Introduction
Human leukotriene C4 synthase (LTC4S) converts leukotriene A4 and glutathione to leukotriene C4. It is part of the arachidonic acid cycle. The structure of human leukotriene C4 synthase in a complex with glutathione sulfonate is shown at the right. LTC4S has a single chain with three transmembrane domains,[1] and the crystallized structure 3HKK has sequence from https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from OCA.
The gene for LTC4S is found on chromosome 5q35.[2]
LTC4S Activity
Leukotriene C4 synthase is a unique membrane-bound enzyme that catalyzes the committed step in the biosynthesis of all the peptidoleukotrienes, also known as cysteinyl leukotrienes because of the presence of cysteine in their structures. The cysteinyl leukotrienes make up the slow-reacting substance of anaphylaxis (SRS-A).
Specifically, LTC4S conjugates reduced glutathione with the unstable epoxide LTA4 to form LTC4, making it a member of the glutathione S-transferase multigene family. Unlike other members of this family, however, LTC4S is not involved in cellular detoxification at all, and instead seems to be exclusively committed to the biosynthesis of LTC4.[3]
Relevance
LTC4S is an integral membrane protein that catalyzes the biosynthesis of leukotrienes, which have implications in the mediation of immediate hypersensitivity and inflammatory conditions, such as asthma and allergic rhinitis.[4] The main function of LTC4S is the conjugation of an epoxide intermediate (LTA4) to reduced glutathione to form a proinflammatory mediator, LTC4, a peptidoleukotriene that mediates an inflammatory response characteristic of asthma attacks.[5]
Structural highlights
The biological assembly of Human leukotriene C4 synthase is homotrimer. GSH is bound to LTC4S in a hydrophobic pore between the 2 monomers[6]. Active site. Water molecules shown as red spheres.
- ↑ Lam BK, Penrose JF, Freeman GJ, Austen KF. Expression cloning of a cDNA for human leukotriene C4 synthase, an integral membrane protein conjugating reduced glutathione to leukotriene A4. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7663-7. PMID:8052639
- ↑ Penrose JF, Spector J, Baldasaro M, Xu K, Boyce J, Arm JP, Austen KF, Lam BK. Molecular cloning of the gene for human leukotriene C4 synthase. Organization, nucleotide sequence, and chromosomal localization to 5q35. J Biol Chem. 1996 May 10;271(19):11356-61. PMID:8626689
- ↑ Nicholson DW, Ali A, Klemba MW, Munday NA, Zamboni RJ, Ford-Hutchinson AW. Human leukotriene C4 synthase expression in dimethyl sulfoxide-differentiated U937 cells. J Biol Chem. 1992 Sep 5;267(25):17849-57. PMID:1517222
- ↑ Welsch DJ, Creely DP, Hauser SD, Mathis KJ, Krivi GG, Isakson PC. Molecular cloning and expression of human leukotriene-C4 synthase. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9745-9. PMID:7937884
- ↑ Lam BK, Penrose JF, Freeman GJ, Austen KF. Expression cloning of a cDNA for human leukotriene C4 synthase, an integral membrane protein conjugating reduced glutathione to leukotriene A4. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7663-7. PMID:8052639
- ↑ Martinez Molina D, Wetterholm A, Kohl A, McCarthy AA, Niegowski D, Ohlson E, Hammarberg T, Eshaghi S, Haeggstrom JZ, Nordlund P. Structural basis for synthesis of inflammatory mediators by human leukotriene C4 synthase. Nature. 2007 Aug 2;448(7153):613-6. Epub 2007 Jul 15. PMID:17632546 doi:10.1038/nature06009
