LCMT2

Summary

LCMT2 (leucine carboxyl methyltransferase 2, HGNC:17558) is a protein-coding gene on chromosome 15q15.3, encoding tRNA wybutosine-synthesizing protein 4 (O60294). Probable S-adenosyl-L-methionine-dependent methyltransferase that acts as a component of the wybutosine biosynthesis pathway.

The protein encoded by this intronless gene belongs to the highly variable methyltransferase superfamily. This gene is the inferred homolog of the Saccharomyces cerevisiae carboxymethyltransferase gene PPM2 that is essential for the synthesis of the hypermodified guanosine Wybutosine (yW).

Source: NCBI Gene 9836 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 173 total
• MANE Select transcript: NM_014793

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17558
Approved symbol	LCMT2
Name	leucine carboxyl methyltransferase 2
Location	15q15.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0547, MGC9534, TYW4, PPM2
Ensembl gene	ENSG00000168806
Ensembl biotype	protein_coding
OMIM	611246
Entrez	9836

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000305641, ENST00000567039

RefSeq mRNA: 1 — MANE Select: NM_014793 NM_014793

CCDS: CCDS10094

Canonical transcript exons

ENST00000305641 — 1 exons

Exon	Start	End
ENSE00001147364	43323649	43330573

Expression profiles

Bgee: expression breadth ubiquitous, 268 present calls, max score 88.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.4972 / max 48.7986, expressed in 1692 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
149605	5.4972	1692

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hair follicle	UBERON:0002073	88.67	gold quality
germinal epithelium of ovary	UBERON:0001304	87.54	gold quality
gingival epithelium	UBERON:0001949	86.84	gold quality
nephron tubule	UBERON:0001231	85.40	gold quality
renal glomerulus	UBERON:0000074	85.29	gold quality
metanephric glomerulus	UBERON:0004736	84.91	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.88	gold quality
palpebral conjunctiva	UBERON:0001812	84.75	gold quality
epithelium of nasopharynx	UBERON:0001951	84.65	gold quality
eye	UBERON:0000970	84.62	gold quality
esophagus squamous epithelium	UBERON:0006920	84.47	gold quality
squamous epithelium	UBERON:0006914	84.35	gold quality
pigmented layer of retina	UBERON:0001782	84.27	gold quality
kidney epithelium	UBERON:0004819	84.04	gold quality
mammary duct	UBERON:0001765	84.03	gold quality
epithelium of esophagus	UBERON:0001976	83.91	gold quality
gingiva	UBERON:0001828	83.72	gold quality
epithelium of mammary gland	UBERON:0003244	83.70	gold quality
endothelial cell	CL:0000115	83.24	gold quality
islet of Langerhans	UBERON:0000006	82.42	gold quality
tibia	UBERON:0000979	82.24	gold quality
bronchial epithelial cell	CL:0002328	82.14	gold quality
parietal pleura	UBERON:0002400	82.04	gold quality
epithelium of bronchus	UBERON:0002031	81.99	gold quality
bronchus	UBERON:0002185	81.66	gold quality
trabecular bone tissue	UBERON:0002483	81.59	gold quality
pleura	UBERON:0000977	81.45	gold quality
cortical plate	UBERON:0005343	81.06	gold quality
metanephros	UBERON:0000081	80.97	gold quality
endometrium	UBERON:0001295	80.51	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.74

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

46 targeting LCMT2, 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-450A-1-3P	100.00	69.33	1837
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-8076	99.78	68.52	1170
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-3685	99.62	68.83	1621
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-6073	99.60	70.36	793
HSA-MIR-6833-5P	99.50	68.93	1161
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-4325	99.49	72.20	1342
HSA-MIR-372-5P	99.41	69.11	2299
HSA-MIR-3140-5P	99.39	69.04	1136
HSA-MIR-6853-3P	99.36	70.79	1558
HSA-MIR-4427	99.34	70.33	1854
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-20B-3P	99.29	67.05	784
HSA-MIR-10522-5P	99.26	68.50	2087
HSA-MIR-4263	99.18	69.25	2236
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-155-3P	99.03	67.99	924

Literature-anchored findings (GeneRIF, showing 2)

• This paper reports crystal structures of a yeast homolog, TYW4. (PMID:19287006)
• Kr-pok interacted directly with the DNA binding and oligomerization domains of p53. This interaction was essential for Kr-pok to bind the distal promoter region of the CDKN1A gene, p21WAF1, and to inhibit p53-mediated transcriptional activation of CDKN1A. (PMID:22253232)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	lcmt2	ENSDARG00000000747
mus_musculus	Lcmt2	ENSMUSG00000074890
rattus_norvegicus	Lcmt2	ENSRNOG00000043002

Paralogs (1): LCMT1 (ENSG00000205629)

Protein

Protein identifiers

tRNA wybutosine-synthesizing protein 4 — O60294 (reviewed: O60294)

Alternative names: Leucine carboxyl methyltransferase 2, tRNA(Phe) (7-(3-amino-3-(methoxycarbonyl)propyl)wyosine(37)-N)-methoxycarbonyltransferase, tRNA(Phe) (7-(3-amino-3-carboxypropyl)wyosine(37)-O)-methyltransferase

All UniProt accessions (2): O60294, H3BU01

UniProt curated annotations — full annotation on UniProt →

Function. Probable S-adenosyl-L-methionine-dependent methyltransferase that acts as a component of the wybutosine biosynthesis pathway. Wybutosine is a hyper modified guanosine with a tricyclic base found at the 3’-position adjacent to the anticodon of eukaryotic phenylalanine tRNA. May methylate the carboxyl group of leucine residues to form alpha-leucine ester residues.

Subunit / interactions. Interacts with RNF144B/IBRDC2.

Pathway. tRNA modification; wybutosine-tRNA(Phe) biosynthesis.

Similarity. Belongs to the methyltransferase superfamily. LCMT family.

RefSeq proteins (1): NP_055608* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007213	Ppm1/Ppm2/Tcmp	Family
IPR015915	Kelch-typ_b-propeller	Homologous_superfamily
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily

Pfam: PF04072, PF24681

Catalyzed reactions (Rhea), 2 shown:

• 7-[(3S)-3-amino-3-carboxypropyl]wyosine(37) in tRNA(Phe) + S-adenosyl-L-methionine = 7-[(3S)-(3-amino-3-methoxycarbonyl)propyl]wyosine(37) in tRNA(Phe) + S-adenosyl-L-homocysteine (RHEA:36903)
• 7-[(3S)-(3-amino-3-methoxycarbonyl)propyl]wyosine(37) in tRNA(Phe) + S-adenosyl-L-methionine + CO2 = wybutosine(37) in tRNA(Phe) + S-adenosyl-L-homocysteine + 2 H(+) (RHEA:37119)

UniProt features (15 total): binding site 5, sequence variant 4, sequence conflict 3, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60294-F1	91.90	0.79

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): 59; 89; 114; 161–162; 188

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6782861	Synthesis of wybutosine at G37 of tRNA(Phe)

MSigDB gene sets: 115 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, FISCHER_G1_S_CELL_CYCLE, GOBP_TRNA_METABOLIC_PROCESS, GOBP_RNA_METHYLATION, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, KEGG_HISTIDINE_METABOLISM, GOBP_RNA_MODIFICATION, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GOBP_TRNA_METHYLATION, GARY_CD5_TARGETS_DN, MORF_EPHA7, FISCHER_DREAM_TARGETS, ACEVEDO_LIVER_CANCER_UP, GOBP_METHYLATION

GO Biological Process (5): tRNA modification (GO:0006400), tRNA methylation (GO:0030488), wybutosine biosynthetic process (GO:0031591), tRNA processing (GO:0008033), methylation (GO:0032259)

GO Molecular Function (4): tRNA methyltransferase activity (GO:0008175), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740)

GO Cellular Component (1): cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
tRNA modification in the nucleus and cytosol	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
tRNA modification	2
tRNA processing	1
RNA modification	1
RNA methylation	1
glycosyl compound biosynthetic process	1
RNA processing	1
tRNA metabolic process	1
metabolic process	1
RNA methyltransferase activity	1
catalytic activity, acting on a tRNA	1
binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

674 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LCMT2	TYW2	Q53H54	902
LCMT2	TYW3	Q6IPR3	901
LCMT2	TYW1	Q9NV66	858
LCMT2	TRMT5	Q32P41	807
LCMT2	TYW5	A2RUC4	619
LCMT2	FTSJ1	Q9UET6	571
LCMT2	TRMT112	Q9UI30	473
LCMT2	RPUSD2	Q8IZ73	470
LCMT2	ASB3	Q9Y575	448
LCMT2	PNO1	Q9NRX1	443
LCMT2	POLR3A	O14802	416
LCMT2	ARRDC3	Q96B67	411
LCMT2	VPS18	Q9P253	388
LCMT2	TMEM126B	Q8IUX1	382
LCMT2	ERCC4	Q92889	382

IntAct

21 interactions, top by confidence:

A	B	Type	Score
FGL1	LCMT2	psi-mi:“MI:0914”(association)	0.640
ACTN4	LCMT2	psi-mi:“MI:0915”(physical association)	0.560
TKT	POTEF	psi-mi:“MI:0914”(association)	0.530
IMPDH1	BCAT2	psi-mi:“MI:0914”(association)	0.530
Ctnnbl1	LCMT2	psi-mi:“MI:0914”(association)	0.350
SNCA	SRRM1	psi-mi:“MI:0914”(association)	0.350
AP4M1		psi-mi:“MI:0914”(association)	0.350
VPS26A	LCMT2	psi-mi:“MI:0914”(association)	0.350
IMPDH1	LCMT2	psi-mi:“MI:0914”(association)	0.350
FGL1	DNM1L	psi-mi:“MI:0914”(association)	0.350
LCMT2	CCT2	psi-mi:“MI:0914”(association)	0.350
ZBED1	SPAG9	psi-mi:“MI:0914”(association)	0.350
LCMT2	DNAJA2	psi-mi:“MI:0914”(association)	0.350
LCMT2	HSPA8	psi-mi:“MI:0914”(association)	0.350
SLC15A1	LCMT2	psi-mi:“MI:0914”(association)	0.350
TCF25	LCMT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (40): LCMT2 (Affinity Capture-MS), LCMT2 (Affinity Capture-MS), LCMT2 (Co-fractionation), LCMT2 (Co-fractionation), LCMT2 (Co-fractionation), LCMT2 (Co-fractionation), LCMT2 (Affinity Capture-MS), LCMT2 (Affinity Capture-MS), LCMT2 (Affinity Capture-MS), LCMT2 (Affinity Capture-MS), LCMT2 (Affinity Capture-MS), LCMT2 (Two-hybrid), LCMT2 (Affinity Capture-MS), UBAC1 (Affinity Capture-MS), RNF123 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5PJB7, A0A1L8HX76, A6QR40, O08764, O60294, O95382, P10938, P70218, P97452, Q12851, Q14137, Q15334, Q16586, Q28686, Q32P44, Q3TJ91, Q499N3, Q499U2, Q4KLI9, Q561R2, Q562C2, Q5RBH8, Q5RCX2, Q61161, Q6AY79, Q6F5E8, Q6P1M3, Q6V7V2, Q7SZE3, Q7TMC8, Q80Y17, Q8BYZ7, Q8C3I8, Q8C6B2, Q8CHW4, Q8K4K5, Q8MKF0, Q8N0W3, Q8VC03, Q91WI7

Diamond homologs: O60294, O94257, P0CO56, P0CO57, P46554, Q3T0H0, Q4ICG8, Q4WS57, Q5AQJ2, Q5XIA3, Q5Z8K3, Q60YU0, Q6C997, Q6P4Z6, Q75AW4, Q8BYR1, Q8VY08, Q9UIC8, Q6BQD2, Q7SAP7, Q4P4G2, Q9P3K9, Q5A387, Q6FUI5, Q04081, O60157, Q759U5, A0A364LYQ6, A5VUS1, A6X554, A9MBM8, A9WYQ7, B2SB67, E9Q4S1, O34627, O48963, O64511, O95263, P15258, P58724

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	166
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

404 predictions. Top by Δscore:

Variant	Effect	Δscore
15:43329586:T:TA	donor_gain	0.9900
15:43329550:C:A	donor_gain	0.9800
15:43329597:T:TA	donor_gain	0.9800
15:43329583:A:AC	donor_gain	0.9700
15:43329584:C:CC	donor_gain	0.9700
15:43329171:A:AC	donor_gain	0.9400
15:43329172:C:CC	donor_gain	0.9400
15:43329549:C:CA	donor_gain	0.9300
15:43329900:T:A	donor_gain	0.9200
15:43324813:A:C	acceptor_gain	0.9100
15:43329598:C:CA	donor_gain	0.9000
15:43327653:CA:C	donor_gain	0.8800
15:43327654:AA:A	donor_gain	0.8800
15:43329626:TTCC:T	donor_gain	0.8600
15:43329012:T:TA	donor_gain	0.8500
15:43329333:A:AC	donor_gain	0.8400
15:43329334:C:CC	donor_gain	0.8400
15:43328511:C:CT	donor_gain	0.8300
15:43329585:T:C	donor_gain	0.8300
15:43329628:C:CT	donor_gain	0.8300
15:43329629:C:CT	donor_gain	0.8200
15:43329778:G:C	donor_gain	0.8200
15:43327597:A:AC	donor_gain	0.8100
15:43327598:C:CC	donor_gain	0.8100
15:43327655:A:C	donor_gain	0.8100
15:43324859:T:TC	acceptor_gain	0.8000
15:43329492:T:C	donor_gain	0.8000
15:43329033:T:TA	donor_gain	0.7900
15:43329289:T:A	donor_gain	0.7900
15:43328512:C:CT	donor_gain	0.7800

AlphaMissense

4425 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:43328555:A:C	S645R	0.997
15:43328555:A:T	S645R	0.997
15:43328557:T:G	S645R	0.997
15:43328498:A:C	F664L	0.990
15:43328498:A:T	F664L	0.990
15:43328500:A:G	F664L	0.990
15:43329183:C:G	R436T	0.988
15:43329809:A:C	F227L	0.988
15:43329809:A:T	F227L	0.988
15:43329811:A:G	F227L	0.988
15:43328501:G:C	C663W	0.987
15:43329703:A:G	W263R	0.987
15:43329703:A:T	W263R	0.987
15:43328731:A:C	Y587D	0.985
15:43329182:T:A	R436S	0.985
15:43329182:T:G	R436S	0.985
15:43329048:C:G	R481P	0.984
15:43329362:A:C	F376L	0.983
15:43329362:A:T	F376L	0.983
15:43329364:A:G	F376L	0.983
15:43329595:A:G	W299R	0.983
15:43329595:A:T	W299R	0.983
15:43328492:A:C	F666L	0.982
15:43328492:A:T	F666L	0.982
15:43328494:A:G	F666L	0.982
15:43330124:T:A	K122N	0.981
15:43330124:T:G	K122N	0.981
15:43330418:C:A	K24N	0.981
15:43330418:C:G	K24N	0.981
15:43328477:G:C	N671K	0.980

dbSNP variants (sampled 300 via entrez): RS1000412189 (15:43324294 T>A), RS1000945158 (15:43324001 G>C), RS1001536599 (15:43329894 G>A,C), RS1001751701 (15:43325749 A>G), RS1001757263 (15:43332342 T>A), RS1001798952 (15:43327787 A>G), RS1002076824 (15:43325399 G>A), RS1002134103 (15:43329239 G>C), RS1002504322 (15:43326478 C>T), RS1002655249 (15:43331720 G>C), RS1002673136 (15:43327303 A>T), RS1002686593 (15:43332001 G>A), RS1003158178 (15:43327701 C>T), RS1003188865 (15:43331990 A>G), RS1005119883 (15:43324404 G>A)

Disease associations

OMIM: gene MIM:611246 | 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
GCST010083_297	Hemoglobin levels	3.000000e-13

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004509	hemoglobin measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
Valproic Acid	affects expression, decreases expression, increases expression	3
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
GSK-J4	decreases expression	1
urushiol	decreases expression	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
pyrrolidine dithiocarbamic acid	affects binding, increases reaction, increases expression	1
perfluorooctanoic acid	decreases expression	1
ferrous chloride	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
avobenzone	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
(+)-JQ1 compound	increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Temozolomide	increases expression	1
Decitabine	affects expression	1
Air Pollutants	affects expression, increases abundance	1
Atrazine	decreases expression	1
Cisplatin	affects expression	1
Coumestrol	increases expression, affects cotreatment	1
Diazinon	increases methylation	1
Doxorubicin	decreases expression	1
Formaldehyde	decreases expression	1
Hydrogen Peroxide	affects expression	1
Niclosamide	decreases expression	1
Oxygen	decreases expression	1
Ozone	affects expression, increases abundance	1

Clinical trials (associated diseases)

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