ME2

Summary

ME2 (malic enzyme 2, HGNC:6984) is a protein-coding gene on chromosome 18q21.2, encoding NAD-dependent malic enzyme, mitochondrial (P23368). NAD-dependent mitochondrial malic enzyme that catalyzes the oxidative decarboxylation of malate to pyruvate.

This gene encodes a mitochondrial NAD-dependent malic enzyme, a homotetrameric protein, that catalyzes the oxidative decarboxylation of malate to pyruvate. It had previously been weakly linked to a syndrome known as Friedreich ataxia that has since been shown to be the result of mutation in a completely different gene. Certain single-nucleotide polymorphism haplotypes of this gene have been shown to increase the risk for idiopathic generalized epilepsy. Alternatively spliced transcript variants encoding different isoforms found for this gene.

Source: NCBI Gene 4200 — RefSeq curated summary.

At a glance

• Gene–disease (curated): inborn disorder of energy metabolism (Limited, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 97 total — 1 likely-pathogenic
• GTEx eGene: eQTL in 27 tissues, sQTL in 7 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.06 (unconstrained)
• MANE Select transcript: NM_002396
• Notable: 97 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6984
Approved symbol	ME2
Name	malic enzyme 2
Location	18q21.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000082212
Ensembl biotype	protein_coding
OMIM	154270
Entrez	4200

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 17 protein_coding, 11 nonsense_mediated_decay, 4 retained_intron

MANE Select: ENST00000321341

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 1, TSL 3: 1, TSL 5: 15

ENST00000321341, ENST00000382927, ENST00000585680, ENST00000589330, ENST00000591925, ENST00000638410, ENST00000638768, ENST00000638937, ENST00000639115, ENST00000639255, ENST00000639398, ENST00000639612, ENST00000639663, ENST00000639665, ENST00000639688, ENST00000639850, ENST00000640530, ENST00000640965, ENST00000640967, ENST00000901565, ENST00000901566, ENST00000901567, ENST00000935531, ENST00000935532, ENST00000953407, ENST00001036800, ENST00001080182, ENST00001080183, ENST00001107566, ENST00001107567, ENST00001122910, ENST00001131779

RefSeq mRNA: 2 — MANE Select: NM_002396 NM_001168335, NM_002396

CCDS: CCDS11948, CCDS54187

Canonical transcript exons

ENST00000321341 — 16 exons

Exon	Start	End
ENSE00000950181	50924098	50924212
ENSE00000950182	50925756	50925898
ENSE00000950184	50939570	50939640
ENSE00000996845	50908063	50908196
ENSE00000996846	50912801	50912950
ENSE00001151634	50921074	50921187
ENSE00001151639	50920661	50920758
ENSE00001151654	50917347	50917508
ENSE00001151659	50916168	50916243
ENSE00001222938	50895809	50895928
ENSE00001605064	50947017	50954257
ENSE00003526712	50932258	50932360
ENSE00003547112	50918110	50918213
ENSE00003564587	50920456	50920565
ENSE00003645078	50940288	50940386
ENSE00003808655	50879118	50879308

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 98.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.5385 / max 937.1130, expressed in 1818 samples.

Highest expression (Bgee): choroid plexus epithelium, jejunal mucosa, cardiac muscle of right atrium, colonic mucosa, myocardium.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ME2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 27 tissues and its splicing (sQTL) in 7 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 34 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	6.9e-41	+0.26	18:50878414:G:A
Testis	eqtl	1.0e-33	+0.34	18:50879109:C:T
Nerve Tibial	eqtl	8.8e-15	-0.18	18:50879111:C:G
Esophagus Muscularis	eqtl	4.7e-13	+0.18	18:50881282:C:T
Spleen	eqtl	4.6e-10	+0.30	18:50836090:C:T
Muscle Skeletal	eqtl	1.0e-09	+0.19	18:50856435:C:T
Artery Tibial	eqtl	6.8e-09	-0.18	18:50887961:A:G
Cells EBV-transformed lymphocytes	eqtl	3.0e-08	+0.17	18:50918879:A:G
Adipose Visceral Omentum	eqtl	1.2e-07	-0.19	18:50856366:T:A
Testis	sqtl	3.7e-07	+0.40	18:50875952:C:T
Adipose Subcutaneous	eqtl	9.4e-07	+0.18	18:50834146:C:G
Colon Sigmoid	eqtl	1.0e-05	+0.16	18:50933765:C:G
Muscle Skeletal	sqtl	1.8e-05	+0.70	18:50883587:G:A
Esophagus Gastroesophageal Junction	eqtl	5.2e-05	+0.13	18:50878414:G:A
Breast Mammary Tissue	eqtl	1.9e-04	+0.12	18:50833552:G:A
Liver	eqtl	2.2e-04	+0.31	18:50846631:T:C
Esophagus Mucosa	eqtl	4.0e-04	-0.13	18:50953868:T:G
Brain Spinal cord cervical c-1	eqtl	4.6e-04	-0.31	18:50947383:G:A
Pancreas	eqtl	1.6e-03	+0.32	18:50788783:T:C
Adrenal Gland	eqtl	1.7e-03	-0.36	18:50912296:T:C

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
170265	38.6615	1815
170264	6.1964	1535
208557	0.6807	417

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
choroid plexus epithelium	UBERON:0003911	98.23	gold quality
jejunal mucosa	UBERON:0000399	97.53	gold quality
cardiac muscle of right atrium	UBERON:0003379	96.78	gold quality
colonic mucosa	UBERON:0000317	96.28	gold quality
myocardium	UBERON:0002349	96.27	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.18	gold quality
monocyte	CL:0000576	96.07	gold quality
duodenum	UBERON:0002114	96.03	gold quality
mononuclear cell	CL:0000842	95.98	gold quality
heart right ventricle	UBERON:0002080	95.89	gold quality
left ventricle myocardium	UBERON:0006566	95.83	gold quality
leukocyte	CL:0000738	95.77	gold quality
jejunum	UBERON:0002115	95.59	gold quality
rectum	UBERON:0001052	95.40	gold quality
trabecular bone tissue	UBERON:0002483	94.82	gold quality
buccal mucosa cell	CL:0002336	94.72	gold quality
ileal mucosa	UBERON:0000331	94.66	gold quality
mucosa of transverse colon	UBERON:0004991	94.59	gold quality
cardiac atrium	UBERON:0002081	94.05	gold quality
right atrium auricular region	UBERON:0006631	93.82	gold quality
vena cava	UBERON:0004087	93.69	gold quality
gluteal muscle	UBERON:0002000	93.62	gold quality
seminal vesicle	UBERON:0000998	93.61	gold quality
vermiform appendix	UBERON:0001154	93.58	gold quality
adrenal tissue	UBERON:0018303	93.53	gold quality
caecum	UBERON:0001153	93.51	gold quality
diaphragm	UBERON:0001103	93.44	gold quality
deltoid	UBERON:0001476	93.36	gold quality
cortical plate	UBERON:0005343	93.35	gold quality
bone marrow	UBERON:0002371	93.34	gold quality
ganglionic eminence	UBERON:0004023	93.12	gold quality
bone marrow cell	CL:0002092	93.00	gold quality
biceps brachii	UBERON:0001507	92.82	gold quality
epithelium of nasopharynx	UBERON:0001951	92.79	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.72	gold quality
ventricular zone	UBERON:0003053	92.53	gold quality
heart	UBERON:0000948	92.46	gold quality
cardiac ventricle	UBERON:0002082	92.43	gold quality
heart left ventricle	UBERON:0002084	92.40	gold quality
muscle tissue	UBERON:0002385	92.39	gold quality
blood	UBERON:0000178	92.37	gold quality
skeletal muscle tissue	UBERON:0001134	92.31	gold quality
gastrocnemius	UBERON:0001388	92.21	gold quality
muscle of leg	UBERON:0001383	92.20	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	92.20	gold quality
muscle organ	UBERON:0001630	92.08	gold quality
pylorus	UBERON:0001166	91.98	gold quality
lymph node	UBERON:0000029	91.83	gold quality
triceps brachii	UBERON:0001509	91.81	gold quality
small intestine	UBERON:0002108	91.75	gold quality
germinal epithelium of ovary	UBERON:0001304	91.74	gold quality
spleen	UBERON:0002106	91.74	gold quality
islet of Langerhans	UBERON:0000006	91.72	gold quality
corpus callosum	UBERON:0002336	91.68	gold quality
intestine	UBERON:0000160	91.67	gold quality
large intestine	UBERON:0000059	91.62	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.48	gold quality
colon	UBERON:0001155	91.46	gold quality
embryo	UBERON:0000922	91.30	gold quality
vastus lateralis	UBERON:0001379	91.28	gold quality
transverse colon	UBERON:0001157	91.27	gold quality
cardia of stomach	UBERON:0001162	91.23	gold quality
small intestine Peyer’s patch	UBERON:0003454	91.22	gold quality
pons	UBERON:0000988	91.19	gold quality
quadriceps femoris	UBERON:0001377	91.07	gold quality
tibialis anterior	UBERON:0001385	90.97	gold quality
granulocyte	CL:0000094	90.90	gold quality
body of stomach	UBERON:0001161	90.67	gold quality
pleura	UBERON:0000977	90.49	gold quality
calcaneal tendon	UBERON:0003701	90.47	gold quality
sigmoid colon	UBERON:0001159	90.45	gold quality
stomach	UBERON:0000945	90.43	gold quality
pigmented layer of retina	UBERON:0001782	90.41	gold quality
parietal pleura	UBERON:0002400	90.40	gold quality
visceral pleura	UBERON:0002401	90.38	gold quality
smooth muscle tissue	UBERON:0001135	90.33	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	90.31	gold quality
right adrenal gland	UBERON:0001233	90.25	gold quality
right adrenal gland cortex	UBERON:0035827	90.19	gold quality
substantia nigra	UBERON:0002038	90.17	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	90.05	gold quality
gall bladder	UBERON:0002110	89.98	gold quality
entorhinal cortex	UBERON:0002728	89.95	gold quality
Brodmann (1909) area 23	UBERON:0013554	89.86	gold quality
Brodmann (1909) area 46	UBERON:0006483	89.85	gold quality
midbrain	UBERON:0001891	89.82	gold quality
hypothalamus	UBERON:0001898	89.82	gold quality
adrenal gland	UBERON:0002369	89.82	gold quality
CA1 field of hippocampus	UBERON:0003881	89.77	gold quality
colonic epithelium	UBERON:0000397	89.76	gold quality
spinal cord	UBERON:0002240	89.76	gold quality
left adrenal gland	UBERON:0001234	89.72	gold quality
urinary bladder	UBERON:0001255	89.60	gold quality
pancreas	UBERON:0001264	89.35	gold quality
middle temporal gyrus	UBERON:0002771	89.31	gold quality
cauda epididymis	UBERON:0004360	89.28	gold quality
subthalamic nucleus	UBERON:0001906	89.26	gold quality
substantia nigra pars compacta	UBERON:0001965	89.24	gold quality
fundus of stomach	UBERON:0001160	89.22	gold quality
superior vestibular nucleus	UBERON:0007227	89.22	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.60
E-CURD-97	no	1131.43
E-GEOD-106540	no	198.25
E-MTAB-6524	no	119.45

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 156 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Choroid plexus	tissue	107.9
Spinal cord	tissue	71.1
Septum	tissue	63.8
Periaqueductal gray	tissue	62.5
Pons	tissue	62.4
Substantia nigra	tissue	62.2
Medulla oblongata	tissue	61.9
Midbrain	tissue	59.0
Ventral forebrain	tissue	58.1
Hypothalamus	tissue	58.0
Corpus callosum	tissue	56.3
Basal ganglia	tissue	56.2	medium
Thalamus	tissue	55.8
Hippocampal formation	tissue	55.5
Putamen	tissue	54.8
Superior colliculi	tissue	45.3
Amygdala	tissue	44.9
Cerebral cortex	tissue	43.2	high
Motor cortex	tissue	43.2
Heart muscle	tissue	42.2	high
Prefrontal cortex	tissue	41.0
Retrosplenial cortex	tissue	41.0
Entorhinal cortex	tissue	40.1
Retrosplenial and cingulate cortex	tissue	39.3
Somatosensory cortex	tissue	39.2
Occipital cortex	tissue	39.1
Temporal cortex	tissue	38.6
Olfactory bulb	tissue	38.1
Insular cortex	tissue	37.7
Duodenum	tissue	36.0	high
Caudate putamen	tissue	34.4
Rectum	tissue	30.4	high
Small intestine	tissue	30.4	high
Parathyroid gland	tissue	30.2	high
Skin 1	tissue	29.8
Cerebellum	tissue	29.0	high
Colon	tissue	28.7	high
Spleen	tissue	25.6	high
Stomach 1	tissue	25.0	high
Skeletal muscle	tissue	24.6	low
Locus coeruleus	tissue	24.3
Lymph node	tissue	24.1	high
Tongue	tissue	21.5
Tonsil	tissue	21.2	high
Appendix	tissue	20.7	high
Thymus	tissue	20.0
Pancreas	tissue	19.7	medium
Seminal vesicle	tissue	18.7	high
Testis	tissue	17.5	high
Smooth muscle	tissue	16.9	medium
Nucleus accumbens	tissue	16.5
Hippocampus	tissue	16.2	medium
Pituitary gland	tissue	16.1
Kidney	tissue	15.9
Postcentral gyrus	tissue	15.9
Urinary bladder	tissue	15.7	medium
Frontal cortex	tissue	14.8
Adrenal gland	tissue	14.8	high
Bone marrow	tissue	14.8	low
Vagina	tissue	14.6

Brain sub-regions (HPA Brain Atlas): detected in 481; highest nTPM — Ventral spinal cord (71.1), Dorsal spinal cord (64.3), White matter (56.3), Dorsal hippocampus (55.5), Ventral hippocampus (51.1).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting ME2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 109 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-4659A-3P	99.80	72.62	4248

Functional genomics

gnomAD constraint: pLI 6.22e-05, LOEUF 1.06, missense Z 1.28 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000321341 — one region, missense o/e 0.84.

Literature-anchored findings (GeneRIF, showing 19)

• An ME2-centered nine-SNP haplotype, when present homozygously, increases the risk for IGE (odds ratio 6.1; 95% confidence interval 2.9-12.7) compared with any other genotype (PMID:15532013)
• Site directed mutagenesis was used to detrmine which amino acids in the active site of human mitochondrial NAD+-dependent malic enzyme are necessary for the inhibitory effects of ATP. (PMID:16171388)
• These findings provide a molecular rationale for the role of hS14 in TR-dependent transcriptional activation of the expression of specific genes. (PMID:17418816)
• Schizophrenic subjects are identified with mitochondrial genes involved in oxidative metabolism as showing consistently decreased expression, including ME2. (PMID:17638511)
• Single nucleotide polymorphism in ME2 gene is associated with acute lymphoblastic leukemia. (PMID:19066393)
• ME2 activity in Islets of Langerhans cells was measured by a spectrophotometric enzyme assay by utilizing the distinct kinetic properties. (PMID:19691144)
• Depletion of malic enzyme 2 induced erythroid differentiation in human erythroleukemia cells. (PMID:20824065)
• p53 represses the expression of the tricarboxylic-acid-cycle-associated malic enzymes ME1 and ME2 in human and mouse cells (PMID:23334421)
• Three SNP alleles in BRD2, Cx-36, and ME2 and microdeletions in 15q13.3, 15q11.2, and 16p13.11 also contribute risk to juvenile myclonic epilepsy. (PMID:23756480)
• Data indicate that malic enzyme 2 knockdown impacts phosphatidylinositol 3-kinases/proto-oncogene protein akt (PI3K/AKT) signaling. (PMID:24957098)
• ME2 might be an important factor in melanoma progression and a novel biomarker of invasion. (PMID:25202825)
• ME1/ME2 expression phenotype may have a potential to be a valuable marker for sebaceous differentiation in sebaceous lesions. (PMID:26381116)
• ME2 was involved in glioblastoma multiforme growth, invasion, migration, Reactive oxygen species and ATP production. (PMID:27166188)
• deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer (PMID:28099419)
• The chromosome 18q21 deletion in nearly one third of pancreatic adenocarcinomas eliminates not only the tumor suppressor SMAD4, but also neighboring genes with important cellular roles, such as ME2 (PMID:28174172)
• influences susceptibility to adolescent-onset genetic generalized epilepsy (PMID:30719716)
• Expression levels of SIX1, ME2, and AP2M1 in adenoid cystic carcinoma and mucoepidermoid carcinoma. (PMID:32564485)
• Malic enzyme 2 maintains protein stability of mutant p53 through 2-hydroxyglutarate. (PMID:35228743)
• SIRT5-mediated ME2 desuccinylation promotes cancer growth by enhancing mitochondrial respiration. (PMID:38007551)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	me2	ENSDARG00000100718
mus_musculus	Me2	ENSMUSG00000024556
rattus_norvegicus	Me2	ENSRNOG00000015582
drosophila_melanogaster	Men	FBGN0002719
drosophila_melanogaster	Menl-2	FBGN0029153
drosophila_melanogaster	Menl-1	FBGN0029154
drosophila_melanogaster	Men-b	FBGN0029155
drosophila_melanogaster	CG7848	FBGN0034127
caenorhabditis_elegans		WBGENE00012983

Paralogs (2): ME1 (ENSG00000065833), ME3 (ENSG00000151376)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2147351) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 10 distinct phenotype terms.

Mouse phenotype (MP)	Records
persistence of hyaloid vascular system	1
abnormal lens morphology	1
cataract	1
abnormal retina morphology	1
abnormal seminal vesicle morphology	1
decreased mean corpuscular volume	1
abnormal retina vasculature morphology	1
increased circulating chloride level	1
increased circulating bilirubin level	1
decreased blood urea nitrogen level	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
Anas platyrhynchos	P28227	94.6%	Diamond
Columba livia	P40927	94.6%	Diamond
Sus scrofa	Q29558	92.6%	Diamond
Arabidopsis thaliana	Q9LYG3	91.0%	Diamond
Flaveria trinervia	P22178	88.6%	Diamond
Flaveria pringlei	P36444	88.6%	Diamond
Populus trichocarpa	P34105	85.3%	Diamond
Vitis vinifera	P51615	85.3%	Diamond
Phaseolus vulgaris	P12628	84.3%	Diamond
Solanum tuberosum	P37221	83.5%	Diamond
Solanum lycopersicum	P37222	82.3%	Diamond
Zea mays	P16243	81.8%	Diamond
Oryza sativa Japonica Group	P43279	81.8%	Diamond
Mesembryanthemum crystallinum	P37223	81.7%	Diamond
Amaranthus hypochondriacus	P37224	78.1%	Diamond
Ascaris suum	P27443	55.5%	Diamond
Dictyostelium discoideum	Q6TU48	49.3%	Diamond
Cryptococcus neoformans H99	J9VVW8	43.4%	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
ELAC1	protein-coding	55520
MRO	protein-coding	83876
MAPK4	protein-coding	5596
SMAD4	protein-coding	4089

Protein

Protein identifiers

NAD-dependent malic enzyme, mitochondrial — P23368 (reviewed: P23368)

Alternative names: Malic enzyme 2

All UniProt accessions (13): A0A1W2PPH1, A0A1W2PPY2, A0A1W2PQ37, A0A1W2PQF8, A0A1W2PQH3, A0A1W2PQH4, A0A1W2PQT3, A0A1W2PQY8, A0A1W2PR68, A0A1W2PRH1, A0A1W2PRS2, A0A1W2PRY9, P23368

UniProt curated annotations — full annotation on UniProt →

Function. NAD-dependent mitochondrial malic enzyme that catalyzes the oxidative decarboxylation of malate to pyruvate.

Subunit / interactions. Homotetramer.

Subcellular location. Mitochondrion matrix.

Activity regulation. Subject to allosteric activation by fumarate.

Cofactor. Divalent metal cations. Prefers magnesium or manganese.

Miscellaneous. This isoenzyme can also use NADP(+) but is more effective with NAD(+).

Similarity. Belongs to the malic enzymes family.

Isoforms (2)

UniProt ID	Names	Canonical?
P23368-1	1	yes
P23368-2	2

RefSeq proteins (2): NP_001161807, NP_002387* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001891	Malic_OxRdtase	Family
IPR012301	Malic_N_dom	Domain
IPR012302	Malic_NAD-bd	Domain
IPR015884	Malic_enzyme_CS	Conserved_site
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily
IPR037062	Malic_N_dom_sf	Homologous_superfamily
IPR046346	Aminoacid_DH-like_N_sf	Homologous_superfamily

Pfam: PF00390, PF03949

Enzyme classification (BRENDA)

• EC 1.1.1.38 — malate dehydrogenase (oxaloacetate-decarboxylating) (BRENDA: 31 organisms, 27 substrates, 60 inhibitors, 84 Km, 25 kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-MALATE	0.19–50	31
NAD+	0.004–17.2	28
NICOTINAMIDE CYTOSINE DINUCLEOTIDE	0.13–102	8
(S)-MALATE	0.42–15.6	5
NADH	0.025–1.4	5
OXALOACETATE	2.1–5	3
MN2+	0.12–0.32	2
NADP+	2.3	1
PYRUVATE	—	0

Catalyzed reactions (Rhea)

• (S)-malate + NAD(+) = pyruvate + CO2 + NADH (RHEA:12653)
• oxaloacetate + H(+) = pyruvate + CO2 (RHEA:15641)

UniProt features (95 total): helix 41, strand 18, binding site 13, turn 8, modified residue 5, active site 2, sequence variant 2, mutagenesis site 2, transit peptide 1, chain 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

19 structures by resolution:

PDB	Title	Method	Resolution (Å)
9AYI	Human malic enzyme 2 cofactor complex at 1.89 Angstrom.	X-RAY DIFFRACTION	1.89
9ZS0	Human malic enzyme 2 complex with FLA at 2 Angstrom.	X-RAY DIFFRACTION	2
1PJ3	Crystal structure of human mitochondrial NAD(P)+-dependent malic enzyme in a pentary …	X-RAY DIFFRACTION	2.1
1QR6	HUMAN MITOCHONDRIAL NAD(P)-DEPENDENT MALIC ENZYME	X-RAY DIFFRACTION	2.1
1DO8	CRYSTAL STRUCTURE OF A CLOSED FORM OF HUMAN MITOCHONDRIAL NAD(P)+-DEPENDENT MALIC ENZYME	X-RAY DIFFRACTION	2.2
1GZ4	molecular mechanism of the regulation of human mitochondrial NAD(P)+-dependent malic …	X-RAY DIFFRACTION	2.2
1GZ3	Molecular mechanism for the regulation of human mitochondrial NAD(P)+-dependent malic …	X-RAY DIFFRACTION	2.3
1PJ2	Crystal structure of human mitochondrial NAD(P)+-dependent malic enzyme in a pentary …	X-RAY DIFFRACTION	2.3
1PJ4	Crystal structure of human mitochondrial NAD(P)+-dependent malic enzyme in a pentary …	X-RAY DIFFRACTION	2.3
9MYF	Human malic enzyme 2 complex with inhibitor NPD-389	X-RAY DIFFRACTION	2.45
7BSJ	Crystal structure of human ME2 R484W	X-RAY DIFFRACTION	2.48
7BSK	Crystal structure of human ME2 R67Q mutant	X-RAY DIFFRACTION	2.55
7BSL	Crystal Structure of human ME2 R67A mutant	X-RAY DIFFRACTION	2.55
1EFK	STRUCTURE OF HUMAN MALIC ENZYME IN COMPLEX WITH KETOMALONATE	X-RAY DIFFRACTION	2.6
1EFL	HUMAN MALIC ENZYME IN A QUATERNARY COMPLEX WITH NAD, MG, AND TARTRONATE	X-RAY DIFFRACTION	2.6
7XDE	Cryo-EM structures of human mitochondrial NAD(P)+-dependent malic enzyme in apo form	ELECTRON MICROSCOPY	2.72
7XDF	Cryo-EM structures of human mitochondrial NAD(P)+-dependent malic enzyme in a ternary …	ELECTRON MICROSCOPY	2.72
7XDG	Cryo-EM structures of human mitochondrial NAD(P)+-dependent malic enzyme in a ternary …	ELECTRON MICROSCOPY	2.84
1PJL	Crystal structure of human m-NAD-ME in ternary complex with NAD and Lu3+	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P23368-F1	94.55	0.91

Human Protein Atlas

Protein class: Transporters, G-protein coupled receptors, GPCRs excl olfactory receptors, Family 2 (B) receptors, Predicted membrane proteins, GPCRHMM predicted membrane proteins, Predicted intracellular proteins, Disease related genes, Potential drug targets, Human disease related genes, Congenital malformations, Congenital malformations of skin

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): plasma membrane; nucleoplasm

Antibody reliability (HPA): 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 (2)

Position	Role
112	proton donor
183	proton acceptor

Ligand- & substrate-binding residues (13)

Position	Role
259	NAD(+)
279	a divalent metal cation
312	NAD(+)
314	NAD(+)
315	NAD(+)
421	(S)-malate
466	(S)-malate
67	fumarate
91	fumarate
165	(S)-malate
165	NAD(+)
255	a divalent metal cation
256	a divalent metal cation

Post-translational modifications (5)

Type	Positions
N6-acetyllysine	156, 224, 240, 272, 346

Mutagenesis-validated functional residues (2)

Position	Phenotype
67	abolishes activation by fumarate.
91	abolishes activation by fumarate.

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 5; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

5 pathways:

ID	Pathway	Evidence
R-HSA-9837999	Mitochondrial protein degradation	curated
R-HSA-70268	Pyruvate metabolism	curated
R-HSA-1428517	Aerobic respiration and respiratory electron transport	—
R-HSA-1430728	Metabolism	—
R-HSA-392499	Metabolism of proteins	—

MSigDB gene sets: 181 (showing top): RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_NADPPLUS_METABOLIC_PROCESS, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, SHAFFER_IRF4_TARGETS_IN_ACTIVATED_B_LYMPHOCYTE, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, MODULE_528, MODULE_16, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, SHIPP_DLBCL_CURED_VS_FATAL_DN, MODULE_503, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS

GO Biological Process (2): malate metabolic process (GO:0006108), regulation of NADP metabolic process (GO:1902031)

GO Molecular Function (10): malic enzyme activity (GO:0004470), malate dehydrogenase (decarboxylating) (NAD+) activity (GO:0004471), malate dehydrogenase (decarboxylating) (NADP+) activity (GO:0004473), oxaloacetate decarboxylase activity (GO:0008948), electron transfer activity (GO:0009055), metal ion binding (GO:0046872), NAD binding (GO:0051287), catalytic activity (GO:0003824), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor (GO:0016616)

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

Reactome top-level categories

3 top-level categories:

Category	Pathways
Aerobic respiration and respiratory electron transport	1
Metabolism of proteins	1
Metabolism	1

GO top-level categories

16 GO namespaces:

Category	Terms
malic enzyme activity	2
oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	2
molecular_function	2
dicarboxylic acid metabolic process	1
NADP+ metabolic process	1
regulation of purine nucleotide metabolic process	1
malate dehydrogenase activity	1
carboxy-lyase activity	1
cation binding	1
adenyl nucleotide binding	1
catalytic activity	1
oxidoreductase activity, acting on CH-OH group of donors	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 3 of 14 annotations. The rest are phylogenetic / computational / electronic (IEA).

3 experimentally-supported GO terms:

GO term	NS	Evidence
regulation of NADP metabolic process	BP	mutant phenotype
mitochondrion	CC	direct assay
malic enzyme activity	MF	mutant phenotype

Protein interactions and networks

STRING

showing 16 of 1,080 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ME2	JRK	O75564	829
ME2	LDHA	P00338	728
ME2	F13A1	P00488	668
ME2	OPRM1	P35372	620
ME2	MDH2	P40926	581
ME2	CACNA1A	P78510	552
ME2	KCNQ3	O43525	523
ME2	POGK	Q9P215	470
ME2	PGD	P52209	466
ME2	ACO2	Q99798	462
ME2	PCK2	Q16822	452
ME2	CS	O75390	432
ME2	IDH2	P48735	426
ME2	IDH1	O75874	420
ME2	BCAT2	O15382	412
ME2	PC	P11498	412

IntAct

Human interaction partners of ME2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

4 partners by confidence:

Partner	Interaction type	MIscore	Records
ATIC	physical association	0.000	1
RAB11A	physical association	0.000	1
USP15	physical association	0.000	1
WNK1	physical association	0.000	1

BioGRID (117 interactions; top human partners by supporting records): CLPP (Co-fractionation; 2 records), CS (Proximity Label-MS; 2 records), HSCB (Affinity Capture-MS; 2 records), SOCS6 (Proximity Label-MS; 2 records), TMEM184A (Affinity Capture-MS; 2 records), AARS2 (Proximity Label-MS), ACAD9 (Proximity Label-MS), ACTR2 (Co-fractionation), ACTR3B (Co-fractionation), AIFM1 (Proximity Label-MS), ARPC1A (Co-fractionation), ARPC2 (Co-fractionation), ARPC3 (Co-fractionation), ARPC4 (Co-fractionation), ARPC5 (Co-fractionation)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
ME2	“up-regulates quantity”	NADPH(4-)	“chemical modification”

Disease & clinical

Genetic variants

Variant evidence for ME2: 97 ClinVar records (1 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	71
Likely benign	5
Benign	3

Top pathogenic / likely-pathogenic (1)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
3390850	NM_002396.5(ME2):c.1379_1380del (p.Phe460fs)	Likely pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore ME2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

AlphaMissense

1,673 missense substitutions predicted likely pathogenic (of 3,814 scored), across 408 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
M177	9	0.813	0.979
D279	8	0.998	1.000
D256	8	0.995	0.999
D278	8	0.993	0.998
D204	8	0.988	0.995
D171	8	0.985	0.996
D162	8	0.983	0.997
N467	8	0.980	0.999
S420	8	0.974	0.997
F471	8	0.972	0.999
F399	8	0.969	0.997
F276	8	0.967	0.998
F257	8	0.962	0.992
N421	8	0.961	0.999
D345	8	0.960	0.993
N466	8	0.959	0.998
F40	8	0.957	0.999
F449	8	0.947	0.996
F254	8	0.946	0.992
F443	8	0.937	0.997

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

6 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	1.03e-07
Pancreatic Adenocarcinoma (validation)	unfavorable	1.28e-05
Liver Hepatocellular Carcinoma (validation)	favorable	9.21e-05
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000529
Colon Adenocarcinoma (TCGA)	favorable	0.00057
Kidney Chromophobe (TCGA)	unfavorable	0.000904

Disease associations

OMIM: gene MIM:154270 | disease phenotypes:

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
inborn disorder of energy metabolism	Limited	Autosomal recessive
Tourette syndrome	No Known Disease Relationship	Unknown

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
epilepsy	Refuted	AR

Mondo (2): Tourette syndrome (MONDO:0007661), inborn disorder of energy metabolism (MONDO:0019243)

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
D005879	Tourette Syndrome	C10.228.140.079.898; C10.228.662.825.800; C10.574.500.850; C16.320.400.820; F03.625.992.850

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5291602 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

30 measured of 30 human assays (30 total across all organisms); most potent 30 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5279096	IC50	150 nM
CHEMBL5284469	IC50	190 nM
3-(4-(4-hydroxyphenyl)piperazin-1-yl)-1-phenylpyrrolidine-2,5-dione	IC50	200 nM
CHEMBL5267207	IC50	200 nM
CHEMBL5287773	IC50	210 nM
CHEMBL5278951	IC50	220 nM
CHEMBL5275653	IC50	230 nM
CHEMBL5289840	IC50	270 nM
CHEMBL5277536	IC50	270 nM
CHEMBL5284610	IC50	350 nM
CHEMBL5289950	IC50	360 nM
CHEMBL5279230	IC50	390 nM
CHEMBL5283020	IC50	410 nM
CHEMBL5218866	IC50	420 nM
CHEMBL5278596	IC50	980 nM
CHEMBL5274945	IC50	1110 nM
CHEMBL5279589	IC50	1290 nM
CHEMBL5267542	IC50	1370 nM
CHEMBL5653589	KD	1440 nM
CHEMBL5273550	IC50	1590 nM
CHEMBL5286488	IC50	1630 nM
CHEMBL5282439	IC50	1660 nM
CHEMBL5283717	IC50	1700 nM
CHEMBL5281297	IC50	1720 nM
CHEMBL5290463	IC50	1970 nM
CHEMBL5270965	IC50	2500 nM
CHEMBL5281258	IC50	2600 nM
CHEMBL5277143	IC50	2800 nM
CHEMBL5286064	IC50	2800 nM
CHEMBL5291081	IC50	3900 nM

ChEMBL bioactivities

31 potent at pChembl≥5 of 31 total, top 31 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.48	Kd	32.97	nM	CHEMBL5653589
7.48	ED50	32.97	nM	CHEMBL5653589
6.82	IC50	150	nM	CHEMBL5279096
6.72	IC50	190	nM	CHEMBL5284469
6.70	IC50	200	nM	CHEMBL372408
6.70	IC50	200	nM	CHEMBL5267207
6.68	IC50	210	nM	CHEMBL5287773
6.66	IC50	220	nM	CHEMBL5278951
6.64	IC50	230	nM	CHEMBL5275653
6.57	IC50	270	nM	CHEMBL5289840
6.57	IC50	270	nM	CHEMBL5277536
6.46	IC50	350	nM	CHEMBL5284610
6.44	IC50	360	nM	CHEMBL5289950
6.41	IC50	390	nM	CHEMBL5279230
6.39	IC50	410	nM	CHEMBL5283020
6.38	IC50	420	nM	CHEMBL5218866
6.01	IC50	980	nM	CHEMBL5278596
5.96	IC50	1110	nM	CHEMBL5274945
5.89	IC50	1290	nM	CHEMBL5279589
5.86	IC50	1370	nM	CHEMBL5267542
5.80	IC50	1590	nM	CHEMBL5273550
5.79	IC50	1630	nM	CHEMBL5286488
5.78	IC50	1660	nM	CHEMBL5282439
5.77	IC50	1700	nM	CHEMBL5283717
5.76	IC50	1720	nM	CHEMBL5281297
5.71	IC50	1970	nM	CHEMBL5290463
5.60	IC50	2500	nM	CHEMBL5270965
5.58	IC50	2600	nM	CHEMBL5281258
5.55	IC50	2800	nM	CHEMBL5277143
5.55	IC50	2800	nM	CHEMBL5286064
5.41	IC50	3900	nM	CHEMBL5291081

PubChem BioAssay actives

30 with measured affinity, of 34 total; 30 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148740: Binding affinity to human ME2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0330	uM
2-(4-chlorophenyl)-1-[4-(4-hydroxyphenyl)piperazin-1-yl]ethanone	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	0.1500	uM
1-[4-(4-hydroxyphenyl)piperazin-1-yl]-2-phenylethanone	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	0.1900	uM
N-(2H-tetrazol-5-yl)-9,9a-dihydro-4aH-xanthene-9-carboxamide	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	0.2000	uM
3-[4-(4-hydroxyphenyl)piperazin-1-yl]-1-phenylpyrrolidine-2,5-dione	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	0.2000	uM
2-(4-fluorophenyl)-1-[4-(4-hydroxyphenyl)piperazin-1-yl]ethanone	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	0.2100	uM
4-(4-hydroxyphenyl)-N-phenylpiperazine-1-carboxamide	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	0.2200	uM
(E)-1-[4-(4-hydroxyphenyl)piperazin-1-yl]-3-phenylprop-2-en-1-one	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	0.2300	uM
1-[4-(4-hydroxyphenyl)piperazin-1-yl]-3-methyl-3-phenylbutan-1-one	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	0.2700	uM
1-[4-(4-hydroxyphenyl)piperazin-1-yl]-3-phenylpropan-1-one	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	0.2700	uM
3-(4-butoxyphenyl)-1-[4-(4-hydroxyphenyl)piperazin-1-yl]propan-1-one	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	0.3500	uM
2-[4-(4-hydroxyphenyl)piperazin-1-yl]-N-phenylacetamide	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	0.3600	uM
1-[4-(4-hydroxyphenyl)piperazin-1-yl]-2-phenoxyethanone	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	0.3900	uM
1-[4-(4-hydroxyphenyl)piperazin-1-yl]-2-[4-(trifluoromethyl)phenyl]ethanone	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	0.4100	uM
2,5-dihydroxy-3,6-bis(4-methoxyphenyl)cyclohexa-2,5-diene-1,4-dione	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	0.4200	uM
1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]-2-phenylethanone	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	0.9800	uM
3-(4-fluorophenyl)-1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]-3-methylbutan-1-one	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	1.1100	uM
1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]-3-thiophen-2-ylpropan-1-one	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	1.2900	uM
1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]-3-methyl-3-phenylbutan-1-one	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	1.3700	uM
3-(4-chlorophenyl)-1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]propan-1-one	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	1.5900	uM
3-(1-benzothiophen-2-yl)-1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]propan-1-one	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	1.6300	uM
3-(4-fluorophenyl)-1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]propan-1-one	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	1.6600	uM
2-phenyl-N-(2H-tetrazol-5-yl)quinoline-4-carboxamide	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	1.7000	uM
1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]-3-phenylpropan-1-one	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	1.7200	uM
1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]-3-(5-phenylthiophen-2-yl)propan-1-one	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	1.9700	uM
1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]-3-(4-methoxyphenyl)propan-1-one	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	2.5000	uM
1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]-3-[4-(2-methoxyethoxy)phenyl]propan-1-one	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	2.6000	uM
3-(4-chlorophenyl)-1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]-3-methylbutan-1-one	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	2.8000	uM
3-[(3-carboxy-2-hydroxynaphthalen-1-yl)methyl]-2-hydroxynaphthalene-1-carboxylic acid	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	2.8000	uM
3-(4-butoxyphenyl)-1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]propan-1-one	1922683: Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	3.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	4
bisphenol A	decreases expression, increases expression	2
Acetaminophen	decreases expression, increases expression	2
Nickel	increases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	increases expression	1
bufotalin	decreases expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
methotrexate polyglutamate	affects abundance	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
perfluorooctanoic acid	increases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
beta-methylcholine	affects expression	1
deguelin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
picoxystrobin	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Acrolein	affects cotreatment, increases expression, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases expression	1
Atrazine	increases expression	1
Vehicle Emissions	decreases expression, increases abundance	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5225648	Binding	Inhibition of His-tagged human recombinant full length ME2 using L-malate and beta-NAD+ as substrate preincubated with enzyme for 5 mins followed by beta-NAD+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs	In the Quest for Potent and Selective Malic Enzyme 3 Inhibitors for the Treatment of Pancreatic Ductal Adenocarcinoma. — *ACS Med Chem Lett*

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1NS	Abcam K-562 ME2 KO	Cancer cell line	Female
CVCL_D2KD	Abcam Raji ME2 KO	Cancer cell line	Male
CVCL_SX70	HAP1 ME2 (-) 1	Cancer cell line	Male
CVCL_UQ94	Abcam Jurkat ME2 KO	Cancer cell line	Male
CVCL_XQ38	HAP1 ME2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

showing 60 of 185 trials:

NCT	Phase	Status	Title
NCT00152750	Phase 4	UNKNOWN	Study of Clonidine on Sleep Architecture in Children With Tourette’s Syndrome (TS) and Comorbid ADHD
NCT00226824	Phase 4	TERMINATED	Safety Study of Galantamine in Tic Disorders
NCT00241176	Phase 4	COMPLETED	Open Label Trial of Aripiprazole in Children and Adolescents With Tourette’s Disorder
NCT00370838	Phase 4	COMPLETED	Comparison of Keppra and Clonidine in the Treatment of Tics
NCT01018056	Phase 4	COMPLETED	Developing New Treatments for Tourette Syndrome: Therapeutic Trials With Modulators of Glutamatergic Neurotransmission
NCT01547000	Phase 4	COMPLETED	Guanfacine in Children With Tic Disorders
NCT03239210	Phase 4	COMPLETED	Effects of Ondansetron in Obsessive-compulsive and Tic Disorders
NCT00004376	Phase 3	COMPLETED	Phase III Randomized, Double-Blind, Placebo-Controlled Study of Guanfacine for Tourette Syndrome and Attention Deficit Hyperactivity Disorder
NCT00206323	Phase 3	COMPLETED	A Randomized, Placebo-controlled, Tourette Syndrome Study.
NCT00206336	Phase 3	COMPLETED	An Open-label Study to Determine the Efficacy and Safety of Topiramate in the Treatment of Tourette Syndrome.
NCT00478842	Phase 3	COMPLETED	Pallidal Stimulation and Gilles de la Tourette Syndrome
NCT00681863	Phase 3	TERMINATED	Open-label Extension Study of Pramipexole in the Treatment of Children and Adolescents With Tourette Syndrome
NCT01501695	Phase 3	COMPLETED	Phase III Study of 5LGr to Treat Tic Disorder
NCT03087201	Phase 3	COMPLETED	CANNAbinoids in the Treatment of TICS (CANNA-TICS)
NCT03487783	Phase 3	COMPLETED	Aripiprazole Oral Solution in the Treatment of Children and Adolescents With Tourette’s Syndrome
NCT03567291	Phase 3	TERMINATED	Evaluation of Safety and Tolerability of Long-term TEV-50717 (Deutetrabenazine) for Treatment of Tourette Syndrome in Children and Adolescents
NCT03571256	Phase 3	COMPLETED	A Study to Test if TEV-50717 is Effective in Relieving Tics Associated With Tourette Syndrome (TS)
NCT06021522	Phase 3	ACTIVE_NOT_RECRUITING	A Study to Evaluate Long-term Safety of Ecopipam Tablets in Children, Adolescents and Adults With Tourette’s Disorder
NCT00004393	Phase 2	COMPLETED	Phase II Double Blind Placebo Controlled Trial of Risperidone in Tourette Syndrome
NCT00004652	Phase 2	COMPLETED	Phase II Pilot Controlled Study of Short Vs Longer Term Pimozide (Orap) Therapy in Tourette Syndrome
NCT00231985	Phase 2	COMPLETED	Effectiveness of Behavior Therapy and Psychosocial Therapy for the Treatment of Tourette Syndrome and Chronic Tic Disorder
NCT00311909	Phase 2	COMPLETED	Thalamic Deep Brain Stimulation for Tourette Syndrome
NCT00529308	Phase 2	COMPLETED	Transcranial Magnetic Stimulation (TMS) for Individuals With Tourette’s Syndrome
NCT00558467	Phase 2	COMPLETED	Pramipexole Pilot Phase II Study in Children and Adolescents With Tourette Disorder According to DSM-IV Criteria
NCT01043549	Phase 2	TERMINATED	Repetitive Transcranial Magnetic Stimulation of the Posterior Parietal Cortex in Patients Suffering From Gilles de la Tourette Syndrome
NCT01133353	Phase 2	WITHDRAWN	A Study of the Effectiveness and Safety of Tetrabenazine MR in Pediatric Subjects With Tourette’s Syndrome
NCT01475383	Phase 2	WITHDRAWN	Study Evaluating The Safety And Efficacy Of PF-03654746 In Adult Subjects With Tourette’s Syndrome
NCT01647269	Phase 2	COMPLETED	A Trial of Bilateral Deep Brain Stimulation to the Globus Pallidus Internum in Tourette Syndrome
NCT01904773	Phase 2	COMPLETED	Safety, Tolerability, Pharmacokinetic, and Efficacy Study of AZD5213 in Adolescents With Tourette’s Disorder
NCT02102698	Phase 2	COMPLETED	Ecopipam Treatment of Tourette’s Syndrome in Subjects 7-17 Years
NCT02217007	Phase 2	WITHDRAWN	A Trial Evaluating the Efficacy, Safety, and Pharmacokinetics of SNC-102 in Subjects With Tourette Syndrome
NCT02247206	Phase 2	COMPLETED	VoIP Delivered Behavior Therapy for Tourette Syndrome
NCT02581865	Phase 2	COMPLETED	Safety and Efficacy Study of NBI-98854 in Adults With Tourette Syndrome
NCT02619084	Phase 2	COMPLETED	Subthalamic Stimulation in Tourette’s Syndrome
NCT02679079	Phase 2	COMPLETED	Safety and Efficacy Study of NBI-98854 in Children and Adolescents With Tourette Syndrome
NCT02879578	Phase 2	COMPLETED	Safety and Tolerability Study of NBI-98854 for the Treatment of Subjects With Tourette Syndrome
NCT03066193	Phase 2	COMPLETED	Efficacy of a Therapeutic Combination of Dronabinol and PEA for Tourette Syndrome
NCT03247244	Phase 2	TERMINATED	Safety and Efficacy of Cannabis in Tourette Syndrome
NCT03325010	Phase 2	COMPLETED	Safety, Tolerability, and Efficacy of NBI-98854 for the Treatment of Pediatric Subjects With Tourette Syndrome
NCT03444038	Phase 2	COMPLETED	Open-Label Safety and Tolerability Study of NBI-98854 for the Treatment of Pediatric Subjects With Tourette Syndrome
NCT03530293	Phase 2	TERMINATED	Safety and Efficacy of NBI-98854 in Pediatric Subjects With Tourette Syndrome
NCT03625453	Phase 2	COMPLETED	Study of ABX-1431 in Adult Patients With Tourette Syndrome or Chronic Motor Tic Disorder
NCT03651726	Phase 2	UNKNOWN	A Study to Examine the Efficacy of a Therapeutic THX-110 for Tourette Syndrome
NCT03732534	Phase 2	TERMINATED	Rollover Study for Continuing NBI-98854 Administration in Pediatric Subjects With Tourette Syndrome
NCT03944447	Phase 2	UNKNOWN	Outcomes Mandate National Integration With Cannabis as Medicine
NCT04007991	Phase 2	COMPLETED	Ecopipam Tablets to Study Tourette’s Syndrome in Children and Adolescents
NCT04354103	Phase 2	TERMINATED	Atomoxetine in Patients With Tourette’s Syndrome
NCT04978428	Phase 2	COMPLETED	Epidiolex in Obsessive Compulsive Disorder and Related Disorders
NCT05126888	Phase 2	NOT_YET_RECRUITING	SCI-110 in the Treatment of Tourette Syndrome
NCT05434546	Phase 2	COMPLETED	A Study to Explore the Effect of Sepranolone in Tourette Syndrome
NCT06081348	Phase 2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06194305	Phase 2	RECRUITING	Multimodal Profiling of Response to Pediatric Comprehensive Behavioral Intervention for Tics
NCT06315751	Phase 2	ACTIVE_NOT_RECRUITING	Efficacy and Safety of Gemlapodect (NOE-105) in Adults and Adolescents With Tourette Syndrome
NCT06678737	Phase 2	RECRUITING	CBIT+TMS R33 Phase
NCT00139308	Phase 1	COMPLETED	High Frequency Stimulation of the GPi or Thalamus in Tourette’s Syndrome
NCT00634556	Phase 1	COMPLETED	Dopaminergic Effects on Cortical Function in Tourette’s (Levodopa Protocol)
NCT00952601	Phase 1	TERMINATED	Pilot Study of the Modified Atkins Diet for Tourette Syndrome
NCT01440023	Phase 1	COMPLETED	Developing Cognitive Training for Tourette Syndrome
NCT01719523	Phase 1	COMPLETED	Open-Trial of EPI-743 for Adults With Tourette Syndrome
NCT02134080	Phase 1	TERMINATED	FAAH Inhibitor Trial for Adults With Tourette Syndrome

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for ME2 across ~30M SureChEMBL compounds — explore on Sugi Predict.