Leukotriene C4 Synthesis Deficiency


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.

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References

  1. OMIM: Entry 246530
  2. Uniprot: Q16873
  3. 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. Epub 2007 Jul 15. Pubmed
  4. 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. Epub 2001 Apr 23. Pubmed
  5. 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
  6. 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. Pubmed
  7. 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