PLA2G4A

Summary

PLA2G4A (phospholipase A2 group IVA, HGNC:9035) is a protein-coding gene on chromosome 1q31.1, encoding Cytosolic phospholipase A2 (P47712). Has primarily calcium-dependent phospholipase and lysophospholipase activities, with a major role in membrane lipid remodeling and biosynthesis of lipid mediators of the inflammatory response.

This gene encodes a member of the cytosolic phospholipase A2 group IV family. The enzyme catalyzes the hydrolysis of membrane phospholipids to release arachidonic acid which is subsequently metabolized into eicosanoids. Eicosanoids, including prostaglandins and leukotrienes, are lipid-based cellular hormones that regulate hemodynamics, inflammatory responses, and other intracellular pathways. The hydrolysis reaction also produces lysophospholipids that are converted into platelet-activating factor. The enzyme is activated by increased intracellular Ca(2+) levels and phosphorylation, resulting in its translocation from the cytosol and nucleus to perinuclear membrane vesicles. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 5321 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 13
• Clinical variants (ClinVar): 214 total — 5 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 9
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_024420

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9035
Approved symbol	PLA2G4A
Name	phospholipase A2 group IVA
Location	1q31.1
Locus type	gene with protein product
Status	Approved
Aliases	cPLA2-alpha
Ensembl gene	ENSG00000116711
Ensembl biotype	protein_coding
OMIM	600522
Entrez	5321

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000367466, ENST00000466600, ENST00000851114, ENST00000851115, ENST00000851116, ENST00000944301, ENST00000944302, ENST00000944303

RefSeq mRNA: 2 — MANE Select: NM_024420 NM_001311193, NM_024420

CCDS: CCDS1372

Canonical transcript exons

ENST00000367466 — 18 exons

Exon	Start	End
ENSE00000790916	186932763	186932899
ENSE00000790918	186939980	186940094
ENSE00000790919	186946637	186946774
ENSE00000790920	186946869	186946961
ENSE00000790921	186950657	186950728
ENSE00000790922	186956102	186956344
ENSE00000790923	186965409	186965593
ENSE00000790924	186977593	186977788
ENSE00000790925	186979315	186979472
ENSE00001934855	186828949	186829035
ENSE00001952949	186988377	186988981
ENSE00003496914	186893011	186893159
ENSE00003556145	186911248	186911389
ENSE00003626987	186906965	186907002
ENSE00003628738	186870435	186870516
ENSE00003634113	186939008	186939230
ENSE00003635335	186854286	186854387
ENSE00003678248	186894098	186894211

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 98.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.9060 / max 367.4415, expressed in 1246 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
7370	7.9060	1246

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
seminal vesicle	UBERON:0000998	98.00	gold quality
cartilage tissue	UBERON:0002418	95.51	gold quality
right uterine tube	UBERON:0001302	88.65	gold quality
urinary bladder	UBERON:0001255	87.53	gold quality
caput epididymis	UBERON:0004358	86.55	gold quality
mucosa of urinary bladder	UBERON:0001259	86.00	gold quality
germinal epithelium of ovary	UBERON:0001304	85.49	gold quality
calcaneal tendon	UBERON:0003701	85.47	gold quality
parietal pleura	UBERON:0002400	84.27	gold quality
jejunal mucosa	UBERON:0000399	83.87	gold quality
metanephros cortex	UBERON:0010533	83.64	gold quality
urethra	UBERON:0000057	83.35	gold quality
endometrium	UBERON:0001295	83.31	gold quality
palpebral conjunctiva	UBERON:0001812	83.16	gold quality
muscle layer of sigmoid colon	UBERON:0035805	82.98	gold quality
smooth muscle tissue	UBERON:0001135	82.97	gold quality
nasal cavity epithelium	UBERON:0005384	82.97	gold quality
oral cavity	UBERON:0000167	82.79	gold quality
corpus epididymis	UBERON:0004359	82.24	gold quality
pericardium	UBERON:0002407	82.20	gold quality
cauda epididymis	UBERON:0004360	81.93	gold quality
duodenum	UBERON:0002114	81.82	gold quality
sigmoid colon	UBERON:0001159	81.50	gold quality
monocyte	CL:0000576	81.35	gold quality
amniotic fluid	UBERON:0000173	81.20	gold quality
mononuclear cell	CL:0000842	81.06	gold quality
leukocyte	CL:0000738	80.79	gold quality
saphenous vein	UBERON:0007318	80.72	gold quality
choroid plexus epithelium	UBERON:0003911	80.50	gold quality
rectum	UBERON:0001052	80.25	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, FOS, HIF1A, JUN, KAT5, KAT7, KLF11, KLF2, MYBL2, MYC, NFE2L2, NFKB, NR3C1, PGR, SP1, TBP

miRNA regulators (miRDB)

38 targeting PLA2G4A, 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-8485	100.00	77.57	4731
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-6516-3P	99.65	68.57	1238
HSA-MIR-891B	99.59	69.81	1083
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-3171	99.49	69.06	776
HSA-MIR-297	99.40	69.58	1418
HSA-MIR-410-3P	99.27	69.98	2457
HSA-MIR-6895-3P	98.79	65.69	996
HSA-MIR-1301-3P	98.64	68.27	1071
HSA-MIR-5047	98.64	68.62	1035

Literature-anchored findings (GeneRIF, showing 40)

• Expressed in human colorectal adenocarcinomas (PMID:12048163)
• PLA2G5 binds to PLA2G4 to induce leukotriene synthesis in neutrophils (PMID:12124392)
• Nuclear localisation was dependent on proliferation, with subconfluent cells containing higher levels of nuclear cPLA(2)-alpha than contact-inhibited confluent or serum-starved cells. (PMID:12414998)
• Polymorphisms in phospholipase A2 gene is associated with type 2 diabetes mellitus (PMID:12765847)
• group IVA cytosolic phospholipase A(2) is activated by phosphorylation (PMID:12885780)
• The proposed model for membrane docking of the C2 domain of cytosolic phospholipase A2 is fully compatible with the biological function of the intact enzyme. (PMID:14609334)
• novel mechanisms involving accessory proteins at the target membrane play a role in the regulation of cPLA2-alpha (PMID:14686920)
• show that Phospholipase A(2) type IVA is present in red cells as a 90-kDa protein (PMID:14726390)
• cPLA2 has a role in B-Myb-dependent regulation of c-Myc expression (PMID:14769798)
• cPLA(2)alpha translocated to forming phagosomes, surrounding the zymosan particle and completely overlapping with early endosome and plasma membrane markers but only partially overlapping with resident endoplasmic reticulum proteins (PMID:14963030)
• Stable expression of human groups IIA and X secreted phospholipases A(2) (hGIIA and hGX) in CHO-K1 and HEK293 cells leads to serum- and interleukin-1beta-promoted arachidonate release. (PMID:15007070)
• SNP4 located in the 5’-flanking region of the PLA2G4A gene was associated with schizophrenia (PMID:15041036)
• The IValpha cytosolic phospholipase A2 at protein levels in articular cartilage from patients with rheumatoid arthritis, osteoarthritis and patients with non-arthritic joints. (PMID:15259375)
• cPLA2 has an influence on IL-8 and COX 2 gene and protein expression at least in part through PPAR-gamma (PMID:15331599)
• Results suggest that a protein kinase C delta-reactive oxygen species-NF-kappaB cascade plays a pivotal role in cytosolic phospholipase A(2)alpha induction by phorbol 12-myristate 13-acetate. (PMID:15358156)
• cPLA(2)-alpha has a role in the regulation of neutrophil-mediated bacterial killing and the innate immune response to bacterial infection (PMID:15475363)
• Group X secretory phospholipase A2 induces potent arachidonic acid release without activation of cPLA2a. (PMID:15789617)
• Increased cPLA(2)alpha activity is associated with colon cancer (PMID:15975962)
• phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] promotes translocation of cPLA2alpha to perinuclear membranes of intact cells in a manner that is independent of rises in the intracellular Ca2+ concentration (PMID:16221889)
• These results suggest that early cell death events promoted by an overload of calcium can be prevented by the activity of cytosolic Group IVA phospholipase A(2)alpha. (PMID:16407173)
• HCy led to the phosphorylation of cytosolic phospholipase A2; HCy promoted cPLA2 activation; cPLA2 phosphorylation and activation required p38 MAPK (PMID:16409471)
• This study reviews the evidence and discusses the potential roles of phospholipase A2 Group 4A for schizophrenia with particular emphasis on published association studies. (PMID:16585943)
• cytosolic and group IIA secreted phospholipases A(2) work together to liberate arachidonate from phospholipids in response to cytokines (PMID:16603549)
• This review summarizes the phenotypes resulting from genetic ablation of cPLA2alpha, and the properties of newly discovered enzymes in the cPLA2 family. (PMID:16754327)
• Our data suggest that PKCalpha, but not PKCbeta, is the predominant cPKC isoenzyme required for cPLA(2) protein phosphorylation and maximal induction of cPLA(2) enzymatic activity upon activation of human monocytes. (PMID:16963226)
• PPARdelta induces COX-2 expression and the COX-2-derived PGE(2) further activates PPARdelta via cPLA(2)alpha. which forms a growth-promoting signaling that may play a role in hepatocarcinogenesis. (PMID:17178883)
• The data presented link the stimulation of ERK-cPLA(2)-15-LO pathway by oxidized LDL to the prooxidant mechanism of the lipoprotein complex. (PMID:17344094)
• Residues specific for binding arachidonic and palmitic acids, preferred substrates for cPLA2 and PLB1, respectively, are identified. These results explan the differences in substrate specificity between lipases sharing the cPLA2 catalytic domain fold. (PMID:17685590)
• the confluence-dependent interaction of cPLA(2)alpha and annexin A1 at the Golgi acts as a novel molecular switch controlling cPLA(2)alpha activity and endothelial cell prostaglandin generation. (PMID:17873281)
• This study showed that cortisol increased PLA2G4A mRNA level via GR-dependent ongoing transcription in human amnion fibroblasts by activating the binding of GR to PLA2G4A promoter directly. (PMID:17901074)
• Cell surface ANXA1 synthesis is capable of blocking beta 2-integrin adhesion in PMNs. Fluticasone propionate does not cause ANXA1 synthesis or nuclear transport of cytosolic gIVaPLA2 & thus does not block beta2-integrin adhesion. (PMID:17971499)
• cytosolic phospholipase A2 and leukotriene B4 may have roles in acute myeloid leukemia (PMID:17976189)
• The mutation of Ser515 to Ala (S515A) did not change cPLA(2)alpha activity, although S228A and S505A completely and partially decreased the activity, respectively. (PMID:18280113)
• Role of cPLA2-alpha in the early action of TCDD through a nongenomic pathway in MCF10A cells is reported. (PMID:18388244)
• human cPLA(2alpha) deficiency is associated with impaired eicosanoid biosynthesis, small intestinal ulceration, and platelet dysfunctio (PMID:18451993)
• Cytosolic phospholipase A2alpha activation induced by S1P is mediated by the S1P3 receptor in lung epithelial cells.( (PMID:18502815)
• BanI polymorphism of PLA2G4A showed a significant impact on mean age of the onset of schizophrenia and schizoaffective disorder in males, indicating lower mean age at admission in homozygous A2A2 males. (PMID:18562188)
• Data show that activation of cytosolic phospholipase A(2) and production of lysophosphatidylcholine are initial events required for radiation-induced activation of Akt and ERK1/2 in vascular endothelial cells. (PMID:18566601)
• a role of cPLA(2)alpha in the formation of nascent lipid droplets from the endoplasmic reticulum (PMID:18632668)
• the inhibition of cPLA(2)alpha activity affected many of the allergen-dependent, asthma-associated gene expression changes. (PMID:18665843)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	pla2g4ab	ENSDARG00000017141
danio_rerio	pla2g4aa	ENSDARG00000024546
mus_musculus	Pla2g4a	ENSMUSG00000056220
rattus_norvegicus	Pla2g4a	ENSRNOG00000002657

Paralogs (5): PLA2G4C (ENSG00000105499), PLA2G4D (ENSG00000159337), PLA2G4F (ENSG00000168907), PLA2G4E (ENSG00000188089), PLA2G4B (ENSG00000243708)

Protein

Protein identifiers

Cytosolic phospholipase A2 — P47712 (reviewed: P47712)

Alternative names: Phospholipase A2 group IVA

All UniProt accessions (1): P47712

UniProt curated annotations — full annotation on UniProt →

Function. Has primarily calcium-dependent phospholipase and lysophospholipase activities, with a major role in membrane lipid remodeling and biosynthesis of lipid mediators of the inflammatory response. Plays an important role in embryo implantation and parturition through its ability to trigger prostanoid production. Preferentially hydrolyzes the ester bond of the fatty acyl group attached at sn-2 position of phospholipids (phospholipase A2 activity). Selectively hydrolyzes sn-2 arachidonoyl group from membrane phospholipids, providing the precursor for eicosanoid biosynthesis via the cyclooxygenase pathway. In an alternative pathway of eicosanoid biosynthesis, hydrolyzes sn-2 fatty acyl chain of eicosanoid lysophopholipids to release free bioactive eicosanoids. Hydrolyzes the ester bond of the fatty acyl group attached at sn-1 position of phospholipids (phospholipase A1 activity) only if an ether linkage rather than an ester linkage is present at the sn-2 position. This hydrolysis is not stereospecific. Has calcium-independent phospholipase A2 and lysophospholipase activities in the presence of phosphoinositides. Has O-acyltransferase activity. Catalyzes the transfer of fatty acyl chains from phospholipids to a primary hydroxyl group of glycerol (sn-1 or sn-3), potentially contributing to monoacylglycerol synthesis.

Subunit / interactions. Interacts with KAT5.

Subcellular location. Cytoplasm. Golgi apparatus membrane. Nucleus envelope.

Tissue specificity. Expressed in various cells and tissues such as macrophages, neutrophils, fibroblasts and lung endothelium. Expressed in platelets (at protein level).

Post-translational modifications. Phosphorylated at both Ser-505 and Ser-727 in response to mitogenic stimuli.

Disease relevance. Gastrointestinal ulceration, recurrent, with dysfunctional platelets (GURDP) [MIM:618372] An autosomal recessive disorder characterized by recurrent gastrointestinal mucosal ulcers, gastrointestinal bleeding, chronic anemia, iron deficiency, and abdominal pain. Disease features also include platelet dysfunction, and globally decreased eicosanoid synthesis. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by cytosolic calcium, which is necessary for binding to membrane lipids. Activated by phosphorylation in response to mitogenic stimuli. Activated by ceramide-1-phosphate. Binding (via C2 domain) to ceramide-1-phosphate increases the affinity for membrane lipids. Can be activated by phosphoinositides in the absence of calcium. Inhibited by ANXA5 in a calcium- and substrate-dependent way.

Domain organisation. The N-terminal C2 domain associates with lipid membranes upon calcium binding. It modulates enzyme activity by presenting the active site to its substrate in response to elevations of cytosolic calcium. In the presence of phosphoinositides, regulates phospholipase A2 and lysophospholipase activities in a calcium-independent way.

Pathway. Membrane lipid metabolism; glycerophospholipid metabolism. Lipid metabolism; arachidonate metabolism. Lipid metabolism; prostaglandin biosynthesis. Lipid metabolism; leukotriene B4 biosynthesis.

RefSeq proteins (2): NP_001298122, NP_077734* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR002642	LysoPLipase_cat_dom	Domain
IPR016035	Acyl_Trfase/lysoPLipase	Homologous_superfamily
IPR035892	C2_domain_sf	Homologous_superfamily
IPR041847	C2_cPLA2	Domain

Pfam: PF00168, PF01735

Enzyme classification (BRENDA):

• EC 3.1.1.4 — phospholipase A2 (BRENDA: 129 organisms, 452 substrates, 710 inhibitors, 90 Km, 14 kcat entries)

Substrate kinetics (BRENDA)

58 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PHOSPHATIDYLCHOLINE	0.05–17	12
1,2-DIHEXANOYL-SN-GLYCERO-3-PHOSPHOCHOLINE	0.94–13.85	7
PHOSPHATIDYLETHANOLAMINE	0.02–10.5	5
1,2-DIHEPTANOYL-SN-GLYCERO-3-PHOPHORYLCHOLINE	1.12–5.13	3
1,2-DIHEPTANOYL-SN-GLYCERO-3-PHOSPHOCHOLINE	3–3.92	3
1,2-DIOCTANOYL-SN-GLYCERO-3-PHOSPHOCHOLINE	0.12–3.2	3
1-HEXADECYL-2-ACETYL-SN-GLYCEROL-3-PHOSPHOCHOLIN	0.0137–0.0142	2
1-PALMITOYL-2-ARACHIDONYLPHOSPHATIDYLCHOLINE	0.0016–0.0033	2
LECITHIN	8.3–8.5	2
(3E)-3-[(3AS,7AS)-3-METHYL-2-OXO-6-(PROPAN-2-YLI	0.742	1
(3R,3AS,5AS,8BR)-3,5A,5B-TRIMETHYL-3A,4,5,5A,5B,	0.746	1
(3R,3AS,5AS,9BR)-3,5A,9-TRIMETHYL-3A,4,5,5A-TETR	0.734	1
(3R,3AS,6R,8S,9BS)-6,8-DIHYDROXY-3,6,9-TRIMETHYL	0.744	1
(3R,3AS,6R,8S,9BS)-8-HYDROXY-3,6,9-TRIMETHYL-2-O	0.738	1
(3R,3AS,6R,9BS)-3,6,9-TRIMETHYL-2,8-DIOXO-2,3,3A	0.742	1

Catalyzed reactions (Rhea), 12 shown:

• a 1-acyl-sn-glycero-3-phosphocholine + H2O = sn-glycerol 3-phosphocholine + a fatty acid + H(+) (RHEA:15177)
• a 1,2-diacyl-sn-glycero-3-phosphocholine + H2O = a 1-acyl-sn-glycero-3-phosphocholine + a fatty acid + H(+) (RHEA:15801)
• a 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine + H2O = a 1-O-alkyl-sn-glycero-3-phosphocholine + a fatty acid + H(+) (RHEA:36231)
• 1-hexadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphocholine + H2O = 1-hexadecanoyl-sn-glycero-3-phosphocholine + (5Z,8Z,11Z,14Z)-eicosatetraenoate + H(+) (RHEA:40427)
• 1-hexadecanoyl-sn-glycero-3-phosphocholine + H2O = sn-glycerol 3-phosphocholine + hexadecanoate + H(+) (RHEA:40435)
• 1-octadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphate + H2O = 1-octadecanoyl-sn-glycero-3-phosphate + (5Z,8Z,11Z,14Z)-eicosatetraenoate + H(+) (RHEA:40451)
• 1-octadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphocholine + H2O = 1-octadecanoyl-sn-glycero-3-phosphocholine + (5Z,8Z,11Z,14Z)-eicosatetraenoate + H(+) (RHEA:40519)
• 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine + H2O = (9Z,12Z)-octadecadienoate + 1-hexadecanoyl-sn-glycero-3-phosphocholine + H(+) (RHEA:40811)
• 1-O-hexadecyl-2-(5Z,8Z,11Z,14Z)-eicosatetraenoyl-sn-glycero-3-phosphocholine + H2O = 1-O-hexadecyl-sn-glycero-3-phosphocholine + (5Z,8Z,11Z,14Z)-eicosatetraenoate + H(+) (RHEA:41067)
• 1-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-2-hexadecanoyl-sn-glycero-3-phosphocholine + H2O = 1-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphocholine + hexadecanoate + H(+) (RHEA:41071)
• 1,2-di-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphocholine + H2O = 1-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphocholine + (5Z,8Z,11Z,14Z)-eicosatetraenoate + H(+) (RHEA:41075)
• 1-octadecanoyl-2-(9Z,12Z,15Z-octadecatrienoyl)-sn-glycero-3-phosphocholine + glycerol = 1-(9Z,12Z,15Z-octadecatrienoyl)-glycerol + 1-octadecanoyl-sn-glycero-3-phosphocholine (RHEA:41087)

UniProt features (124 total): helix 30, mutagenesis site 28, strand 26, binding site 9, modified residue 9, sequence variant 8, turn 5, domain 2, cross-link 2, region of interest 2, active site 2, chain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1RLW	X-RAY DIFFRACTION	2.4
1CJY	X-RAY DIFFRACTION	2.5
1BCI	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P47712-F1	84.15	0.61

Functional residue map

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

Catalytic / active sites (2): 228 (nucleophile); 549 (proton acceptor)

Ligand- & substrate-binding residues (9): 43; 43; 65; 93; 94; 95; 40; 40; 41

Post-translational modifications (11): 2, 268, 434, 435, 437, 505, 515, 727, 729, 541, 606

Mutagenesis-validated functional residues (28):

Position	Phenotype
43	impairs phospholipase a2 and lysophospholipase activities in the absence of phosphoinositides. has full activity in the
57–59	impairs binding to ceramide-1-phosphate.
139	no effect on phospholipase activity; when associated with a-141 and a-151.
141	no effect on phospholipase activity; when associated with a-139 and a-151.
151	no effect on phospholipase activity; when associated with a-139 and a-141.
195	5-fold reduced phospholipase and lysophospholipase activities. 100-fold reduced phospholipase and lysophospholipase acti
200	abolishes phospholipase activity.
200	reduces phospholipase activity 200-fold.
215	no effect on phospholipase or lysophospholipase activity.
220	no effect on phospholipase activity.
228	abolishes both phospholipase and lysophospholipase activities.
324	no effect on phospholipase activity; when associated with a-331.
331	no effect on phospholipase activity; when associated with a-324.
437	reduces phospholipase a2 activity; when associated with a-454; a-505 and a-727.
454	reduces phospholipase a2 activity; when associated with a-437; a-505 and a-727.
488	impairs phosphoinositide-stimulated phospholipase a2 activity.
505	decreases agonist-stimulated release of arachidonic acid. reduces phospholipase a2 activity; when associated with a-437;
541	impairs phosphoinositide-stimulated phospholipase a2 activity; when associated with a-543 and a-544.
543	impairs phosphoinositide-stimulated phospholipase a2 activity.; when associated with a-541 and a-544.
544	impairs phosphoinositide-stimulated phospholipase a2 activity.; when associated with a-541 and a-543.
549	abolishes phospholipiase activity.
549	reduces phospholipase activity 2000-fold.
549	reduces phospholipase activity 300-fold.
577	7-fold reduced phospholipase and lysophospholipase activities. 100-fold reduced phospholipase and lysophospholipase acti
620	no effect on phospholipase activity; when associated with a-634.

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-111995	phospho-PLA2 pathway
R-HSA-1482788	Acyl chain remodelling of PC
R-HSA-1482798	Acyl chain remodeling of CL
R-HSA-1482801	Acyl chain remodelling of PS
R-HSA-1482839	Acyl chain remodelling of PE
R-HSA-1482922	Acyl chain remodelling of PI
R-HSA-1482925	Acyl chain remodelling of PG
R-HSA-1483115	Hydrolysis of LPC
R-HSA-1483166	Synthesis of PA
R-HSA-2142753	Arachidonate metabolism
R-HSA-418592	ADP signalling through P2Y purinoceptor 1
R-HSA-432142	Platelet sensitization by LDL
R-HSA-6811436	COPI-independent Golgi-to-ER retrograde traffic

MSigDB gene sets: 442 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, GOBP_REGULATION_OF_CELL_ACTIVATION, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLCHOLINE_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_ICOSANOID_SECRETION, GOBP_POSITIVE_REGULATION_OF_MACROPHAGE_ACTIVATION, GOBP_REGULATION_OF_PROSTAGLANDIN_SECRETION, GOBP_REGULATION_OF_ORGANIC_ACID_TRANSPORT, BROWNE_HCMV_INFECTION_8HR_UP, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_PLATELET_ACTIVATION

GO Biological Process (27): prostaglandin biosynthetic process (GO:0001516), positive regulation of T-helper 1 type immune response (GO:0002827), glycerol metabolic process (GO:0006071), monoacylglycerol biosynthetic process (GO:0006640), platelet activating factor biosynthetic process (GO:0006663), icosanoid metabolic process (GO:0006690), positive regulation of platelet activation (GO:0010572), arachidonate metabolic process (GO:0019369), leukotriene biosynthetic process (GO:0019370), positive regulation of prostaglandin secretion (GO:0032308), phosphatidylglycerol catabolic process (GO:0034478), phosphatidylcholine catabolic process (GO:0034638), phosphatidylcholine acyl-chain remodeling (GO:0036151), regulation of cell population proliferation (GO:0042127), positive regulation of macrophage activation (GO:0043032), glycerophospholipid catabolic process (GO:0046475), arachidonate secretion (GO:0050482), establishment of localization in cell (GO:0051649), cellular response to antibiotic (GO:0071236), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631), fatty acid biosynthetic process (GO:0006633), glycerophospholipid metabolic process (GO:0006650), prostaglandin metabolic process (GO:0006693), phospholipid catabolic process (GO:0009395), lipid catabolic process (GO:0016042), icosanoid biosynthetic process (GO:0046456)

GO Molecular Function (16): phosphatidylcholine lysophospholipase A1 activity (GO:0004622), A2-type glycerophospholipase activity (GO:0004623), calcium ion binding (GO:0005509), calcium-dependent phospholipid binding (GO:0005544), obsolete O-acyltransferase activity (GO:0008374), phosphatidylinositol-5-phosphate binding (GO:0010314), phosphatidylinositol-3-phosphate binding (GO:0032266), obsolete calcium-dependent phospholipase A2 activity (GO:0047498), obsolete calcium-independent phospholipase A2 activity (GO:0047499), phosphatidylinositol-4-phosphate binding (GO:0070273), ceramide 1-phosphate binding (GO:1902387), glycerophospholipase activity (GO:0004620), lipid binding (GO:0008289), hydrolase activity (GO:0016787), metal ion binding (GO:0046872), carboxylic ester hydrolase activity (GO:0052689)

GO Cellular Component (10): Golgi membrane (GO:0000139), nucleus (GO:0005634), nuclear envelope (GO:0005635), cytoplasm (GO:0005737), mitochondrial inner membrane (GO:0005743), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Glycerophospholipid biosynthesis	8
Ca-dependent events	1
Fatty acid metabolism	1
Signal amplification	1
Platelet homeostasis	1
Golgi-to-ER retrograde transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anion binding	3
phosphatidylinositol phosphate binding	3
intracellular membrane-bounded organelle	3
endomembrane system	3
cellular anatomical structure	3
cytoplasm	3
glycerophospholipid catabolic process	2
phosphatidylcholine metabolic process	2
phospholipid binding	2
prostaglandin metabolic process	1
prostanoid biosynthetic process	1
positive regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
regulation of T-helper 1 type immune response	1
T-helper 1 type immune response	1
carbohydrate metabolic process	1
polyol metabolic process	1
monoacylglycerol metabolic process	1
acylglycerol biosynthetic process	1
ether lipid biosynthetic process	1
platelet activating factor metabolic process	1
glycerophospholipid biosynthetic process	1
carboxylic acid metabolic process	1
regulation of platelet activation	1
platelet activation	1
positive regulation of cell activation	1
long-chain fatty acid metabolic process	1
icosanoid metabolic process	1
unsaturated fatty acid metabolic process	1
olefinic compound metabolic process	1
leukotriene metabolic process	1
icosanoid biosynthetic process	1
positive regulation of icosanoid secretion	1
regulation of prostaglandin secretion	1
prostaglandin secretion	1
positive regulation of secretion by cell	1
phosphatidylglycerol metabolic process	1
cell population proliferation	1
regulation of cellular process	1
positive regulation of leukocyte activation	1
macrophage activation	1

Protein interactions and networks

STRING

2418 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLA2G4A	PLA2G2A	P14555	918
PLA2G4A	PLA2G10	O15496	858
PLA2G4A	PLA2G1B	P04054	814
PLA2G4A	PTGS2	P35354	812
PLA2G4A	ALOX5	P09917	783
PLA2G4A	PLA2G6	O60733	743
PLA2G4A	ALOX5AP	P20292	741
PLA2G4A	CERK	Q8TCT0	720
PLA2G4A	PLA2G2D	Q9UNK4	692
PLA2G4A	PTGES	O14684	657
PLA2G4A	MGLL	Q99685	641
PLA2G4A	MAVS	Q7Z434	632
PLA2G4A	PLA2G7	Q13093	624
PLA2G4A	EPHX2	P34913	621
PLA2G4A	LTA4H	P09960	620

IntAct

26 interactions, top by confidence:

A	B	Type	Score
STAT3	STAT3	psi-mi:“MI:0914”(association)	0.840
	MYL12B	psi-mi:“MI:0914”(association)	0.460
PLA2G4A	DDX1	psi-mi:“MI:0915”(physical association)	0.400
PLA2G4A	PB2	psi-mi:“MI:0915”(physical association)	0.370
PLA2G4A	RELA	psi-mi:“MI:0915”(physical association)	0.370
PLA2G4A	CAP1	psi-mi:“MI:0915”(physical association)	0.370
PLA2G4A	UBXN1	psi-mi:“MI:0915”(physical association)	0.370
PLA2G4A	BORCS6	psi-mi:“MI:0915”(physical association)	0.370
Ccdc9	ACIN1	psi-mi:“MI:0914”(association)	0.350
Eif3e	RPSA	psi-mi:“MI:0914”(association)	0.350
PLA2G4A	Vav2	psi-mi:“MI:0914”(association)	0.350
ZDHHC5	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
MYC		psi-mi:“MI:0914”(association)	0.350
	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
	HLA-C	psi-mi:“MI:0914”(association)	0.350
PLA2G4A	AHSA1	psi-mi:“MI:0914”(association)	0.350
	MYO1C	psi-mi:“MI:0914”(association)	0.350
CFTR	UBA6	psi-mi:“MI:2364”(proximity)	0.270
ELF3	PLA2G4A	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (91): C17orf59 (Two-hybrid), CAP1 (Two-hybrid), UBXN1 (Two-hybrid), RELA (Two-hybrid), XAGE1E (Two-hybrid), S100A10 (Affinity Capture-Western), ANXA2 (Affinity Capture-Western), PLA2G4A (Affinity Capture-Western), PLA2G4A (Affinity Capture-Western), EHD1 (Affinity Capture-Western), PLA2G4A (Affinity Capture-RNA), PLA2G4A (Affinity Capture-RNA), EHD1 (Co-localization), PLA2G4A (Affinity Capture-MS), PLA2G4A (Affinity Capture-MS)

ESM2 similar proteins: A2VE39, A4IFJ5, A4IHT9, A8K855, B1WAZ6, D2HRF1, O00763, O02697, O60551, O70310, O77793, P19447, P30419, P31717, P35574, P47712, P47713, P48736, P49147, P50392, P50393, Q0E908, Q2PQH8, Q2TBU5, Q4R6Y8, Q5R8A5, Q5R981, Q5U2Z5, Q5ZJT0, Q641K1, Q66HX8, Q6DD21, Q7K556, Q7T0T9, Q7XQT2, Q80YD1, Q811C2, Q8C5P5, Q8IYB8, Q8K1Q0

Diamond homologs: A0JJX5, A4IFJ5, B1WAZ6, O77793, P47712, P47713, P49147, P50392, P50393, Q08108, Q3MJ16, Q50L41, Q50L42, Q50L43, Q5R8A5, Q60EW9, Q68DD2, Q7T0T9, Q7XA06, Q8L706, Q8RXU9, Q9LEX1, Q9M2D4, Q9TT38, B6ETT4, P0C871, P34693, P53541, Q06846, Q15111, Q3USB7, Q62688, Q8K394, Q9FL59, Q9Y2J0, A0FGR9, Q69ZN7, Q9NZM1, Q9SKR2, A8KBH6

SIGNOR signaling

14 interactions.

A	Effect	B	Mechanism
PRKCA	up-regulates	PLA2G4A	phosphorylation
MKNK1	“up-regulates activity”	PLA2G4A	phosphorylation
RPS6KA5	“up-regulates activity”	PLA2G4A	phosphorylation
MAPKAPK5	“up-regulates activity”	PLA2G4A	phosphorylation
“arachidonic acid”	up-regulates	PLA2G4A
PLA2G4A	up-regulates	“arachidonic acid”	“chemical modification”
Gbeta	up-regulates	PLA2G4A	phosphorylation
ERK1/2	up-regulates	PLA2G4A	phosphorylation
PRKCZ	“up-regulates activity”	PLA2G4A	phosphorylation
calcium(2+)	up-regulates	PLA2G4A	relocalization
MAPK3	up-regulates	PLA2G4A	phosphorylation
MAPK14	“up-regulates activity”	PLA2G4A	phosphorylation
MAPK1	unknown	PLA2G4A	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	2
Uncertain significance	59
Likely benign	113
Benign	16

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
253546	GRCh37/hg19 1q25.3-31.2(chr1:181572003-191524283)x1	Pathogenic
624621	NM_024420.3(PLA2G4A):c.1723G>C (p.Asp575His)	Pathogenic
624622	NM_024420.3(PLA2G4A):c.2118+4_2118+7del	Pathogenic
9079	NM_024420.3(PLA2G4A):c.331T>C (p.Ser111Pro)	Pathogenic
9080	NM_024420.3(PLA2G4A):c.1454G>A (p.Arg485His)	Pathogenic
3362555	NM_024420.3(PLA2G4A):c.607del (p.Val203fs)	Likely pathogenic
979314	GRCh37/hg19 1q31.1(chr1:186912015-187132574)x3	Likely pathogenic

SpliceAI

3167 predictions. Top by Δscore:

Variant	Effect	Δscore
1:186829035:GG:G	donor_loss	1.0000
1:186829037:T:C	donor_loss	1.0000
1:186854388:G:GG	donor_gain	1.0000
1:186870429:TTCCA:T	acceptor_loss	1.0000
1:186870430:TCCA:T	acceptor_loss	1.0000
1:186870431:CCA:C	acceptor_loss	1.0000
1:186870432:CAG:C	acceptor_loss	1.0000
1:186870433:A:AT	acceptor_loss	1.0000
1:186870514:TGC:T	donor_gain	1.0000
1:186870515:GC:G	donor_gain	1.0000
1:186870515:GCG:G	donor_gain	1.0000
1:186870517:G:GG	donor_gain	1.0000
1:186893004:T:G	acceptor_gain	1.0000
1:186893008:TAGTT:T	acceptor_loss	1.0000
1:186893009:A:AG	acceptor_gain	1.0000
1:186893009:AGTT:A	acceptor_gain	1.0000
1:186893010:G:C	acceptor_loss	1.0000
1:186893010:G:GA	acceptor_gain	1.0000
1:186893010:GT:G	acceptor_gain	1.0000
1:186893010:GTT:G	acceptor_gain	1.0000
1:186893010:GTTG:G	acceptor_gain	1.0000
1:186893156:GGAG:G	donor_gain	1.0000
1:186893157:GAG:G	donor_gain	1.0000
1:186893157:GAGG:G	donor_gain	1.0000
1:186893160:G:C	donor_loss	1.0000
1:186893160:G:GG	donor_gain	1.0000
1:186893161:T:A	donor_loss	1.0000
1:186894085:T:G	acceptor_gain	1.0000
1:186894096:A:AG	acceptor_gain	1.0000
1:186894097:G:GG	acceptor_gain	1.0000

AlphaMissense

5047 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:186893106:T:A	W71R	1.000
1:186893106:T:C	W71R	1.000
1:186932890:G:A	G229D	1.000
1:186932898:T:A	W232R	1.000
1:186932898:T:C	W232R	1.000
1:186940088:T:C	F343L	1.000
1:186940090:T:A	F343L	1.000
1:186940090:T:G	F343L	1.000
1:186946639:T:A	W346R	1.000
1:186946639:T:C	W346R	1.000
1:186946874:T:A	W393R	1.000
1:186946874:T:C	W393R	1.000
1:186965474:G:C	D549H	1.000
1:186965475:A:C	D549A	1.000
1:186965475:A:T	D549V	1.000
1:186965527:A:C	R566S	1.000
1:186965527:A:T	R566S	1.000
1:186977614:T:A	W596R	1.000
1:186977614:T:C	W596R	1.000
1:186977616:G:C	W596C	1.000
1:186977616:G:T	W596C	1.000
1:186979441:T:C	L696P	1.000
1:186893038:T:C	L48P	0.999
1:186893107:G:C	W71S	0.999
1:186932776:C:A	A191D	0.999
1:186932784:G:C	G194R	0.999
1:186932785:G:A	G194D	0.999
1:186932791:G:A	G196D	0.999
1:186932794:G:A	G197E	0.999
1:186932794:G:T	G197V	0.999

dbSNP variants (sampled 300 via entrez): RS1000032699 (1:186933864 A>G), RS1000038276 (1:186940819 C>G,T), RS1000069988 (1:186884242 A>T), RS1000101354 (1:186874412 A>C), RS1000111909 (1:186940246 G>A,C), RS1000116634 (1:186977791 A>G), RS1000118594 (1:186984347 G>A), RS1000148540 (1:186827798 G>A,C), RS1000150664 (1:186847070 A>G), RS1000151293 (1:186853110 G>A), RS1000200709 (1:186840713 T>C), RS1000225863 (1:186978094 C>T), RS1000233612 (1:186911016 T>G), RS1000259110 (1:186846743 C>T), RS1000286411 (1:186966518 G>A)

Disease associations

OMIM: gene MIM:600522 | disease phenotypes: MIM:618372

GenCC curated gene-disease

Disease	Classification	Inheritance
cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder	Strong	Autosomal recessive
cryptogenic multifocal ulcerous stenosing enteritis	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder	Moderate	AR

Mondo (2): cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder (MONDO:0018794), cryptogenic multifocal ulcerous stenosing enteritis (MONDO:0018765)

Orphanet (1): Cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder (Orphanet:477787)

HPO phenotypes

9 total (9 of 9 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001891	Iron deficiency anemia
HP:0002588	Duodenal ulcer
HP:0002592	Gastric ulcer
HP:0003540	Impaired platelet aggregation
HP:0004791	Esophageal ulceration
HP:0030361	Abnormal circulating eicosanoid concentration
HP:0032244	Decreased serum thromboxane B2
HP:0032575	Decreased circulating 12-HETE

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST000186_1	Knee osteoarthritis	3.000000e-06
GCST001662_5	Generalized epilepsy	9.000000e-06
GCST002934_3	Zinc levels	8.000000e-07
GCST003043_178	Inflammatory bowel disease	2.000000e-07
GCST003044_111	Crohn’s disease	4.000000e-09
GCST006617_1	Uterine fibroid size (maximum volume)	8.000000e-08
GCST007766_1	Hyperinsulinemia x saturated fatty acids interaction	9.000000e-06
GCST007773_1	Hyperinsulinemia in less-fat diet	5.000000e-08
GCST008058_286	Estimated glomerular filtration rate	1.000000e-11
GCST008062_129	Blood urea nitrogen levels	4.000000e-08
GCST008156_63	Hip circumference adjusted for BMI	4.000000e-06
GCST009516_7	Non-del(5q) myelodysplastic syndromes	6.000000e-06
GCST010989_188	Body size at age 10	4.000000e-11

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0009410	uterine fibroid measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0009819	comparative body size at age 10, self-reported

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3816 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 23,387 (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
CHEMBL603	ZAFIRLUKAST	4	23,220
CHEMBL269787	ECOPLADIB	2	73
CHEMBL272342	EFIPLADIB	2	94

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs10157410	Toxicity	3	atenolol	Hypertension
rs12746200	Toxicity	3	acetaminophen;aspirin;diclofenac;propionic acid derivatives;Pyrazolones

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10157410	PLA2G4A	3	1.50	1	atenolol
rs12746200	PLA2G4A	3	3.00	1	acetaminophen;aspirin;diclofenac;propionic acid derivatives;Pyrazolones

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Phospholipase A₂

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 57 [PMID: 16610804]	Inhibition	8.37	pIC50

Binding affinities (BindingDB)

5 measured of 7 human assays (7 total across all organisms); most potent 5 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-(4-octylphenoxy)-1-(1,3-thiazol-2-yl)ethanone	IC50	2000 nM	US-9597318: 2-oxothiazole compounds and method of using same for chronic inflammatory disorders
5-Phenyl-1-(thiazol-2-yl)pentan-1-one	IC50	3050 nM	US-9597318: 2-oxothiazole compounds and method of using same for chronic inflammatory disorders
4-(4-Octylphenoxy)-1-(thiazol-2-yl)butan-1-one	IC50	3650 nM	US-9597318: 2-oxothiazole compounds and method of using same for chronic inflammatory disorders
2-Fluoro-5-(4-(hexyloxy)phenyl)-1-(thiazol-2-yl)pentan-1-one	IC50	3700 nM	US-9597318: 2-oxothiazole compounds and method of using same for chronic inflammatory disorders
2-pentadecanoyl-1,3-thiazole-4-carboxylic acid	IC50	7200 nM	US-9597318: 2-oxothiazole compounds and method of using same for chronic inflammatory disorders

ChEMBL bioactivities

331 potent at pChembl≥5 of 377 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.27	IC50	0.54	nM	EFIPLADIB
9.05	IC50	0.9	nM	CHEMBL443834
8.96	IC50	1.1	nM	CHEMBL426665
8.74	IC50	1.8	nM	CHEMBL441326
8.68	IC50	2.1	nM	CHEMBL9161
8.51	IC50	3.1	nM	CHEMBL267258
8.37	IC50	4.3	nM	CHEMBL443834
8.31	IC50	4.9	nM	CHEMBL426665
8.30	IC50	5	nM	CHEMBL426665
8.30	IC50	5	nM	CHEMBL484413
8.28	IC50	5.3	nM	CHEMBL8973
8.22	IC50	6	nM	CHEMBL451642
8.21	IC50	6.2	nM	CHEMBL8970
8.19	IC50	6.4	nM	CHEMBL207977
8.15	IC50	7	nM	CHEMBL3327088
8.15	IC50	7	nM	CHEMBL3326971
8.15	IC50	7	nM	CHEMBL30108
8.11	IC50	7.8	nM	CHEMBL208401
8.01	IC50	9.7	nM	CHEMBL204618
8.00	IC50	10	nM	CHEMBL4097068
8.00	IC50	10	nM	CHEMBL1800991
8.00	IC50	10	nM	CHEMBL507864
8.00	IC50	10	nM	CHEMBL404529
7.96	IC50	11	nM	CHEMBL3326966
7.96	IC50	11	nM	CHEMBL30108
7.96	IC50	11	nM	CHEMBL381294
7.92	IC50	12	nM	CHEMBL1085637
7.92	IC50	12	nM	CHEMBL207977
7.89	IC50	13	nM	CHEMBL504617
7.89	Kd	13	nM	CHEMBL5561299
7.85	IC50	14	nM	CHEMBL3327089
7.82	IC50	15	nM	CHEMBL3326970
7.82	IC50	15	nM	CHEMBL381294
7.82	IC50	15	nM	CHEMBL4079052
7.80	IC50	16	nM	CHEMBL207977
7.80	IC50	16	nM	CHEMBL204618
7.80	IC50	16	nM	CHEMBL484954
7.75	IC50	18	nM	CHEMBL205892
7.70	IC50	20	nM	CHEMBL3327092
7.70	IC50	20	nM	CHEMBL208401
7.70	IC50	20	nM	CHEMBL505593
7.68	IC50	21	nM	CHEMBL428996
7.66	IC50	22	nM	CHEMBL1801026
7.66	IC50	22	nM	CHEMBL506097
7.66	IC50	22	nM	CHEMBL266374
7.64	IC50	23	nM	CHEMBL4086908
7.62	IC50	24	nM	CHEMBL205892
7.58	IC50	26	nM	CHEMBL3326969
7.58	IC50	26	nM	CHEMBL505164
7.58	IC50	26	nM	CHEMBL484953

PubChem BioAssay actives

322 with measured affinity, of 769 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
4-[3-[1-benzhydryl-5-chloro-2-[2-[(3,4-dichlorophenyl)methylsulfonylamino]ethyl]indol-3-yl]propyl]benzoic acid	1187018: Inhibition of cPLA2alpha isolated from human U937 cell cytoplasm assessed as suppression of [14C]arachidonic acid release from L-alpha-1-palmitoyl-2-[14C]arachidonyl-phosphatidylcholine liposomes substrate by scintillation counting	ic50	0.0005	uM
1-[3-(4-decoxyphenoxy)-2-oxopropyl]-3-methoxycarbonylindole-5-carboxylic acid	262677: Inhibition of cPLA2-alpha activity assessed by TPA-induced arachidonic acid release in human platelet	ic50	0.0009	uM
3-methoxycarbonyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid	262677: Inhibition of cPLA2-alpha activity assessed by TPA-induced arachidonic acid release in human platelet	ic50	0.0011	uM
(E)-N-[[(2S,4R)-1-[2-(2,4-difluorobenzoyl)benzoyl]-4-[2-methylpropyl-[(2-phenylphenyl)methyl]amino]pyrrolidin-2-yl]methyl]-3-[4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl]prop-2-enamide	220179: Inhibition of Human cPLA2 alpha using Enzyme assay(PC/DOG assay)	ic50	0.0018	uM
N-[[(2S,4R)-1-[2-(2,4-difluorobenzoyl)benzoyl]-4-[2-(2-methylpropyl)-6-(2-propan-2-ylphenyl)phenoxy]pyrrolidin-2-yl]methyl]-4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzamide	220179: Inhibition of Human cPLA2 alpha using Enzyme assay(PC/DOG assay)	ic50	0.0021	uM
(E)-3-[4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl]-N-[[(2S,4R)-1-[2-(4-fluorobenzoyl)benzoyl]-4-[2-methylpropyl-[(2-phenylphenyl)methyl]amino]pyrrolidin-2-yl]methyl]prop-2-enamide	220179: Inhibition of Human cPLA2 alpha using Enzyme assay(PC/DOG assay)	ic50	0.0031	uM
1-[3-(4-octylphenoxy)-2-oxopropyl]indazole-5-carboxylic acid	353690: Inhibition of cPLA2 in human platelets assessed as arachidonic acid release	ic50	0.0050	uM
4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-N-[[(2S,4R)-1-[2-(4-fluorobenzoyl)benzoyl]-4-[2-(2-methylpropyl)-6-(2-propan-2-ylphenyl)phenoxy]pyrrolidin-2-yl]methyl]benzamide	220179: Inhibition of Human cPLA2 alpha using Enzyme assay(PC/DOG assay)	ic50	0.0053	uM
4-[3-[2-[2-[[2-[(4-acetylpiperazin-1-yl)methyl]phenyl]methylsulfonylamino]ethyl]-1-benzhydryl-5-chloroindol-3-yl]propyl]benzoic acid	345901: Inhibition of human cytosolic PLA2alpha by GLU micelle assay	ic50	0.0060	uM
N-[[(2S,4R)-1-[2-(2,4-difluorobenzoyl)benzoyl]-4-[2-methylpropyl-[(2-phenylphenyl)methyl]amino]pyrrolidin-2-yl]methyl]-4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzamide	220179: Inhibition of Human cPLA2 alpha using Enzyme assay(PC/DOG assay)	ic50	0.0062	uM
3-acetyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid	262677: Inhibition of cPLA2-alpha activity assessed by TPA-induced arachidonic acid release in human platelet	ic50	0.0064	uM
3-[3-(2-phenylethyl)-1-(4-propoxyphenyl)indol-5-yl]propanoic acid	1187018: Inhibition of cPLA2alpha isolated from human U937 cell cytoplasm assessed as suppression of [14C]arachidonic acid release from L-alpha-1-palmitoyl-2-[14C]arachidonyl-phosphatidylcholine liposomes substrate by scintillation counting	ic50	0.0070	uM
3-[3-(2-phenylethyl)-1-(4-propan-2-yloxyphenyl)indol-5-yl]propanoic acid	1187018: Inhibition of cPLA2alpha isolated from human U937 cell cytoplasm assessed as suppression of [14C]arachidonic acid release from L-alpha-1-palmitoyl-2-[14C]arachidonyl-phosphatidylcholine liposomes substrate by scintillation counting	ic50	0.0070	uM
4-[3-(4-decoxyphenoxy)-2-oxopropoxy]benzoic acid	2003985: Inhibition of cPLA2 alpha (unknown origin)	ic50	0.0070	uM
1-[3-(4-decoxyphenoxy)-2-oxopropyl]indole-5-carboxylic acid	262677: Inhibition of cPLA2-alpha activity assessed by TPA-induced arachidonic acid release in human platelet	ic50	0.0078	uM
3-formyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid	262677: Inhibition of cPLA2-alpha activity assessed by TPA-induced arachidonic acid release in human platelet	ic50	0.0097	uM
4-[3-[1-benzhydryl-5-chloro-2-[2-[(2,6-dimethylphenyl)methylsulfonylamino]ethyl]indol-3-yl]propyl]benzoic acid	345901: Inhibition of human cytosolic PLA2alpha by GLU micelle assay	ic50	0.0100	uM
4-[3-[1-benzhydryl-5-chloro-2-[2-[[2-(morpholin-4-ylmethyl)phenyl]methylsulfonylamino]ethyl]indol-3-yl]propyl]benzoic acid	345901: Inhibition of human cytosolic PLA2alpha by GLU micelle assay	ic50	0.0100	uM
3-butanoyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid	1433580: Inhibition of human platelet cytosolic phospholipase alpha-2 using 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphocholine/1,2-dioleoyl-sn-glycerol as substrate after 60 mins by UV-HPLC method	ic50	0.0100	uM
3-(2-methylpropanoyl)-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid	1433580: Inhibition of human platelet cytosolic phospholipase alpha-2 using 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphocholine/1,2-dioleoyl-sn-glycerol as substrate after 60 mins by UV-HPLC method	ic50	0.0100	uM
3-cyano-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid	262677: Inhibition of cPLA2-alpha activity assessed by TPA-induced arachidonic acid release in human platelet	ic50	0.0110	uM
3-[1-(4-hydroxyphenyl)-3-(2-phenylethyl)indol-5-yl]propanoic acid	1187018: Inhibition of cPLA2alpha isolated from human U937 cell cytoplasm assessed as suppression of [14C]arachidonic acid release from L-alpha-1-palmitoyl-2-[14C]arachidonyl-phosphatidylcholine liposomes substrate by scintillation counting	ic50	0.0110	uM
3-(2-methylpropanoyl)-1-[2-oxo-3-(4-phenoxyphenoxy)propyl]indole-5-carboxylic acid	1433580: Inhibition of human platelet cytosolic phospholipase alpha-2 using 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphocholine/1,2-dioleoyl-sn-glycerol as substrate after 60 mins by UV-HPLC method	ic50	0.0120	uM
azane;[(2S,3R)-2-(hexadecanoylamino)-3-hydroxyoctadecyl] dihydrogen phosphate	2084470: Binding affinity to cPLA2-alpha using POPC as substrate assessed as equlibrium dissociation constant by SPR analysis (Rvb = 47 +/- 30 10^-8M)	kd	0.0130	uM
4-[3-[1-benzhydryl-5-chloro-2-[2-[[2-(piperazin-1-ylmethyl)phenyl]methylsulfonylamino]ethyl]indol-3-yl]propyl]benzoic acid	345901: Inhibition of human cytosolic PLA2alpha by GLU micelle assay	ic50	0.0130	uM
2-amino-2-(hydroxymethyl)propane-1,3-diol;3-[1-[4-(2-hydroxyethoxy)phenyl]-3-(2-phenylethyl)indol-5-yl]propanoic acid	1187018: Inhibition of cPLA2alpha isolated from human U937 cell cytoplasm assessed as suppression of [14C]arachidonic acid release from L-alpha-1-palmitoyl-2-[14C]arachidonyl-phosphatidylcholine liposomes substrate by scintillation counting	ic50	0.0140	uM
2-amino-2-(hydroxymethyl)propane-1,3-diol;3-[1-(4-ethoxyphenyl)-3-(2-phenylethyl)indol-5-yl]propanoic acid	1187018: Inhibition of cPLA2alpha isolated from human U937 cell cytoplasm assessed as suppression of [14C]arachidonic acid release from L-alpha-1-palmitoyl-2-[14C]arachidonyl-phosphatidylcholine liposomes substrate by scintillation counting	ic50	0.0150	uM
3-(4-methoxybutanoyl)-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid	1433580: Inhibition of human platelet cytosolic phospholipase alpha-2 using 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphocholine/1,2-dioleoyl-sn-glycerol as substrate after 60 mins by UV-HPLC method	ic50	0.0150	uM
3-[3-(4-octylphenoxy)-2-oxopropyl]benzotriazole-5-carboxylic acid	353690: Inhibition of cPLA2 in human platelets assessed as arachidonic acid release	ic50	0.0160	uM
1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid	262677: Inhibition of cPLA2-alpha activity assessed by TPA-induced arachidonic acid release in human platelet	ic50	0.0180	uM
4-[3-[1-benzhydryl-5-chloro-2-[2-[[2-[(4-methylpiperazin-1-yl)methyl]phenyl]methylsulfonylamino]ethyl]indol-3-yl]propyl]benzoic acid	345901: Inhibition of human cytosolic PLA2alpha by GLU micelle assay	ic50	0.0200	uM
2-amino-2-(hydroxymethyl)propane-1,3-diol;3-[1-(4-phenoxyphenyl)-3-(2-phenylethyl)indol-5-yl]propanoic acid	1187018: Inhibition of cPLA2alpha isolated from human U937 cell cytoplasm assessed as suppression of [14C]arachidonic acid release from L-alpha-1-palmitoyl-2-[14C]arachidonyl-phosphatidylcholine liposomes substrate by scintillation counting	ic50	0.0200	uM
4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-N-[[(2S,4R)-1-[2-(4-fluorobenzoyl)benzoyl]-4-[2-methylpropyl-[(2-phenylphenyl)methyl]amino]pyrrolidin-2-yl]methyl]benzamide	220179: Inhibition of Human cPLA2 alpha using Enzyme assay(PC/DOG assay)	ic50	0.0210	uM
N-[[(2S,4R)-4-[2-bromo-6-(2-methylpropyl)phenoxy]-1-[2-(2,4-difluorobenzoyl)benzoyl]pyrrolidin-2-yl]methyl]-4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzamide	220179: Inhibition of Human cPLA2 alpha using Enzyme assay(PC/DOG assay)	ic50	0.0220	uM
4-[3-[1-benzhydryl-5-chloro-2-[2-[[2-(hydroxymethyl)phenyl]methylsulfonylamino]ethyl]indol-3-yl]propyl]benzoic acid	345901: Inhibition of human cytosolic PLA2alpha by GLU micelle assay	ic50	0.0220	uM
3-(5-carboxypentanoyl)-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid	1433580: Inhibition of human platelet cytosolic phospholipase alpha-2 using 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphocholine/1,2-dioleoyl-sn-glycerol as substrate after 60 mins by UV-HPLC method	ic50	0.0220	uM
3-(4-hydroxybutanoyl)-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid	1433580: Inhibition of human platelet cytosolic phospholipase alpha-2 using 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphocholine/1,2-dioleoyl-sn-glycerol as substrate after 60 mins by UV-HPLC method	ic50	0.0230	uM
4-[3-[1-benzhydryl-5-chloro-2-[2-[(2-methylphenyl)methylsulfonylamino]ethyl]indol-3-yl]propyl]benzoic acid	345901: Inhibition of human cytosolic PLA2alpha by GLU micelle assay	ic50	0.0260	uM
1-[3-(4-octylphenoxy)-2-oxopropyl]benzotriazole-5-carboxylic acid	353690: Inhibition of cPLA2 in human platelets assessed as arachidonic acid release	ic50	0.0260	uM
1-[3-(4-octylphenoxy)-2-oxopropyl]indazole-6-carboxylic acid	353690: Inhibition of cPLA2 in human platelets assessed as arachidonic acid release	ic50	0.0260	uM
2-amino-2-(hydroxymethyl)propane-1,3-diol;3-[1-(4-methoxyphenyl)-3-(2-phenylethyl)indol-5-yl]propanoic acid	1187018: Inhibition of cPLA2alpha isolated from human U937 cell cytoplasm assessed as suppression of [14C]arachidonic acid release from L-alpha-1-palmitoyl-2-[14C]arachidonyl-phosphatidylcholine liposomes substrate by scintillation counting	ic50	0.0260	uM
2-amino-2-(hydroxymethyl)propane-1,3-diol;3-[1-[4-(difluoromethoxy)phenyl]-3-(2-phenylethyl)indol-5-yl]propanoic acid	1187018: Inhibition of cPLA2alpha isolated from human U937 cell cytoplasm assessed as suppression of [14C]arachidonic acid release from L-alpha-1-palmitoyl-2-[14C]arachidonyl-phosphatidylcholine liposomes substrate by scintillation counting	ic50	0.0280	uM
4-[3-[1-benzhydryl-5-chloro-2-[2-[[2-(diethylaminomethyl)phenyl]methylsulfonylamino]ethyl]indol-3-yl]propyl]benzoic acid	345901: Inhibition of human cytosolic PLA2alpha by GLU micelle assay	ic50	0.0300	uM
3-(6-hydroxyhexanoyl)-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid	1433580: Inhibition of human platelet cytosolic phospholipase alpha-2 using 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphocholine/1,2-dioleoyl-sn-glycerol as substrate after 60 mins by UV-HPLC method	ic50	0.0310	uM
4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-N-[[(2S,4R)-1-[2-(4-fluorobenzoyl)benzoyl]-4-[(2-phenylphenyl)methylsulfanyl]pyrrolidin-2-yl]methyl]benzamide	220179: Inhibition of Human cPLA2 alpha using Enzyme assay(PC/DOG assay)	ic50	0.0340	uM
2-amino-2-(hydroxymethyl)propane-1,3-diol;3-[1-(4-chlorophenyl)-3-(2-phenylethyl)indol-5-yl]propanoic acid	1187018: Inhibition of cPLA2alpha isolated from human U937 cell cytoplasm assessed as suppression of [14C]arachidonic acid release from L-alpha-1-palmitoyl-2-[14C]arachidonyl-phosphatidylcholine liposomes substrate by scintillation counting	ic50	0.0360	uM
N-[[(2S,4R)-4-[2-bromo-6-(2-methylpropyl)phenoxy]-1-[2-(4-fluorobenzoyl)benzoyl]pyrrolidin-2-yl]methyl]-4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzamide	220179: Inhibition of Human cPLA2 alpha using Enzyme assay(PC/DOG assay)	ic50	0.0380	uM
4-[2-oxo-3-[4-(5-phenylpentylsulfanyl)phenoxy]propoxy]benzoic acid	259339: Inhibition of cytosolic phospholipase A2-alpha in GLU micelle assay	ic50	0.0400	uM
azane;[(E,2S,3R)-2-(hexadecanoylamino)-3-hydroxyoctadec-4-enyl] dihydrogen phosphate	2084470: Binding affinity to cPLA2-alpha using POPC as substrate assessed as equlibrium dissociation constant by SPR analysis (Rvb = 47 +/- 30 10^-8M)	kd	0.0460	uM
N-[[(2S,4R)-1-[2-(2,4-difluorobenzoyl)benzoyl]-4-[(2-phenylphenyl)methoxy]pyrrolidin-2-yl]methyl]-4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzamide	220179: Inhibition of Human cPLA2 alpha using Enzyme assay(PC/DOG assay)	ic50	0.0490	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	8
Particulate Matter	increases abundance, increases expression, decreases expression	6
sodium arsenite	affects expression, decreases expression, increases expression	5
trichostatin A	affects cotreatment, increases expression	3
Air Pollutants	decreases expression, increases abundance, increases expression	3
Lipopolysaccharides	decreases reaction, increases expression, increases reaction	3
Silicon Dioxide	increases expression, decreases expression	3
Tetrachlorodibenzodioxin	affects cotreatment, increases activity, increases expression, increases reaction, increases secretion (+3 more)	3
arsenite	increases reaction, decreases expression, affects binding	2
cobaltous chloride	affects cotreatment, increases expression, decreases expression	2
mercuric bromide	increases expression, affects cotreatment	2
arachidonyltrifluoromethane	decreases reaction, increases expression	2
2-aminoethoxydiphenyl borate	affects cotreatment, decreases reaction, increases expression	2
entinostat	affects cotreatment, increases expression	2
belinostat	increases expression, affects cotreatment	2
Vorinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Beclomethasone	decreases reaction, increases expression, decreases activity	2
Benzo(a)pyrene	decreases expression, increases expression	2
Dexamethasone	decreases reaction, increases expression	2
Estradiol	increases expression, affects cotreatment, decreases expression	2
Nifedipine	increases expression, affects cotreatment, decreases reaction	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Tobacco Smoke Pollution	increases expression	2
Tretinoin	increases expression	2
Zymosan	affects localization, increases reaction, increases metabolic processing	2
Dinoprostone	decreases reaction, increases expression, increases secretion, increases reaction, affects reaction	2
Arachidonic Acid	increases reaction, increases secretion, increases expression, decreases reaction, affects reaction	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2

ChEMBL screening assays

95 unique, capped per target: 91 binding, 4 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1011800	Binding	Inhibition of human group 4A cPLA2 at 0.091 mol fraction by mixed micelle-based assay	Synthesis of polyfluoro ketones for selective inhibition of human phospholipase A2 enzymes. — J Med Chem
CHEMBL6193895	Functional	Inhibition of human PLA2G4A in recombinant human protein using Biochemical human PLA2G4A assay	Data for DCP probe BAY-439

Cellosaurus cell lines

10 cell lines: 9 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2B2	Abcam HeLa PLA2G4A KO	Cancer cell line	Female
CVCL_B7YT	Abcam Raji PLA2G4A KO	Cancer cell line	Male
CVCL_B9ZI	Abcam THP-1 PLA2G4A KO	Cancer cell line	Male
CVCL_C7B7	Abcam PC-3 PLA2G4A KO	Cancer cell line	Male
CVCL_D7XR	Ubigene A-549 PLA2G4A KO	Cancer cell line	Male
CVCL_D9NR	Ubigene HEK293 PLA2G4A KO	Transformed cell line	Female
CVCL_E0L3	Ubigene HeLa PLA2G4A KO	Cancer cell line	Female
CVCL_TE09	HAP1 PLA2G4A (-) 1	Cancer cell line	Male
CVCL_TE10	HAP1 PLA2G4A (-) 2	Cancer cell line	Male
CVCL_TE11	HAP1 PLA2G4A (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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