NTMT2

Summary

NTMT2 (N-terminal Xaa-Pro-Lys N-methyltransferase 2, HGNC:31932) is a protein-coding gene on chromosome 1q24.2, encoding N-terminal Xaa-Pro-Lys N-methyltransferase 2 (Q5VVY1). Alpha N-methyltransferase that methylates the N-terminus of target proteins containing the N-terminal motif [Ala/Pro/Ser]-Pro-Lys when the initiator Met is cleaved.

Enables N-terminal protein N-methyltransferase activity. Involved in N-terminal protein amino acid methylation. Located in nucleus.

Source: NCBI Gene 149281 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 45 total
• Druggable target: yes
• MANE Select transcript: NM_001136107

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:31932
Approved symbol	NTMT2
Name	N-terminal Xaa-Pro-Lys N-methyltransferase 2
Location	1q24.2
Locus type	gene with protein product
Status	Approved
Aliases	HOMT1B
Ensembl gene	ENSG00000203740
Ensembl biotype	protein_coding
Entrez	149281

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000367764, ENST00000439373, ENST00000962802

RefSeq mRNA: 1 — MANE Select: NM_001136107 NM_001136107

CCDS: CCDS44275

Canonical transcript exons

ENST00000439373 — 4 exons

Exon	Start	End
ENSE00001639870	170145959	170146261
ENSE00001790129	170167486	170168866
ENSE00003512238	170166502	170166751
ENSE00003521774	170160518	170160693

Expression profiles

Bgee: expression breadth broad, 25 present calls, max score 83.11.

Top tissues by expression

108 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	83.11	gold quality
apex of heart	UBERON:0002098	69.25	gold quality
heart left ventricle	UBERON:0002084	67.04	gold quality
right atrium auricular region	UBERON:0006631	65.62	gold quality
heart	UBERON:0000948	62.02	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	55.39	gold quality
ganglionic eminence	UBERON:0004023	48.13	gold quality
skeletal muscle tissue	UBERON:0001134	47.71	gold quality
muscle tissue	UBERON:0002385	44.54	gold quality
caudate nucleus	UBERON:0001873	40.33	gold quality
putamen	UBERON:0001874	40.07	gold quality
sural nerve	UBERON:0015488	40.03	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
muscle of leg	UBERON:0001383	36.24	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
hindlimb stylopod muscle	UBERON:0004252	35.54	gold quality
granulocyte	CL:0000094	35.01	gold quality
mucosa of transverse colon	UBERON:0004991	34.50	gold quality
bone marrow	UBERON:0002371	34.08	gold quality
placenta	UBERON:0001987	33.91	silver quality
testis	UBERON:0000473	33.90	silver quality
gall bladder	UBERON:0002110	33.10	gold quality
gastrocnemius	UBERON:0001388	33.00	gold quality
right testis	UBERON:0004534	32.97	gold quality
hypothalamus	UBERON:0001898	32.85	gold quality
leukocyte	CL:0000738	32.68	gold quality
monocyte	CL:0000576	32.63	gold quality
left testis	UBERON:0004533	32.60	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.11

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 1)

• Concurrent expression of NRMT1 and NRMT2 accelerates the production of trimethylation, and we propose that NRMT2 activates NRMT1 by priming its substrates for trimethylation. (PMID:24090352)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ntmt2	ENSDARG00000042033
mus_musculus	Ntmt2	ENSMUSG00000040113
rattus_norvegicus	Ntmt2	ENSRNOG00000025415
drosophila_melanogaster	Ntmt	FBGN0033457
caenorhabditis_elegans	homt-1	WBGENE00022277

Paralogs (1): NTMT1 (ENSG00000148335)

Protein

Protein identifiers

N-terminal Xaa-Pro-Lys N-methyltransferase 2 — Q5VVY1 (reviewed: Q5VVY1)

Alternative names: Alpha N-terminal protein methyltransferase 1B, Methyltransferase-like protein 11B, X-Pro-Lys N-terminal protein methyltransferase 1B

All UniProt accessions (1): Q5VVY1

UniProt curated annotations — full annotation on UniProt →

Function. Alpha N-methyltransferase that methylates the N-terminus of target proteins containing the N-terminal motif [Ala/Pro/Ser]-Pro-Lys when the initiator Met is cleaved. Specifically catalyzes monomethylation of exposed alpha-amino group of Ala or Ser residue in the [Ala/Ser]-Pro-Lys motif and Pro in the Pro-Pro-Lys motif. Predominantly functions as a mono-methyltransferase but is also able to di-/tri-methylate the GPKRIA peptide and di-methylate the PPKRIA peptide (in vitro). May activate NTMT1 by priming its substrates for trimethylation.

Subcellular location. Nucleus.

Similarity. Belongs to the methyltransferase superfamily. NTM1 family.

RefSeq proteins (1): NP_001129579* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008576	MeTrfase_NTM1	Family
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily

Pfam: PF05891

Enzyme classification (BRENDA):

• EC 2.1.1.299 — protein N-terminal monomethyltransferase (BRENDA: 3 organisms, 28 substrates, 1 inhibitors, 1 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
SPKRIAKRRSPPADA	0.0556	1

Catalyzed reactions (Rhea), 3 shown:

• N-terminal L-alanyl-L-prolyl-L-lysyl-[protein] + S-adenosyl-L-methionine = N-terminal N-methyl-L-alanyl-L-prolyl-L-lysyl-[protein] + S-adenosyl-L-homocysteine + H(+) (RHEA:54096)
• N-terminal L-prolyl-L-prolyl-L-lysyl-[protein] + S-adenosyl-L-methionine = N-terminal N-methyl-L-prolyl-L-prolyl-L-lysyl-[protein] + S-adenosyl-L-homocysteine + H(+) (RHEA:54100)
• N-terminal L-seryl-L-prolyl-L-lysyl-[protein] + S-adenosyl-L-methionine = N-terminal N-methyl-L-seryl-L-prolyl-L-lysyl-[protein] + S-adenosyl-L-homocysteine + H(+) (RHEA:54104)

UniProt features (37 total): helix 11, strand 9, binding site 6, turn 6, sequence variant 3, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
6DUB	X-RAY DIFFRACTION	1.2
6KDS	X-RAY DIFFRACTION	1.84
5UBB	X-RAY DIFFRACTION	2
6KDR	X-RAY DIFFRACTION	2.11

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5VVY1-F1	90.30	0.72

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 (6): 124; 129; 146; 174–175; 190; 195

Mutagenesis-validated functional residues (1):

Position	Phenotype
89	increases methylation activity. higher affinity for mono-methylated peptide than wild-type.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 21 (showing top): GOBP_METHYLATION, GOBP_N_TERMINAL_PROTEIN_AMINO_ACID_MODIFICATION, GOMF_PROTEIN_METHYLTRANSFERASE_ACTIVITY, GOMF_S_ADENOSYLMETHIONINE_DEPENDENT_METHYLTRANSFERASE_ACTIVITY, GOMF_TRANSFERASE_ACTIVITY_TRANSFERRING_ONE_CARBON_GROUPS, GOBP_PROTEIN_METHYLATION, GSE13522_WT_VS_IFNG_KO_SKING_T_CRUZI_Y_STRAIN_INF_UP, GSE15324_NAIVE_VS_ACTIVATED_ELF4_KO_CD8_TCELL_DN, DESCARTES_MAIN_FETAL_CARDIOMYOCYTES, ZNF134_TARGET_GENES, GSE20366_TREG_VS_TCONV_UP, GOBP_MACROMOLECULE_METHYLATION, FONG_MCMASTER_OPA1_CARDIOPROTECTION_UP, GOBP_PROTEIN_MODIFICATION_PROCESS, chr1q24

GO Biological Process (2): N-terminal protein amino acid methylation (GO:0006480), methylation (GO:0032259)

GO Molecular Function (3): N-terminal protein N-methyltransferase activity (GO:0071885), methyltransferase activity (GO:0008168), transferase activity (GO:0016740)

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein methylation	1
N-terminal protein amino acid modification	1
metabolic process	1
protein methyltransferase activity	1
S-adenosylmethionine-dependent methyltransferase activity	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

794 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NTMT2	METTL18	O95568	558
NTMT2	KIFAP3	Q92845	545
NTMT2	METTL27	Q8N6F8	534
NTMT2	METTL17	Q9H7H0	526
NTMT2	IGLON5	A6NGN9	507
NTMT2	METTL25B	Q96FB5	484
NTMT2	CRYAA	P02489	479
NTMT2	METTL25	Q8N6Q8	474
NTMT2	METTL26	Q96S19	453
NTMT2	METTL9	Q9H1A3	449
NTMT2	METTL5	Q9NRN9	441
NTMT2	FAM13B	Q9NYF5	440
NTMT2	MYL7	Q01449	438
NTMT2	METTL21A	Q8WXB1	433
NTMT2	NTM	Q9P121	430

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A0A8X8M4W6, A2XMJ1, A2XYY8, A2YP56, A3BMN9, A8WVR2, A8XI07, B2RXM4, B8JM82, C0SQ89, D3ZVR1, O22285, O44410, O81263, P32783, Q01H90, Q08A71, Q0WVD6, Q10CT5, Q5PP70, Q5VVY1, Q5XI06, Q61E36, Q6C4F8, Q6C710, Q6NN40, Q6YV04, Q6YYZ1, Q6Z690, Q7K2B0, Q7M753, Q7XI41, Q7XKC0, Q7XUR2, Q7Y0Y6, Q7YTB0, Q8H8N3, Q8LI34, Q8LPU5, Q8VXV7

Diamond homologs: A2XMJ1, A8WVR2, B1H2P7, B2RXM4, B8JM82, D2H163, D3ZVR1, O13748, P38340, Q10CT5, Q2T9N3, Q4KL94, Q4KLE6, Q55DH6, Q5BJX0, Q5PP70, Q5VVY1, Q6NN40, Q6NWX7, Q8R2U4, Q9BV86, Q9N4D9, Q23552, Q89XU2, Q9M571

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	42
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1285 predictions. Top by Δscore:

Variant	Effect	Δscore
1:170158005:A:AG	acceptor_gain	1.0000
1:170158005:ATT:A	acceptor_gain	1.0000
1:170158005:ATTG:A	acceptor_gain	1.0000
1:170160516:A:AG	acceptor_gain	1.0000
1:170160517:G:GC	acceptor_gain	1.0000
1:170160517:GTGA:G	acceptor_gain	1.0000
1:170160517:GTGAA:G	acceptor_gain	1.0000
1:170166717:G:GT	donor_gain	1.0000
1:170166741:G:GG	donor_gain	1.0000
1:170146259:TGGG:T	donor_loss	0.9900
1:170146260:GG:G	donor_gain	0.9900
1:170146261:GG:G	donor_gain	0.9900
1:170146262:G:C	donor_loss	0.9900
1:170157549:G:GG	donor_gain	0.9900
1:170157558:GTT:G	donor_gain	0.9900
1:170157559:T:TA	donor_gain	0.9900
1:170157963:TTCCA:T	acceptor_loss	0.9900
1:170157964:TCCA:T	acceptor_loss	0.9900
1:170157965:CCA:C	acceptor_loss	0.9900
1:170157966:CA:C	acceptor_loss	0.9900
1:170157967:A:AG	acceptor_gain	0.9900
1:170157967:AGATC:A	acceptor_loss	0.9900
1:170157968:G:GG	acceptor_gain	0.9900
1:170157968:G:GT	acceptor_loss	0.9900
1:170157968:GATCT:G	acceptor_gain	0.9900
1:170157991:T:TA	acceptor_gain	0.9900
1:170157992:G:A	acceptor_gain	0.9900
1:170158006:T:G	acceptor_gain	0.9900
1:170158007:T:A	acceptor_gain	0.9900
1:170158015:T:A	acceptor_gain	0.9900

AlphaMissense

1896 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:170167568:G:C	K221N	0.995
1:170167568:G:T	K221N	0.995
1:170166733:T:A	W188R	0.991
1:170166733:T:C	W188R	0.991
1:170166562:A:C	S131R	0.990
1:170166564:C:A	S131R	0.990
1:170166564:C:G	S131R	0.990
1:170167561:T:A	I219K	0.990
1:170167507:T:C	L201P	0.989
1:170166586:T:C	F139L	0.988
1:170166588:C:A	F139L	0.988
1:170166588:C:G	F139L	0.988
1:170166530:C:A	A120D	0.987
1:170166742:T:A	W191R	0.985
1:170166742:T:C	W191R	0.985
1:170160565:T:C	F68L	0.984
1:170160567:C:A	F68L	0.984
1:170160567:C:G	F68L	0.984
1:170166575:T:C	L135S	0.984
1:170167492:T:C	L196P	0.981
1:170167527:T:C	C208R	0.981
1:170160665:C:T	S101F	0.980
1:170166538:T:C	C123R	0.980
1:170167567:A:C	K221T	0.980
1:170166558:G:C	R129S	0.978
1:170166558:G:T	R129S	0.978
1:170166554:G:A	G128E	0.977
1:170166572:T:A	V134D	0.977
1:170167561:T:G	I219R	0.977
1:170167569:G:C	D222H	0.977

dbSNP variants (sampled 300 via entrez): RS1000076342 (1:170148511 T>A), RS1000132332 (1:170162409 T>C), RS1000213023 (1:170157443 A>AT), RS1000245848 (1:170157071 G>A), RS1000279681 (1:170155426 A>G), RS1000476874 (1:170150614 G>A,T), RS1000597016 (1:170150269 TC>T), RS1000632348 (1:170160483 A>C,G,T), RS1000663579 (1:170160750 C>T), RS1000736078 (1:170163830 A>G), RS1000820983 (1:170167271 G>A,C), RS1001029068 (1:170147537 C>T), RS1001256392 (1:170153550 T>C), RS1001359840 (1:170169255 C>T), RS1001557229 (1:170157085 C>A)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST003983_30	Male-pattern baldness	1.000000e-09
GCST004296_1	Atrial fibrillation	3.000000e-07
GCST004297_1	Atrial fibrillation	2.000000e-11
GCST005956_24	Waist-to-hip ratio adjusted for BMI	5.000000e-07
GCST005962_31	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	3.000000e-07
GCST006061_212	Atrial fibrillation	8.000000e-34
GCST006061_51	Atrial fibrillation	7.000000e-48
GCST006061_52	Atrial fibrillation	1.000000e-46

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4630834 (SINGLE PROTEIN), CHEMBL5291693 (PROTEIN-PROTEIN INTERACTION)

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.00	Kd	1000	nM	CHEMBL4787034
5.47	Kd	3400	nM	CHEMBL4777235
5.43	Kd	3700	nM	CHEMBL4757419

PubChem BioAssay actives

3 with measured affinity, of 10 total; 3 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
(2S)-N-[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]-1-[2-(4-hydroxyphenyl)acetyl]pyrrolidine-2-carboxamide	1721200: Binding affinity to recombinant human full-length His6-tagged NTMT2 by ITC assay	kd	1.0000	uM
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-1-[2-(4-hydroxyphenyl)acetyl]pyrrolidine-2-carbonyl]amino]hexanoyl]amino]-5-carbamimidamidopentanoyl]amino]acetyl]amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]hexanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-N-[(2S)-1-[[(2S)-1-[[(2S)-1-amino-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]pentanediamide	1721200: Binding affinity to recombinant human full-length His6-tagged NTMT2 by ITC assay	kd	3.4000	uM
(2S)-N-[(2S)-6-amino-1-[[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]-1-[2-(4-hydroxyphenyl)acetyl]pyrrolidine-2-carboxamide	1721200: Binding affinity to recombinant human full-length His6-tagged NTMT2 by ITC assay	kd	3.7000	uM

CTD chemical–gene interactions

3 total (human), top 3 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
ferrous chloride	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Valproic Acid	decreases methylation	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4621555	Binding	Binding affinity to NNMT2 (unknown origin) by ITC assay	Probing the Plasticity in the Active Site of Protein N-terminal Methyltransferase 1 Using Bisubstrate Analogues. — J Med Chem

Clinical trials (associated diseases)

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