ETNPPL

Summary

ETNPPL (ethanolamine-phosphate phospho-lyase, HGNC:14404) is a protein-coding gene on chromosome 4q25, encoding Ethanolamine-phosphate phospho-lyase (Q8TBG4). Catalyzes the pyridoxal-phosphate-dependent breakdown of phosphoethanolamine, converting it to ammonia, inorganic phosphate and acetaldehyde.

Enables ethanolamine-phosphate phospho-lyase activity. Predicted to act upstream of or within several processes, including cellular response to glucocorticoid stimulus; ceramide phosphoethanolamine catabolic process; and phospholipid transfer to membrane. Predicted to be located in mitochondrial matrix.

Source: NCBI Gene 64850 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 65 total
• MANE Select transcript: NM_031279

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14404
Approved symbol	ETNPPL
Name	ethanolamine-phosphate phospho-lyase
Location	4q25
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000164089
Ensembl biotype	protein_coding
OMIM	614682
Entrez	64850

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 16 protein_coding, 2 retained_intron, 2 nonsense_mediated_decay

ENST00000296486, ENST00000411864, ENST00000503912, ENST00000505233, ENST00000509402, ENST00000510706, ENST00000510723, ENST00000511923, ENST00000512320, ENST00000512646, ENST00000882435, ENST00000882436, ENST00000882437, ENST00000882438, ENST00000882439, ENST00000882440, ENST00000882441, ENST00000882442, ENST00000882443, ENST00000882444

RefSeq mRNA: 6 — MANE Select: NM_031279 NM_001146590, NM_001146627, NM_001331031, NM_001331032, NM_001331033, NM_031279

CCDS: CCDS3682, CCDS54792, CCDS54793, CCDS82944

Canonical transcript exons

ENST00000296486 — 13 exons

Exon	Start	End
ENSE00001081302	108748005	108748159
ENSE00001081306	108743789	108743856
ENSE00001081308	108746762	108746851
ENSE00001081319	108746399	108746529
ENSE00001302560	108762843	108763053
ENSE00002071189	108742053	108742612
ENSE00003477420	108756418	108756492
ENSE00003491063	108749238	108749463
ENSE00003501542	108760188	108760306
ENSE00003557469	108752895	108753011
ENSE00003620789	108754620	108754710
ENSE00003675030	108759749	108759908
ENSE00003675477	108750936	108751018

Expression profiles

Bgee: expression breadth ubiquitous, 204 present calls, max score 99.14.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 5.4669 / max 335.3361, expressed in 139 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53588	5.4031	137
53587	0.0638	39

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cranial nerve II	UBERON:0000941	99.14	gold quality
lateral globus pallidus	UBERON:0002476	98.95	gold quality
putamen	UBERON:0001874	98.87	gold quality
nucleus accumbens	UBERON:0001882	98.86	gold quality
amygdala	UBERON:0001876	98.75	gold quality
caudate nucleus	UBERON:0001873	98.69	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	98.23	gold quality
temporal lobe	UBERON:0001871	98.22	gold quality
parotid gland	UBERON:0001831	97.73	gold quality
entorhinal cortex	UBERON:0002728	97.71	gold quality
globus pallidus	UBERON:0001875	97.63	gold quality
superior vestibular nucleus	UBERON:0007227	97.47	gold quality
medial globus pallidus	UBERON:0002477	97.39	gold quality
substantia nigra	UBERON:0002038	97.38	gold quality
CA1 field of hippocampus	UBERON:0003881	97.31	gold quality
midbrain	UBERON:0001891	97.22	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.20	gold quality
hypothalamus	UBERON:0001898	97.12	gold quality
ventral tegmental area	UBERON:0002691	96.99	gold quality
Ammon’s horn	UBERON:0001954	96.89	gold quality
substantia nigra pars compacta	UBERON:0001965	96.50	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.32	gold quality
subthalamic nucleus	UBERON:0001906	95.91	gold quality
medulla oblongata	UBERON:0001896	95.87	gold quality
right frontal lobe	UBERON:0002810	95.78	gold quality
anterior cingulate cortex	UBERON:0009835	95.42	gold quality
dorsal plus ventral thalamus	UBERON:0001897	95.40	gold quality
cingulate cortex	UBERON:0003027	95.40	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.28	gold quality
telencephalon	UBERON:0001893	94.82	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	2235.11
E-MTAB-3929	yes	467.81
E-HCAD-25	yes	21.50
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

27 targeting ETNPPL, 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-190A-3P	100.00	80.35	5520
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-12113	99.32	67.54	1072
HSA-MIR-3614-5P	99.30	65.25	837
HSA-MIR-642A-3P	99.23	67.67	1258
HSA-MIR-642B-3P	99.23	67.67	1258
HSA-MIR-4727-5P	99.23	67.55	1154
HSA-MIR-4528	99.18	69.77	1936
HSA-MIR-10399-5P	99.17	69.87	2610
HSA-MIR-6504-3P	99.17	69.31	2891
HSA-MIR-4539	98.78	67.18	888
HSA-MIR-4438	97.96	63.70	947
HSA-MIR-1279	97.83	67.50	1898
HSA-MIR-3920	97.75	69.02	1168
HSA-MIR-3184-3P	96.96	66.91	845
HSA-MIR-6866-5P	96.64	68.06	624
HSA-MIR-514A-3P	96.43	67.77	1048
HSA-MIR-514B-3P	96.43	67.77	1048

Literature-anchored findings (GeneRIF, showing 6)

• AGXT2L1 function appears to be rigidly confined to phospholipid metabolism, which is altered in neuropsychiatric disturbances. (PMID:23761375)
• The pH dependence of the catalytic parameters and the pattern of inhibition by the product phosphate and by other anionic compounds suggest that the active site of PEA phospho-lyase is optimized to bind dianionic groups. (PMID:25327712)
• AGXT2L1 is down-regulated in hepatocellular carcinoma and its low expression indicates a poor prognosis. AGXT2L1 is a crucial gene in the abnormal lipogenesis of HCC tissue. (PMID:26294768)
• Lipidomic analysis of human primary hepatocytes following LXR activation with GW3965 identifies AGXT2L1 as a main target associated to changes in phosphatidylethanolamine. (PMID:31783151)
• Transformation Foci in IDH1-mutated Gliomas Show STAT3 Phosphorylation and Downregulate the Metabolic Enzyme ETNPPL, a Negative Regulator of Glioma Growth. (PMID:32218467)
• ETNPPL modulates hyperinsulinemia-induced insulin resistance through the SIK1/ROS-mediated inactivation of the PI3K/AKT signaling pathway in hepatocytes. (PMID:36924049)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	etnppl	ENSDARG00000035544
mus_musculus	Etnppl	ENSMUSG00000019232
rattus_norvegicus	Etnppl	ENSRNOG00000045743

Paralogs (4): OAT (ENSG00000065154), AGXT2 (ENSG00000113492), PHYKPL (ENSG00000175309), ABAT (ENSG00000183044)

Protein

Protein identifiers

Ethanolamine-phosphate phospho-lyase — Q8TBG4 (reviewed: Q8TBG4)

Alternative names: Alanine–glyoxylate aminotransferase 2-like 1

All UniProt accessions (6): Q8TBG4, D6R9Y3, D6RE94, D6RFL9, D6RGG2, E7ENR6

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the pyridoxal-phosphate-dependent breakdown of phosphoethanolamine, converting it to ammonia, inorganic phosphate and acetaldehyde.

Subunit / interactions. Homotetramer.

Subcellular location. Mitochondrion.

Similarity. Belongs to the class-III pyridoxal-phosphate-dependent aminotransferase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8TBG4-1	1	yes
Q8TBG4-2	2
Q8TBG4-3	3

RefSeq proteins (6): NP_001140062, NP_001140099, NP_001317960, NP_001317961, NP_001317962, NP_112569* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005814	Aminotrans_3	Family
IPR015421	PyrdxlP-dep_Trfase_major	Homologous_superfamily
IPR015422	PyrdxlP-dep_Trfase_small	Homologous_superfamily
IPR015424	PyrdxlP-dep_Trfase	Homologous_superfamily
IPR049704	Aminotrans_3_PPA_site	Conserved_site

Pfam: PF00202

Catalyzed reactions (Rhea), 1 shown:

• phosphoethanolamine + H2O = acetaldehyde + NH4(+) + phosphate (RHEA:17889)

UniProt features (44 total): strand 16, helix 14, turn 6, splice variant 2, chain 1, region of interest 1, compositionally biased region 1, modified residue 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6TOR	X-RAY DIFFRACTION	2.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TBG4-F1	89.93	0.85

Functional residue map

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

Post-translational modifications (1): 278

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-1483213	Synthesis of PE
R-HSA-1430728	Metabolism
R-HSA-1483206	Glycerophospholipid biosynthesis
R-HSA-1483257	Phospholipid metabolism
R-HSA-556833	Metabolism of lipids

MSigDB gene sets: 89 (showing top): chr4q25, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_RESPONSE_TO_CORTICOSTEROID, GOBP_RESPONSE_TO_FOOD, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, LUCAS_HNF4A_TARGETS_UP, GOBP_MEMBRANE_LIPID_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_ESTER_TRANSPORT, GOBP_LIPID_HOMEOSTASIS, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, GOBP_CELLULAR_RESPONSE_TO_CORTICOSTEROID_STIMULUS, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, CAIRO_HEPATOBLASTOMA_DN, GOBP_ORGANOPHOSPHATE_CATABOLIC_PROCESS

GO Biological Process (5): phospholipid transfer to membrane (GO:0006649), response to food (GO:0032094), lipid homeostasis (GO:0055088), cellular response to glucocorticoid stimulus (GO:0071385), ceramide phosphoethanolamine catabolic process (GO:1905372)

GO Molecular Function (5): transaminase activity (GO:0008483), pyridoxal phosphate binding (GO:0030170), ethanolamine-phosphate phospho-lyase activity (GO:0050459), protein binding (GO:0005515), lyase activity (GO:0016829)

GO Cellular Component (3): mitochondrial matrix (GO:0005759), membrane (GO:0016020), mitochondrion (GO:0005739)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Glycerophospholipid biosynthesis	1
Phospholipid metabolism	1
Metabolism of lipids	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phospholipid transport	1
membrane organization	1
response to nutrient levels	1
response to chemical	1
chemical homeostasis	1
response to glucocorticoid	1
cellular response to corticosteroid stimulus	1
phospholipid catabolic process	1
sphingolipid catabolic process	1
transferase activity, transferring nitrogenous groups	1
anion binding	1
vitamin B6 binding	1
carbon-oxygen lyase activity, acting on phosphates	1
binding	1
catalytic activity	1
mitochondrion	1
intracellular organelle lumen	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1618 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ETNPPL	RASL10B	Q96S79	628
ETNPPL	LSMEM1	Q8N8F7	490
ETNPPL	GPC4	O75487	425
ETNPPL	SYT3	Q9BQG1	411
ETNPPL	GOT1L1	Q8NHS2	409
ETNPPL	ETNK2	Q9NVF9	395
ETNPPL	ZBTB1	Q9Y2K1	383
ETNPPL	AGXT	P21549	380
ETNPPL	NRIP2	Q9BQI9	359
ETNPPL	HACD2	Q6Y1H2	356
ETNPPL	GLDC	P23378	354
ETNPPL	AASDH	Q4L235	351
ETNPPL	ALDH18A1	P54886	351
ETNPPL	MCAT	Q8IVS2	348
ETNPPL	ERICH4	A6NGS2	348

IntAct

6 interactions, top by confidence:

A	B	Type	Score
ETNPPL	ZC3HC1	psi-mi:“MI:0915”(physical association)	0.560
ETNPPL	ZC3HC1	psi-mi:“MI:0914”(association)	0.560
PB2	PIK3R2	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
TNFAIP6	ITIH2	psi-mi:“MI:0914”(association)	0.350

BioGRID (8): ZC3HC1 (Affinity Capture-MS), ETNPPL (Affinity Capture-MS), LIPG (Affinity Capture-MS), ZC3HC1 (Affinity Capture-MS), ETNPPL (Affinity Capture-MS), HNRNPK (Cross-Linking-MS (XL-MS)), ETNPPL (Cross-Linking-MS (XL-MS)), APP (Reconstituted Complex)

ESM2 similar proteins: A6QLI6, B0XS72, F4I7I0, O14092, O54694, O94069, P07997, P08680, P09950, P13195, P13196, P22557, P22944, P38092, P43090, P43091, P49604, P52893, P54889, P78698, P91408, P97363, Q04792, Q09925, Q1K8G0, Q20375, Q3B7D2, Q3ZC31, Q4X1D4, Q5E9S4, Q5R557, Q5R9R9, Q63147, Q6BX71, Q6CCW0, Q6DEB1, Q6FXE3, Q75DX7, Q7RVY5, Q7SY54

Diamond homologs: A0QYS9, A1AFZ3, A1B9Z3, A4WEQ6, A7MIU0, A7ZRV6, A8A4N0, A8APX8, B1IRP4, B1LF65, B1XG77, B5FHV3, B5QZ53, B5YRB3, B6I445, B7GHM5, B7LH08, B7MB08, B7N0M2, B7ND61, B7UIY0, B8BBZ7, B9DIU0, B9EAM9, B9ITF9, C1EL61, C3LBX0, C3P3K3, C4ZQY9, D5AKY0, D6R3B6, E1AQY3, E1V7V7, E5Y945, M1GRN3, O27392, O30156, O34662, O50131, O53379

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	55
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1993 predictions. Top by Δscore:

Variant	Effect	Δscore
4:108743783:CCTTA:C	donor_loss	1.0000
4:108743784:CTTA:C	donor_loss	1.0000
4:108743785:TTA:T	donor_loss	1.0000
4:108743786:TA:T	donor_loss	1.0000
4:108743874:T:TC	acceptor_gain	1.0000
4:108743876:A:C	acceptor_gain	1.0000
4:108746394:CCCA:C	donor_loss	1.0000
4:108746395:CCA:C	donor_loss	1.0000
4:108746396:CA:C	donor_loss	1.0000
4:108746398:C:CT	donor_loss	1.0000
4:108748000:CATA:C	donor_loss	1.0000
4:108748001:ATAC:A	donor_loss	1.0000
4:108748002:TAC:T	donor_loss	1.0000
4:108748003:A:AC	donor_gain	1.0000
4:108748003:A:C	donor_loss	1.0000
4:108748004:C:CC	donor_gain	1.0000
4:108748031:AG:A	donor_gain	1.0000
4:108748072:CT:C	donor_gain	1.0000
4:108748072:CTCT:C	donor_gain	1.0000
4:108748075:T:A	donor_gain	1.0000
4:108748085:T:TA	donor_gain	1.0000
4:108748155:CCATA:C	acceptor_gain	1.0000
4:108748156:CATA:C	acceptor_gain	1.0000
4:108748156:CATAC:C	acceptor_gain	1.0000
4:108748157:ATA:A	acceptor_gain	1.0000
4:108748158:TA:T	acceptor_gain	1.0000
4:108748159:AC:A	acceptor_loss	1.0000
4:108748160:C:CC	acceptor_gain	1.0000
4:108748160:CTGTA:C	acceptor_loss	1.0000
4:108748162:G:C	acceptor_gain	1.0000

AlphaMissense

3315 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:108754671:G:C	S150R	0.998
4:108754671:G:T	S150R	0.998
4:108754673:T:G	S150R	0.998
4:108759753:A:G	S111P	0.997
4:108754699:C:T	G141D	0.996
4:108756485:C:G	A115P	0.996
4:108760198:A:C	N55K	0.996
4:108760198:A:T	N55K	0.996
4:108749241:A:C	N308K	0.995
4:108749241:A:T	N308K	0.995
4:108749244:A:C	F307L	0.995
4:108749244:A:T	F307L	0.995
4:108749246:A:G	F307L	0.995
4:108749344:A:T	V274D	0.995
4:108749434:A:T	I244K	0.995
4:108750986:A:C	S217R	0.995
4:108750986:A:T	S217R	0.995
4:108750988:T:G	S217R	0.995
4:108754699:C:A	G141V	0.995
4:108749335:C:T	G277E	0.994
4:108756491:A:G	S113P	0.994
4:108748148:A:C	N313K	0.993
4:108748148:A:T	N313K	0.993
4:108749305:G:T	A287E	0.993
4:108749336:C:G	G277R	0.993
4:108749336:C:T	G277R	0.993
4:108754700:C:G	G141R	0.993
4:108759844:A:C	N80K	0.993
4:108759844:A:T	N80K	0.993
4:108749306:C:G	A287P	0.992

dbSNP variants (sampled 300 via entrez): RS1000082968 (4:108743513 A>C,G), RS1000138048 (4:108756511 G>A,C), RS10002058 (4:108759930 C>T), RS1000216775 (4:108748427 C>G), RS1000367064 (4:108755048 T>C), RS1000682472 (4:108759730 G>A), RS1000707451 (4:108753357 G>A), RS1001122815 (4:108764315 T>G), RS1001146156 (4:108754898 C>G), RS1001153885 (4:108757255 CA>C), RS1001178152 (4:108759484 G>A), RS1001204824 (4:108757009 A>G), RS1001263530 (4:108763202 A>C), RS1001494271 (4:108755289 T>G), RS1001885226 (4:108750000 A>T)

Disease associations

OMIM: gene MIM:614682 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002337_124	Amyotrophic lateral sclerosis (sporadic)	1.000000e-07
GCST008058_128	Estimated glomerular filtration rate	4.000000e-16
GCST008059_15	Estimated glomerular filtration rate	1.000000e-15
GCST008747_179	Estimated glomerular filtration rate	5.000000e-09
GCST008747_38	Estimated glomerular filtration rate	6.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	8
Cyclosporine	decreases expression	3
Aflatoxin B1	affects expression, decreases expression, decreases methylation	3
entinostat	increases expression, affects cotreatment	2
Acetaminophen	decreases expression	2
Benzo(a)pyrene	increases methylation, affects methylation, decreases expression	2
aminomethylphosphonic acid (AMPA)	decreases expression	1
dicrotophos	decreases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
trichostatin A	increases expression	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	increases expression	1
sulindac sulfide	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	increases expression, affects cotreatment	1
Vehicle Emissions	decreases methylation	1
Chenodeoxycholic Acid	affects cotreatment, decreases expression	1
Deoxycholic Acid	affects cotreatment, decreases expression	1
Glycochenodeoxycholic Acid	affects cotreatment, decreases expression	1
Glycocholic Acid	decreases expression, affects cotreatment	1
Glycodeoxycholic Acid	affects cotreatment, decreases expression	1
Quercetin	decreases expression	1
Rifampin	increases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Triclosan	affects cotreatment, decreases expression	1
2,4-Dichlorophenoxyacetic Acid	decreases expression	1

Clinical trials (associated diseases)

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