LTC4S

Summary

LTC4S (leukotriene C4 synthase, HGNC:6719) is a protein-coding gene on chromosome 5q35.3, encoding Leukotriene C4 synthase (Q16873). Catalyzes the conjugation of leukotriene A4 with reduced glutathione (GSH) to form leukotriene C4 with high specificity.

The MAPEG (Membrane Associated Proteins in Eicosanoid and Glutathione metabolism) family includes a number of human proteins, several of which are involved the production of leukotrienes. This gene encodes an enzyme that catalyzes the first step in the biosynthesis of cysteinyl leukotrienes, potent biological compounds derived from arachidonic acid. Leukotrienes have been implicated as mediators of anaphylaxis and inflammatory conditions such as human bronchial asthma. This protein localizes to the nuclear envelope and adjacent endoplasmic reticulum.

Source: NCBI Gene 4056 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 31 total
• Phenotypes (HPO): 7
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_145867

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6719
Approved symbol	LTC4S
Name	leukotriene C4 synthase
Location	5q35.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC33147
Ensembl gene	ENSG00000213316
Ensembl biotype	protein_coding
OMIM	246530
Entrez	4056

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 5 protein_coding, 4 retained_intron, 1 nonsense_mediated_decay

ENST00000292596, ENST00000401985, ENST00000465572, ENST00000466071, ENST00000486713, ENST00000505170, ENST00000509898, ENST00000510544, ENST00000910216, ENST00000967865

RefSeq mRNA: 1 — MANE Select: NM_145867 NM_145867

CCDS: CCDS34316

Canonical transcript exons

ENST00000292596 — 5 exons

Exon	Start	End
ENSE00001194180	179793986	179794138
ENSE00002050377	179796253	179796647
ENSE00003524989	179795941	179796022
ENSE00003540036	179795786	179795856
ENSE00003631757	179795584	179795683

Expression profiles

Bgee: expression breadth ubiquitous, 133 present calls, max score 92.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.3735 / max 2639.3814, expressed in 950 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
60592	3.7678	502
60591	3.2397	482
60593	0.6713	114
60594	0.5461	284
60595	0.1391	17
60596	0.0094	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	92.64	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.51	silver quality
apex of heart	UBERON:0002098	87.62	gold quality
right coronary artery	UBERON:0001625	87.17	gold quality
left uterine tube	UBERON:0001303	85.74	gold quality
right atrium auricular region	UBERON:0006631	85.04	gold quality
left coronary artery	UBERON:0001626	84.33	gold quality
right adrenal gland cortex	UBERON:0035827	84.24	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	83.84	gold quality
right adrenal gland	UBERON:0001233	83.54	gold quality
right hemisphere of cerebellum	UBERON:0014890	83.38	gold quality
fallopian tube	UBERON:0003889	83.12	gold quality
left adrenal gland cortex	UBERON:0035825	82.87	gold quality
left adrenal gland	UBERON:0001234	82.57	gold quality
right ovary	UBERON:0002118	82.14	gold quality
cerebellar hemisphere	UBERON:0002245	82.07	gold quality
right lung	UBERON:0002167	82.02	gold quality
cerebellar cortex	UBERON:0002129	81.98	gold quality
cerebellum	UBERON:0002037	81.94	gold quality
descending thoracic aorta	UBERON:0002345	81.73	gold quality
tibial nerve	UBERON:0001323	81.09	gold quality
omental fat pad	UBERON:0010414	80.95	gold quality
hindlimb stylopod muscle	UBERON:0004252	80.94	gold quality
ascending aorta	UBERON:0001496	80.93	gold quality
thoracic aorta	UBERON:0001515	80.89	gold quality
spleen	UBERON:0002106	80.76	gold quality
blood	UBERON:0000178	80.71	gold quality
mucosa of transverse colon	UBERON:0004991	80.68	gold quality
heart	UBERON:0000948	80.31	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	80.01	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	1113.50
E-MTAB-9067	yes	14.78
E-ANND-3	yes	9.05
E-MTAB-9801	no	2.64

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI2, KLF6, NFKB1, RELA, SP1, SP3

Literature-anchored findings (GeneRIF, showing 39)

• Distinct roles of receptor phosphorylation, G protein usage, and mitogen-activated protein kinase activation on platelet activating factor-induced leukotriene C(4) generation (PMID:11934880)
• no relationship between the polymorphism and LTC4S activity in eosinophils, although LTC4S activities were significantly higher in patients with aspirin induced asthma than in patients with aspirin tolerant asthma (PMID:12063521)
• A(-444)C polymorphism of this gene and clinical response to pranlukast in Japanses patients with moderate asthma (PMID:12360108)
• C-to-A promoter polymorphism was associated with the increased presence of chronic hyperplastic eosinophilic sinusitis and the expression of cysteinyl leukotrienes (PMID:12589355)
• expression of LTC(4)S during normal and leukemic myelopoiesis and correlation with the activity of the disease-specific tyrosine kinase p210 BCR-ABL in CML myeloid cells. (PMID:12591277)
• Gene expression in mononuclear phagocytes is regulated by SP1 and SP3. (PMID:12664565)
• Data show that mucosal mast cells, and not eosinophils, were the dominating leukotriene C4 synthase-containing cells in both untreated and treated aspirin-tolerant asthma. (PMID:12816731)
• We further conclude that the A(-444)C polymorphism in the LTC(4) synthase gene probably contributes to asthma interpatient variability in montelukast-evoked changes in FE(NO)* and warrants further study. (PMID:14520724)
• independent of transcriptional activity, the C(-444) allele in the LTC(4) synthase gene is weakly associated with the asthma phenotype, but it is not related to disease severity or aspirin intolerance (PMID:15131571)
• calculated a projection map of recombinant human LTC(4) synthase at a resolution of 4.5 A by electron crystallography (PMID:15530365)
• leukotriene C4 synthase gene promoter polymorphism is associated with asthma and/or atopy (PMID:16024972)
• Glu 4 Lys amino acid substitution in the LTC4S might be associated with allergic diseases. (PMID:16211251)
• The C allele of the leukotriene C4 synthase (A-444C) polymorphism is associated with asthma phenotype or severity. (PMID:16675353)
• LTC4S plays a key role in the process of inflammation as the rate limiting enzyme in the conversion of arachidonic acid to cysteinyl-leukotrienes, important mediators of inflammatory responses. (PMID:17110605)
• The combination of 927T CYSLTR1 and -444A LTC4S was less common in male patients with asthma than in controls and the combination of 927C CYSLTR1 and -444A LTC4S was slightly more frequent in patients with asthma (PMID:17153879)
• The results of a case-control study aimed at investigating the association of MGST1 gene locus polymorphisms with colorectal cancer risk among Han Chinese are presented. (PMID:17483957)
• crystal structure of the human LTC4 synthase in its apo and GSH-complexed forms to 2.00 and 2.15 A resolution, respectively (PMID:17632546)
• atomic structure of human LTC4S in a complex with glutathione at 3.3 A resolution by X-ray crystallography (PMID:17632548)
• Leukotriene C(4) synthase -1072 AA genotype predict increased risk, whereas -444 CC genotype predict decreased risk of ischemic cerebrovascular disease. (PMID:18276912)
• Genetic variation in leukotriene pathway members and their receptors confer an increased risk of ischemic stroke in 2 independent populations (PMID:18323512)
• In a Southwest Chinese Han population LTC(4)S A(-444)C polymorphism might be a determinant factor in the clinical response of asthma to leukotriene receptor antagonists. (PMID:19080532)
• The combined study of polymorphisms in genes of the leukotriene pathway could explain the differences observed in the studies reported on polymorphism -444A < C LTC4S individually analysed. (PMID:19080797)
• LTC(4)S interacts in vitro with both FLAP and 5-LO and that these interactions involve distinct parts of LTC(4)S. (PMID:19233132)
• Leukotriene C4 synthase promoter genotypes influence risk of transient ischemic attack and ischemic stroke, but not risk of ischemic heart disease/coronary atherosclerosis, asthma, or chronic obstructive pulmonary disease. (PMID:19280718)
• no association between gene polymorphism and bronchial asthma in a Spanish population (PMID:20128419)
• Arginine 104 is a key catalytic residue in leukotriene C4 synthase. (PMID:20980252)
• The increased expression of LTC(4)S, together with the predominant formation of cysteinyl-leukotrienes and effects on MMPs production, suggests a mechanism by which LTs may promote matrix degradation in the AAA wall (PMID:21078989)
• Polymorphisms of the PTGDR and LTC4S influence responsiveness to leukotriene receptor antagonists in Korean children with asthma. (PMID:21307858)
• The catalytic architecture of leukotriene C4 synthase with two arginine residues. (PMID:21454538)
• The SNPs of ALOX(5)AP and LTC(4)S are associated with asthma. (PMID:21729626)
• investigation of catalytic mechanism of LTC4S: Data suggest that glutathione thiolate anion formation in LTC4S is not rate-limiting for overall reaction of leukotriene C4 production. Thiolate anion is stabilized by Arg104 at all three active sites. (PMID:22217203)
• A significant association has been found between the -1072G/A (rs3776944) SNP in the LTC4S gene and atopic asthma in the family-based analysis. (PMID:22722751)
• meta-analysis suggested that the -444A/C polymorphism in the LTC4S gene would be a risk factor for asthma in Caucasians and aspirin-tolerant populations (PMID:22884858)
• genetic association studies in population of Han Chinese in Eastern China: Data suggest that an SNP in LTC4S (rs730012) is associated with risk of ischemic stroke; carriers of C allele of rs730012 in LTC4S are most susceptible to ischemic stroke. (PMID:23079278)
• The results of our study failed to confirm whether the selected variants in LTC4S gene within the LT metabolism pathway contribute to platelet reactivity in a diabetic population treated with ASA. (PMID:23828562)
• Elevated levels of leukotriene C4 synthase mRNA distinguish a subpopulation of eosinophilic oesophagitis patients. (PMID:23889244)
• Biochemical and structural characterization of LTC4S mutants along with crystal structures of the wild type and mutated enzymes in complex with three product analogs, provide new insights to binding of substrates and product. (PMID:24366866)
• mutational and kinetic data, together with molecular simulations, suggest that phosphorylation of Ser(36) inhibits the catalytic function of LTC4S by interference with the catalytic machinery. (PMID:27365393)
• Effect of TGF-beta1 on eosinophils to induce cysteinyl leukotriene E4 production in aspirin-exacerbated respiratory disease. (PMID:34437574)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
danio_rerio	ltc4s	ENSDARG00000062598
mus_musculus	Ltc4s	ENSMUSG00000020377

Paralogs (3): MGST2 (ENSG00000085871), ALOX5AP (ENSG00000132965), MGST3 (ENSG00000143198)

Protein

Protein identifiers

Leukotriene C4 synthase — Q16873 (reviewed: Q16873)

Alternative names: Glutathione S-transferase LTC4, Leukotriene-C(4) synthase, Leukotriene-C4 synthase

All UniProt accessions (4): A0A286YF10, B5MCC3, D6RJA1, Q16873

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the conjugation of leukotriene A4 with reduced glutathione (GSH) to form leukotriene C4 with high specificity. Can also catalyze the transfer of a glutathionyl group from glutathione (GSH) to 13(S),14(S)-epoxy-docosahexaenoic acid to form maresin conjugate in tissue regeneration 1 (MCTR1), a bioactive lipid mediator that possess potent anti-inflammatory and proresolving actions.

Subunit / interactions. Homotrimer. Interacts with ALOX5AP and ALOX5.

Subcellular location. Nucleus outer membrane. Endoplasmic reticulum membrane. Nucleus membrane.

Tissue specificity. Detected in lung, platelets and the myelogenous leukemia cell line KG-1 (at protein level). LTC4S activity is present in eosinophils, basophils, mast cells, certain phagocytic mononuclear cells, endothelial cells, vascular smooth muscle cells and platelets.

Post-translational modifications. Phosphorylation at Ser-36 by RPS6KB1 inhibits the leukotriene-C4 synthase activity.

Disease relevance. LTC4 synthase deficiency is associated with a neurometabolic developmental disorder characterized by muscular hypotonia, psychomotor retardation, failure to thrive, and microcephaly.

Activity regulation. Inhibited by MK886.

Pathway. Lipid metabolism; leukotriene C4 biosynthesis.

Similarity. Belongs to the MAPEG family.

RefSeq proteins (1): NP_665874* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001129	Membr-assoc_MAPEG	Family
IPR001446	5_LipOase_AP	Family
IPR018295	FLAP/GST2/LTC4S_CS	Conserved_site
IPR023352	MAPEG-like_dom_sf	Homologous_superfamily
IPR050997	MAPEG	Family

Pfam: PF01124

Enzyme classification (BRENDA):

• EC 4.4.1.20 — leukotriene-C4 synthase (BRENDA: 10 organisms, 28 substrates, 80 inhibitors, 56 Km, 36 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GLUTATHIONE	0.0004–24.6	20
LEUKOTRIENE A4	0.0036–2.38	19
LEUKOTRIENE A4 METHYL ESTER	0.0034–0.02	13
14,15-LEUKOTRIENE A4	0.13	1
14,15-LEUKOTRIENE A4 METHYL ESTER	0.07	1
LEUKOTRIENE A4 FREE ACID	0.0188	1

Catalyzed reactions (Rhea), 2 shown:

• leukotriene C4 = leukotriene A4 + glutathione (RHEA:17617)
• (13S,14S)-epoxy-(4Z,7Z,9E,11E,16Z,19Z)-docosahexaenoate + glutathione = (13R)-S-glutathionyl-(14S)-hydroxy-(4Z,7Z,9E,11E,16Z,19Z)-docosahexaenoate (RHEA:53508)

UniProt features (31 total): mutagenesis site 7, topological domain 5, helix 5, binding site 4, transmembrane region 4, active site 2, chain 1, modified residue 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
3PCV	X-RAY DIFFRACTION	1.9
2UUI	X-RAY DIFFRACTION	2
4BPM	X-RAY DIFFRACTION	2.08
3LEO	X-RAY DIFFRACTION	2.1
2UUH	X-RAY DIFFRACTION	2.15
9G14	X-RAY DIFFRACTION	2.24
6R7D	X-RAY DIFFRACTION	2.35
4JRZ	X-RAY DIFFRACTION	2.4
9G0U	X-RAY DIFFRACTION	2.5
4JC7	X-RAY DIFFRACTION	2.7
4WAB	X-RAY DIFFRACTION	2.7
4JCZ	X-RAY DIFFRACTION	2.75
9G0V	X-RAY DIFFRACTION	2.78
3HKK	X-RAY DIFFRACTION	2.9
4J7Y	X-RAY DIFFRACTION	2.9
5HV9	X-RAY DIFFRACTION	3
9G1T	X-RAY DIFFRACTION	3
3B29	X-RAY DIFFRACTION	3.2
4J7T	X-RAY DIFFRACTION	3.2
2PNO	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16873-F1	97.08	0.95

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): 31 (proton donor); 104 (proton acceptor)

Ligand- & substrate-binding residues (4): 30; 51–55; 58–59; 93–97

Post-translational modifications (1): 36

Mutagenesis-validated functional residues (7):

Position	Phenotype
36	reduced leukotriene-c4 synthase activity by nearly 80%.
40	leukotriene-c4 synthaseactivity is reduced by 30%.
51	loss of leukotriene-c4 synthase activity.
55	does not affect leukotriene-c4 synthase activity but substantially increased km for gsh.
59	does not affect leukotriene-c4 synthase activity but substantially increased km for gsh.
93	reduces leukotriene-c4 synthase activity and increases the optimum for ph-dependent activity.
97	does not affect leukotriene-c4 synthase activity but substantially increased km for gsh.

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-2142688	Synthesis of 5-eicosatetraenoic acids
R-HSA-2142691	Synthesis of Leukotrienes (LT) and Eoxins (EX)
R-HSA-2142700	Biosynthesis of Lipoxins (LX)
R-HSA-9026762	Biosynthesis of maresin conjugates in tissue regeneration (MCTR)
R-HSA-9026766	Biosynthesis of protectin and resolvin conjugates in tissue regeneration (PCTR and RCTR)
R-HSA-1430728	Metabolism
R-HSA-2142753	Arachidonate metabolism
R-HSA-556833	Metabolism of lipids
R-HSA-8978868	Fatty acid metabolism
R-HSA-9018677	Biosynthesis of DHA-derived SPMs
R-HSA-9018678	Biosynthesis of specialized proresolving mediators (SPMs)
R-HSA-9026395	Biosynthesis of DHA-derived sulfido conjugates

MSigDB gene sets: 204 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, GOBP_LONG_CHAIN_FATTY_ACID_METABOLIC_PROCESS, GOBP_LEUKOTRIENE_BIOSYNTHETIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOMF_GLUTATHIONE_TRANSFERASE_ACTIVITY, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_ERYTHROCYTE_DN, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, MARTINEZ_RB1_TARGETS_UP, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN, GOBP_CELLULAR_RESPONSE_TO_TOXIC_SUBSTANCE, GOBP_DETOXIFICATION, GOBP_FATTY_ACID_BIOSYNTHETIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS

GO Biological Process (6): leukotriene metabolic process (GO:0006691), leukotriene biosynthetic process (GO:0019370), long-chain fatty acid biosynthetic process (GO:0042759), lipid metabolic process (GO:0006629), carboxylic acid biosynthetic process (GO:0046394), cellular oxidant detoxification (GO:0098869)

GO Molecular Function (9): glutathione transferase activity (GO:0004364), leukotriene-C4 synthase activity (GO:0004464), glutathione peroxidase activity (GO:0004602), enzyme activator activity (GO:0008047), lipid binding (GO:0008289), identical protein binding (GO:0042802), protein binding (GO:0005515), transferase activity (GO:0016740), lyase activity (GO:0016829)

GO Cellular Component (8): nuclear envelope (GO:0005635), nuclear outer membrane (GO:0005640), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), nuclear membrane (GO:0031965), intracellular membrane-bounded organelle (GO:0043231), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Arachidonate metabolism	2
Biosynthesis of specialized proresolving mediators (SPMs)	2
Biosynthesis of DHA-derived sulfido conjugates	2
Metabolism of lipids	2
Fatty acid metabolism	1
Metabolism	1
Biosynthesis of DHA-derived SPMs	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
catalytic activity	3
binding	2
nucleus	2
endomembrane system	2
nuclear outer membrane-endoplasmic reticulum membrane network	2
intracellular membrane-bounded organelle	2
organelle membrane	2
icosanoid metabolic process	1
leukotriene metabolic process	1
icosanoid biosynthetic process	1
long-chain fatty acid metabolic process	1
fatty acid biosynthetic process	1
primary metabolic process	1
carboxylic acid metabolic process	1
small molecule biosynthetic process	1
cellular detoxification	1
transferase activity, transferring alkyl or aryl (other than methyl) groups	1
carbon-sulfur lyase activity	1
peroxidase activity	1
enzyme regulator activity	1
molecular function activator activity	1
protein binding	1
organelle envelope	1
nuclear membrane	1
organelle outer membrane	1
cytoplasm	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1
nuclear envelope	1
intracellular anatomical structure	1
membrane-bounded organelle	1
intracellular organelle	1

Protein interactions and networks

STRING

700 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LTC4S	CYSLTR1	Q9Y271	946
LTC4S	LTA4H	P09960	931
LTC4S	CYSLTR2	Q9NS75	930
LTC4S	MGST1	P10620	916
LTC4S	MGST3	O14880	896
LTC4S	PTGES	O14684	870
LTC4S	LTB4R2	Q9NPC1	870
LTC4S	ALOX5	P09917	812
LTC4S	PTGS1	P23219	703
LTC4S	ABCC1	P33527	674
LTC4S	LTB4R	Q15722	634
LTC4S	PTGER4	P35408	625
LTC4S	PLA2G4A	P47712	607
LTC4S	OXGR1	Q96P68	588
LTC4S	PTGER2	P43116	576

IntAct

34 interactions, top by confidence:

A	B	Type	Score
LTC4S	LTC4S	psi-mi:“MI:0407”(direct interaction)	0.750
LTC4S	EBP	psi-mi:“MI:0915”(physical association)	0.560
LTC4S	GPR42	psi-mi:“MI:0915”(physical association)	0.560
LTC4S	SLC7A14	psi-mi:“MI:0915”(physical association)	0.560
LTC4S	FXYD3	psi-mi:“MI:0915”(physical association)	0.560
LTC4S	CREB3L1	psi-mi:“MI:0915”(physical association)	0.560
CD79A	LTC4S	psi-mi:“MI:0915”(physical association)	0.560
LTC4S	GPR152	psi-mi:“MI:0915”(physical association)	0.560
EBP	LTC4S	psi-mi:“MI:0915”(physical association)	0.560
FXYD3	LTC4S	psi-mi:“MI:0915”(physical association)	0.560
FFAR3	LTC4S	psi-mi:“MI:0915”(physical association)	0.560
LTC4S	TMEM52B	psi-mi:“MI:0915”(physical association)	0.560
GPR42	LTC4S	psi-mi:“MI:0915”(physical association)	0.560
LTC4S	CREB3L1	psi-mi:“MI:0915”(physical association)	0.000
LTC4S	GPR152	psi-mi:“MI:0915”(physical association)	0.000
LTC4S	TMEM52B	psi-mi:“MI:0915”(physical association)	0.000
LTC4S	CD79A	psi-mi:“MI:0915”(physical association)	0.000
LTC4S	FFAR3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (24): LTC4S (Two-hybrid), PRKDC (Negative Genetic), LTC4S (Negative Genetic), LTC4S (Negative Genetic), PRKCD (Negative Genetic), LTC4S (Negative Genetic), LTC4S (Negative Genetic), TAOK2 (Positive Genetic), LTC4S (Two-hybrid), LTC4S (Two-hybrid), LTC4S (Two-hybrid), LTC4S (Two-hybrid), LTC4S (Two-hybrid), LTC4S (Two-hybrid), LTC4S (Two-hybrid)

ESM2 similar proteins: A0A2I1C3V3, A0SYQ0, A1L2F6, A2RST1, A4DA06, A6XA80, A8X8R3, J7FIJ6, O14684, O14880, O74507, O94511, P08011, P0DN89, P10620, P64515, P64516, P70245, P73795, P79382, Q15125, Q16873, Q17428, Q28GF8, Q296J9, Q2KJG4, Q2NKS0, Q3T100, Q41745, Q54GA9, Q57ZC7, Q5R9A6, Q60490, Q60860, Q64L89, Q6GNM0, Q6GPW4, Q6PWL6, Q8HZJ2, Q91VS7

Diamond homologs: A2RST1, A6XA80, O14880, P20291, P20292, P30353, P30354, P30355, P30356, P30357, P30358, P73795, Q148F2, Q16873, Q2KJG4, Q2NKS0, Q2PG08, Q3T100, Q60860, Q925U2, Q99735, Q9CPU4, Q54GA9

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
NfKb-p65/p50	“down-regulates quantity by repression”	LTC4S	“transcriptional regulation”
LTC4S	“up-regulates quantity”	“leukotriene C4(2-)”	“chemical modification”
LTC4S	“down-regulates quantity”	“leukotriene A4(1-)”	“chemical modification”
LTC4S	“down-regulates quantity”	glutathionate(1-)	“chemical modification”
RPS6KB1	“down-regulates activity”	LTC4S	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	21
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

627 predictions. Top by Δscore:

Variant	Effect	Δscore
5:179794123:G:GT	donor_gain	1.0000
5:179795679:GCCCA:G	donor_gain	1.0000
5:179795684:G:GG	donor_gain	1.0000
5:179794123:G:T	donor_gain	0.9900
5:179794135:CAAG:C	donor_loss	0.9900
5:179794136:AAGG:A	donor_loss	0.9900
5:179794137:AGGT:A	donor_loss	0.9900
5:179794138:GGTG:G	donor_loss	0.9900
5:179794139:G:C	donor_loss	0.9900
5:179794140:T:C	donor_loss	0.9900
5:179796021:AGGT:A	donor_loss	0.9900
5:179796022:GGTG:G	donor_loss	0.9900
5:179796023:GTG:G	donor_loss	0.9900
5:179796024:T:G	donor_loss	0.9900
5:179794087:G:GT	donor_gain	0.9800
5:179795853:G:GT	donor_gain	0.9800
5:179795854:A:T	donor_gain	0.9800
5:179795935:TCGCA:T	acceptor_loss	0.9700
5:179795936:CGCA:C	acceptor_loss	0.9700
5:179795937:GCA:G	acceptor_loss	0.9700
5:179795938:CA:C	acceptor_loss	0.9700
5:179795939:A:C	acceptor_loss	0.9700
5:179795939:AG:A	acceptor_gain	0.9700
5:179795939:AGG:A	acceptor_gain	0.9700
5:179795940:G:A	acceptor_loss	0.9700
5:179795940:GG:G	acceptor_gain	0.9700
5:179795940:GGG:G	acceptor_gain	0.9700
5:179795940:GGGGC:G	acceptor_gain	0.9700
5:179795582:A:AG	acceptor_gain	0.9600
5:179795583:G:GG	acceptor_gain	0.9600

AlphaMissense

919 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:179795661:T:C	F46L	0.990
5:179795663:C:A	F46L	0.990
5:179795663:C:G	F46L	0.990
5:179795792:C:A	N55K	0.988
5:179795792:C:G	N55K	0.988
5:179794123:G:A	G15R	0.987
5:179794123:G:C	G15R	0.987
5:179796022:G:T	R104M	0.985
5:179795662:T:G	F46C	0.983
5:179796272:A:C	S111R	0.983
5:179796274:C:A	S111R	0.983
5:179796274:C:G	S111R	0.983
5:179795829:T:A	W68R	0.982
5:179795829:T:C	W68R	0.982
5:179795959:G:A	G83D	0.981
5:179795613:C:A	R30S	0.979
5:179795662:T:C	F46S	0.978
5:179795680:C:A	A52D	0.978
5:179795795:C:G	C56W	0.978
5:179795991:T:C	F94L	0.978
5:179795993:C:A	F94L	0.978
5:179795993:C:G	F94L	0.978
5:179795958:G:C	G83R	0.976
5:179795793:T:C	C56R	0.975
5:179795677:G:C	R51P	0.974
5:179796022:G:C	R104T	0.972
5:179795610:G:C	A29P	0.968
5:179795838:G:C	G71R	0.967
5:179795839:G:A	G71D	0.966
5:179794124:G:A	G15E	0.965

dbSNP variants (sampled 300 via entrez): RS1000228921 (5:179794001 C>G,T), RS1000945538 (5:179795971 T>C), RS1001503392 (5:179792798 C>T), RS1001760304 (5:179792079 G>T), RS1001845743 (5:179793536 TG>T,TGG,TGGG), RS1002108623 (5:179796753 C>G), RS1002418565 (5:179796597 C>A,T), RS1005687898 (5:179793052 C>T), RS1005857527 (5:179792734 G>A,C), RS1006241769 (5:179797098 A>G,T), RS1006579016 (5:179796165 G>A), RS1006630825 (5:179796408 G>A,C), RS1007660981 (5:179794131 G>A), RS1007857105 (5:179795179 C>A), RS1008200074 (5:179794951 G>A,C)

Disease associations

OMIM: gene MIM:246530 | disease phenotypes: MIM:614037, MIM:208550, MIM:105550, MIM:602080

GenCC curated gene-disease

Mondo (4): hypotonia-failure to thrive-microcephaly syndrome (MONDO:0013539), asthma, nasal polyps, and aspirin intolerance (MONDO:0008834), frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (MONDO:0007105), Paget disease of bone 2, early-onset (MONDO:0011183)

Orphanet (2): Hypotonia-failure to thrive-microcephaly syndrome (Orphanet:79507), Frontotemporal dementia with motor neuron disease (Orphanet:275872)

HPO phenotypes

7 total (7 of 7 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001522	Death in infancy
HP:0001531	Failure to thrive in infancy
HP:0030390	Reduced circulating leukotriene C4 concentration

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C565439	Leukotriene C4 Synthase Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1743183 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 342 (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
CHEMBL1922660	FIBOFLAPON	3	303
CHEMBL3961833	AZD-9898	1	39

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs730012	Efficacy	3	montelukast	Asthma
rs730012	Toxicity	3	aspirin	Urticaria

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs730012	LTC4S, MGAT4B	3	4.50	2	aspirin;montelukast

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Leukotriene and lipoxin metabolism

Most potent curated ligand interactions (5 total), top 5:

Ligand	Action	Affinity	Parameter
AZD9898	Inhibition	9.54	pIC50
TK05	Inhibition	8.22	pKi
example 36 [WO2016177845]	Inhibition	8.05	pIC50
GJG057	Inhibition	7.36	pIC50
compound 39 [PMID: 23623673]	Inhibition	5.52	pIC50

Binding affinities (BindingDB)

70 measured of 70 human assays (70 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(1S,2S)-2-[(5-{(2-Fluoro-2-methylpropyl)[2-fluoro-5-(trifluoromethyl)phenyl]amino}-3-methoxypyrazin-2-yl)carbonyl]cyclopropanecarboxylic acid	IC50	0.248 nM	US-9657001: Compounds and uses
(1S,2S)-2-({5-[(5-Chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid	IC50	0.289 nM	US-9657001: Compounds and uses
(1S,2S)-2-({5-[(5-Chloro-2,4-difluorophenyl)(propyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid	IC50	0.483 nM	US-20160326143: COMPOUNDS AND USES
(1S)-2-[5-(5-chloro-2,4-difluoro-N-propylanilino)-3-methoxypyrazine-2-carbonyl]cyclopropane-1-carboxylic acid	IC50	0.483 nM	US-9657001: Compounds and uses
(1S,2S)-2-[(5-{2-Fluoro-5-(trifluoromethyl)phenylamino}-3-methoxypyridin-2-yl)carbonyl]cyclopropanecarboxylic acid	IC50	0.658 nM	US-9657001: Compounds and uses
2-(5-((Cyclopropylmethyl)(1,2-dihydroacenaphthylen-5-yl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid	IC50	9 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((Cyclopropylmethyl)(naphthalen-1-yl)amino)-4-methoxypyrimidine-2-carbonyl)cyclopropanecarboxylic acid	IC50	17 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((4-Chloronaphthalen-1-yl)(cyclopropylmethyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid	IC50	18 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((Cyclopropylmethyl)(4-fluoronaphthalen-1-yl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid	IC50	18 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((Cyclopropylmethyl)(4-methylnaphthalen-1-yl)amino)-4-methoxypyrimidine-2-carbonyl)cyclopropanecarboxylic acid	IC50	18 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((Cyclopropylmethyl)(4-(trifluoromethyl)naphthalen-1-yl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid	IC50	19 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((Cyclopropylmethyl)(4-fluoronaphthalen-1-yl)amino)-4-methoxypyrimidine-2-carbonyl)cyclopropanecarboxylic acid	IC50	19 nM	US-20160326143: COMPOUNDS AND USES
ethyl 2-[5-[cyclopropylmethyl-[4-(trifluoromethyl)naphthalen-1-yl]amino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylate	IC50	19 nM	US-9657001: Compounds and uses
2-(5-((Cyclopropylmethyl)(4-methylbenzyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid	IC50	22 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((Cyclopropylmethyl)(naphthalen-1-yl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid	IC50	24 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((Cyclopropylmethyl)(5-(trifluoromethyl)naphthalen-1-yl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid	IC50	25 nM	US-20160326143: COMPOUNDS AND USES
2-(4-((Cyclopropylmethyl)(4-fluoronaphthalen-1-yl)amino)-2-methoxybenzoyl)cyclopropanecarboxylic acid	IC50	26 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((Cyclopropylmethyl)(naphthalen-2-yl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid	IC50	28 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((Cyclopropylmethyl)(1,2-dihydroacenaphthylen-3-yl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid	IC50	31 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((4-Chlorobenzyl)(cyclopropylmethyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid	IC50	34 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((Cyclopropylmethyl)(naphthalen-2-ylmethyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid	IC50	34 nM	US-20160326143: COMPOUNDS AND USES
2-[5-[(4-chlorophenyl)methyl-(cyclopropylmethyl)amino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid	IC50	34 nM	US-9657001: Compounds and uses
2-(5-((Cyclopropylmethyl)(4-methylnaphthalen-1-yl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid	IC50	35 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((4-Chlorophenyl)((1-methylcyclopropyl)methyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid	IC50	38 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((3-Chlorobenzyl)(cyclopropylmethyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid	IC50	39 nM	US-20160326143: COMPOUNDS AND USES
(2-(1H-Tetrazol-5-yl)cyclopropyl)(5-((cyclopropylmethyl)(4-fluoronaphthalen-1-yl)amino)-3-methoxypyridin-2-yl)methanone	IC50	39 nM	US-20160326143: COMPOUNDS AND USES
2-(4-((Cyclopropylmethyl)(naphthalen-1-yl)amino)-2-methoxybenzoyl)cyclopropanecarboxylic acid	IC50	46 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((2,3-Dihydro-1H-inden-5-yl)((1-methylcyclopropyl)methyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid	IC50	47 nM	US-20160326143: COMPOUNDS AND USES
2-[5-[cyclopropylmethyl(2,3-dihydro-1H-inden-5-yl)amino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid	IC50	47 nM	US-9657001: Compounds and uses
2-(5-((Cyclopropylmethyl)(naphthalen-1-yl)amino)-4-methoxypyrimidine-2-carbonyl)cyclopropanecarboxylic acid	IC50	50 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((Cyclopropylmethyl)(2-fluoro-4-(trifluoromethyl)benzyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid	IC50	53 nM	US-20160326143: COMPOUNDS AND USES
2-(6-(Cyclopropylmethyl)(4-methylnaphthalen-1-yl)amino)-4-methoxynicotinoyl)cyclopropanecarboxylic acid	IC50	56 nM	US-20160326143: COMPOUNDS AND USES
2-(4-((4-Chloronaphthalen-1-yl)(cyclopropylmethyl)amino)-2-methoxybenzoyl)cyclopropanecarboxylic acid	IC50	61 nM	US-20160326143: COMPOUNDS AND USES
2-(4-((Cyclopropylmethyl)(4-methylnaphthalen-1-yl)amino)-2-methoxybenzoyl)cyclopropanecarboxylic acid	IC50	62 nM	US-20160326143: COMPOUNDS AND USES
2-(4-((4-Chlorophenyl)(cyclopropylmethyl)amino)-2-methoxybenzoyl)cyclopropanecarboxylic acid	IC50	65 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((Cyclopropylmethyl)(naphthalen-1-ylmethyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid	IC50	66 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((Cyclopropylmethyl)(2,3-dimethylbenzyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid	IC50	67 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((4-Chlorophenyl)(cyclopropylmethyl)amino)-3-methoxypicolinoyl)-N-(phenylsulfonyl)cyclopropanecarboxamide	IC50	68 nM	US-20160326143: COMPOUNDS AND USES
2-(4-((4-Chlorobenzyl)(cyclopropylmethyl)amino)-2-methoxybenzoyl)cyclopropanecarboxylic acid	IC50	68 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((4-Chlorophenyl)(cyclopropylmethyl)amino)-3-methoxypicolinoyl)-N-((2-fluorophenyl)sulfonyl)-cyclopropanecarboxamide	IC50	74 nM	US-20160326143: COMPOUNDS AND USES
2-(4-((Cyclopropylmethyl)(3,4-dimethylphenyl)amino)-2-methoxybenzoyl)cyclopropanecarboxylic acid	IC50	75 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((4-Chlorophenyl)(cyclopropylmethyl)amino)-3-methoxypicolinoyl)-N-((4-methoxyphenyl)sulfonyl)-cyclopropanecarboxamide	IC50	81 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((Cyclopropylmethyl)(2-methyl-3-(trifluoromethyl)benzyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid	IC50	88 nM	US-20160326143: COMPOUNDS AND USES
(2-(1H-Tetrazol-5-yl)cyclopropyl)(5-((cyclopropylmethyl)(naphthalen-1-yl)amino)-3-methoxypyridin-2-yl)methanone	IC50	96 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((Cyclopropylmethyl)(4-fluorobenzyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid	IC50	105 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((2-Chloro-3-(trifluoromethyl)benzyl)(cyclopropylmethyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid	IC50	112 nM	US-20160326143: COMPOUNDS AND USES
2-(5-((4-Chlorophenyl)((1-(trifluoromethyl)cyclopropyl)methyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid	IC50	149 nM	US-20160326143: COMPOUNDS AND USES
2-[5-[4-chloro-N-[[1-(trifluoromethyl)cyclopropyl]methyl]anilino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid	IC50	149 nM	US-9657001: Compounds and uses
2-(5-((3-Chloro-2,4-difluorobenzyl)(cyclopropylmethyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid	IC50	152 nM	US-20160326143: COMPOUNDS AND USES
2-(4-((Cyclopropylmethyl)(5-(trifluoromethyl)quinolin-8-yl)amino)-2-methoxybenzoyl)cyclopropanecarboxylic acid	IC50	152 nM	US-20160326143: COMPOUNDS AND USES

ChEMBL bioactivities

283 potent at pChembl≥5 of 285 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.61	IC50	0.248	nM	CHEMBL3903201
9.60	IC50	0.25	nM	CHEMBL3903201
9.55	IC50	0.28	nM	CHEMBL4549822
9.55	IC50	0.28	nM	AZD-9898
9.54	IC50	0.289	nM	AZD-9898
9.44	IC50	0.36	nM	CHEMBL4567083
9.42	IC50	0.381	nM	CHEMBL4464773
9.32	IC50	0.483	nM	CHEMBL3914270
9.32	IC50	0.483	nM	CHEMBL5980428
9.22	IC50	0.6	nM	CHEMBL4562583
9.20	IC50	0.626	nM	CHEMBL4563433
9.20	IC50	0.63	nM	CHEMBL4584584
9.18	IC50	0.658	nM	CHEMBL3971210
9.18	IC50	0.66	nM	CHEMBL3971210
9.15	IC50	0.7	nM	CHEMBL4574439
9.12	IC50	0.758	nM	CHEMBL4441362
8.98	IC50	1.05	nM	CHEMBL4476024
8.85	IC50	1.41	nM	CHEMBL4454609
8.71	IC50	1.97	nM	CHEMBL4545014
8.70	IC50	2	nM	CHEMBL5417047
8.70	IC50	2	nM	CHEMBL6174532
8.68	IC50	2.08	nM	CHEMBL4545950
8.65	IC50	2.26	nM	CHEMBL4464773
8.62	IC50	2.4	nM	CHEMBL4525972
8.48	IC50	3.3	nM	AZD-9898
8.46	IC50	3.5	nM	CHEMBL4567083
8.43	IC50	3.71	nM	CHEMBL4467942
8.39	IC50	4.1	nM	CHEMBL4549822
8.32	IC50	4.74	nM	CHEMBL4574370
8.31	IC50	4.94	nM	CHEMBL4442047
8.30	IC50	5	nM	CHEMBL5432381
8.28	IC50	5.26	nM	CHEMBL4576647
8.19	IC50	6.42	nM	CHEMBL4567339
8.17	IC50	6.8	nM	CHEMBL3971210
8.15	IC50	7.09	nM	CHEMBL4563433
8.12	IC50	7.5	nM	CHEMBL6177429
8.11	IC50	7.8	nM	CHEMBL3903201
8.10	IC50	7.9	nM	CHEMBL4439499
8.10	IC50	8	nM	CHEMBL6176885
8.07	IC50	8.5	nM	CHEMBL4574439
8.06	IC50	8.65	nM	CHEMBL4439148
8.05	IC50	9	nM	CHEMBL3910305
8.03	IC50	9.41	nM	CHEMBL4454609
8.03	IC50	9.4	nM	CHEMBL6175315
8.00	IC50	10	nM	AZD-9898
8.00	IC50	10	nM	CHEMBL6175315
7.94	IC50	11.5	nM	CHEMBL4445815
7.89	IC50	13	nM	CHEMBL4531985
7.87	IC50	13.5	nM	CHEMBL4565208
7.85	IC50	14	nM	CHEMBL4545950

PubChem BioAssay actives

76 with measured affinity, of 93 total; 47 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
trans-(1S,2S)-2-[5-[2-fluoro-N-(2-fluoro-2-methylpropyl)-5-(trifluoromethyl)anilino]-3-methoxypyrazine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0003	uM
trans-(1S,2S)-2-[5-(5-chloro-2,4-difluoro-N-(2-fluoro-2-methylpropyl)anilino)-3-methoxypyrazine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0003	uM
trans-(1S,2S)-2-[5-[5-chloro-2,4-difluoro-N-(2-methylpropyl)anilino]-3-methoxypyrazine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0003	uM
trans-(1S,2S)-2-[5-[(4-fluoronaphthalen-1-yl)-(2-methylpropyl)amino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0004	uM
trans-(1S,2S)-2-[5-[2-fluoro-N-(2-methylpropyl)-5-(trifluoromethyl)anilino]-3-methoxypyrazine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0004	uM
trans-(1S,2S)-2-[5-(5-chloro-2,4-difluoro-N-(2-fluoro-2-methylpropyl)anilino)-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0006	uM
trans-(1S,2S)-2-[5-[(4-fluoronaphthalen-1-yl)-propylamino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0006	uM
trans-(1S,2S)-2-[5-[2-fluoro-N-(2-fluoro-2-methylpropyl)-5-(trifluoromethyl)anilino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0006	uM
trans-(1S,2S)-2-[5-[2-fluoro-N-(2-methylpropyl)-5-(trifluoromethyl)anilino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0007	uM
trans-(1S,2S)-2-[5-[5-chloro-2,4-difluoro-N-(2-methylpropyl)anilino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0007	uM
trans-(1S,2S)-2-[5-[cyclopropylmethyl-(4-fluoronaphthalen-1-yl)amino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0008	uM
trans-(1S,2S)-2-[5-[ethyl-(4-fluoronaphthalen-1-yl)amino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0010	uM
trans-(1S,2S)-2-[5-[(4-chloronaphthalen-1-yl)-(cyclopropylmethyl)amino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0014	uM
trans-(1S,2S)-2-[5-[5-chloro-N-(cyclopropylmethyl)-2,4-difluoroanilino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0020	uM
ethyl 2-[2-(1-naphthalen-1-ylethylcarbamothioylamino)-1,3-thiazol-4-yl]acetate	1995361: Inhibition of LTC4 (unknown origin)	ic50	0.0020	uM
trans-(1S,2S)-2-[5-[N-(cyclopropylmethyl)-2-fluoro-5-(trifluoromethyl)anilino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0021	uM
trans-(1S,2S)-2-[5-[cyclopropylmethyl(naphthalen-1-yl)amino]-4-methoxypyrimidine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0024	uM
trans-(1S,2S)-2-[5-[5-chloro-N-(cyclopropylmethyl)-2-fluoroanilino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0037	uM
trans-(1S,2S)-2-[3-methoxy-5-[N-(2-methylpropyl)-3-(trifluoromethyl)anilino]pyridine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0047	uM
trans-(1S,2S)-2-[5-[3,4-dichloro-N-(cyclopropylmethyl)anilino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0049	uM
1-(5-methyl-2-pyridinyl)-3-(1-naphthalen-1-ylethyl)thiourea	1995361: Inhibition of LTC4 (unknown origin)	ic50	0.0050	uM
trans-(1S,2S)-2-[5-[3-chloro-N-(cyclopropylmethyl)-4-fluoroanilino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0053	uM
trans-(1S,2S)-2-[5-[N-(cyclopropylmethyl)-3-(trifluoromethyl)anilino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0064	uM
trans-(1S,2S)-2-[3-methoxy-5-[N-propyl-3-(trifluoromethyl)anilino]pyridine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0079	uM
trans-(1S,2S)-2-[5-[N-(2-fluoro-2-methylpropyl)-3-(trifluoromethyl)anilino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0086	uM
trans-(1S,2S)-2-[3-methoxy-5-[N-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)anilino]pyridine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0115	uM
trans-(1S,2S)-2-[5-[N-ethyl-3-(trifluoromethyl)anilino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0130	uM
trans-(1S,2S)-2-[5-[N-[(4-fluorophenyl)methyl]-3-(trifluoromethyl)anilino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0135	uM
trans-(1R,2R)-2-[5-[(4-chloronaphthalen-1-yl)-(cyclopropylmethyl)amino]-4-methoxypyrimidine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0155	uM
trans-(1R,2R)-2-[5-[4-chloro-N-(cyclopropylmethyl)anilino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0243	uM
3-[5-[4-chloro-N-(cyclopropylmethyl)anilino]-3-methoxypyridine-2-carbonyl]benzoic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0274	uM
3-[1-[(2-chlorophenyl)methyl]-2-[1-[4-(2-methylpropyl)phenyl]ethyl]benzimidazol-5-yl]propanoic acid	1395147: Inhibition of LTC4 synthase in LPS/fMLP-stimulated human monocytes assessed as decrease in cys-LT formation pre-incubated with LPS for 30 mins and later stimulated with fMLP for 10 mins by ELISA	ic50	0.0300	uM
trans-(1S,2S)-2-[5-[N-(2-hydroxy-2-methylpropyl)-3-(trifluoromethyl)anilino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0318	uM
5-[5-(4-chloro-N-methylanilino)pyridine-2-carbonyl]-2-[(2-methoxybenzoyl)amino]benzoic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.0350	uM
5-[5-[(4-chloronaphthalen-1-yl)-(cyclopropylmethyl)amino]-3-methoxy-2-pyridinyl]-5-oxopentanoic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.1090	uM
trans-(1S,2S)-2-[5-[N-(cyclopropylmethyl)anilino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	0.1580	uM
5-[2-[1-(4-phenoxyphenyl)ethyl]-3H-benzimidazol-5-yl]-3H-1,3,4-oxadiazole-2-thione	1902160: Inhibition of human recombinant LTC4S expressed in HEK293 cell microsomal fraction preincubated for 10 mins followed by LTA4-methyl ester addition and measured after 10 mins by UPLC-MS/MS analysis	ic50	0.4000	uM
5-[2-(4-phenylmethoxyphenyl)-3H-benzimidazol-5-yl]-3H-1,3,4-oxadiazole-2-thione	1902160: Inhibition of human recombinant LTC4S expressed in HEK293 cell microsomal fraction preincubated for 10 mins followed by LTA4-methyl ester addition and measured after 10 mins by UPLC-MS/MS analysis	ic50	0.7000	uM
1-(6-methyl-2-pyridinyl)-3-(1-naphthalen-1-ylethyl)thiourea	1995361: Inhibition of LTC4 (unknown origin)	ic50	1.6000	uM
4-[(4-phenylbenzoyl)-[(3-phenylmethoxyphenyl)methyl]amino]benzoic acid	1406537: Inhibition of LTC4 synthase (unknown origin)	ic50	1.8000	uM
2-benzamido-5-[(4-benzamido-3-carboxyphenyl)methyl]benzoic acid	1579826: Inhibition of human N-terminal His6-tagged LTC4S expressed in Pichia pastoris X33 using LTA4 methyl ester and glutathione as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins by LC-MS/MS analysis	ic50	1.9000	uM
5-[2-(4-phenoxyphenyl)-3H-benzimidazol-5-yl]-3H-1,3,4-oxadiazole-2-thione	1902160: Inhibition of human recombinant LTC4S expressed in HEK293 cell microsomal fraction preincubated for 10 mins followed by LTA4-methyl ester addition and measured after 10 mins by UPLC-MS/MS analysis	ic50	2.8000	uM
3-[3-tert-butylsulfanyl-1-[(4-chlorophenyl)methyl]-5-propan-2-ylindol-2-yl]-2,2-dimethylpropanoic acid	1902162: Inhibition of recombinant LTC4S (unknown origin) expressed in COS cells	ic50	3.0000	uM
1-(5-bromo-2-pyridinyl)-3-[2-(4-hydroxyphenyl)ethyl]thiourea	1995361: Inhibition of LTC4 (unknown origin)	ic50	5.0000	uM
1-(5-chloro-2-pyridinyl)-3-[2-(1H-indol-3-yl)ethyl]thiourea	1995361: Inhibition of LTC4 (unknown origin)	ic50	5.0000	uM
Montelukast	1579865: Inhibition of recombinant human N-terminal His6-tagged LTC4S expressed in in Pichia pastoris X33 assessed as inhibition of EXC4 formation using EXA4 as substrate preincubated for 10 mins followed by substrate addition and measured after 1 min by EIA	ic50	5.0000	uM
5-[1-[(2-chlorophenyl)methyl]-2-[1-[4-(2-methylpropyl)phenyl]ethyl]benzimidazol-5-yl]-3H-1,3,4-oxadiazole-2-thione	1395153: Inhibition of human LTC4 synthase expressed in HEK293 cell microsomes preincubated for 10 mins followed by LTA4-methyl ester addition and measured after 10 mins by UPLC-MS/MS analysis	ic50	6.1900	uM

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aspirin	affects response to substance	5
sodium arsenite	decreases expression	2
Arsenic Trioxide	decreases expression, increases expression	2
Estradiol	affects cotreatment, decreases expression	2
parthenolide	decreases reaction, decreases expression	1
triphenyl phosphate	affects expression	1
aflatoxin B2	decreases methylation	1
2-chloroethyl ethyl sulfide	increases expression	1
pranlukast	affects response to substance	1
montelukast	affects response to substance	1
bisperoxovanadium	decreases expression	1
Dexamethasone	increases expression	1
Bucladesine	decreases secretion	1
Etazolate	decreases secretion	1
Colforsin	decreases secretion	1
Histamine	decreases response to substance	1
Lipopolysaccharides	affects reaction, decreases expression, decreases reaction	1
Smoke	decreases expression	1
Theophylline	decreases secretion	1
Valproic Acid	increases methylation	1
Leukotriene C4	affects chemical synthesis	1
Rolipram	decreases secretion	1

ChEMBL screening assays

37 unique, capped per target: 36 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1743238	ADMET	Substrates for human microsomal glutathione transferase LTC4S	Casarett and Doull’s Toxicology The Basic Science of Poisons, 7th edition
CHEMBL1924715	Binding	Inhibition of LTC4 synthase	5-Lipoxygenase-activating protein (FLAP) inhibitors. Part 4: development of 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid (AM803), a potent, oral, once daily FLAP inhibitor. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01681615	Not specified	UNKNOWN	Challenge Test for Acetylsalicylic Acid Hypersensitivity
NCT02064738	Not specified	COMPLETED	High Omega-3/Low Omega-6 Treatment Diet for Aspirin-exacerbated Respiratory Disease (AERD)
NCT02964637	Not specified	RECRUITING	Diagnosing Frontotemporal Lobar Degeneration
NCT06051123	Not specified	RECRUITING	Effects of Probiotics in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia Spectrum Disorder (ALS-FTDSD) Patients