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| leukotriene-C4 synthase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 Leukotriene C4 synthase dodekamer, Human | |||||||||
| Identifiers | |||||||||
| EC no. | 4.4.1.20 | ||||||||
| CAS no. | 90698-32-1 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
| |||||||||
The systematic name of this enzyme class is leukotriene-C4 glutathione-lyase (leukotriene-A4-forming). Other names in common use include leukotriene C4 synthetase, LTC4 synthase, LTC4 synthetase, leukotriene A4:glutathione S-leukotrienyltransferase, (7E,9E,11Z,14Z)-(5S,6R)-5,6-epoxyicosa-7,9,11,14-, tetraenoate:glutathione leukotriene-transferase, (epoxide-ring-opening), (7E,9E,11Z,14Z)-(5S,6R)-6-(glutathion-S-yl)-5-hydroxyicosa-, and 7,9,11,14-tetraenoate glutathione-lyase (epoxide-forming). This enzyme participates in arachidonic acid metabolism.
Mechanism of reaction
[edit]The EC number of Leukotriene-C4 synthase is 4.4.1.20. This number signifies that the enzyme belongs to the family of lyases, specifically the class of carbon-sulfur lyases. These enzymes catalyze non-hydrolytic additions or removals of groups from substrates. Bonds such as those of carbon bound to another carbon, nitrogen, oxygen, or sulfur could be cleaved.[1]
In enzymology, a leukotriene-C4 synthase (EC 4.4.1.20) is an enzyme that catalyzes the chemical reaction
- leukotriene C4 leukotriene A4 + glutathione
Hence, this enzyme has one substrate, leukotriene C4, and two products, leukotriene A4 and glutathione.
Leukotriene (LT) C4 synthase is a trimeric integral membrane protein and conjugates LTA4, an epoxide intermediate, to glutathione (GSH) to form a pro-inflammatory mediator LTC4.[2] This enzyme is part of the MAPEG (Membrane Associated Proteins in Eicosanoid and Glutathione metabolism) transmembrane proteins. This enzyme catalyzes the first step of the biosynthesis of cysteinyl leukotrienes which are derived from arachidonic acid. A trimer of LTC4 synthase is found on the outer nuclear membrane and endoplasmic reticulum where it complexes with 5-Lipoxygenase-activating protein.[3]
This enzyme is found in both human and mouse and their gene locations have been identified. The family of MAPEG is comprised of proteins involved with the production of leukotrienes. Leukotrienes have been found to play a role in mediating anaphylaxis and inflammatory conditions like human bronchial asthma.[3] Additionally, the pro-inflammatory factor, LTC4S, acts on plasma membrane cysteinyl leukotriene receptors and it is a cytosolic second messenger that can activate store-independent LTC4-regulated calcium channels encoded by Orai1/Orai3 heteromultimers in vascular smooth muscle cells. The role of LTC4S, however, remains unclear in neointima formation.[4]
Leukotriene C4 and its metabolites LTD4 and LTE4 are the components of the slow-reacting substances of anaphylaxis which are lipid mediators of both smooth muscle constriction and inflammation, specifically with bronchial asthma. LTC4S, a crucial enzyme for the biosynthesis of LTC4 is a 18kDa integral nuclear membrane protein. It belongs to the membrane-associated proteins in eicosanoid and glutathione metabolism.[5]
Crystal structures
[edit]LTC4S monomer has 4 transmembrane alpha-helices and it forms a trimeric integral membrane protein. Glutathione is in a U-shaped conformation and this binding is stabilized by a loop structure at the top of the interface between the adjacent monomers.[5] The enzyme-substrate complex shows the active site forms a horseshoe-shaped structure on GSH. This positions the thiol group for activation by arginine at the membrane-enzyme interface. The structure also shows the omega-end of the lipophillic co-substrate at one end of the hydrophobic cleft serving to align the epoxide at the thiol of glutathione. This information suggests the observed activation of GSH may be found in the family of homologous proteins frequently and therefore have an important role in inflammatory and detoxification responses.[6]
Structural studies
[edit]As of late 2007, 3 structures have been solved for this class of enzymes, with PDB accession codes 2PNO, 2UUH, and 2UUI.
References
[edit]- ^ "BRENDA - Information on EC 4.4.1.1 - cystathionine gamma-lyase". www.brenda-enzymes.org. Retrieved 2021-10-21.
- ^ Lam, B K; Penrose, J F; Freeman, G J; Austen, K F (1994-08-02). "Expression cloning of a cDNA for human leukotriene C4 synthase, an integral membrane protein conjugating reduced glutathione to leukotriene A4". Proceedings of the National Academy of Sciences of the United States of America. 91 (16): 7663–7667. ISSN 0027-8424. PMID 8052639.
- ^ a b "LTC4S leukotriene C4 synthase [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2021-10-20.
- ^ Zhang, Wei; Zhang, Xuexin; González-Cobos, José C.; Stolwijk, Judith A.; Matrougui, Khalid; Trebak, Mohamed (2015-02-20). "Leukotriene-C4 Synthase, a Critical Enzyme in the Activation of Store-independent Orai1/Orai3 Channels, Is Required for Neointimal Hyperplasia *". Journal of Biological Chemistry. 290 (8): 5015–5027. doi:10.1074/jbc.M114.625822. ISSN 0021-9258. PMID 25540197.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ a b Ago, Hideo; Kanaoka, Yoshihide; Irikura, Daisuke; Lam, Bing K.; Shimamura, Tatsuro; Austen, K. Frank; Miyano, Masashi (2007-08-02). "Crystal structure of a human membrane protein involved in cysteinyl leukotriene biosynthesis". Nature. 448 (7153): 609–612. doi:10.1038/nature05936. ISSN 1476-4687. PMID 17632548.
- ^ Martinez Molina, Daniel; Wetterholm, Anders; Kohl, Andreas; McCarthy, Andrew A.; Niegowski, Damian; Ohlson, Eva; Hammarberg, Tove; Eshaghi, Said; Haeggström, Jesper Z.; Nordlund, Pär (2007-08-02). "Structural basis for synthesis of inflammatory mediators by human leukotriene C4 synthase". Nature. 448 (7153): 613–616. doi:10.1038/nature06009. ISSN 1476-4687. PMID 17632546.
- Bach MK, Brashler JR, Morton DR Jr (1984). "Solubilization and characterization of the leukotriene C4 synthetase of rat basophil leukemia cells: a novel, particulate glutathione S-transferase". Arch. Biochem. Biophys. 230 (2): 455–65. doi:10.1016/0003-9861(84)90426-0. PMID 6324687.
- Shimizu T (1988). "Enzymes functional in the syntheses of leukotrienes and related compounds". Int. J. Biochem. 20 (7): 661–6. doi:10.1016/0020-711X(88)90160-7. PMID 2846379.
- Lam BK, Austen KF (2002). "Leukotriene C4 synthase: a pivotal enzyme in cellular biosynthesis of the cysteinyl leukotrienes". Prostaglandins. Other. Lipid. Mediat. 68–69: 511–20. doi:10.1016/S0090-6980(02)00052-7. PMID 12432940.
- Christmas P, Weber BM, McKee M, Brown D, Soberman RJ (2002). "Membrane localization and topology of leukotriene C4 synthase". J. Biol. Chem. 277 (32): 28902–8. doi:10.1074/jbc.M203074200. PMID 12023288.
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