CS

Summary

CS (citrate synthase, HGNC:2422) is a protein-coding gene on chromosome 12q13.3, encoding Citrate synthase, mitochondrial (O75390). Key enzyme of the Krebs tricarboxylic acid cycle which catalyzes the synthesis of citrate from acetyl coenzyme A and oxaloacetate. It is a selective cancer dependency (DepMap: 36.6% of cell lines).

The protein encoded by this gene is a Krebs tricarboxylic acid cycle enzyme that catalyzes the synthesis of citrate from oxaloacetate and acetyl coenzyme A. The enzyme is found in nearly all cells capable of oxidative metablism. This protein is nuclear encoded and transported into the mitochondrial matrix, where the mature form is found.

Source: NCBI Gene 1431 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 44 total
• GTEx eGene: eQTL in 9 tissues, sQTL in 13 (q < 0.05)
• Cancer dependency (DepMap): dependent in 36.6% of screened cell lines
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.36 (moderately constrained)
• MANE Select transcript: NM_004077
• Interaction hub: 3,695 STRING partners (top 1% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2422
Approved symbol	CS
Name	citrate synthase
Location	12q13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000062485
Ensembl biotype	protein_coding
OMIM	118950
Entrez	1431

Gene structure

Transcript identifiers

Ensembl transcripts: 53 — 32 protein_coding, 11 retained_intron, 10 nonsense_mediated_decay

MANE Select: ENST00000351328

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 10, TSL 3: 9, TSL 4: 9, TSL 5: 3

ENST00000351328, ENST00000542324, ENST00000546585, ENST00000546621, ENST00000546891, ENST00000546930, ENST00000547283, ENST00000547298, ENST00000547449, ENST00000547912, ENST00000548041, ENST00000548567, ENST00000548746, ENST00000548849, ENST00000549143, ENST00000549221, ENST00000550044, ENST00000550159, ENST00000550655, ENST00000550700, ENST00000550734, ENST00000550996, ENST00000551137, ENST00000551155, ENST00000551253, ENST00000551430, ENST00000551441, ENST00000551473, ENST00000551936, ENST00000551968, ENST00000552222, ENST00000552331, ENST00000552688, ENST00000904224, ENST00000904225, ENST00000921535, ENST00000921536, ENST00000947272, ENST00000947273, ENST00000991491, ENST00000991492, ENST00001056701, ENST00001056702, ENST00001056704, ENST00001056706, ENST00001091666, ENST00001091667, ENST00001091668, ENST00001091669, ENST00001091670, ENST00001124711, ENST00001129837, ENST00001138979

RefSeq mRNA: 1 — MANE Select: NM_004077 NM_004077

CCDS: CCDS8913

Canonical transcript exons

ENST00000351328 — 11 exons

Exon	Start	End
ENSE00003462969	56275002	56275131
ENSE00003480306	56275996	56276195
ENSE00003501837	56285916	56286023
ENSE00003501898	56273587	56273796
ENSE00003513078	56282420	56282608
ENSE00003533644	56283792	56283857
ENSE00003541640	56274777	56274878
ENSE00003562168	56300160	56300330
ENSE00003629831	56286595	56286645
ENSE00003656673	56282860	56282991
ENSE00003841381	56271699	56273254

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 99.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 132.1132 / max 1009.6120, expressed in 1828 samples.

Highest expression (Bgee): ventricle myocardium, cardiac muscle of right atrium, heart right ventricle, gastrocnemius, vastus lateralis.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CS is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 9 tissues and its splicing (sQTL) in 13 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 22 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Muscle Skeletal	sqtl	3.2e-20	+0.49	12:56298926:C:T
Cells Cultured fibroblasts	sqtl	2.6e-12	+0.45	12:56298926:C:T
Skin Sun Exposed Lower leg	sqtl	4.0e-06	-0.68	12:56360038:C:A
Heart Atrial Appendage	sqtl	4.1e-05	-0.83	12:56233835:A:G
Artery Tibial	eqtl	5.6e-05	-0.30	12:56300123:A:C
Esophagus Muscularis	sqtl	7.3e-05	+0.74	12:56251102:A:G
Esophagus Muscularis	eqtl	1.4e-04	-0.31	12:56300123:A:C
Heart Atrial Appendage	eqtl	3.1e-04	+0.27	12:55301436:T:G
Nerve Tibial	sqtl	9.2e-04	+0.30	12:56298926:C:T
Breast Mammary Tissue	sqtl	9.6e-04	-0.67	12:56116134:G:C
Skin Sun Exposed Lower leg	eqtl	1.1e-03	+0.15	12:56166056:G:A
Cells EBV-transformed lymphocytes	sqtl	2.4e-03	-0.87	12:56240855:G:C
Adrenal Gland	sqtl	2.6e-03	-0.33	12:56297816:T:C
Esophagus Gastroesophageal Junction	sqtl	6.1e-03	-0.78	12:56233835:A:G
Adipose Visceral Omentum	sqtl	7.1e-03	+0.67	12:56241296:G:C
Brain Cortex	eqtl	9.0e-03	+1.04	12:57182156:G:A
Esophagus Mucosa	sqtl	1.0e-02	+0.26	12:56298926:C:T
Adipose Visceral Omentum	eqtl	1.1e-02	-0.20	12:55679762:T:A
Skin Not Sun Exposed Suprapubic	eqtl	2.0e-02	-0.30	12:55944654:TG:T
Cells EBV-transformed lymphocytes	eqtl	2.9e-02	+0.29	12:56300123:A:C

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
131504	106.7404	1827
131505	23.4241	1815
131503	1.9487	1043

Top tissues by expression

showing 100 of 295 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	99.45	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.17	gold quality
heart right ventricle	UBERON:0002080	99.06	gold quality
gastrocnemius	UBERON:0001388	99.03	gold quality
vastus lateralis	UBERON:0001379	99.02	gold quality
myocardium	UBERON:0002349	98.99	gold quality
body of tongue	UBERON:0011876	98.95	gold quality
diaphragm	UBERON:0001103	98.94	gold quality
cardiac ventricle	UBERON:0002082	98.92	gold quality
heart left ventricle	UBERON:0002084	98.92	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.86	gold quality
skeletal muscle tissue	UBERON:0001134	98.83	gold quality
triceps brachii	UBERON:0001509	98.83	gold quality
biceps brachii	UBERON:0001507	98.81	gold quality
cardiac atrium	UBERON:0002081	98.80	gold quality
gluteal muscle	UBERON:0002000	98.79	gold quality
quadriceps femoris	UBERON:0001377	98.77	gold quality
apex of heart	UBERON:0002098	98.77	gold quality
muscle tissue	UBERON:0002385	98.77	gold quality
right atrium auricular region	UBERON:0006631	98.76	gold quality
deltoid	UBERON:0001476	98.72	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.72	gold quality
muscle organ	UBERON:0001630	98.67	gold quality
muscle of leg	UBERON:0001383	98.62	gold quality
heart	UBERON:0000948	98.60	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.58	gold quality
tibialis anterior	UBERON:0001385	98.43	gold quality
right adrenal gland	UBERON:0001233	98.36	gold quality
right adrenal gland cortex	UBERON:0035827	98.36	gold quality
rectum	UBERON:0001052	98.35	gold quality
tongue	UBERON:0001723	98.29	gold quality
left adrenal gland	UBERON:0001234	98.26	gold quality
left adrenal gland cortex	UBERON:0035825	98.18	gold quality
mammalian vulva	UBERON:0000997	98.17	gold quality
cortical plate	UBERON:0005343	98.17	gold quality
pharyngeal mucosa	UBERON:0000355	98.15	gold quality
upper leg skin	UBERON:0004262	98.15	gold quality
adrenal cortex	UBERON:0001235	98.13	gold quality
adrenal gland	UBERON:0002369	98.13	gold quality
upper arm skin	UBERON:0004263	98.12	gold quality
colonic epithelium	UBERON:0000397	98.08	gold quality
transverse colon	UBERON:0001157	98.01	gold quality
vena cava	UBERON:0004087	97.97	gold quality
ganglionic eminence	UBERON:0004023	97.93	gold quality
adrenal tissue	UBERON:0018303	97.85	gold quality
mucosa of transverse colon	UBERON:0004991	97.78	gold quality
olfactory bulb	UBERON:0002264	97.74	silver quality
cerebellar hemisphere	UBERON:0002245	97.73	gold quality
esophagus mucosa	UBERON:0002469	97.73	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.73	gold quality
skin of leg	UBERON:0001511	97.70	gold quality
cerebellar cortex	UBERON:0002129	97.69	gold quality
superior surface of tongue	UBERON:0007371	97.69	gold quality
skin of abdomen	UBERON:0001416	97.66	gold quality
skin of hip	UBERON:0001554	97.64	gold quality
cerebellum	UBERON:0002037	97.60	gold quality
smooth muscle tissue	UBERON:0001135	97.59	gold quality
esophagus	UBERON:0001043	97.58	gold quality
colon	UBERON:0001155	97.56	gold quality
large intestine	UBERON:0000059	97.55	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.55	gold quality
islet of Langerhans	UBERON:0000006	97.51	gold quality
bone marrow cell	CL:0002092	97.49	gold quality
zone of skin	UBERON:0000014	97.46	gold quality
metanephros cortex	UBERON:0010533	97.46	gold quality
intestine	UBERON:0000160	97.42	gold quality
colonic mucosa	UBERON:0000317	97.41	gold quality
paraflocculus	UBERON:0005351	97.39	gold quality
body of stomach	UBERON:0001161	97.38	gold quality
lower esophagus	UBERON:0013473	97.38	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.38	gold quality
ventricular zone	UBERON:0003053	97.37	gold quality
type B pancreatic cell	CL:0000169	97.36	gold quality
adipose tissue of abdominal region	UBERON:0007808	97.36	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.35	gold quality
sigmoid colon	UBERON:0001159	97.34	gold quality
embryo	UBERON:0000922	97.33	gold quality
postcentral gyrus	UBERON:0002581	97.33	gold quality
minor salivary gland	UBERON:0001830	97.32	gold quality
body of pancreas	UBERON:0001150	97.31	gold quality
lower esophagus mucosa	UBERON:0035834	97.31	gold quality
adipose tissue	UBERON:0001013	97.30	gold quality
peritoneum	UBERON:0002358	97.30	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.30	gold quality
omental fat pad	UBERON:0010414	97.30	gold quality
vagina	UBERON:0000996	97.28	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.26	gold quality
nipple	UBERON:0002030	97.25	gold quality
pons	UBERON:0000988	97.24	gold quality
stromal cell of endometrium	CL:0002255	97.19	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.18	gold quality
stomach	UBERON:0000945	97.17	gold quality
small intestine	UBERON:0002108	97.16	gold quality
parietal lobe	UBERON:0001872	97.15	gold quality
tongue squamous epithelium	UBERON:0006919	97.15	gold quality
caecum	UBERON:0001153	97.13	gold quality
renal medulla	UBERON:0000362	97.06	gold quality
Brodmann (1909) area 46	UBERON:0006483	97.04	gold quality
mucosa of stomach	UBERON:0001199	97.03	gold quality
connective tissue	UBERON:0002384	97.01	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	15.89
E-MTAB-9801	no	2.84

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Tongue	tissue	561.0
Skeletal muscle	tissue	515.2	medium
Heart muscle	tissue	298.9	high
Frontal cortex	tissue	221.3
Caudate putamen	tissue	201.7
Superior colliculi	tissue	157.7
Thalamus	tissue	153.1
Spinal cord	tissue	150.7
Cerebral cortex	tissue	145.3	high
Somatosensory cortex	tissue	145.3
Adipose tissue	tissue	144.7	high
Medulla oblongata	tissue	140.8
Pons	tissue	139.4
Midbrain	tissue	134.2
Postcentral gyrus	tissue	130.9
Occipital cortex	tissue	130.5
Motor cortex	tissue	120.5
Parathyroid gland	tissue	119.8	high
Retina	tissue	119.5
Rectum	tissue	116.6	high
Choroid plexus	tissue	115.4
Hippocampal formation	tissue	112.0
Substantia nigra	tissue	111.6
Temporal cortex	tissue	107.0
Prefrontal cortex	tissue	105.8
Bone marrow	tissue	104.8	high
Retrosplenial and cingulate cortex	tissue	103.4
Colon	tissue	103.2	high
Putamen	tissue	103.1
Entorhinal cortex	tissue	102.7
Cerebellum	tissue	101.6	high
Retrosplenial cortex	tissue	99.5
Tonsil	tissue	99.4	high
Ventral forebrain	tissue	97.0
Hypothalamus	tissue	94.0
Periaqueductal gray	tissue	93.2
Duodenum	tissue	92.0	high
Locus coeruleus	tissue	92.0
Septum	tissue	90.3
Insular cortex	tissue	90.2
Basal ganglia	tissue	90.1	high
Esophagus	tissue	89.9	high
Olfactory bulb	tissue	87.2
Kidney	tissue	80.8	high
Adrenal gland	tissue	80.1	high
Amygdala	tissue	78.7
Nucleus accumbens	tissue	78.4
Small intestine	tissue	76.5	high
Corpus callosum	tissue	73.5
Smooth muscle	tissue	72.4	medium
Hippocampus	tissue	70.8	high
Salivary gland	tissue	69.5	high
Vagina	tissue	65.6	high
Urinary bladder	tissue	65.6	high
Thymus	tissue	64.7
Skin 1	tissue	63.5	high
Lymph node	tissue	62.7	high
Stomach 1	tissue	62.7	high
Appendix	tissue	58.2	high
Pancreas	tissue	58.0	high

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Ventral spinal cord (150.7), Dorsal spinal cord (116.5), Pulvinar (115.5), Lateral geniculate body (113.9), Precentral gyrus, middle (112.9).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FEZF2, MAF, MYB, POU1F1, RORA, SP1, TBR1, TEAD1

miRNA regulators (miRDB)

Targeting CS by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 108 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.356, missense Z 4.36 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000351328 splits into 2 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
12:56,273,087–56,285,946	223 / 503.5	0.44	no
12:56,285,947–56,300,201	55 / 69.9	0.79	no
DepMap (CRISPR cell-line fitness): dependent in 36.6% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): OCI-AML3 (-1.841), OCI-AML2 (-1.154), LS1034 (-1.13), Ki-JK (-1.119), TUHR10TKB (-1.113), SK-N-BE(2) (-1.095), SU-DHL-10 (-1.092), MEL-HO (-1.054), HEC-59 (-1.041), MCF-7 (-1.013), KPL-1 (-1.009), NCI-H23 (-1.007), SNU-398 (-0.996), TALL-1 (-0.979), HCC2998 (-0.974).

Literature-anchored findings (GeneRIF, showing 19)

• Responses of skeletal and cardiac muscles in CS activity and gene expression at 1 and 48 h after endurance training. Acute effect of exercise on training-induced elevation in CS activity in rat soleus but not ventricle muscles. (PMID:12531911)
• possible role of CS-specific autoantibodies in the pathomechanism of allograft vasculopathy (PMID:15711981)
• It is likely that enhanced citrate synthase activity contributes to the conversion of glucose to lipids in pancreatic cancer providing substrate for membrane lipids synthesis. (PMID:15714131)
• These results provide an important basis for the study of mitochondrial dysfunction due to aberrant CSa trafficking. (PMID:19479947)
• Citrate synthase (CS) is a direct RORalpha target gene and one mechanism by which RORalpha regulates lipid metabolism is via regulation of CS expression. (PMID:22485150)
• The citrate synthase knockdown cells exhibited severe defects in respiratory activity and marked decreases in ATP production, but great increases in glycolytic metabolism. (PMID:23139858)
• Paretic muscle in hemiparetic stroke survivors had lower CS concentration. (PMID:26361074)
• Citrate synthase activity was lower in patients with heart failure with preserved ejection fraction compared to controls. (PMID:27179829)
• citrate synthase and ACSS1 have tumorigenic functions in hepatocellular carcinoma (PMID:27363021)
• mir-122 and its targets G6PC3, ALDOA and CS play roles in the hypoxia responses that regulate glucose and energy metabolism and can serve as hypoxia biomarkers. (PMID:27793029)
• Hence, we conclude that SIRT3 exhibits neuroprotection via deacetylating and increasing mitochondrial enzyme activities. (PMID:28161643)
• Data suggest that downregulation of citrate synthase (CS) expression in 293T cells leads to low level of ATP production, excessive superoxide formation and cell apoptosis, which implies a possible mechanism for hearing loss in A/J mice. (PMID:28216161)
• 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. (METTL12 = methyltransferase-like protein 12) (PMID:28391595)
• METTL12 methylates CS on Lys-395, which is localized in the CS active site. Interestingly, the METTL12-mediated methylation inhibited CS activity and was blocked by the CS substrate oxaloacetate. (PMID:28887308)
• The active sites of the citrate synthase is almost identical, the differences in reactions catalyzed by citrate synthase are caused by residues that are in the vicinity of the active site and influence conformational changes of the citrate synthase. (PMID:31141475)
• Rethinking the Citric Acid Cycle: Connecting Pyruvate Carboxylase and Citrate Synthase to the Flow of Energy and Material. (PMID:33435350)
• The left-lateralisation of citrate synthase activity in the anterior cingulate cortex of male violent suicide victims. (PMID:36350374)
• The Novel Role of Mitochondrial Citrate Synthase and Citrate in the Pathophysiology of Alzheimer’s Disease. (PMID:37393492)
• Citrate synthase lysine K215 hypoacetylation contributes to microglial citrate accumulation and pro-inflammatory functions after traumatic brain injury. (PMID:38421106)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cs	ENSDARG00000103364
mus_musculus	Cs	ENSMUSG00000005683
mus_musculus	Csl	ENSMUSG00000046934
rattus_norvegicus	Cs	ENSRNOG00000023520
drosophila_melanogaster	kdn	FBGN0261955
caenorhabditis_elegans		WBGENE00000833

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:88529) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 9 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased or absent threshold for auditory brainstem response	2
abnormal digit morphology	1
abnormal auditory brainstem response	1
increased susceptibility to age-related hearing loss	1
impaired glucose tolerance	1
impaired hearing	1
decreased prepulse inhibition	1
abnormal retina blood vessel morphology	1
preweaning lethality, complete penetrance	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Aspergillus fumigatus A1163	B0YD89	100.0%	Diamond
Aspergillus fumigatus	Q50I20	100.0%	Diamond
Thunnus obesus	Q6S9V8	100.0%	Diamond
Thunnus albacares	Q6S9V9	100.0%	Diamond
Iguana iguana	Q0GNE0	99.8%	Diamond
Amblyrhynchus cristatus	Q0GNE1	99.8%	Diamond
Aedes aegypti	Q16P20	99.8%	Diamond
Katsuwonus pelamis	Q6S9V7	99.4%	Diamond
Kajikia audax	Q6S9V5	99.1%	Diamond
Xiphias gladius	Q6S9V6	99.1%	Diamond
Macaca fascicularis	P0C1Z2	98.9%	Diamond
Mesocricetus auratus	Q0QEL7	98.1%	Diamond
Sus scrofa	P00889	97.2%	Diamond
Bos taurus	Q29RK1	97.2%	Diamond
Caenorhabditis briggsae	Q61JF9	97.0%	Diamond
Fusarium solani	C7C435	96.2%	Diamond
Fusarium verticillioides	C7C436	96.2%	Diamond
Xenopus tropicalis	Q28DK1	95.7%	Diamond
Xenopus laevis	Q7ZWZ5	95.7%	Diamond
Tetraodon nigroviridis	Q4S5X1	95.5%	Diamond
Leishmania infantum	A4HXU4	95.1%	Diamond
Leishmania major	Q4QDX3	95.1%	Diamond
Aspergillus nidulans FGSC A4	O00098	92.1%	Diamond
Aspergillus niger	P51044	92.1%	Diamond
Gallus gallus	P23007	91.9%	Diamond
Glossina morsitans morsitans	Q0QHL3	90.6%	Diamond
Leishmania braziliensis	A4H9H8	86.7%	Diamond
Arabidopsis thaliana	P20115	85.8%	Diamond
Citrus maxima	P49298	83.7%	Diamond
Daucus carota	O80433	83.5%	Diamond
Neurospora crassa OR74A	P34085	81.9%	Diamond
Saccharomyces cerevisiae S288C	P08679	81.6%	Diamond
Candida tropicalis	P79024	80.8%	Diamond
Solanum tuberosum	Q43175	80.8%	Diamond
Fragaria x ananassa	P83372	78.4%	Diamond
Yarrowia lipolytica CLIB122	Q6C793	76.0%	Diamond
Dictyostelium discoideum	Q553V1	73.6%	Diamond
Schizosaccharomyces pombe 972h-	Q10306	71.0%	Diamond
Thermosulfidibacter takaii ABI70S6	A0A0S3QTD0	64.2%	Diamond
Tetrahymena thermophila	P24118	61.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
CNPY2-AS1	ncRNA	112268098
IL23A	protein-coding	51561
COQ10A	protein-coding	93058
PAN2	protein-coding	9924
CNPY2	protein-coding	10330
ANKRD52	protein-coding	283373
SLC39A5	protein-coding	283375
NABP2	protein-coding	79035
STAT2	protein-coding	6773
RNF41	protein-coding	10193

Protein

Protein identifiers

Citrate synthase, mitochondrial — O75390 (reviewed: O75390)

Alternative names: Citrate (Si)-synthase

All UniProt accessions (21): A0A0C4DGI3, B4DJV2, O75390, F8VPA1, F8VPF9, F8VR34, F8VRI6, F8VRP1, F8VTT8, F8VU34, F8VVY4, F8VWQ5, F8VX07, F8VX68, F8VZK9, F8W0J2, F8W1S4, F8W4S1, F8W642, H0YH82, H0YIC4

UniProt curated annotations — full annotation on UniProt →

Function. Key enzyme of the Krebs tricarboxylic acid cycle which catalyzes the synthesis of citrate from acetyl coenzyme A and oxaloacetate.

Subunit / interactions. Homodimer.

Subcellular location. Mitochondrion matrix.

Post-translational modifications. Methylated. Trimethylation at Lys-395 by CSKMT decreases citrate synthase activity. In response to mitochondrial stress, the precursor protein is ubiquitinated by the SIFI complex in the cytoplasm before mitochondrial import, leading to its degradation. Within the SIFI complex, UBR4 initiates ubiquitin chain that are further elongated or branched by KCMF1.

Pathway. Carbohydrate metabolism; tricarboxylic acid cycle; isocitrate from oxaloacetate: step 1/2.

Miscellaneous. Citrate synthase is found in nearly all cells capable of oxidative metabolism.

Similarity. Belongs to the citrate synthase family.

RefSeq proteins (1): NP_004068* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002020	Citrate_synthase	Family
IPR010109	Citrate_synthase_euk	Family
IPR016142	Citrate_synth-like_lrg_a-sub	Homologous_superfamily
IPR016143	Citrate_synth-like_sm_a-sub	Homologous_superfamily
IPR019810	Citrate_synthase_AS	Active_site
IPR036969	Citrate_synthase_sf	Homologous_superfamily

Pfam: PF00285

Enzyme classification (BRENDA)

• EC 2.3.3.1 — citrate (Si)-synthase (BRENDA: 15 organisms, 9 substrates, 48 inhibitors, 28 Km, 18 kcat entries)
• EC 2.3.3.16 — citrate synthase (unknown stereospecificity) (BRENDA: 100 organisms, 82 substrates, 183 inhibitors, 214 Km, 98 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ACETYL-COA	0.0007–125	101
OXALOACETATE	0.0011–90.3	93
ACETYL-COA	0.005–10	14
OXALOACETATE	0.0036–5	14
PROPIONYL-COA	0.0017–0.016	5
CITRATE	0.0005–0.001	4

Catalyzed reactions (Rhea)

• oxaloacetate + acetyl-CoA + H2O = citrate + CoA + H(+) (RHEA:16845)

UniProt features (77 total): helix 28, modified residue 18, sequence conflict 8, strand 8, turn 4, active site 3, binding site 3, mutagenesis site 2, transit peptide 1, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

11 structures by resolution:

PDB	Title	Method	Resolution (Å)
8ZVV	human citrate synthase complexed with citrate	X-RAY DIFFRACTION	1.59
8ZVU	Human citrate synthase intermediate 4	X-RAY DIFFRACTION	1.78
8ZVR	Human citrate synthase intermediate 2	X-RAY DIFFRACTION	1.8
8ZVW	human citrate synthase complexed with oxaloacetate and coenzyme A	X-RAY DIFFRACTION	1.82
8ZVL	human citrate synthases complexed with oxaloacetate	X-RAY DIFFRACTION	2.05
8ZVT	Human citrate synthase intermediate 3	X-RAY DIFFRACTION	2.05
8ZW1	citrate synthases complexed with oxaloacetate and acetyl-CoA	X-RAY DIFFRACTION	2.1
5UZQ	Crystal structure of citrate synthase from homo sapiens	X-RAY DIFFRACTION	2.16
8ZVM	Human citrate synthase intermediate 1	X-RAY DIFFRACTION	2.27
5UZP	Crystal structure of citrate synthase mutant A348G from homo sapiens	X-RAY DIFFRACTION	2.29
5UZR	Crystal structure of citrate synthase from homo sapiens	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75390-F1	94.56	0.93

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Metabolic proteins, Predicted membrane proteins, Predicted intracellular proteins, Plasma proteins, Citric acid cycle related proteins, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): mitochondria

Antibody reliability (HPA): IH enhanced · IF enhanced

Functional residue map

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

Catalytic / active sites (3)

Position	Role
301
347
402

Ligand- & substrate-binding residues (3)

Position	Role
356	oxaloacetate
428	oxaloacetate
448	oxaloacetate

Post-translational modifications (18)

Type	Positions
N6-acetyllysine	76, 321, 327, 375, 382, 393, 459
N6-succinyllysine	76, 103, 193, 321, 327, 375, 393, 450, 459, 57
N6,n6,n6-trimethyllysine	395

Mutagenesis-validated functional residues (2)

Position	Phenotype
393	does not inhibit methylation.
395	inhibits methylation.

Function

Pathways and Gene Ontology

Reactome pathways

3 curated (TAS) of 8; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

8 pathways:

ID	Pathway	Evidence
R-HSA-71403	Citric acid cycle (TCA cycle)	curated
R-HSA-9854311	Maturation of TCA enzymes and regulation of TCA cycle	curated
R-HSA-9837999	Mitochondrial protein degradation	curated
R-HSA-1428517	Aerobic respiration and respiratory electron transport	—
R-HSA-1430728	Metabolism	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-1268020	Mitochondrial protein import	electronic
R-HSA-9609507	Protein localization	—

MSigDB gene sets: 304 (showing top): MORF_MTA1, MORF_DNMT1, MORF_ESPL1, WWTAAGGC_UNKNOWN, GCM_GSPT1, MORF_UBE2I, MORF_RRM1, MORF_HDAC1, MORF_CDK2, TGACCTY_ERR1_Q2, MORF_HDAC2, HNF1_Q6, CHX10_01, GGGTGGRR_PAX4_03, GCM_BCL2L1

GO Biological Process (3): carbohydrate metabolic process (GO:0005975), tricarboxylic acid cycle (GO:0006099), citrate metabolic process (GO:0006101)

GO Molecular Function (5): RNA binding (GO:0003723), citrate synthase activity (GO:0036440), identical protein binding (GO:0042802), transferase activity (GO:0016740), acyltransferase activity, acyl groups converted into alkyl on transfer (GO:0046912)

GO Cellular Component (4): nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), extracellular exosome (GO:0070062)

Reactome top-level categories

5 top-level categories:

Category	Pathways
Protein localization	1
Aerobic respiration and respiratory electron transport	1
Metabolism of proteins	1
Citric acid cycle (TCA cycle)	1
Metabolism	1

GO top-level categories

13 GO namespaces:

Category	Terms
primary metabolic process	2
intracellular membrane-bounded organelle	2
aerobic respiration	1
tricarboxylic acid metabolic process	1
nucleic acid binding	1
acyltransferase activity, acyl groups converted into alkyl on transfer	1
protein binding	1
catalytic activity	1
acyltransferase activity	1
cytoplasm	1
mitochondrion	1
intracellular organelle lumen	1
extracellular vesicle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 8 of 12 annotations. The rest are phylogenetic / computational / electronic (IEA).

8 experimentally-supported GO terms:

GO term	NS	Evidence
carbohydrate metabolic process	BP	direct assay
extracellular exosome	CC	high-throughput assay
mitochondrial matrix	CC	direct assay
mitochondrion	CC	direct assay
nucleus	CC	high-throughput assay
RNA binding	MF	high-throughput assay
citrate synthase activity	MF	direct assay
identical protein binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 3,695 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CS	IDH2	P48735	914
CS	IDH1	O75874	892
CS	ACO2	Q99798	854
CS	PKM	P14618	834
CS	FH	P07954	830
CS	ACO1	P21399	822
CS	SLC25A16	P16260	809
CS	MDH2	P40926	800
CS	PC	P11498	787
CS	VDAC3	Q9Y277	777
CS	GAPDH	P00354	776
CS	ACLY	P53396	773
CS	OGDH	Q02218	763
CS	PDIA6	Q15084	763
CS	LDHC	P07864	729

IntAct

Human interaction partners of CS in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

25 partners by confidence:

Partner	Interaction type	MIscore	Records
NEK10	proximity	0.420	1
ATXN7L1	physical association	0.400	1
HSPE1	physical association	0.400	1
PLEC	physical association	0.400	1
NS	association	0.350	1
OPA3	association	0.350	1
PAK2	association	0.350	1
SLC25A32	association	0.350	1
ANXA5	physical association	0.000	1
ARF6	physical association	0.000	1
EIF5B	physical association	0.000	1
EIF6	physical association	0.000	1
GPI	physical association	0.000	1
HLA-B	physical association	0.000	1
LCOR	physical association	0.000	1
MCC	physical association	0.000	1
PA2G4	physical association	0.000	1
SGK1	physical association	0.000	1
SND1	physical association	0.000	1
SNRPB2	physical association	0.000	1
TAB2	physical association	0.000	1
TRAF6	physical association	0.000	1
TRAP1	physical association	0.000	1
UBE2N	physical association	0.000	1
ZNF207	physical association	0.000	1

BioGRID (721 interactions; top human partners by supporting records in a sample of 600 records): ACAD9 (Proximity Label-MS; 3 records), CLPP (Proximity Label-MS; 3 records), DLAT (Co-fractionation; 3 records), ECHS1 (Co-fractionation; 3 records), GFM1 (Proximity Label-MS; 3 records), GRSF1 (Proximity Label-MS; 3 records), HINT2 (Proximity Label-MS; 3 records), HSD17B10 (Two-hybrid; 3 records), LRPPRC (Proximity Label-MS; 3 records), MDH2 (Proximity Label-MS; 3 records), MRPS26 (Proximity Label-MS; 3 records), MTERF3 (Proximity Label-MS; 3 records), MTIF2 (Proximity Label-MS; 3 records), OAT (Co-fractionation; 3 records), SDHA (Co-fractionation; 3 records)

SIGNOR signaling

showing 4 of 6 signaling interactions:

A	Effect	B	Mechanism
CS	“down-regulates quantity”	acetyl-CoA	“chemical modification”
CS	“down-regulates quantity”	oxaloacetate(2-)	“chemical modification”
CS	“up-regulates quantity”	citrate(3-)	“chemical modification”
CSKMT	“down-regulates activity”	CS	methylation

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
CS-MAP3K7IP1-MAP3K7IP2 complex	3	CS, TAB1, TAB2

Disease & clinical

Genetic variants

Variant evidence for CS: 44 ClinVar records (0 pathogenic / likely pathogenic); 5 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	33
Likely benign	1
Benign	2

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 27 predictions of 852):

Position(s)	Effect	Δscore	Sites
12:56273585–56273586	donor_loss	1.0000	4
12:56273797–56273798	acceptor_loss	1.0000	5
12:56273799	acceptor_gain	1.0000
12:56273806	acceptor_gain	1.0000
12:56274775–56274776	donor_loss	1.0000	5
12:56274879–56274881	acceptor_gain	1.0000	2
12:56274879–56274880	acceptor_loss	1.0000	4
12:56274885	acceptor_gain	1.0000
12:56274890–56274892	acceptor_gain	1.0000	3
12:56275158	acceptor_gain	1.0000

AlphaMissense

1,530 missense substitutions predicted likely pathogenic (of 3,028 scored), across 354 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M165	9	0.894	0.983
H347	8	0.999	1.000
D354	8	0.999	0.999
D402	8	0.999	1.000
H265	8	0.997	0.999
F424	8	0.997	1.000
H301	8	0.996	0.999
D264	8	0.993	0.998
H262	8	0.986	0.999
N400	8	0.982	1.000
D235	8	0.981	0.991
H273	8	0.977	0.997
D201	8	0.976	0.995
N269	8	0.969	0.999
H163	8	0.956	0.995
S405	8	0.956	0.999
S271	8	0.946	0.999
F93	8	0.944	0.997
N396	8	0.942	0.998
H404	8	0.928	0.990

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	2.13e-07
Lung Adenocarcinoma (validation)	unfavorable	0.000651

Disease associations

OMIM: gene MIM:118950 | disease phenotypes:

GWAS associations

5 associations:

Study	Trait	p-value
GCST008839_127	Height	1e-189
GCST010002_69	Refractive error	6e-174
GCST90090967_16	Height	2e-12
GCST002740_7	Inflammatory skin disease	3e-12
GCST001885_1	Height	3e-9

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295678 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (2 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Doxorubicin	decreases expression, decreases reaction	3
bisphenol A	affects expression, increases expression	2
bisphenol S	increases expression	2
Resveratrol	decreases expression, decreases reaction, increases activity	2
Dronabinol	decreases expression, increases expression	2
Zidovudine	affects expression, decreases expression	2
Particulate Matter	affects cotreatment, increases abundance, increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression, decreases expression	1
6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid	decreases activity, decreases reaction	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	increases expression	1
ochratoxin A	decreases expression	1
acipimox	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation	1
ebselen	decreases activity, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
manganese(III)-tetrakis(4-benzoic acid)porphyrin	decreases reaction, decreases activity	1
nutlin 3	affects cotreatment, increases secretion	1
2,3-bis(4-hydroxyphenyl)-propionitrile	increases activity, decreases reaction	1
4,4’,4’’-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol	decreases reaction, increases activity	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118555	Binding	Binding affinity to CS in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — *Bioorg Med Chem*

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for CS across ~30M SureChEMBL compounds — explore on Sugi Predict.