release factor] + S-adenosyl-L-methionine = N(5)-methyl-L-glutaminyl-[peptide chain release factor] + S-adenosyl-L-homocysteine + H(+) (RHEA:42896)

UniProt features (8 total): binding site 5, sequence variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5R4-F1	88.08	0.81

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 (5): 167–171; 190; 225; 239–242; 239

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 146 (showing top): GOBP_TRANSLATIONAL_TERMINATION, GOBP_TRANSLATION, KEGG_HISTIDINE_METABOLISM, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, GOBP_METHYLATION, KEGG_TYROSINE_METABOLISM, MULLIGHAN_MLL_SIGNATURE_2_DN, LEIN_CHOROID_PLEXUS_MARKERS, KIM_WT1_TARGETS_DN, GOMF_N_METHYLTRANSFERASE_ACTIVITY, GOMF_PROTEIN_METHYLTRANSFERASE_ACTIVITY, GOMF_S_ADENOSYLMETHIONINE_DEPENDENT_METHYLTRANSFERASE_ACTIVITY, GOMF_TRANSFERASE_ACTIVITY_TRANSFERRING_ONE_CARBON_GROUPS, GAZDA_DIAMOND_BLACKFAN_ANEMIA_ERYTHROID_DN, DODD_NASOPHARYNGEAL_CARCINOMA_DN

GO Biological Process (3): translational termination (GO:0006415), methylation (GO:0032259), protein methylation (GO:0006479)

GO Molecular Function (10): DNA binding (GO:0003677), protein-glutamine N-methyltransferase activity (GO:0036009), peptide chain release factor N(5)-glutamine methyltransferase activity (GO:0102559), nucleic acid binding (GO:0003676), protein binding (GO:0005515), methyltransferase activity (GO:0008168), N-methyltransferase activity (GO:0008170), protein methyltransferase activity (GO:0008276), S-adenosylmethionine-dependent methyltransferase activity (GO:0008757), transferase activity (GO:0016740)

GO Cellular Component (1): mitochondrion (GO:0005739)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
methyltransferase activity	3
binding	2
translation	1
protein-containing complex disassembly	1
metabolic process	1
protein alkylation	1
macromolecule methylation	1
nucleic acid binding	1
N-methyltransferase activity	1
protein methyltransferase activity	1
S-adenosylmethionine-dependent methyltransferase activity	1
protein-glutamine N-methyltransferase activity	1
transferase activity, transferring one-carbon groups	1
catalytic activity, acting on a protein	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1248 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HEMK1	HEMK2	Q9Y5N5	811
HEMK1	MTRF1	O75570	725
HEMK1	TRMT112	Q9UI30	696
HEMK1	MTRF1L	Q9UGC7	673
HEMK1	ETF1	P46055	587
HEMK1	TRMT11	Q7Z4G4	545
HEMK1	ALKBH4	Q9NXW9	543
HEMK1	METTL4	Q8N3J2	529
HEMK1	TYW2	Q53H54	502
HEMK1	DERA	Q9Y315	497
HEMK1	EEF1AKMT1	Q8WVE0	473
HEMK1	ALKBH8	Q96BT7	472
HEMK1	EEF1AKMT2	Q5JPI9	465
HEMK1	TBCEL	Q5QJ74	462
HEMK1	BTBD8	Q5XKL5	429

IntAct

85 interactions, top by confidence:

A	B	Type	Score
CHN1	HEMK1	psi-mi:“MI:0915”(physical association)	0.780
HEMK1	CHN1	psi-mi:“MI:0915”(physical association)	0.780
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
HEMK1	CDC23	psi-mi:“MI:0915”(physical association)	0.560
HEMK1	SERTAD3	psi-mi:“MI:0915”(physical association)	0.560
HEMK1	DAZAP2	psi-mi:“MI:0915”(physical association)	0.560
HEMK1	SPAG8	psi-mi:“MI:0915”(physical association)	0.560
SERTAD3	HEMK1	psi-mi:“MI:0915”(physical association)	0.560
DAZAP2	HEMK1	psi-mi:“MI:0915”(physical association)	0.560
AKAP8L	HEMK1	psi-mi:“MI:0915”(physical association)	0.560
SPAG8	HEMK1	psi-mi:“MI:0915”(physical association)	0.560
HEMK1	MAGED1	psi-mi:“MI:0915”(physical association)	0.560
UBQLN2	HEMK1	psi-mi:“MI:0915”(physical association)	0.560
HEATR9	HEMK1	psi-mi:“MI:0915”(physical association)	0.560
SHOX	HEMK1	psi-mi:“MI:0915”(physical association)	0.560
SPRYD7	HEMK1	psi-mi:“MI:0915”(physical association)	0.560
PEF1	HEMK1	psi-mi:“MI:0915”(physical association)	0.560
INCA1	HEMK1	psi-mi:“MI:0915”(physical association)	0.560
ASCL3	HEMK1	psi-mi:“MI:0915”(physical association)	0.560
POU2AF1	HEMK1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (38): HEMK1 (Two-hybrid), HEMK1 (Two-hybrid), HEMK1 (Affinity Capture-MS), HEMK1 (Affinity Capture-MS), HEMK1 (Affinity Capture-MS), HEMK1 (Affinity Capture-MS), HEMK1 (Affinity Capture-MS), HEMK1 (Two-hybrid), HEMK1 (Two-hybrid), SPRYD7 (Two-hybrid), CHN1 (Two-hybrid), PSMB4 (Two-hybrid), PEF1 (Two-hybrid), SOHLH1 (Two-hybrid), ASCL3 (Two-hybrid)

ESM2 similar proteins: A5PK43, D2GU20, D3KCC4, E1BCH6, E2RDP2, O60294, O75616, O75808, O95382, P56201, Q05932, Q0VC80, Q13608, Q1JPJ9, Q3U5F4, Q3U5Q7, Q499R4, Q561R2, Q5D0E6, Q5EBA0, Q5EBM0, Q5QJC3, Q5RJG7, Q5S6T3, Q5XIA3, Q60806, Q641Y9, Q643R3, Q6IN84, Q6PAT0, Q6PJN8, Q86U90, Q8BYR1, Q8JIF5, Q8NCV1, Q8NFF5, Q924L9, Q95JV3, Q99LC9, Q9BG99

Diamond homologs: A0R213, A1S8P4, A4QDG2, A4W687, A6H162, A8ALZ1, A9CG70, A9WBM9, B0B9D1, B2RK25, B8E004, C6Y2G0, O66506, O84027, P0A293, P0A294, P0ACC1, P0ACC2, P0DJB1, P39199, P39200, P40816, P45253, P45832, P72542, P74003, P75419, P9WHV2, P9WHV3, Q0WDE1, Q1II29, Q2FWE1, Q2RFW1, Q2RWE0, Q2S0V8, Q32DK7, Q32GZ5, Q3J2B7, Q49404, Q5E3U5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2349 predictions. Top by Δscore:

Variant	Effect	Δscore
3:50577502:G:A	acceptor_gain	1.0000
3:50569262:G:GT	donor_gain	0.9900
3:50569345:G:GT	donor_gain	0.9900
3:50569470:G:GT	donor_gain	0.9900
3:50569487:G:GT	donor_gain	0.9900
3:50577046:TCACA:T	acceptor_loss	0.9900
3:50577047:CACA:C	acceptor_loss	0.9900
3:50577049:CAGGA:C	acceptor_loss	0.9900
3:50577051:G:C	acceptor_loss	0.9900
3:50577183:CCAGG:C	donor_loss	0.9900
3:50577184:CAGGT:C	donor_loss	0.9900
3:50577185:AGG:A	donor_loss	0.9900
3:50577187:GT:G	donor_loss	0.9900
3:50577188:T:G	donor_loss	0.9900
3:50577501:T:TA	acceptor_gain	0.9900
3:50577571:GAG:G	donor_gain	0.9900
3:50578930:C:G	donor_gain	0.9900
3:50580115:GTA:G	acceptor_gain	0.9900
3:50569271:C:T	donor_gain	0.9800
3:50577050:A:AG	acceptor_gain	0.9800
3:50577051:G:GG	acceptor_gain	0.9800
3:50577507:A:AG	acceptor_gain	0.9800
3:50577508:G:GG	acceptor_gain	0.9800
3:50580111:T:G	acceptor_gain	0.9800
3:50580115:GTAGT:G	acceptor_gain	0.9800
3:50582347:TCC:T	donor_gain	0.9800
3:50569515:G:GT	donor_gain	0.9700
3:50577508:GA:G	acceptor_gain	0.9700
3:50577050:AG:A	acceptor_gain	0.9600
3:50577051:GG:G	acceptor_gain	0.9600

AlphaMissense

2197 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:50578868:A:C	S238R	0.989
3:50578870:C:A	S238R	0.989
3:50578870:C:G	S238R	0.989
3:50571294:A:C	S64R	0.973
3:50571296:T:A	S64R	0.973
3:50571296:T:G	S64R	0.973
3:50572149:T:C	F119L	0.971
3:50572151:C:A	F119L	0.971
3:50572151:C:G	F119L	0.971
3:50577565:T:A	N202K	0.960
3:50577565:T:G	N202K	0.960
3:50578866:T:A	V237D	0.947
3:50577522:C:A	A188D	0.946
3:50580388:T:C	F330L	0.946
3:50580390:C:A	F330L	0.946
3:50580390:C:G	F330L	0.946
3:50580131:A:C	E294D	0.944
3:50580131:A:T	E294D	0.944
3:50572150:T:C	F119S	0.938
3:50577563:A:G	N202D	0.938
3:50571309:G:C	A69P	0.926
3:50577149:G:A	G171E	0.926
3:50577149:G:T	G171V	0.926
3:50572143:T:A	W117R	0.925
3:50572143:T:C	W117R	0.925
3:50577143:G:A	G169E	0.925
3:50571304:T:A	I67N	0.922
3:50578873:C:A	N239K	0.922
3:50578873:C:G	N239K	0.922
3:50580218:C:A	D323E	0.922

dbSNP variants (sampled 300 via entrez): RS1000108966 (3:50572428 C>A,T), RS1000142602 (3:50591562 C>T), RS1000214896 (3:50591413 C>T), RS1000381217 (3:50573014 C>T), RS1000496406 (3:50587365 G>C), RS1000544415 (3:50572112 C>T), RS1000710626 (3:50567526 C>G,T), RS1000768005 (3:50580601 C>A), RS1001051982 (3:50568400 G>A), RS1001194228 (3:50584400 A>G), RS1001244843 (3:50580892 A>T), RS1001318279 (3:50580720 C>T), RS1001430710 (3:50588193 A>G), RS1001508421 (3:50567548 G>A,T), RS1001518557 (3:50570984 G>A,C)

Disease associations

OMIM: gene MIM:618609 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST005860_2	Cholangiocarcinoma in primary sclerosing cholangitis (time to event)	4.000000e-06
GCST008163_474	Height	5.000000e-07
GCST008399_4	Cocaine dependence	7.000000e-06
GCST008843_1	Depressive symptom (appetite changes) (binary trait)	9.000000e-09
GCST008848_2	Depressive symptoms (sum-score)	1.000000e-09
GCST008849_3	Depressive symptoms (binary sum-score)	1.000000e-10
GCST90000025_937	Appendicular lean mass	1.000000e-22

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007006	depressive symptom measurement
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
manganese chloride	increases abundance, decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
pentanal	decreases expression	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	decreases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
perfluorooctane sulfonic acid	increases expression	1
jinfukang	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Benzo(a)pyrene	affects methylation	1
Camptothecin	decreases response to substance	1
Cisplatin	affects cotreatment, increases expression	1
Diazinon	increases methylation	1
Diuron	decreases expression	1
Hydrogen Peroxide	affects cotreatment, decreases expression	1
Lead	decreases expression	1
Manganese	decreases expression, increases abundance	1
Smoke	decreases expression	1
Theophylline	decreases expression, affects cotreatment	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	decreases methylation	1
Vitamin E	increases expression	1
Cyclosporine	increases expression	1

Clinical trials (associated diseases)

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