ME1

Summary

ME1 (malic enzyme 1, HGNC:6983) is a protein-coding gene on chromosome 6q14.2, encoding NADP-dependent malic enzyme (P48163). Catalyzes the oxidative decarboxylation of (S)-malate in the presence of NADP(+) and divalent metal ions, and decarboxylation of oxaloacetate.

This gene encodes a cytosolic, NADP-dependent enzyme that generates NADPH for fatty acid biosynthesis. The activity of this enzyme, the reversible oxidative decarboxylation of malate, links the glycolytic and citric acid cycles. The regulation of expression for this gene is complex. Increased expression can result from elevated levels of thyroid hormones or by higher proportions of carbohydrates in the diet.

Source: NCBI Gene 4199 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 78 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_002395

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6983
Approved symbol	ME1
Name	malic enzyme 1
Location	6q14.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000065833
Ensembl biotype	protein_coding
OMIM	154250
Entrez	4199

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 13 protein_coding

ENST00000369705, ENST00000901909, ENST00000901910, ENST00000901911, ENST00000901912, ENST00000901913, ENST00000956342, ENST00000956343, ENST00000956344, ENST00000956345, ENST00000956346, ENST00000956347, ENST00000956348

RefSeq mRNA: 1 — MANE Select: NM_002395 NM_002395

CCDS: CCDS34492

Canonical transcript exons

ENST00000369705 — 14 exons

Exon	Start	End
ENSE00000531502	83407768	83407901
ENSE00000760014	83216498	83216596
ENSE00000760015	83223760	83223933
ENSE00000760016	83227335	83227477
ENSE00000760017	83228826	83228931
ENSE00000760018	83237717	83237830
ENSE00000760019	83239539	83239636
ENSE00000760020	83253629	83253738
ENSE00000760021	83315310	83315413
ENSE00000760044	83430877	83431051
ENSE00001450687	83210402	83212094
ENSE00003478257	83352064	83352139
ENSE00003566327	83346173	83346334
ENSE00003566911	83398367	83398516

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 97.21.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.4646 / max 2092.2880, expressed in 1643 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74558	32.0694	1634
74557	0.8119	506
74559	0.5080	317
74553	0.0753	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.21	gold quality
dorsal root ganglion	UBERON:0000044	96.86	gold quality
trigeminal ganglion	UBERON:0001675	96.66	gold quality
substantia nigra pars compacta	UBERON:0001965	96.64	gold quality
upper leg skin	UBERON:0004262	96.39	gold quality
biceps brachii	UBERON:0001507	96.29	gold quality
esophagus squamous epithelium	UBERON:0006920	96.19	gold quality
substantia nigra pars reticulata	UBERON:0001966	95.85	gold quality
right adrenal gland cortex	UBERON:0035827	95.77	gold quality
epithelium of esophagus	UBERON:0001976	95.74	gold quality
mammalian vulva	UBERON:0000997	95.63	gold quality
gingiva	UBERON:0001828	95.25	gold quality
right adrenal gland	UBERON:0001233	95.08	gold quality
gingival epithelium	UBERON:0001949	95.08	gold quality
squamous epithelium	UBERON:0006914	94.87	gold quality
lateral globus pallidus	UBERON:0002476	94.81	gold quality
adrenal tissue	UBERON:0018303	94.68	gold quality
jejunal mucosa	UBERON:0000399	94.48	gold quality
adrenal cortex	UBERON:0001235	94.48	gold quality
left adrenal gland	UBERON:0001234	94.47	gold quality
oral cavity	UBERON:0000167	94.43	gold quality
adrenal gland	UBERON:0002369	94.05	gold quality
tongue squamous epithelium	UBERON:0006919	93.99	gold quality
left adrenal gland cortex	UBERON:0035825	93.86	gold quality
lateral nuclear group of thalamus	UBERON:0002736	93.74	gold quality
superior vestibular nucleus	UBERON:0007227	93.36	gold quality
secondary oocyte	CL:0000655	93.23	gold quality
seminal vesicle	UBERON:0000998	92.98	gold quality
vastus lateralis	UBERON:0001379	92.91	gold quality
jejunum	UBERON:0002115	92.48	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.70

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO1, NEUROD6, SP1, SREBF1, SREBF2, TEAD2, TP53

miRNA regulators (miRDB)

115 targeting ME1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
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

Literature-anchored findings (GeneRIF, showing 25)

• that the single mutation of Gln362 to Lys in human m-NAD-ME changes it to an NADP+-dependent enzyme, which is characteristic because it is non-allosteric, non-cooperative, and NADP+-specific (PMID:16757477)
• although ME1 overexpression augments anaplerosis and glucose stimulated insulin secretion in INS-1 832/13 cells, it is not likely involved in methyl succinate and glucose stimulated insulin secretion in pancreatic islets (PMID:19293334)
• human c-NADP-ME exists mainly as a tetramer, whereas human m-NAD(P)-ME exists as a mixture of dimers and tetramers (PMID:19416979)
• A series of R98/D102 mutants examined the possible interactions between Arg98 and Asp102 using double-mutant cycle analysis. Kinetic analysis revealed that the catalytic efficiency of was severely affected by mutating both Arg98 and Asp102 residues. (PMID:19464998)
• ME1 is a functional target gene of the BACH1 transcription factor according to ChIP-seq and knockdown analysis in HEK 293 cells. (PMID:21555518)
• cytosolic malic enzyme 1 gene polymorphism is associated with the degree of suppression of parathyroid hormone after long-term calcium supplementation; the effect is probably mediated through an increase in intestinal calcium absorption (PMID:22456781)
• essential role for ME1 in the production of cytosolic NADPH and maintenance of migratory and invasive abilities of nasopharyngeal carcinoma cells (PMID:23114090)
• the differential protein stability between dimer and tetramer interface interactions of human c-NADP-ME (PMID:23284632)
• p53 represses the expression of the tricarboxylic-acid-cycle-associated malic enzymes ME1 and ME2 in human and mouse cells (PMID:23334421)
• ME1 overexpression associates with unfavorable prognoses in patients with HCC, suggesting that ME1 is a poor prognostic predictor of hepatocellular carcinoma. (PMID:25753478)
• ME1 expression was found to be mutant-KRAS-associated in NSCLC cancer cell lines. Patients with elevated ME1 had worse outcomes after radiotherapy. Transamination generating cytosolic NADPH via ME1 may contribute to radioresistance. (PMID:26173780)
• ME1/ME2 expression phenotype may have a potential to be a valuable marker for sebaceous differentiation in sebaceous lesions. (PMID:26381116)
• The critical roles of miR-30a and ME1 in the development of KRAS-mutant colorectal cancer indicate therapy potentials for this subtype of cancer. (PMID:28475173)
• these findings uncover a direct cross-talk mechanism between ME1 and PPP, may reveal an alternative model for signaling transduction via protein conformational simulation, and pave the way for better understanding how metabolic pathways are coordinated in cancer. (PMID:28848047)
• Findings indicate that malic enzyme 1 (ME1) is a valid target for molecular therapy in oral squamous cell carcinomas (OSCCs). (PMID:29601126)
• Bioinformatics analysis identified that miR612 targeted ME1, which expression was high and inversely associated with miR612 expression in bladder cancer tissues. (PMID:29620192)
• results shed light on crucial roles of ME1-mediated production of NADPH in gastric cancer growth and metastasis (PMID:29654155)
• A small molecule inhibitor of ME1 suppressed growth of human CRC cells in vitro, but had little effect on normal rat intestinal epithelial cells. Targeting of ME1 may add to the armentarium of therapies for cancers of the gastrointestinal tract. (PMID:30250042)
• ME1 promotes basal-like breast cancer progression and associates with poor prognosis (PMID:30425310)
• In which ME1 transcripts are upregulated. (PMID:31735643)
• Malic Enzyme 1 Is Associated with Tumor Budding in Oral Squamous Cell Carcinomas. (PMID:32998265)
• Adaptive and Constitutive Activations of Malic Enzymes Confer Liver Cancer Multilayered Protection Against Reactive Oxygen Species. (PMID:33619771)
• miR-885-5p Inhibits Invasion and Metastasis in Gastric Cancer by Targeting Malic Enzyme 1. (PMID:33751897)
• Targeting Ferroptosis Vulnerability in Synovial Sarcoma: Is It All About ME1? (PMID:35727698)
• Cytosolic malic enzyme and glucose-6-phosphate dehydrogenase modulate redox balance in NSCLC with acquired drug resistance. (PMID:37410361)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	me1	ENSDARG00000053215
		ENSDARG00000099419
mus_musculus	Me1	ENSMUSG00000032418
rattus_norvegicus	Me1	ENSRNOG00000009715
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): ME2 (ENSG00000082212), ME3 (ENSG00000151376)

Protein

Protein identifiers

NADP-dependent malic enzyme — P48163 (reviewed: P48163)

Alternative names: Malic enzyme 1

All UniProt accessions (1): P48163

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the oxidative decarboxylation of (S)-malate in the presence of NADP(+) and divalent metal ions, and decarboxylation of oxaloacetate.

Subunit / interactions. Homotetramer.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in all tissues tested including liver, placenta and white adipose tissue.

Cofactor. Divalent metal cations. Prefers magnesium or manganese.

Similarity. Belongs to the malic enzymes family.

Isoforms (2)

UniProt ID	Names	Canonical?
P48163-1	1	yes
P48163-2	2

RefSeq proteins (1): NP_002386* (*=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 1.1.1.40 — malate dehydrogenase (oxaloacetate-decarboxylating) (NADP+) (BRENDA: 112 organisms, 148 substrates, 190 inhibitors, 430 Km, 222 kcat entries)

Substrate kinetics (BRENDA)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
NADP+	0.0012–116	158
(S)-MALATE	0.0001–36	149
L-MALATE	0.04–4.5	37
NAD+	0.25–20	29
PYRUVATE	0.5–138.9	27
NADPH	0.0018–0.06	18
CO2	13.3–27.9	3

Catalyzed reactions (Rhea), 2 shown:

• oxaloacetate + H(+) = pyruvate + CO2 (RHEA:15641)
• (S)-malate + NADP(+) = pyruvate + CO2 + NADPH (RHEA:18253)

UniProt features (82 total): helix 34, sequence conflict 16, strand 12, binding site 7, turn 6, active site 2, modified residue 2, chain 1, site 1, splice variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7X11	X-RAY DIFFRACTION	2.07
7X12	X-RAY DIFFRACTION	2.07
2AW5	X-RAY DIFFRACTION	2.5
3WJA	X-RAY DIFFRACTION	2.55

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48163-F1	95.43	0.91

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): 102 (proton donor); 269 (important for activity); 173 (proton acceptor)

Ligand- & substrate-binding residues (7): 155; 245; 246; 269; 269; 301–318; 408

Post-translational modifications (2): 1, 336

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-1989781	PPARA activates gene expression
R-HSA-70268	Pyruvate metabolism
R-HSA-9818025	NFE2L2 regulating TCA cycle genes
R-HSA-9861718	Regulation of pyruvate metabolism
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism
R-HSA-2262752	Cellular responses to stress
R-HSA-400206	Regulation of lipid metabolism by PPARalpha
R-HSA-556833	Metabolism of lipids
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9711123	Cellular response to chemical stress
R-HSA-9755511	KEAP1-NFE2L2 pathway
R-HSA-9759194	Nuclear events mediated by NFE2L2

MSigDB gene sets: 290 (showing top): GOBP_PROTEIN_HOMOTETRAMERIZATION, YAO_HOXA10_TARGETS_VIA_PROGESTERONE_UP, GOBP_NADPPLUS_METABOLIC_PROCESS, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_NADPLUS_METABOLIC_PROCESS, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, MAHAJAN_RESPONSE_TO_IL1A_DN, WEI_MYCN_TARGETS_WITH_E_BOX, ONKEN_UVEAL_MELANOMA_UP, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP

GO Biological Process (10): carbohydrate metabolic process (GO:0005975), malate metabolic process (GO:0006108), NADP+ metabolic process (GO:0006739), nucleotide biosynthetic process (GO:0009165), response to hormone (GO:0009725), response to carbohydrate (GO:0009743), NAD+ metabolic process (GO:0019674), protein homotetramerization (GO:0051289), regulation of NADP metabolic process (GO:1902031), obsolete NADH metabolic process (GO:0006734)

GO Molecular Function (14): magnesium ion binding (GO:0000287), malic enzyme activity (GO:0004470), malate dehydrogenase (decarboxylating) (NADP+) activity (GO:0004473), oxaloacetate decarboxylase activity (GO:0008948), electron transfer activity (GO:0009055), manganese ion binding (GO:0030145), identical protein binding (GO:0042802), ADP binding (GO:0043531), NADP binding (GO:0050661), NAD binding (GO:0051287), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor (GO:0016616), metal ion binding (GO:0046872)

GO Cellular Component (3): cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Metabolism	2
Regulation of lipid metabolism by PPARalpha	1
Aerobic respiration and respiratory electron transport	1
Nuclear events mediated by NFE2L2	1
Pyruvate metabolism	1
Cellular responses to stimuli	1
Metabolism of lipids	1
Cellular responses to stress	1
Cellular response to chemical stress	1
KEAP1-NFE2L2 pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
purine nucleotide metabolic process	2
nicotinamide nucleotide metabolic process	2
adenyl nucleotide binding	2
cellular anatomical structure	2
cytoplasm	2
primary metabolic process	1
dicarboxylic acid metabolic process	1
nucleotide metabolic process	1
nucleoside phosphate biosynthetic process	1
response to endogenous stimulus	1
response to chemical	1
response to oxygen-containing compound	1
protein homooligomerization	1
protein tetramerization	1
NADP+ metabolic process	1
regulation of purine nucleotide metabolic process	1
metal ion binding	1
malate dehydrogenase activity	1
malic enzyme activity	1
oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	1
carboxy-lyase activity	1
molecular_function	1
transition metal ion binding	1
protein binding	1
adenyl ribonucleotide binding	1
anion binding	1
binding	1
catalytic activity	1
oxidoreductase activity, acting on CH-OH group of donors	1
cation binding	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1982 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ME1	PC	P11498	875
ME1	PGD	P52209	819
ME1	H6PD	O95479	794
ME1	G6PD	P11413	778
ME1	LAMA4	Q16363	728
ME1	PGM3	O95394	712
ME1	MDH2	P40926	707
ME1	IDH1	O75874	700
ME1	ACLY	P53396	654
ME1	TALDO1	P37837	647
ME1	IDH2	P48735	636
ME1	GPI	P06744	596
ME1	TKT	P29401	588
ME1	TKTL2	Q9H0I9	586
ME1	CS	O75390	570

IntAct

57 interactions, top by confidence:

A	B	Type	Score
OAZ3	AZIN1	psi-mi:“MI:0914”(association)	0.800
PSMD10	PSMD11	psi-mi:“MI:0914”(association)	0.800
ME1	ME1	psi-mi:“MI:0915”(physical association)	0.680
ME1	ME1	psi-mi:“MI:0407”(direct interaction)	0.680
ME1	PC	psi-mi:“MI:0403”(colocalization)	0.670
ME1	PC	psi-mi:“MI:0914”(association)	0.670
ME1	PC	psi-mi:“MI:0915”(physical association)	0.670
PC	ME1	psi-mi:“MI:2364”(proximity)	0.670
MDH1	ME1	psi-mi:“MI:2364”(proximity)	0.620
ZSCAN12	A2ML1	psi-mi:“MI:0914”(association)	0.530
NPPA	A2ML1	psi-mi:“MI:0914”(association)	0.530
FTH1	A2ML1	psi-mi:“MI:0914”(association)	0.530
EFNB2	FAM171A2	psi-mi:“MI:0914”(association)	0.530
PC	MDH1	psi-mi:“MI:0914”(association)	0.460
MDH1	PC	psi-mi:“MI:0914”(association)	0.460
ME1	ARPC1B	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
CDK15	A2ML1	psi-mi:“MI:0914”(association)	0.350
FCRL5	A2ML1	psi-mi:“MI:0914”(association)	0.350

BioGRID (81): ME1 (Affinity Capture-MS), ME1 (Affinity Capture-MS), GSTK1 (Co-fractionation), ME1 (Co-fractionation), ME1 (Co-fractionation), ME1 (Co-fractionation), MSN (Co-fractionation), PREP (Co-fractionation), ME1 (Affinity Capture-MS), ME1 (Affinity Capture-MS), ME1 (Affinity Capture-MS), ME1 (Affinity Capture-MS), ME1 (Affinity Capture-MS), ME1 (Affinity Capture-MS), ME1 (Affinity Capture-MS)

ESM2 similar proteins: A2VCW9, A2X0Q3, A3KMV5, A7YW45, A8E657, O14744, O17732, O65041, O94609, O95352, P06801, P11498, P13697, P22314, P22515, P28227, P31254, P40927, P48163, P52873, Q02053, Q05920, Q16798, Q28GH3, Q29504, Q29558, Q29RK2, Q4R5M3, Q5R698, Q5U300, Q641Y5, Q642Q1, Q64I01, Q66H61, Q6IQS6, Q6YXZ7, Q7SXG4, Q7ZVX6, Q7ZY60, Q8BMF3

Diamond homologs: A0KHR8, A0KT69, A1JTY5, A1RNF8, A1S8W7, A3D0E1, A3QH80, A4SKE9, A4TKN8, A4WAJ3, A4Y3I1, A5F1Z0, A6V1V5, A6WSH0, A7FJK4, A7N025, A7ZLS1, A8AGN6, A8FZ49, A8GC31, A8H7G5, A9L2F4, A9MR05, A9MYU8, B0TRQ2, B1JPZ6, B1KFN0, B2JZJ5, B4ESY2, B4T5V6, B4TII8, B4TW15, B5F5W5, B5FHJ6, B5QTN6, B5RAB4, B5Z1T9, B7L7H9, B7UWK9, B8CQT6

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
ME1	“up-regulates quantity”	NADPH(4-)	“chemical modification”
ME1	“down-regulates quantity”	(S)-malate(2-)	“chemical modification”
ME1	“down-regulates quantity”	NADP(3-)	“chemical modification”
ME1	“up-regulates quantity”	pyruvate	“chemical modification”
PGAM5	“up-regulates activity”	ME1	dephosphorylation
NEK1	“down-regulates activity”	ME1	phosphorylation
ACAT1	“up-regulates activity”	ME1	acetylation
SIRT6	“down-regulates activity”	ME1	deacetylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	58
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3246041	NC_000006.11:g.(?83881756)(84086643_?)del	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

3755 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:83223847:A:C	N454K	1.000
6:83223847:A:T	N454K	1.000
6:83227386:A:C	N408K	1.000
6:83227386:A:T	N408K	1.000
6:83253637:T:A	D269V	1.000
6:83253637:T:G	D269A	1.000
6:83223835:G:C	F458L	0.999
6:83223835:G:T	F458L	0.999
6:83223837:A:G	F458L	0.999
6:83223850:G:C	N453K	0.999
6:83223850:G:T	N453K	0.999
6:83227388:T:C	N408D	0.999
6:83227389:A:C	S407R	0.999
6:83227389:A:T	S407R	0.999
6:83227391:T:G	S407R	0.999
6:83253636:A:C	D269E	0.999
6:83253636:A:T	D269E	0.999
6:83253637:T:C	D269G	0.999
6:83253638:C:G	D269H	0.999
6:83253639:A:C	D268E	0.999
6:83253639:A:T	D268E	0.999
6:83253640:T:A	D268V	0.999
6:83253640:T:G	D268A	0.999
6:83253641:C:G	D268H	0.999
6:83253642:A:C	N267K	0.999
6:83253642:A:T	N267K	0.999
6:83253705:A:C	D246E	0.999
6:83253705:A:T	D246E	0.999
6:83253706:T:A	D246V	0.999
6:83253706:T:G	D246A	0.999

dbSNP variants (sampled 300 via entrez): RS1000008415 (6:83293516 C>T), RS1000018592 (6:83243844 T>A,C), RS1000026127 (6:83428739 G>A), RS1000036907 (6:83332415 A>G), RS1000044950 (6:83334062 T>A), RS1000084432 (6:83344985 T>C), RS1000104910 (6:83299852 A>G), RS1000132772 (6:83222982 T>C), RS1000132854 (6:83414144 A>T), RS1000136392 (6:83391488 T>G), RS1000136552 (6:83235751 C>T), RS1000164151 (6:83411534 A>T), RS1000167276 (6:83364386 A>C), RS1000169375 (6:83319045 T>C), RS1000217458 (6:83346587 C>T)

Disease associations

OMIM: gene MIM:154250 | disease phenotypes: MIM:216920, MIM:615816

GenCC curated gene-disease

Mondo (1): immunodeficiency 23 (MONDO:0014353)

Orphanet (1): PGM3-CDG (Orphanet:443811)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C565684	Combined Inflammatory and Immunologic Defect (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3495 (SINGLE PROTEIN)

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

ChEMBL bioactivities

33 potent at pChembl≥5 of 35 total, top 33 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.82	IC50	150	nM	CHEMBL372408
6.82	IC50	150	nM	CHEMBL5279096
6.82	IC50	150	nM	CHEMBL5277536
6.77	IC50	170	nM	CHEMBL5275653
6.75	IC50	180	nM	CHEMBL5284469
6.75	IC50	180	nM	CHEMBL5287773
6.70	IC50	200	nM	CHEMBL5278951
6.68	IC50	210	nM	CHEMBL5283020
6.66	IC50	220	nM	CHEMBL372408
6.66	IC50	220	nM	CHEMBL5267207
6.57	IC50	270	nM	CHEMBL5289840
6.47	IC50	340	nM	CHEMBL5289950
6.38	IC50	420	nM	CHEMBL5284610
6.35	IC50	450	nM	CHEMBL201911
6.25	IC50	560	nM	CHEMBL202332
6.20	IC50	630	nM	CHEMBL5279230
6.03	IC50	940	nM	CHEMBL5218866
5.99	IC50	1020	nM	CHEMBL5273550
5.92	IC50	1200	nM	CHEMBL5286488
5.89	IC50	1300	nM	CHEMBL5274945
5.88	IC50	1310	nM	CHEMBL5291081
5.88	IC50	1320	nM	CHEMBL5279589
5.82	IC50	1500	nM	CHEMBL5281297
5.82	IC50	1500	nM	CHEMBL5286064
5.80	IC50	1600	nM	CHEMBL5278596
5.76	IC50	1740	nM	CHEMBL5282439
5.75	IC50	1800	nM	CHEMBL5290463
5.72	IC50	1900	nM	CHEMBL5270965
5.62	IC50	2370	nM	CHEMBL5267542
5.50	IC50	3150	nM	CHEMBL202380
5.46	IC50	3500	nM	CHEMBL5281258
5.00	IC50	1e+04	nM	CHEMBL201154
5.00	IC50	1e+04	nM	CHEMBL369996

PubChem BioAssay actives

33 with measured affinity, of 42 total; 32 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
1-[4-(4-hydroxyphenyl)piperazin-1-yl]-3-methyl-3-phenylbutan-1-one	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ 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
2-(4-chlorophenyl)-1-[4-(4-hydroxyphenyl)piperazin-1-yl]ethanone	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ 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
3-[4-(4-hydroxyphenyl)piperazin-1-yl]-1-phenylpyrrolidine-2,5-dione	259976: Inhibitory activity against cytosolic malic enzyme	ic50	0.1500	uM
(E)-1-[4-(4-hydroxyphenyl)piperazin-1-yl]-3-phenylprop-2-en-1-one	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	0.1700	uM
1-[4-(4-hydroxyphenyl)piperazin-1-yl]-2-phenylethanone	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	0.1800	uM
2-(4-fluorophenyl)-1-[4-(4-hydroxyphenyl)piperazin-1-yl]ethanone	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	0.1800	uM
4-(4-hydroxyphenyl)-N-phenylpiperazine-1-carboxamide	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ 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
1-[4-(4-hydroxyphenyl)piperazin-1-yl]-2-[4-(trifluoromethyl)phenyl]ethanone	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ 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
N-(2H-tetrazol-5-yl)-9,9a-dihydro-4aH-xanthene-9-carboxamide	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ 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
1-[4-(4-hydroxyphenyl)piperazin-1-yl]-3-phenylpropan-1-one	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ 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
2-[4-(4-hydroxyphenyl)piperazin-1-yl]-N-phenylacetamide	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	0.3400	uM
3-(4-butoxyphenyl)-1-[4-(4-hydroxyphenyl)piperazin-1-yl]propan-1-one	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ 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-benzyl-3-[4-(4-hydroxyphenyl)piperazin-1-yl]pyrrolidine-2,5-dione	259976: Inhibitory activity against cytosolic malic enzyme	ic50	0.4500	uM
1-(3-chloro-4-methylphenyl)-3-[4-(4-hydroxyphenyl)piperazin-1-yl]pyrrolidine-2,5-dione	259976: Inhibitory activity against cytosolic malic enzyme	ic50	0.5600	uM
1-[4-(4-hydroxyphenyl)piperazin-1-yl]-2-phenoxyethanone	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	0.6300	uM
2,5-dihydroxy-3,6-bis(4-methoxyphenyl)cyclohexa-2,5-diene-1,4-dione	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	0.9400	uM
3-(4-chlorophenyl)-1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]propan-1-one	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	1.0200	uM
3-(1-benzothiophen-2-yl)-1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]propan-1-one	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	1.2000	uM
3-(4-fluorophenyl)-1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]-3-methylbutan-1-one	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	1.3000	uM
3-(4-butoxyphenyl)-1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]propan-1-one	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	1.3100	uM
1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]-3-thiophen-2-ylpropan-1-one	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	1.3200	uM
1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]-3-phenylpropan-1-one	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	1.5000	uM
3-(4-chlorophenyl)-1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]-3-methylbutan-1-one	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	1.5000	uM
1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]-2-phenylethanone	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	1.6000	uM
3-(4-fluorophenyl)-1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]propan-1-one	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	1.7400	uM
1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]-3-(5-phenylthiophen-2-yl)propan-1-one	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	1.8000	uM
1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]-3-(4-methoxyphenyl)propan-1-one	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	1.9000	uM
1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]-3-methyl-3-phenylbutan-1-one	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	2.3700	uM
1-phenyl-3-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]pyrrolidine-2,5-dione	259976: Inhibitory activity against cytosolic malic enzyme	ic50	3.1500	uM
1-[4-(5-hydroxy-2-pyridinyl)piperazin-1-yl]-3-[4-(2-methoxyethoxy)phenyl]propan-1-one	1922684: Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ challenge and incubated under shaking for 5 mins followed by incubation for 2 hrs without shaking by resorufin dye based fluorescence analysis	ic50	3.5000	uM
3-[4-(4-fluorophenyl)piperazin-1-yl]-1-phenylpyrrolidine-2,5-dione	259976: Inhibitory activity against cytosolic malic enzyme	ic50	10.0000	uM
1-benzyl-3-[4-(3-hydroxyphenyl)piperazin-1-yl]pyrrolidine-2,5-dione	259976: Inhibitory activity against cytosolic malic enzyme	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression, increases methylation	9
sodium arsenite	increases expression, affects cotreatment, increases abundance	7
Arsenic Trioxide	affects cotreatment, increases expression, decreases response to substance	7
Tobacco Smoke Pollution	affects expression, increases expression	5
methylmercuric chloride	increases expression, affects cotreatment	4
bisphenol A	affects expression, increases expression, affects cotreatment, decreases expression	4
lead acetate	increases expression	3
Air Pollutants	increases expression, decreases expression, increases abundance	3
Benzo(a)pyrene	affects methylation, increases expression	3
Tetrachlorodibenzodioxin	affects cotreatment, increases expression	3
Tretinoin	increases expression, decreases expression, affects cotreatment	3
Particulate Matter	decreases expression, increases abundance, increases expression	3
trichostatin A	increases expression	2
sulforaphane	increases expression	2
cobaltous chloride	increases expression	2
nickel sulfate	increases expression	2
S-(1,2-dichlorovinyl)cysteine	increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
Resveratrol	affects cotreatment, decreases expression, increases expression	2
Zoledronic Acid	increases expression	2
Arsenic	increases expression, affects cotreatment, increases abundance	2
Dinitrochlorobenzene	affects binding, increases expression	2
Ethinyl Estradiol	affects expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cyclosporine	increases expression	2
Aflatoxin B1	increases methylation	2
Cadmium Chloride	increases expression	2
Lactic Acid	decreases expression, increases expression	2
Genistein	affects expression, increases expression	2
tert-Butylhydroperoxide	increases expression	2

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5225649	Binding	Inhibition of His-tagged human recombinant full length ME1 using L-malate and beta-NADP+ as substrate preincubated with enzyme for 5 mins followed by beta-NADP+ challenge and incubated under shaking for 5 mins followed by incubation for 2 h	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

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C7D8	Abcam A-549 ME1 KO	Cancer cell line	Male
CVCL_C7DY	Abcam HCT 116 ME1 KO	Cancer cell line	Male
CVCL_SX69	HAP1 ME1 (-) 1	Cancer cell line	Male
CVCL_XQ37	HAP1 ME1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01454856	Not specified	TERMINATED	Perioperative Evaluation of Immuno-inflammatory Parameters