Leukotriene C4 synthase

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Template:STRUCTURE 3hkk

Human leukotriene C₄ synthase (LTC₄S) converts leukotriene A4 and glutathione to leukotriene C4. It is part of the arachidonic acid cycle. 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.^[1] 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.^[2]

The structure of human leukotriene C₄ synthase in a complex with glutathione sulfonate is shown at the left and right. LTC₄S has a single chain with three transmembrane domains,^[3] and the crystallized structure 3HKK has sequence from http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from OCA.

The gene for LTC₄S is found on chromosome 5q35.^[4]

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.^[5]

3D Structures of Leukotriene C4 synthase

Updated on 19-August-2014

2pno, 2uui, 3pcv – hLC4S - human
3leo – hLC4S (mutant)+glutathione
3hkk, 2uuh - hLC4S +glutathione
3b29 – hLC4S + dodecyl-β-D-selenomaltoside
4j7t, 4j7y, 4jcz, 4jrz – hLC4S + product analog
4jc7 – hLC4S (mutant) + product analog

References

1. ↑ 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
2. ↑ 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
3. ↑ 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
4. ↑ 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
5. ↑ 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

• Created with the participation of Shilpa Nadimpalli.