CSKMT

Summary

CSKMT (citrate synthase lysine methyltransferase, HGNC:33113) is a protein-coding gene on chromosome 11q12.3, encoding Citrate synthase-lysine N-methyltransferase CSKMT, mitochondrial (A8MUP2). Protein-lysine methyltransferase that selectively trimethylates citrate synthase (CS) in mitochondria.

Enables protein-lysine N-methyltransferase activity. Involved in peptidyl-lysine dimethylation; peptidyl-lysine monomethylation; and peptidyl-lysine trimethylation. Located in mitochondrion.

Source: NCBI Gene 751071 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 61 total
• MANE Select transcript: NM_001043229

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:33113
Approved symbol	CSKMT
Name	citrate synthase lysine methyltransferase
Location	11q12.3
Locus type	gene with protein product
Status	Approved
Aliases	U99HG, CS-KMT
Ensembl gene	ENSG00000214756
Ensembl biotype	protein_coding
OMIM	617897
Entrez	751071

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 2 protein_coding_CDS_not_defined, 2 protein_coding, 1 retained_intron

ENST00000398922, ENST00000529868, ENST00000532971, ENST00000594728, ENST00000913097

RefSeq mRNA: 1 — MANE Select: NM_001043229 NM_001043229

CCDS: CCDS41657

Canonical transcript exons

ENST00000532971 — 3 exons

Exon	Start	End
ENSE00002162029	62666396	62668108
ENSE00003675691	62665647	62665946
ENSE00003849012	62665312	62665332

Expression profiles

Bgee: expression breadth ubiquitous, 167 present calls, max score 99.42.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.2052 / max 856.5251, expressed in 1753 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114722	23.2052	1753

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
colonic epithelium	UBERON:0000397	99.42	gold quality
bone marrow cell	CL:0002092	97.92	gold quality
granulocyte	CL:0000094	90.05	gold quality
lower esophagus mucosa	UBERON:0035834	88.98	gold quality
pancreatic ductal cell	CL:0002079	85.58	silver quality
sural nerve	UBERON:0015488	82.18	gold quality
tibialis anterior	UBERON:0001385	81.45	silver quality
mucosa of transverse colon	UBERON:0004991	80.80	gold quality
right adrenal gland cortex	UBERON:0035827	80.65	gold quality
right uterine tube	UBERON:0001302	80.57	gold quality
left ovary	UBERON:0002119	79.38	gold quality
right adrenal gland	UBERON:0001233	78.65	gold quality
cerebellar cortex	UBERON:0002129	78.62	gold quality
cerebellar hemisphere	UBERON:0002245	78.60	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	78.58	gold quality
esophagus mucosa	UBERON:0002469	78.52	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.26	gold quality
right hemisphere of cerebellum	UBERON:0014890	78.25	gold quality
right ovary	UBERON:0002118	78.16	gold quality
left adrenal gland cortex	UBERON:0035825	77.79	gold quality
transverse colon	UBERON:0001157	77.65	gold quality
ectocervix	UBERON:0012249	77.52	gold quality
esophagus	UBERON:0001043	77.35	gold quality
left adrenal gland	UBERON:0001234	77.15	gold quality
spleen	UBERON:0002106	77.06	gold quality
body of stomach	UBERON:0001161	77.02	gold quality
metanephros cortex	UBERON:0010533	77.00	gold quality
ileal mucosa	UBERON:0000331	76.96	gold quality
left uterine tube	UBERON:0001303	76.76	gold quality
stromal cell of endometrium	CL:0002255	76.62	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.61

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

29 targeting CSKMT, 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-3925-3P	100.00	69.95	1237
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-3975	99.62	65.97	697
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-2113	99.58	71.22	1521
HSA-MIR-6882-5P	99.35	71.13	1206
HSA-MIR-183-5P	99.31	72.27	1164
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-4504	99.10	69.14	1328
HSA-MIR-628-3P	99.04	68.37	814
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-3188	98.58	65.60	878
HSA-MIR-7156-3P	98.25	67.66	859
HSA-MIR-4717-5P	98.19	67.97	894
HSA-MIR-8089	97.74	66.21	1698
HSA-MIR-4667-5P	97.61	66.67	1683
HSA-MIR-15A-3P	97.47	65.08	527
HSA-MIR-2467-5P	97.36	67.71	991
HSA-MIR-125A-3P	97.04	66.92	902
HSA-MIR-552-3P	96.68	64.12	1026
HSA-MIR-3139	96.68	66.77	652
HSA-MIR-28-5P	96.16	66.12	579
HSA-MIR-708-5P	96.16	66.12	576
HSA-MIR-5704	94.82	67.46	448

Literature-anchored findings (GeneRIF, showing 1)

• Data suggest that METTL12, localized in mitochondrial matrix, modifies/methylates Lys368 of citrate synthase in external surface region close to its catalytic site; addition/removal of methylation has no effect on citrate synthase activity; Lys368 occurs in highly conserved sequence of amino acid residues of citrate synthase. (PMID:28391595)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	cskmt	ENSDARG00000054856
caenorhabditis_elegans	F52F12.9	WBGENE00009942
caenorhabditis_elegans		WBGENE00016868
caenorhabditis_elegans		WBGENE00021323

Paralogs (2): METTL13 (ENSG00000010165), EEF1AKMT4 (ENSG00000284753)

Protein

Protein identifiers

Citrate synthase-lysine N-methyltransferase CSKMT, mitochondrial — A8MUP2 (reviewed: A8MUP2)

Alternative names: Methyltransferase-like protein 12, mitochondrial

All UniProt accessions (1): A8MUP2

UniProt curated annotations — full annotation on UniProt →

Function. Protein-lysine methyltransferase that selectively trimethylates citrate synthase (CS) in mitochondria. Seems to conduct trimethylation in a highly distributive manner rather than in a processive manner, and thus introduces a single methyl group per binding event.

Subcellular location. Mitochondrion.

Activity regulation. Citrate synthase-lysine methyltransferase activity is inhibited by S-adenosylhomocysteine (AdoHcy) and oxaloacetate (OAA).

Similarity. Belongs to the methyltransferase superfamily.

RefSeq proteins (1): NP_001036694* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR025714	Methyltranfer_dom	Domain
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily
IPR051419	Lys/N-term_MeTrsfase_sf	Family

Pfam: PF13847

Catalyzed reactions (Rhea), 3 shown:

• L-lysyl-[citrate synthase] + S-adenosyl-L-methionine = N(6)-methyl-L-lysyl-[citrate synthase] + S-adenosyl-L-homocysteine + H(+) (RHEA:55544)
• N(6)-methyl-L-lysyl-[citrate synthase] + S-adenosyl-L-methionine = N(6),N(6)-dimethyl-L-lysyl-[citrate synthase] + S-adenosyl-L-homocysteine + H(+) (RHEA:55548)
• N(6),N(6)-dimethyl-L-lysyl-[citrate synthase] + S-adenosyl-L-methionine = N(6),N(6),N(6)-trimethyl-L-lysyl-[citrate synthase] + S-adenosyl-L-homocysteine + H(+) (RHEA:55552)

UniProt features (4 total): transit peptide 1, chain 1, sequence variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A8MUP2-F1	87.80	0.77

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (1):

Position	Phenotype
107	inhibits citrate synthase-lysine methyltransferase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9854311	Maturation of TCA enzymes and regulation of TCA cycle

MSigDB gene sets: 62 (showing top): GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_PEPTIDYL_LYSINE_MODIFICATION, GOBP_PEPTIDYL_LYSINE_TRIMETHYLATION, GOBP_CELLULAR_RESPIRATION, GOBP_METHYLATION, GOBP_PEPTIDYL_LYSINE_METHYLATION, GOBP_PEPTIDYL_LYSINE_DIMETHYLATION, GOCC_MITOCHONDRIAL_MATRIX, GOMF_N_METHYLTRANSFERASE_ACTIVITY, GOMF_PROTEIN_METHYLTRANSFERASE_ACTIVITY, GOMF_S_ADENOSYLMETHIONINE_DEPENDENT_METHYLTRANSFERASE_ACTIVITY, GOMF_TRANSFERASE_ACTIVITY_TRANSFERRING_ONE_CARBON_GROUPS, GOMF_LYSINE_N_METHYLTRANSFERASE_ACTIVITY, GOBP_TRICARBOXYLIC_ACID_CYCLE, GOBP_PROTEIN_METHYLATION

GO Biological Process (6): tricarboxylic acid cycle (GO:0006099), protein methylation (GO:0006479), peptidyl-lysine trimethylation (GO:0018023), peptidyl-lysine monomethylation (GO:0018026), peptidyl-lysine dimethylation (GO:0018027), methylation (GO:0032259)

GO Molecular Function (5): lysine N-methyltransferase activity (GO:0016278), protein-lysine N-methyltransferase activity (GO:0016279), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Citric acid cycle (TCA cycle)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
peptidyl-lysine methylation	3
aerobic respiration	1
primary metabolic process	1
protein alkylation	1
macromolecule methylation	1
metabolic process	1
N-methyltransferase activity	1
S-adenosylmethionine-dependent methyltransferase activity	1
protein methyltransferase activity	1
lysine N-methyltransferase activity	1
binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

336 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CSKMT	EEF1AKMT2	Q5JPI9	717
CSKMT	ETFBKMT	Q8IXQ9	609
CSKMT	EEF1AKMT3	Q96AZ1	538
CSKMT	VCPKMT	Q9H867	531
CSKMT	METTL22	Q9BUU2	513
CSKMT	NDUFAF7	Q7L592	509
CSKMT	METTL21A	Q8WXB1	501
CSKMT	METTL25	Q8N6Q8	490
CSKMT	METTL25B	Q96FB5	490
CSKMT	METTL18	O95568	464
CSKMT	SH3RF1	Q7Z6J0	452
CSKMT	MTRF1L	Q9UGC7	452
CSKMT	FAM163A	Q96GL9	448
CSKMT	EEF1AKMT4-ECE2	P0DPD8	448
CSKMT	NDUFAF5	Q5TEU4	446

IntAct

19 interactions, top by confidence:

A	B	Type	Score
CSKMT	TEKT5	psi-mi:“MI:0915”(physical association)	0.560
CSKMT	KRTAP19-6	psi-mi:“MI:0915”(physical association)	0.560
CSKMT	BPIFA1	psi-mi:“MI:0915”(physical association)	0.560
CSKMT	STK16	psi-mi:“MI:0915”(physical association)	0.560
CSKMT	KRTAP13-2	psi-mi:“MI:0915”(physical association)	0.560
CSKMT	KRTAP11-1	psi-mi:“MI:0915”(physical association)	0.560
CSKMT	STK16	psi-mi:“MI:0915”(physical association)	0.000
CSKMT	KRTAP13-2	psi-mi:“MI:0915”(physical association)	0.000
CSKMT	TEKT5	psi-mi:“MI:0915”(physical association)	0.000
CSKMT	KRTAP19-6	psi-mi:“MI:0915”(physical association)	0.000
CSKMT	BPIFA1	psi-mi:“MI:0915”(physical association)	0.000
CSKMT	KRTAP11-1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (7): METTL12 (Affinity Capture-RNA), METTL12 (Two-hybrid), METTL12 (Two-hybrid), METTL12 (Two-hybrid), METTL12 (Two-hybrid), METTL12 (Two-hybrid), METTL12 (Two-hybrid)

ESM2 similar proteins: A4FV98, A5D7B1, A5PK51, A6QLN9, A8MUP2, D3ZVU9, O15527, O35595, O75078, O95848, P57775, Q05B60, Q06643, Q14728, Q14CX5, Q1LZB9, Q27HK4, Q2T9T5, Q2TBS1, Q3UGX3, Q4R3I0, Q4V892, Q58CT4, Q5E9H2, Q5RCI5, Q5SUV1, Q5TM22, Q642A6, Q6IA17, Q6PCB0, Q6XQN6, Q862Z7, Q8N8L6, Q8R2R5, Q8R2Z5, Q8R366, Q8WUG5, Q95JH0, Q95JH2, Q969P0

Diamond homologs: A5PK19, A5WVX1, A8MUP2, P0DPD7, P0DPD8, P0DPD9, P0DPE0, P0DPE1, P0DPE2, Q29LW1, Q5RCI5, Q6NTR1, Q8N6R0, Q91YR5, Q9VIK9, Q501S4, A0A0B4K692, B2RQR8, F1N476, O16796, O44857, O95672, P07861, P08049, P08473, P0C1T0, P0DPD6, P23276, P42891, P42892, P42893, P70669, P78562, P97739, Q18673, Q22523, Q495T6, Q4PZA2, Q5RE69, Q61391

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CSKMT	“down-regulates activity”	CS	methylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	52
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

492 predictions. Top by Δscore:

Variant	Effect	Δscore
11:62667517:ACTT:A	donor_loss	1.0000
11:62667518:CTT:C	donor_loss	1.0000
11:62667519:TTAC:T	donor_loss	1.0000
11:62667521:A:AC	donor_gain	1.0000
11:62667521:A:AT	donor_loss	1.0000
11:62667521:AC:A	donor_gain	1.0000
11:62667521:ACC:A	donor_gain	1.0000
11:62667521:ACCCT:A	donor_gain	1.0000
11:62667522:C:CT	donor_gain	1.0000
11:62667522:CC:C	donor_gain	1.0000
11:62667522:CCC:C	donor_gain	1.0000
11:62667522:CCCT:C	donor_gain	1.0000
11:62667522:CCCTC:C	donor_gain	1.0000
11:62667743:CCAGC:C	acceptor_gain	1.0000
11:62667744:CAGC:C	acceptor_gain	1.0000
11:62667744:CAGCC:C	acceptor_gain	1.0000
11:62667745:AGC:A	acceptor_gain	1.0000
11:62667746:GC:G	acceptor_gain	1.0000
11:62667746:GCC:G	acceptor_loss	1.0000
11:62667747:CC:C	acceptor_gain	1.0000
11:62667748:C:CC	acceptor_gain	1.0000
11:62667748:C:T	acceptor_gain	1.0000
11:62667753:A:AC	acceptor_gain	1.0000
11:62667753:A:C	acceptor_gain	1.0000
11:62665927:G:GT	donor_gain	0.9900
11:62665927:G:T	donor_gain	0.9900
11:62667749:T:A	acceptor_gain	0.9800
11:62665329:GCTA:G	donor_gain	0.9700
11:62667624:T:TA	donor_gain	0.9700
11:62667745:AGCC:A	acceptor_gain	0.9700

AlphaMissense

1525 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:62666816:A:T	K163I	0.994
11:62666817:A:C	K163N	0.984
11:62666817:A:T	K163N	0.984
11:62666918:T:C	F197S	0.981
11:62666824:T:A	W166R	0.980
11:62666824:T:C	W166R	0.980
11:62666920:T:C	S198P	0.980
11:62666582:G:T	G85V	0.973
11:62666647:G:C	D107H	0.971
11:62666827:G:C	D167H	0.971
11:62666663:C:A	A112D	0.970
11:62667022:T:C	F232L	0.970
11:62667024:T:A	F232L	0.970
11:62667024:T:G	F232L	0.970
11:62666818:G:C	G164R	0.969
11:62666828:A:C	D167A	0.969
11:62666828:A:T	D167V	0.969
11:62667028:T:G	Y234D	0.969
11:62666641:G:T	G105W	0.968
11:62666582:G:A	G85E	0.967
11:62666797:T:C	F157L	0.967
11:62666799:C:A	F157L	0.967
11:62666799:C:G	F157L	0.967
11:62666578:T:C	C84R	0.966
11:62666649:C:A	D107E	0.966
11:62666649:C:G	D107E	0.966
11:62666909:T:C	L194P	0.966
11:62666436:G:C	W36C	0.965
11:62666436:G:T	W36C	0.965
11:62666747:T:C	F140S	0.964

dbSNP variants (sampled 300 via entrez): RS1000900240 (11:62667298 A>G), RS1001255103 (11:62667674 G>C,T), RS1002647003 (11:62668148 C>A), RS1003009191 (11:62665794 C>A,T), RS1003195972 (11:62664525 T>C), RS1003659267 (11:62664236 T>C), RS1004282067 (11:62668088 A>G), RS1004740319 (11:62667838 C>A,T), RS1005090602 (11:62666935 G>A), RS1005348888 (11:62666518 C>T), RS1005510640 (11:62663454 C>G,T), RS1006499837 (11:62668442 A>G), RS1006581488 (11:62666118 C>A,G,T), RS1007577564 (11:62665300 G>A,T), RS1007809209 (11:62663859 G>A,C)

Disease associations

OMIM: gene MIM:617897 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST005956_2	Waist-to-hip ratio adjusted for BMI	1.000000e-08
GCST005962_51	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	1.000000e-07

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: no

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

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	increases expression	2
2-methyl-4-isothiazolin-3-one	increases expression	1
beta-lapachone	decreases expression	1
sodium arsenite	increases stability	1
jinfukang	increases expression, affects cotreatment	1
(+)-JQ1 compound	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
DDT	increases expression	1
Doxorubicin	increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Quercetin	increases expression	1
Silicon Dioxide	increases expression	1
Testosterone	decreases expression	1
Cyclosporine	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SX88	HAP1 METTL12 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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