NAPEPLD

Summary

NAPEPLD (N-acyl phosphatidylethanolamine phospholipase D, HGNC:21683) is a protein-coding gene on chromosome 7q22.1, encoding N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (Q6IQ20). D-type phospholipase that hydrolyzes N-acyl-phosphatidylethanolamines (NAPEs) to produce bioactive N-acylethanolamines/fatty acid ethanolamides (NAEs/FAEs) and phosphatidic acid.

NAPEPLD is a phospholipase D type enzyme that catalyzes the release of N-acylethanolamine (NAE) from N-acyl-phosphatidylethanolamine (NAPE) in the second step of the biosynthesis of N-acylethanolamine (Okamoto et al., 2004 [PubMed 14634025]).

Source: NCBI Gene 222236 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 78 total — 1 pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001122838

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21683
Approved symbol	NAPEPLD
Name	N-acyl phosphatidylethanolamine phospholipase D
Location	7q22.1
Locus type	gene with protein product
Status	Approved
Aliases	FMP30, C7orf18, NAPE-PLD
Ensembl gene	ENSG00000161048
Ensembl biotype	protein_coding
OMIM	612334
Entrez	222236

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 20 protein_coding, 2 retained_intron, 2 nonsense_mediated_decay

ENST00000341533, ENST00000414118, ENST00000417955, ENST00000418294, ENST00000420631, ENST00000422589, ENST00000425379, ENST00000427257, ENST00000465647, ENST00000479761, ENST00000873865, ENST00000873866, ENST00000873867, ENST00000873868, ENST00000873869, ENST00000873870, ENST00000873871, ENST00000873872, ENST00000873873, ENST00000873874, ENST00000873875, ENST00000965816, ENST00000965817, ENST00000965818

RefSeq mRNA: 20 — MANE Select: NM_001122838 NM_001122838, NM_001386176, NM_001386177, NM_001386179, NM_001386182, NM_001386185, NM_001386190, NM_001386191, NM_001386193, NM_001386194, NM_001386204, NM_001386205, NM_001386207, NM_001386208, NM_001386209, NM_001386210, NM_001386211, NM_001386212, NM_001386213, NM_198990

CCDS: CCDS5729

Canonical transcript exons

ENST00000465647 — 5 exons

Exon	Start	End
ENSE00001056131	103115060	103115174
ENSE00001132741	103119577	103120223
ENSE00001375894	103148811	103149099
ENSE00001894315	103099776	103103554
ENSE00003496286	103128483	103128792

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 95.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.3350 / max 172.2434, expressed in 1161 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
85368	2.5003	997
85369	0.4008	204
85365	0.2102	75
85366	0.1545	78
85367	0.0691	29

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	95.38	gold quality
ventricular zone	UBERON:0003053	95.36	gold quality
superior frontal gyrus	UBERON:0002661	91.93	gold quality
duodenum	UBERON:0002114	90.66	gold quality
primary visual cortex	UBERON:0002436	90.53	gold quality
Brodmann (1909) area 9	UBERON:0013540	90.32	gold quality
prefrontal cortex	UBERON:0000451	90.05	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	89.31	gold quality
rectum	UBERON:0001052	89.10	gold quality
frontal cortex	UBERON:0001870	88.88	gold quality
cerebellar cortex	UBERON:0002129	88.65	gold quality
cerebellar hemisphere	UBERON:0002245	88.63	gold quality
mucosa of transverse colon	UBERON:0004991	88.59	gold quality
cerebellum	UBERON:0002037	88.51	gold quality
cerebral cortex	UBERON:0000956	88.28	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.22	gold quality
ganglionic eminence	UBERON:0004023	87.29	gold quality
metanephros cortex	UBERON:0010533	87.25	gold quality
right frontal lobe	UBERON:0002810	86.81	gold quality
anterior cingulate cortex	UBERON:0009835	86.68	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	86.46	gold quality
brain	UBERON:0000955	86.19	gold quality
colonic epithelium	UBERON:0000397	86.12	gold quality
Ammon’s horn	UBERON:0001954	86.05	gold quality
adrenal tissue	UBERON:0018303	85.87	gold quality
substantia nigra	UBERON:0002038	85.68	gold quality
amygdala	UBERON:0001876	85.61	gold quality
kidney	UBERON:0002113	85.57	gold quality
temporal lobe	UBERON:0001871	85.53	gold quality
endometrium	UBERON:0001295	85.51	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.07
E-GEOD-99795	no	175.32

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): IRF6, SP1

miRNA regulators (miRDB)

182 targeting NAPEPLD, 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-6867-5P	100.00	82.21	3464
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872

Literature-anchored findings (GeneRIF, showing 12)

• The human NAPE-PLD was activated by phosphatidylethanolamine and inhibited by the beta-lactamase substrate nitrocefin. (PMID:19715685)
• During the menstrual cycle, NAPE-PLD immunoreactivity was down-regulated in the secretory epithelial gland compared to the proliferative epithelial gland and unaffected in the stroma. (PMID:20369362)
• a common haplotype in NAPEPLD, an enzyme involved in endocannabinoid synthesis, was protective against obesity. (PMID:20885390)
• The results of this study suggested that NAPEPLD was alterated in multip;e sclerosis. (PMID:21251115)
• NAPE-PLD expression increase steadily after infancy, peaking in adulthood. (PMID:22827915)
• The differential expression of NAPE-PLD and FAAH suggests that Anandamide could play an important role in the pathophysiology of preeclampsia. (PMID:23122699)
• a major physiological role of NAPE-PLD (PMID:24018423)
• our results do not support a clear role of FAAH, CNR1 and NAPE-PLD in BD and lithium response. (PMID:24126189)
• NAPE-PLD forms homodimers partly separated by an internal channel and uniquely adapted to associate with phospholipids. (PMID:25684574)
• The AC genotype and C allele of NAPE-PLD rs12540583 locus are risk factors for schizophrenia. (PMID:29652995)
• Transcriptome analysis revealed that deletion of NAPE-PLD activates a transcriptional program for nutrient transportation, including lipids and lipoproteins, and inactivates cell-cycle or mitosis-related genes in Caco-2 cells. (PMID:30399323)
• NAPE-PLD is target of thiazide diuretics for hypertension. Its internal channel promotes transport of the cofactor PLP across cell membranes. (PMID:39999832)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	napepld	ENSDARG00000009252
mus_musculus	Napepld	ENSMUSG00000044968
rattus_norvegicus	Napepld	ENSRNOG00000011363
caenorhabditis_elegans		WBGENE00021370
caenorhabditis_elegans		WBGENE00021371

Protein

Protein identifiers

N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D — Q6IQ20 (reviewed: Q6IQ20)

All UniProt accessions (3): Q6IQ20, C9JGB1, H0Y4Y2

UniProt curated annotations — full annotation on UniProt →

Function. D-type phospholipase that hydrolyzes N-acyl-phosphatidylethanolamines (NAPEs) to produce bioactive N-acylethanolamines/fatty acid ethanolamides (NAEs/FAEs) and phosphatidic acid. Cleaves the terminal phosphodiester bond of diacyl- and alkenylacyl-NAPEs, primarily playing a role in the generation of long-chain saturated and monounsaturated NAEs in the brain. May control NAPE homeostasis in dopaminergic neuron membranes and regulate neuron survival, partly through RAC1 activation. As a regulator of lipid metabolism in the adipose tissue, mediates the crosstalk between adipocytes, gut microbiota and immune cells to control body temperature and weight. In particular, regulates energy homeostasis by promoting cold-induced brown or beige adipocyte differentiation program to generate heat from fatty acids and glucose. Has limited D-type phospholipase activity toward N-acyl lyso-NAPEs.

Subunit / interactions. Homodimer. Bile acids promote the assembly of inactive monomers into an active dimer and enable catalysis.

Subcellular location. Golgi apparatus membrane. Early endosome membrane. Nucleus envelope. Nucleus. Nucleoplasm.

Tissue specificity. Widely expressed. Highest expression in brain, kidney and testis (at protein level). Expressed in adipose tissue (at protein level).

Activity regulation. Activated by divalent cations. Activated by bile acids and their conjugates, except for lithocholic acid which is rather inhibitory. Binding of deoxycholic acid favors the selective release of anandamide and likely other unsatured long FAEs. Inhibited by phosphatidylethanolamines.

Cofactor. Binds 2 zinc divalent cations per subunit.

Similarity. Belongs to the NAPE-PLD family.

RefSeq proteins (20): NP_001116310, NP_001373105, NP_001373106, NP_001373108, NP_001373111, NP_001373114, NP_001373119, NP_001373120, NP_001373122, NP_001373123, NP_001373133, NP_001373134, NP_001373136, NP_001373137, NP_001373138, NP_001373139, NP_001373140, NP_001373141, NP_001373142, NP_945341 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001279	Metallo-B-lactamas	Domain
IPR024884	NAPE-PLD	Family
IPR036866	RibonucZ/Hydroxyglut_hydro	Homologous_superfamily

Pfam: PF12706

Enzyme classification (BRENDA):

• EC 3.1.4.54 — N-acetylphosphatidylethanolamine-hydrolysing phospholipase D (BRENDA: 4 organisms, 50 substrates, 156 inhibitors, 35 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

12 substrates with measured Km, best-characterized 12. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
N-PALMITOYL-1,2-DIOLEOYL-PHOSPHATIDYLETHANOLAMIN	0.002–0.0647	15
N-PALMITOYLPHOSPHATIDYLETHANOLAMINE	0.0017–0.045	10
DIFLUORIDO[2-(HEXYLOXY)-3-(PHOSPHONOOXY)PROPYL 5	0.004	1
DIFLUORIDO[2-(HEXYLOXY)-3-(PHOSPHONOOXY)PROPYL 5	0.003	1
FLAME-NAPE	0.0092	1
N-ARACHIDONOYL-1,2-DIOLEOYLPHOSPHATIDYLETHANOLAM	0.0028	1
N-ARACHIDONOYL-1-OLEOYL-2-LYSOPHOSPHATIDYLETHANO	0.004	1
N-ARACHIDONOYLPHOSPHATIDYLETHANOLAMINE	0.04	1
N-OLEOYL-1,2-DIOLEOYLPHOSPHATIDYLETHANOLAMINE	0.0029	1
N-PALMITOYL-1-PALMITOYL-2-LINOLEOYLPHOSPHATIDYLE	0.0033	1
N-PALMITOYL-1-PALMITOYL-2-LYSOPHOSPHATIDYLETHANO	0.004	1
N-STEAROYL-1,2-DIOLEOYLPHOSPHATIDYLETHANOLAMINE	0.0034	1

Catalyzed reactions (Rhea), 12 shown:

• an N-acyl-1,2-diacyl-sn-glycero-3-phosphoethanolamine + H2O = an N-acylethanolamine + a 1,2-diacyl-sn-glycero-3-phosphate + H(+) (RHEA:33159)
• N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphoethanolamine + H2O = N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-ethanolamine + 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphate + H(+) (RHEA:45528)
• N,1,2-tri-(9Z-octadecenoyl)-sn-glycero-3-phosphoethanolamine + H2O = N-(9Z-octadecenoyl) ethanolamine + 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphate + H(+) (RHEA:45532)
• N-octadecanoyl-1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphoethanolamine + H2O = N-octadecanoyl ethanolamine + 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphate + H(+) (RHEA:45536)
• N-hexadecanoyl-1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphoethanolamine + H2O = N-hexadecanoylethanolamine + 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphate + H(+) (RHEA:45540)
• N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-1-(9Z-octadecenoyl)-sn-glycero-3-phosphoethanolamine + H2O = N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-ethanolamine + 1-(9Z-octadecenoyl)-sn-glycero-3-phosphate + H(+) (RHEA:45544)
• N-tetradecanoyl-1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphoethanolamine + H2O = N-tetradecanoylethanolamine + 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphate + H(+) (RHEA:45552)
• N-dodecanoyl-1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphoethanolamine + H2O = N-dodecanoylethanolamine + 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphate + H(+) (RHEA:45556)
• N,1-dihexadecanoyl-sn-glycero-3-phosphoethanolamine + H2O = N-hexadecanoylethanolamine + 1-hexadecanoyl-sn-glycero-3-phosphate + H(+) (RHEA:45592)
• N,1-dihexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphoethanolamine + H2O = 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphate + N-hexadecanoylethanolamine + H(+) (RHEA:45596)
• N-decanoyl-1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphoethanolamine + H2O = N-decanoyl ethanolamine + 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphate + H(+) (RHEA:45608)
• N-octanoyl-1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphoethanolamine + H2O = N-octanoyl ethanolamine + 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphate + H(+) (RHEA:45612)

UniProt features (58 total): strand 20, binding site 13, helix 7, mutagenesis site 5, turn 5, sequence variant 2, sequence conflict 2, chain 1, region of interest 1, modified residue 1, compositionally biased region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
4QN9	X-RAY DIFFRACTION	2.65
8P90	X-RAY DIFFRACTION	2.8
8PC4	X-RAY DIFFRACTION	2.85
8P96	X-RAY DIFFRACTION	2.86

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6IQ20-F1	87.36	0.78

Functional residue map

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

Ligand- & substrate-binding residues (13): 260; 284; 284; 321; 343; 348; 185; 187; 188; 189; 190; 253 …

Post-translational modifications (1): 1

Mutagenesis-validated functional residues (5):

Position	Phenotype
158	impairs homodimerization resulting in loss of activity; when associated with s-159.
159	impairs homodimerization resulting in loss of activity; when associated with s-158.
207	loss of activity.
257	impairs binding to bile acids resulting in loss of activity.
380	loss of activity.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-2466712	Biosynthesis of A2E, implicated in retinal degradation
R-HSA-1643685	Disease
R-HSA-2453864	Retinoid cycle disease events
R-HSA-2474795	Diseases associated with visual transduction
R-HSA-9675143	Diseases of the neuronal system

MSigDB gene sets: 228 (showing top): SHEPARD_BMYB_MORPHOLINO_UP, GOBP_RESPONSE_TO_ETHANOL, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_BEHAVIOR, GOBP_INFLAMMATORY_RESPONSE, GCANCTGNY_MYOD_Q6, GOBP_POSITIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_MODULATION_OF_PROCESS_OF_ANOTHER_ORGANISM, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_REGULATION_OF_BROWN_FAT_CELL_DIFFERENTIATION, CAGCTG_AP4_Q5, YY1_Q6, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS

GO Biological Process (12): temperature homeostasis (GO:0001659), phospholipid catabolic process (GO:0009395), response to isolation stress (GO:0035900), host-mediated modulation of intestinal microbiota composition (GO:0048874), positive regulation of inflammatory response (GO:0050729), N-acylethanolamine metabolic process (GO:0070291), N-acylphosphatidylethanolamine metabolic process (GO:0070292), positive regulation of brown fat cell differentiation (GO:0090336), negative regulation of eating behavior (GO:1903999), lipid metabolic process (GO:0006629), phospholipid metabolic process (GO:0006644), lipid catabolic process (GO:0016042)

GO Molecular Function (7): zinc ion binding (GO:0008270), bile acid binding (GO:0032052), identical protein binding (GO:0042802), N-acylphosphatidylethanolamine-specific phospholipase D activity (GO:0070290), glycerophospholipase activity (GO:0004620), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (19): Golgi membrane (GO:0000139), nuclear envelope (GO:0005635), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), early endosome (GO:0005769), Golgi apparatus (GO:0005794), smooth endoplasmic reticulum membrane (GO:0030868), early endosome membrane (GO:0031901), photoreceptor outer segment membrane (GO:0042622), presynaptic membrane (GO:0042734), neuron projection (GO:0043005), neuronal cell body (GO:0043025), postsynaptic membrane (GO:0045211), extracellular exosome (GO:0070062), hippocampal mossy fiber to CA3 synapse (GO:0098686), nucleus (GO:0005634), endosome (GO:0005768), membrane (GO:0016020), presynapse (GO:0098793)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Retinoid cycle disease events	1
Diseases associated with visual transduction	1
Diseases of the neuronal system	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
endomembrane system	3
lipid metabolic process	2
bounding membrane of organelle	2
intracellular membrane-bounded organelle	2
synaptic membrane	2
multicellular organismal-level homeostasis	1
phospholipid metabolic process	1
lipid catabolic process	1
organophosphate catabolic process	1
multicellular organismal response to stress	1
homeostasis of number of cells	1
host-mediated perturbation of symbiont process	1
inflammatory response	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
regulation of inflammatory response	1
primary alcohol metabolic process	1
phosphatidylethanolamine metabolic process	1
positive regulation of fat cell differentiation	1
brown fat cell differentiation	1
regulation of brown fat cell differentiation	1
eating behavior	1
regulation of eating behavior	1
negative regulation of feeding behavior	1
primary metabolic process	1
organophosphate metabolic process	1
catabolic process	1
transition metal ion binding	1
monocarboxylic acid binding	1
protein binding	1
D-type glycerophospholipase activity	1
phospholipase activity	1
catalytic activity	1
cation binding	1
Golgi apparatus	1
nucleus	1
organelle envelope	1
nuclear lumen	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

876 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NAPEPLD	FAAH	O00519	925
NAPEPLD	MGLL	Q99685	920
NAPEPLD	PLD2	O14939	919
NAPEPLD	DAGLA	Q9Y4D2	895
NAPEPLD	DAGLB	Q8NCG7	890
NAPEPLD	GDE1	Q9NZC3	854
NAPEPLD	ABHD4	Q8TB40	852
NAPEPLD	NAAA	Q02083	816
NAPEPLD	ABHD6	Q9BV23	812
NAPEPLD	GPR55	Q9Y2T6	802
NAPEPLD	CNR1	P21554	801
NAPEPLD	ABHD12	Q8N2K0	800
NAPEPLD	FAAH2	Q6GMR7	791
NAPEPLD	TRPV1	Q8NER1	767
NAPEPLD	GPR119	Q8TDV5	685

IntAct

6 interactions, top by confidence:

A	B	Type	Score
NAPEPLD	NAPEPLD	psi-mi:“MI:0407”(direct interaction)	0.620
CLEC4M	GRN	psi-mi:“MI:0914”(association)	0.500
DISC1	NAPEPLD	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (5): NAPEPLD (Affinity Capture-RNA), NAPEPLD (Affinity Capture-MS), NAPEPLD (Cross-Linking-MS (XL-MS)), NAPEPLD (Affinity Capture-RNA), NAPEPLD (Two-hybrid)

ESM2 similar proteins: A0A067XMV3, A0A179HLJ8, A0A1L9WLF1, A0A2I1C3U0, A0A411PQM3, A0A4P8DJU1, A0A7R7ZLL0, A1D8J2, A2QX23, C5FM60, D7PHZ8, E1ACR1, E4V2N5, F2T0M3, G3KLH5, G3Y417, K3VFR8, M1WCF7, M2PP75, M3ANL0, N4WYI1, O59954, P0CM88, P0CM89, P0CU68, P22945, P25170, P39863, P43100, P9WEG2, Q05531, Q0CCY4, Q0CS61, Q4WA58, Q58CN9, Q5AQJ2, Q5AXB0, Q5B0C9, Q5BH31, Q5RCU3

Diamond homologs: A0A179HLJ8, P64760, P9WKP2, P9WKP3, Q58CN9, Q5RCU3, Q6IQ20, Q769K2, Q8BH82, Q965X7, Q965X9, Q02883, Q48412, A8F681, C5D672

SIGNOR signaling

0 interactions.

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	2
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
4070958	NM_001122838.3(NAPEPLD):c.945G>T (p.Trp315Cys)	Pathogenic

SpliceAI

1943 predictions. Top by Δscore:

Variant	Effect	Δscore
7:103117673:C:CT	donor_gain	1.0000
7:103128597:T:A	donor_gain	1.0000
7:103128789:AGAA:A	acceptor_gain	1.0000
7:103128790:GAA:G	acceptor_gain	1.0000
7:103128791:AA:A	acceptor_gain	1.0000
7:103128793:C:CC	acceptor_gain	1.0000
7:103129562:CA:C	donor_gain	1.0000
7:103148359:ACTC:A	donor_gain	1.0000
7:103148360:CTCC:C	donor_gain	1.0000
7:103103422:A:AC	donor_gain	0.9900
7:103103423:C:CC	donor_gain	0.9900
7:103103459:T:C	donor_gain	0.9900
7:103103560:C:CT	acceptor_gain	0.9900
7:103103561:A:T	acceptor_gain	0.9900
7:103117683:A:C	donor_gain	0.9900
7:103120223:CCTT:C	acceptor_gain	0.9900
7:103120226:T:TC	acceptor_gain	0.9900
7:103120228:G:C	acceptor_gain	0.9900
7:103120228:G:GC	acceptor_gain	0.9900
7:103120230:G:C	acceptor_gain	0.9900
7:103120230:G:GC	acceptor_gain	0.9900
7:103120232:A:C	acceptor_gain	0.9900
7:103128484:T:TA	donor_gain	0.9900
7:103128495:TGGA:T	donor_gain	0.9900
7:103128715:A:AC	donor_gain	0.9900
7:103128716:C:CC	donor_gain	0.9900
7:103128716:CTG:C	donor_gain	0.9900
7:103128788:AAGAA:A	acceptor_gain	0.9900
7:103128792:AC:A	acceptor_loss	0.9900
7:103128793:C:CA	acceptor_loss	0.9900

AlphaMissense

2628 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:103119893:A:G	W209R	0.999
7:103119893:A:T	W209R	0.999
7:103119966:A:C	S184R	0.999
7:103119966:A:T	S184R	0.999
7:103119968:T:G	S184R	0.999
7:103119703:A:T	V272D	0.998
7:103119710:A:G	W270R	0.998
7:103119710:A:T	W270R	0.998
7:103119711:G:C	S269R	0.998
7:103119711:G:T	S269R	0.998
7:103119713:T:G	S269R	0.998
7:103119719:A:G	W267R	0.998
7:103119719:A:T	W267R	0.998
7:103119824:A:G	W232R	0.998
7:103119824:A:T	W232R	0.998
7:103119946:A:G	L191P	0.998
7:103119976:A:T	V181D	0.998
7:103115137:C:G	A327P	0.997
7:103119931:A:T	V196D	0.997
7:103119821:A:G	W233R	0.996
7:103119821:A:T	W233R	0.996
7:103119667:T:A	D284V	0.995
7:103119822:C:A	W232C	0.995
7:103119822:C:G	W232C	0.995
7:103120133:A:G	W129R	0.995
7:103120133:A:T	W129R	0.995
7:103103469:C:T	G381E	0.994
7:103119715:C:T	G268D	0.994
7:103119716:C:G	G268R	0.994
7:103119967:C:A	S184I	0.994

dbSNP variants (sampled 300 via entrez): RS1000037912 (7:103106159 C>T), RS1000055745 (7:103123322 CAACAAA>C), RS1000060284 (7:103109016 G>C), RS1000147546 (7:103112831 T>A,C), RS1000164420 (7:103149614 G>A), RS1000229415 (7:103103690 C>T), RS1000253182 (7:103145917 A>G), RS1000442401 (7:103142903 T>C), RS1000485483 (7:103111473 G>T), RS1000568162 (7:103117471 C>G), RS1000767194 (7:103118912 A>G), RS1000831363 (7:103120707 T>A,C), RS1000961075 (7:103140382 G>A), RS1000968466 (7:103125696 A>C), RS1001150832 (7:103114415 C>T)

Disease associations

OMIM: gene MIM:612334 | disease phenotypes: MIM:143890

GenCC curated gene-disease

Mondo (1): hypercholesterolemia, familial, 1 (MONDO:0007750)

Orphanet (1): Homozygous familial hypercholesterolemia (Orphanet:391665)

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630839 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 26,164 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL496	HEXACHLOROPHENE	4	26,164

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — N-Acylethanolamine turnover

Most potent curated ligand interactions (8 total), top 8:

Ligand	Action	Affinity	Parameter
LEI-401	Inhibition	7.57	pKi
N3SA	Binding	7.48	pKd
indapamide	Binding	6.24	pKd
chlorthalidone	Binding	6.17	pKd
hydrochlorothiazide	Binding	5.1	pKd
hexachlorophene	Inhibition	5.01	pIC50
bithionol	Inhibition	4.97	pIC50
ARN19874	Inhibition	4.47	pIC50

ChEMBL bioactivities

82 potent at pChembl≥5 of 106 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.14	IC50	72.44	nM	CHEMBL4794048
6.96	IC50	109.7	nM	CHEMBL4761882
6.95	IC50	112.2	nM	CHEMBL4782800
6.81	IC50	154.9	nM	CHEMBL4752937
6.68	IC50	208.9	nM	CHEMBL4754918
6.65	IC50	223.9	nM	CHEMBL4751223
6.65	IC50	223.9	nM	CHEMBL4783103
6.63	IC50	234.4	nM	CHEMBL4759968
6.60	IC50	251.2	nM	CHEMBL4760293
6.55	IC50	281.8	nM	CHEMBL4752023
6.54	IC50	288.4	nM	CHEMBL4747615
6.52	IC50	302	nM	CHEMBL4764910
6.49	IC50	323.6	nM	CHEMBL4750592
6.42	IC50	380.2	nM	CHEMBL4760794
6.42	IC50	380.2	nM	CHEMBL4752088
6.41	IC50	389.1	nM	CHEMBL4746912
6.39	IC50	407.4	nM	CHEMBL4750134
6.37	IC50	426.6	nM	CHEMBL4795010
6.31	IC50	489.8	nM	CHEMBL4764783
6.30	IC50	501.2	nM	CHEMBL4787774
6.28	IC50	524.8	nM	CHEMBL4743071
6.22	IC50	602.6	nM	CHEMBL4750396
6.19	IC50	645.6	nM	CHEMBL4756143
6.19	IC50	645.6	nM	CHEMBL4741598
6.15	IC50	708	nM	CHEMBL4792394
6.13	IC50	741.3	nM	CHEMBL4764562
6.13	IC50	741.3	nM	CHEMBL4787757
6.11	IC50	776.2	nM	CHEMBL4795013
6.09	IC50	812.8	nM	CHEMBL4790197
6.08	IC50	831.8	nM	CHEMBL4747267
6.07	IC50	851.1	nM	CHEMBL4762577
6.05	IC50	891.2	nM	CHEMBL4789858
6.04	IC50	912	nM	CHEMBL4795197
6.01	IC50	977.2	nM	CHEMBL4745098
6.00	IC50	1000	nM	CHEMBL4764089
6.00	IC50	1000	nM	CHEMBL4777828
5.97	IC50	1072	nM	CHEMBL4750056
5.96	IC50	1096	nM	CHEMBL4764340
5.96	IC50	1096	nM	CHEMBL4756683
5.95	IC50	1122	nM	CHEMBL4751965
5.93	IC50	1175	nM	CHEMBL4779869
5.92	IC50	1202	nM	CHEMBL4776045
5.92	IC50	1202	nM	CHEMBL4757430
5.91	IC50	1230	nM	CHEMBL4786525
5.85	IC50	1413	nM	CHEMBL4749127
5.84	IC50	1445	nM	CHEMBL4762175
5.80	IC50	1585	nM	CHEMBL4740570
5.80	IC50	1600	nM	HEXACHLOROPHENE
5.78	IC50	1660	nM	CHEMBL4740363
5.74	IC50	1820	nM	CHEMBL4755036

PubChem BioAssay actives

82 with measured affinity, of 117 total; 50 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
N-(cyclopropylmethyl)-6-[(3S)-3-hydroxypyrrolidin-1-yl]-2-[(3S)-3-phenylpiperidin-1-yl]pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.0724	uM
N-(cyclopropylmethyl)-6-[(3R)-3-hydroxypyrrolidin-1-yl]-2-[(3S)-3-phenylpiperidin-1-yl]pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.1096	uM
N-(cyclopropylmethyl)-6-(dimethylamino)-2-[(3S)-3-phenylpiperidin-1-yl]pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.1122	uM
N-(cyclopropylmethyl)-2,6-bis[methyl(2-phenylethyl)amino]pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.1549	uM
N-(cyclopropylmethyl)-6-morpholin-4-yl-2-[(3S)-3-phenylpiperidin-1-yl]pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.2089	uM
N-(cyclopropylmethyl)-6-(3-hydroxypyrrolidin-1-yl)-2-[methyl(2-phenylethyl)amino]pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.2239	uM
N-(cyclopropylmethyl)-2-[methyl(2-phenylethyl)amino]-6-pyrrolidin-1-ylpyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.2239	uM
N-(cyclopropylmethyl)-6-[(3S)-3-hydroxypyrrolidin-1-yl]-2-[methyl(2-phenylethyl)amino]pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.2344	uM
N-(cyclopropylmethyl)-6-[(3S)-3-hydroxypyrrolidin-1-yl]-2-[(3R)-3-phenylpiperidin-1-yl]pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.2512	uM
N-(cyclopropylmethyl)-6-morpholin-4-yl-2-[2-phenylethyl(propan-2-yl)amino]pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.2818	uM
N-(cyclopropylmethyl)-6-(dimethylamino)-2-[methyl(2-phenylethyl)amino]pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.2884	uM
N-(cyclopropylmethyl)-6-[(3R)-3-hydroxypyrrolidin-1-yl]-2-[methyl(2-phenylethyl)amino]pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.3020	uM
N-(cyclopropylmethyl)-6-[(3R)-3-hydroxypyrrolidin-1-yl]-2-[(3R)-3-phenylpiperidin-1-yl]pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.3236	uM
N-(cyclopropylmethyl)-6-morpholin-4-yl-2-(3-phenylpiperidin-1-yl)pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.3802	uM
2-(2-benzylpyrrolidin-1-yl)-N-(cyclopropylmethyl)-6-morpholin-4-ylpyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.3802	uM
N-(cyclopropylmethyl)-6-(3,3-difluoropiperidin-1-yl)-2-[methyl(2-phenylethyl)amino]pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.3891	uM
N-(cyclopropylmethyl)-6-(dimethylamino)-2-[(3R)-3-phenylpiperidin-1-yl]pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.4074	uM
6-(azetidin-1-yl)-N-(cyclopropylmethyl)-2-[methyl(2-phenylethyl)amino]pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.4266	uM
N-(cyclopropylmethyl)-2-[methyl-[2-(2-phenylphenyl)ethyl]amino]-6-morpholin-4-ylpyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.4898	uM
N-(cyclopropylmethyl)-6-(diethylamino)-2-[methyl(2-phenylethyl)amino]pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.5012	uM
2-[bis(2-phenylethyl)amino]-N-(cyclopropylmethyl)-6-morpholin-4-ylpyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.5248	uM
N-(cyclopropylmethyl)-2-[methyl-[2-(2-phenoxyphenyl)ethyl]amino]-6-morpholin-4-ylpyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.6026	uM
N-(cyclopropylmethyl)-2-[ethyl(2-phenylethyl)amino]-6-morpholin-4-ylpyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.6456	uM
N-(cyclopropylmethyl)-2-[methyl(2-phenylethyl)amino]-6-piperidin-1-ylpyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.6456	uM
N-(cyclopropylmethyl)-6-(3-methoxypyrrolidin-1-yl)-2-[methyl(2-phenylethyl)amino]pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.7079	uM
2-[benzyl(2-phenylethyl)amino]-N-(cyclopropylmethyl)-6-morpholin-4-ylpyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.7413	uM
2-(2-benzylpiperidin-1-yl)-N-(cyclopropylmethyl)-6-morpholin-4-ylpyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.7413	uM
N-(cyclopropylmethyl)-2-[2-(2-methoxyphenyl)ethyl-methylamino]-6-morpholin-4-ylpyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.7762	uM
N-(cyclopropylmethyl)-2-[methyl(2-phenylethyl)amino]-6-morpholin-4-ylpyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.8128	uM
methyl 2-[[2-[methyl(2-phenylethyl)amino]-6-morpholin-4-ylpyrimidine-4-carbonyl]amino]acetate	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.8318	uM
N-(cyclopropylmethyl)-6-(methylamino)-2-[methyl(2-phenylethyl)amino]pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.8511	uM
N-(cyclopropylmethyl)-2-[methyl-[2-(2-methylphenyl)ethyl]amino]-6-morpholin-4-ylpyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.8912	uM
2-[methyl(2-phenylethyl)amino]-6-morpholin-4-yl-N-prop-2-ynylpyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.9120	uM
2-[2-(2-chlorophenyl)ethyl-methylamino]-N-(cyclopropylmethyl)-6-morpholin-4-ylpyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	0.9772	uM
2-(4-benzyl-3-phenylpiperazin-1-yl)-N-(cyclopropylmethyl)-6-morpholin-4-ylpyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	1.0000	uM
N-(cyclopropylmethyl)-6-[2-hydroxyethyl(methyl)amino]-2-[methyl(2-phenylethyl)amino]pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	1.0000	uM
N-(cyclopropylmethyl)-2-[methyl(2-thiophen-2-ylethyl)amino]-6-morpholin-4-ylpyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	1.0715	uM
N-(cyclopropylmethyl)-2-[cyclopropyl(2-phenylethyl)amino]-6-morpholin-4-ylpyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	1.0965	uM
6-[benzyl(methyl)amino]-N-(cyclopropylmethyl)-2-[methyl(2-phenylethyl)amino]pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	1.0965	uM
N-(cyclopropylmethyl)-6-morpholin-4-yl-2-[N-(2-phenylethyl)anilino]pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	1.1220	uM
N-(cyclopropylmethyl)-6-(3,3-difluoropyrrolidin-1-yl)-2-[methyl(2-phenylethyl)amino]pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	1.1749	uM
6-(4-acetylpiperazin-1-yl)-N-(cyclopropylmethyl)-2-[methyl(2-phenylethyl)amino]pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	1.2023	uM
N-(cyclopropylmethyl)-2-[methyl(2-phenylethyl)amino]-6-pyrazol-1-ylpyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	1.2023	uM
N-(cyclopropylmethyl)-6-morpholin-4-yl-2-(2-phenylmorpholin-4-yl)pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	1.2303	uM
N-(cyclopropylmethyl)-2-[methyl(2-phenylethyl)amino]-6-(3-phenylpyrrolidin-1-yl)pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	1.4125	uM
N-(cyclopropylmethyl)-2-[methyl(2-phenylethyl)amino]-6-morpholin-4-ylpyridine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	1.4454	uM
N-(cyclopropylmethyl)-2-[methyl(2-phenylethyl)amino]-6-(4-methylpiperazin-1-yl)pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	1.5849	uM
3,4,6-trichloro-2-[(2,3,5-trichloro-6-hydroxyphenyl)methyl]phenol	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	1.6000	uM
N-(cyclopropylmethyl)-2-[methyl(2-phenylethyl)amino]-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	1.6596	uM
2-[methyl(2-phenylethyl)amino]-6-morpholin-4-yl-N-propylpyrimidine-4-carboxamide	1707626: Inhibition of full length human NAPE-PLD expressed in HEK293T cell lysate using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured at 2 mins interval for 1 hr by tecan-plate reader analysis	ic50	1.8197	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
potassium chromate(VI)	affects cotreatment, decreases expression	2
Dronabinol	affects expression, decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
Cyclosporine	decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
cannabichromene	decreases expression, increases expression	1
trichostatin A	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
Temozolomide	decreases expression	1
Zoledronic Acid	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Air Pollutants, Occupational	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Cannabidiol	increases expression	1
Cannabinol	decreases expression	1
Carbamazepine	affects expression	1
Diclofenac	affects expression	1
Gold	decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4626925	Binding	Inhibition of full length human NAPE-PLD expressed in HEK293T cells assessed as enzyme remaining activity at 10 uM using PED6 as substrate preincubated for 30 mins followed by substrate addition and measured for 1 hr at 2 mins relative to c	Structure-Activity Relationship Studies of α-Ketoamides as Inhibitors of the Phospholipase A and Acyltransferase Enzyme Family. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06231459	PHASE4	COMPLETED	Expression of Pro- and Anti-inflammatory Cytokines During Anti-PCSK9 in Familial Hypercholesterolemia
NCT00000594	PHASE3	COMPLETED	NHLBI Type II Coronary Intervention Study
NCT00092833	PHASE3	TERMINATED	Investigational Drug in Patients With Hypercholesterolemia or in Patients With Sitosterolemia (0653-026)(COMPLETED)
NCT00134485	PHASE3	COMPLETED	Study To Evaluate The Safety And Efficacy Of Torcetrapib/Atorvastatin In Subjects With Familial Hypercholerolemia
NCT00134511	PHASE3	COMPLETED	Study To Evaluate The Effect Of Torcetrapib/Atorvastatin In Patients With Genetic High Cholesterol Disorder
NCT00136981	PHASE3	COMPLETED	Carotid B-Mode Ultrasound Study to Compare Anti-Atherosclerotic Effect of Torcetrpib/Atorvastatin to Atorvastatin Alone.
NCT00384293	PHASE3	TERMINATED	Carotid IMT (Intima Media Thickening) Study (0524A-041)(TERMINATED)
NCT01524289	PHASE3	COMPLETED	Study to Assess the Tolerability and Efficacy of Anacetrapib (MK-0859) Co-Administered With Statin in Participants With Heterozygous Familial Hypercholesterolemia (MK-0859-020)
NCT00280995	PHASE2	COMPLETED	Dose-escalating Safety Study of ISIS 301012 in Homozygous Familial Hypercholesterolemia Subjects on Lipid Lowering Therapy
NCT00281008	PHASE2	COMPLETED	Study of ISIS 301012 (Mipomersen) in Heterozygous Familial Hypercholesterolemia Subjects on Lipid Lowering Therapy
NCT01375751	PHASE2	COMPLETED	Reduction of Low-Density Lipoprotein Cholesterol (LDL-C) With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder Study
NCT00515307	PHASE1	COMPLETED	Bone Marrow Stem Cells as a Source of Allogenic Hepatocyte Transplantation in Homozygous Familial Hypercholesterolemia
NCT01583647	PHASE1	TERMINATED	A Study of Extended-release (ER) Niacin/Laropiprant in Adolescents With Heterozygous Familial Hypercholesterolemia (MK-0524A-158)
NCT00005168	Not specified	COMPLETED	Hyperapo B and Coronary Heart Disease
NCT01753232	Not specified	COMPLETED	Safety and Efficacy of the DALI LDL-adsorber and MONET Lipoprotein Filter
NCT03018678	Not specified	COMPLETED	Screening Protocol for a Gene Therapy Trial in Subjects With Homozygous Familial Hypercholesterolemia
NCT03110432	Not specified	COMPLETED	Prospective German Very High Cardiovascular Risk Patients Dyslipidemia Treatment Indication Registry
NCT03795038	Not specified	COMPLETED	Comparison of the Plasma Lipoprotein Apheresis Systems DIAMED and MONET vs. the Whole Blood Apheresis System DALI
NCT03989167	Not specified	RECRUITING	Clinical Decision Support for Familial Hypercholesterolemia
NCT04073797	Not specified	RECRUITING	PET Imaging of Inflammation and Lipid Lowering Study
NCT04118348	Not specified	COMPLETED	Evaluating the Efficacy of Pediatric Lipid Screening Alerts
NCT04313270	Not specified	UNKNOWN	Subclinical Atherosclerosis in Patients With Familial Hypercholesterolemia Treated With Evolocumab®
NCT04526457	Not specified	COMPLETED	Is Family Screening Improved by Genetic Testing of Familial Hypercholesterolemia
NCT04656028	Not specified	ACTIVE_NOT_RECRUITING	Genetic Testing and Motivational Counseling for FH
NCT04722068	Not specified	COMPLETED	Regeneron 1331 Kinetics Sub-Study HoFH
NCT04837638	Not specified	UNKNOWN	Diet Quality and Coronary Artery Calcification in Adults With Heterozygous Familial Hypercholesterolemia
NCT06555120	Not specified	RECRUITING	Screening for Familial Hypercholesterolemia in Children
NCT07543731	Not specified	NOT_YET_RECRUITING	A Real-World Study of Long-Term Adherence and Persistence to Inclisiran, Evolocumab, and Alirocumab