Details for: LTC4S

Gene ID: 4056

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: LTC4S

Ensembl ID: ENSG00000213316

Description: leukotriene C4 synthase

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • secretory cell CL0000151
    CSI 18.39
    rCSI 19.18%
    PRS 91.54
  • mast cell CL0000097
    CSI 7.78
    rCSI 16.8%
    PRS 90.52
  • endothelial cell of artery CL1000413
    CSI 6.81
    rCSI 9.97%
    PRS 94.17
  • basophil CL0000767
    CSI 6.24
    rCSI 13.2%
    PRS 96.1
  • myeloid leukocyte CL0000766
    CSI 4.99
    rCSI 4.61%
    PRS 93.56
  • pulmonary artery endothelial cell CL1001568
    CSI 4.08
    rCSI 5.55%
    PRS 95.94
  • monocyte CL0000576
    CSI 3.7
    rCSI 6.69%
    PRS 93.68
  • myofibroblast cell CL0000186
    CSI 3.62
    rCSI 5.01%
    PRS 89.49
  • blood vessel endothelial cell CL0000071
    CSI 3.55
    rCSI 7.36%
    PRS 91.07
  • alternatively activated macrophage CL0000890
    CSI 3.11
    rCSI 3.91%
    PRS 96.76
  • dendritic cell CL0000451
    CSI 3.04
    rCSI 3.74%
    PRS 91.97
  • pulmonary capillary endothelial cell CL4028001
    CSI 3.02
    rCSI 5.75%
    PRS 96.47
  • macrophage CL0000235
    CSI 3.01
    rCSI 5.48%
    PRS 92.74
  • microglial cell CL0000129
    CSI 2.97
    rCSI 11.95%
    PRS 91.07
  • group 3 innate lymphoid cell CL0001071
    CSI 2.77
    rCSI 2.08%
    PRS 94.77
  • basal cell CL0000646
    CSI 2.75
    rCSI 3.67%
    PRS 89.99
  • ciliated epithelial cell CL0000067
    CSI 2.74
    rCSI 2.41%
    PRS 84.78
  • kidney interstitial alternatively activated macrophage CL1000695
    CSI 2.72
    rCSI 7.08%
    PRS 94.16
  • mononuclear phagocyte CL0000113
    CSI 2.68
    rCSI 5.9%
    PRS 94.63
  • common myeloid progenitor CL0000049
    CSI 2.66
    rCSI 2.15%
    PRS 93.48
  • duct epithelial cell CL0000068
    CSI 2.39
    rCSI 3.5%
    PRS 95.14
  • granulocyte CL0000094
    CSI 2.38
    rCSI 3.63%
    PRS 95.69
  • Hofbauer cell CL3000001
    CSI 2.32
    rCSI 4.38%
    PRS 96.1
  • epithelial cell of lung CL0000082
    CSI 2.28
    rCSI 1.89%
    PRS 93.33
  • promyelocyte CL0000836
    CSI 2.23
    rCSI 3.22%
    PRS 94.09
  • fallopian tube secretory epithelial cell CL4030006
    CSI 2.15
    rCSI 2.07%
    PRS 91.24
  • megakaryocyte-erythroid progenitor cell CL0000050
    CSI 2.08
    rCSI 1.88%
    PRS 91.43
  • granulocyte monocyte progenitor cell CL0000557
    CSI 2.05
    rCSI 1.78%
    PRS 94.17
  • endocardial cell CL0002350
    CSI 1.96
    rCSI 9.39%
    PRS 89.61
  • Langerhans cell CL0000453
    CSI 1.88
    rCSI 2.87%
    PRS 96.92
  • CD1c-positive myeloid dendritic cell CL0002399
    CSI 1.8
    rCSI 2.17%
    PRS 96.12
  • myeloid dendritic cell CL0000782
    CSI 1.55
    rCSI 2.25%
    PRS 97.98
  • lung macrophage CL1001603
    CSI 1.33
    rCSI 2.98%
    PRS 96.15
  • vein endothelial cell of respiratory system CL4033008
    CSI 0.89
    rCSI 6.11%
    PRS 95.12
  • eosinophil CL0000771
    CSI 0.65
    rCSI 4.27%
    PRS 97.33
  • lung microvascular endothelial cell CL2000016
    CSI 0.42
    rCSI 8.15%
    PRS 95.66

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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  • Node Color (Target Cell CSI, relative to current network):
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    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary Leukotriene C4 synthase ([LTC4S](/details-gene/4056)) is an integral membrane protein that functions as a glutathione S-transferase. It catalyzes the final and rate-limiting step in the biosynthesis of leukotriene C4 (LTC4), a potent pro-inflammatory mediator derived from arachidonic acid. Its expression is particularly significant in myeloid and secretory cell populations, including [mast cell](/details-cell/CL0000097)s, [basophil](/details-cell/CL0000767)s, and [macrophage](/details-cell/CL0000235)s, establishing it as a key enzyme in allergic and inflammatory responses. Genetic defects in [LTC4S](/details-gene/4056) are associated with a rare and severe inborn error of metabolism ([OMIM [246530](https://omim.org/entry/246530)]), highlighting its critical physiological role. ## Cellular Roles and Expression Landscape The expression profile of [LTC4S](/details-gene/4056) firmly establishes its role in innate immunity and inflammatory pathways. **Overall**, the gene shows exceptionally high significance in [secretory cell](/details-cell/CL0000151)s (CSI: 18.39), which likely reflects its function in cells specialized for producing and releasing inflammatory mediators. Its prominence is most notable within the myeloid lineage. [LTC4S](/details-gene/4056) is a key marker for granulocytes such as [mast cell](/details-cell/CL0000097)s and [basophil](/details-cell/CL0000767)s, which are primary sources of cysteinyl leukotrienes during allergic reactions. The gene is also highly significant in other [myeloid leukocyte](/details-cell/CL0000766)s, including [monocyte](/details-cell/CL0000576)s, [macrophage](/details-cell/CL0000235)s (including [alternatively activated macrophage](/details-cell/CL0000890)s), and [dendritic cell](/details-cell/CL0000451)s, suggesting a broad role in antigen presentation and inflammatory signaling. Beyond classical immune cells, [LTC4S](/details-gene/4056) shows significant expression in stromal and endothelial populations, such as [myofibroblast cell](/details-cell/CL0000186)s and various [blood vessel endothelial cell](/details-cell/CL0000071)s. This expression pattern suggests a potential role in mediating vascular permeability, bronchoconstriction, and tissue remodeling during chronic inflammation. ## Pathways and Molecular Function [LTC4S](/details-gene/4056) functions as an enzyme catalyzing the conjugation of leukotriene A4 (LTA4) with reduced glutathione, a critical reaction in the [Leukotriene biosynthetic process](/details-gene/GO:0019370) ([Link](https://doi.org/10.1073/pnas.91.16.7663)). This function is annotated as both [Leukotriene-c4 synthase activity](/details-gene/GO:0004464) and a specialized [Glutathione transferase activity](/details-gene/GO:0004364). Consistent with its function, [LTC4S](/details-gene/4056) is a central component of the Reactome pathway for 'Synthesis of leukotrienes (lt) and eoxins (ex)' ([R-HSA-2142691](https://reactome.org/content/detail/R-HSA-2142691)) within the broader 'Arachidonate metabolism' pathway ([R-HSA-2142753](https://reactome.org/content/detail/R-HSA-2142753)). Its involvement is also noted in the synthesis of specialized pro-resolving mediators (SPMs), such as maresin and protectin conjugates, indicating a potential role in both the initiation and resolution phases of inflammation. As an integral membrane protein, it is localized to the [nuclear envelope](/details-gene/GO:0005635) and [endoplasmic reticulum membrane](/details-gene/GO:0005789). This localization is critical as it facilitates the coupling of LTA4 generation by 5-lipoxygenase with its subsequent conversion to LTC4 ([Link](https://doi.org/10.1016/j.bbrc.2009.02.074)). ## Research Directions The well-defined role of [LTC4S](/details-gene/4056) in inflammation presents several avenues for further investigation, particularly concerning its function in specific cell types during disease. Based on its expression profile and known function, two testable hypotheses are: 1. Given its high significance in [myofibroblast cell](/details-cell/CL0000186)s and [pulmonary artery endothelial cell](/details-cell/CL1001568)s, [LTC4S](/details-gene/4056)-mediated leukotriene production may directly contribute to pathogenic tissue remodeling and vascular dysfunction in chronic inflammatory diseases like pulmonary fibrosis or asthma, independent of its role in infiltrating immune cells. 2. The significant expression of [LTC4S](/details-gene/4056) in [alternatively activated macrophage](/details-cell/CL0000890)s suggests that local LTC4 production could be a metabolic checkpoint that reinforces the M2 phenotype, promoting functions like tissue repair and fibrosis while potentially suppressing pro-inflammatory M1 responses. To test the second hypothesis regarding macrophage polarization, a key experiment could involve the use of myeloid-specific *Ltc4s* knockout mice. Bone marrow-derived macrophages from these animals and wild-type controls could be polarized *in vitro* towards M1 (LPS/IFN-gamma) and M2 (IL-4/IL-13) states. The impact of [LTC4S](/details-gene/4056) ablation on polarization efficiency would be assessed by measuring canonical marker gene expression (e.g., *Nos2*, *Arg1*) via qPCR, analyzing secreted cytokine profiles, and evaluating phagocytic and metabolic functions. As a pivotal enzyme in the production of potent pro-inflammatory mediators, [LTC4S](/details-gene/4056) is a validated therapeutic target. Its **inhibition**, rather than activation, is the relevant strategy for treating inflammatory conditions like asthma, where leukotriene receptor antagonists are already in clinical use. The development of direct, highly specific small-molecule inhibitors for [LTC4S](/details-gene/4056) remains an area of interest. However, the severe pathology associated with its complete loss-of-function, as seen in the rare genetic disorder ([Link](https://doi.org/10.1016/s0140-6736(98)01186-6)), suggests that therapeutic strategies must achieve carefully titrated or localized inhibition to avoid systemic toxicity.

Genular Protein ID: 4213866900

Symbol: LTC4S_HUMAN

Name: Leukotriene C4 synthase

UniProtKB Accession Codes:

Q16873 Q8N6P0 Q9UC73 Q9UD18

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BindingDB 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 ChEBI 10 ChEMBL 1 ChiTaRS 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 2 EC 1 EMBL 5 Ensembl 2 EvolutionaryTrace 1 ExpressionAtlas 1 GO 16 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 5 KEGG 1 MANE-Select 1 MIM 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 16 PDBsum 16 PIR 2 PRINTS 1 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 5 RefSeq 1 Rhea 4 SABIO-RK 1 SIGNOR 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 SwissLipids 1 TreeFam 1 UCSC 1 UniPathway 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 8052639

Title: Expression cloning of a cDNA for human leukotriene C4 synthase, an integral membrane protein conjugating reduced glutathione to leukotriene A4.

PubMed ID: 8052639

DOI: 10.1073/pnas.91.16.7663

PubMed ID: 7937884

Title: Molecular cloning and expression of human leukotriene-C4 synthase.

PubMed ID: 7937884

DOI: 10.1073/pnas.91.21.9745

PubMed ID: 8626689

Title: Molecular cloning of the gene for human leukotriene C4 synthase. Organization, nucleotide sequence, and chromosomal localization to 5q35.

PubMed ID: 8626689

DOI: 10.1074/jbc.271.19.11356

PubMed ID: 8898379

Title: Molecular cloning of the human leukotriene C4 synthase gene and assignment to chromosome 5q35.

PubMed ID: 8898379

DOI: 10.1007/bf03401647

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 8446623

Title: Purification to homogeneity and the N-terminal sequence of human leukotriene C4 synthase: a homodimeric glutathione S-transferase composed of 18-kDa subunits.

PubMed ID: 8446623

DOI: 10.1073/pnas.90.5.2015

PubMed ID: 7599836

Title: Purification of human lung leukotriene C4 synthase and preparation of a polyclonal antibody.

PubMed ID: 7599836

DOI: 10.1164/ajrccm.152.1.7599836

PubMed ID: 7766706

Title: Two step purification of human and murine leukotriene C4 synthase.

PubMed ID: 7766706

DOI: 10.1016/0005-2760(95)00031-7

PubMed ID: 9153254

Title: Site-directed mutagenesis of human leukotriene C4 synthase.

PubMed ID: 9153254

DOI: 10.1074/jbc.272.21.13923

PubMed ID: 9820300

Title: Leukotriene C4-synthesis deficiency: a new inborn error of metabolism linked to a fatal developmental syndrome.

PubMed ID: 9820300

DOI: 10.1016/s0140-6736(98)01186-6

PubMed ID: 10896305

Title: Defects in the synthesis of cysteinyl leukotrienes: a new group of inborn errors of metabolism.

PubMed ID: 10896305

DOI: 10.1023/a:1005664204956

PubMed ID: 12023288

Title: Membrane localization and topology of leukotriene C4 synthase.

PubMed ID: 12023288

DOI: 10.1074/jbc.m203074200

PubMed ID: 19233132

Title: Distinct parts of leukotriene C(4) synthase interact with 5-lipoxygenase and 5-lipoxygenase activating protein.

PubMed ID: 19233132

DOI: 10.1016/j.bbrc.2009.02.074

PubMed ID: 17632548

Title: Crystal structure of a human membrane protein involved in cysteinyl leukotriene biosynthesis.

PubMed ID: 17632548

DOI: 10.1038/nature05936

PubMed ID: 17632546

Title: Structural basis for synthesis of inflammatory mediators by human leukotriene C4 synthase.

PubMed ID: 17632546

DOI: 10.1038/nature06009

PubMed ID: 23409838

Title: Catalytic characterization of human microsomal glutathione S-transferase 2: identification of rate-limiting steps.

PubMed ID: 23409838

DOI: 10.1021/bi3014104

PubMed ID: 27791009

Title: Maresin conjugates in tissue regeneration biosynthesis enzymes in human macrophages.

PubMed ID: 27791009

DOI: 10.1073/pnas.1607003113

PubMed ID: 27365393

Title: Phosphorylation of Leukotriene C4 Synthase at Serine 36 Impairs Catalytic Activity.

PubMed ID: 27365393

DOI: 10.1074/jbc.m116.735647

Sequence Information:

  • Length: 150
  • Mass: 16567
  • Checksum: 04E269B475063037
  • Sequence:
    • MKDEVALLAA VTLLGVLLQA YFSLQVISAR RAFRVSPPLT TGPPEFERVY RAQVNCSEYF 
PLFLATLWVA GIFFHEGAAA LCGLVYLFAR LRYFQGYARS AQLRLAPLYA SARALWLLVA 
LAALGLLAHF LPAALRAALL GRLRTLLPWA