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Pathway Description
Leukotriene C4 Synthesis Deficiency
Homo sapiens
Disease Pathway
Leukotriene C4 synthetase deficiency is caused by a defect in the enzyme leukotriene C4 synthetase (LTC4S). This enzyme catalyzes the synthesis of leukotriene C4 (LTC4) through conjugation of LTA4 with reduced glutathione (GSH), which is synthesized by glutathione synthetase. Leukotriene C4 and its receptor-binding metabolites LTD4 and LTE4 are cysteinyl leukotrienes that are potent lipid mediators of tissue inflammation. In general, leukotrienes are potent proinflammatory mediators synthesized from membrane-derived arachidonic acid after activation of certain granulocytes. A defect in LTC4 results in decreased concentrations of cysteinyl leukotrienes LTC4, LTD4 and LTE4 in plasma, spinal fluid and urine. Symptoms include early death, failure to thrive, motor retardation, microcephaly, and progressive neurological defect.
References
Leukotriene C4 Synthesis Deficiency References
[OMIM: Entry 246530](http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=246530)
[Uniprot: Q16873](http://www.uniprot.org/uniprot/Q16873)
Ago H, Kanaoka Y, Irikura D, Lam BK, Shimamura T, Austen KF, Miyano M: Crystal structure of a human membrane protein involved in cysteinyl leukotriene biosynthesis. Nature. 2007 Aug 2;448(7153):609-12. doi: 10.1038/nature05936. Epub 2007 Jul 15.
Pubmed: 17632548
Kanaoka Y, Maekawa A, Penrose JF, Austen KF, Lam BK: Attenuated zymosan-induced peritoneal vascular permeability and IgE-dependent passive cutaneous anaphylaxis in mice lacking leukotriene C4 synthase. J Biol Chem. 2001 Jun 22;276(25):22608-13. doi: 10.1074/jbc.M103562200. Epub 2001 Apr 23.
Pubmed: 11319240
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.
Pubmed: 8052639
Mayatepek E, Flock B: Leukotriene C4-synthesis deficiency: a new inborn error of metabolism linked to a fatal developmental syndrome. Lancet. 1998 Nov 7;352(9139):1514-7. doi: 10.1016/S0140-6736(98)01186-6.
Pubmed: 9820300
Pace-Asciak CR, Klein J, Spielberg SP: Human genetic defect in leukotriene C4 synthesis. Biochem Biophys Res Commun. 1986 Nov 14;140(3):857-60.
Pubmed: 3022737
Mayatepek E: Leukotriene C4 synthesis deficiency: a member of a probably underdiagnosed new group of neurometabolic diseases. Eur J Pediatr. 2000 Nov;159(11):811-8.
Pubmed: 11079193
Arachidonic Acid Metabolism References
Lehninger, A.L. Lehninger principles of biochemistry (4th ed.) (2005). New York: W.H Freeman.
Vance, D.E., and Vance, J.E. Biochemistry of lipids, lipoproteins, and membranes (4th ed.) (2002) Amsterdam; Boston: Elsevier.
Salway, J.G. Metabolism at a glance (3rd ed.) (2004). Alden, Mass.: Blackwell Pub.
Kroetz DL, Zeldin DC: Cytochrome P450 pathways of arachidonic acid metabolism. Curr Opin Lipidol. 2002 Jun;13(3):273-83.
Pubmed: 12045397
Zeldin DC: Epoxygenase pathways of arachidonic acid metabolism. J Biol Chem. 2001 Sep 28;276(39):36059-62. doi: 10.1074/jbc.R100030200. Epub 2001 Jul 12.
Pubmed: 11451964
Ondrey FG: Arachidonic acid metabolism: a primer for head and neck surgeons. Head Neck. 1998 Jul;20(4):334-49.
Pubmed: 9588707
Sigal E: The molecular biology of mammalian arachidonic acid metabolism. Am J Physiol. 1991 Feb;260(2 Pt 1):L13-28. doi: 10.1152/ajplung.1991.260.2.L13.
Pubmed: 1899973
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