Cysteinyl leukotrienes biosynthesis

Lam BK, Austen KF. Leukotriene C-4 synthase - a pivotal enzyme in the biosynthesis of the cysteinyl leukotrienes. Am J Respir Crit Care Med 2000 161 16-19. 

Fig. 3.8 Biosynthesis of cysteinyl leukotrienes from arachidonic acid showing the pathways to the formation of LTAi, LTB4, LTC4, LTD4, and LTE4...

Recently, total absence of cysteinyl leukotrienes in the CSF of patients with a severe neurodevelopmental syndrome led to the discovery of LTC4-synthase deficiency [6, 7]. In the meantime there is evidence of two further defects in the biosynthesis of leukotrienes representing a new group of neurometabolic disorders [8]. 

Assay methods using combined gas chromatography-mass spectrometry with selected ion monitoring and addition of stable isotopes as carriers and internal standards have been published for the different HETE isomers [208,236,385]. However, so far no GC-MS-assay for LTB4 and related dihydroxy acids or the cysteinyl-containing leukotrienes have been described. Deuterated standards of HETEs were prepared from octadeuterated arachidonic acid either by biosynthesis in mammalian tissues [236,385] or by chemical methods [208]. Preparation of internal standards by chemical methods resulted in deuterated standards with minimal contamination of unlabeled material. This resulted in assays with a detection limit of about 1 pmol for the different HETEs. A GC-MS assay without addition of deuterated internal standards has also been described for analysis of the ratio between different HETEs in the same sample [210]. 

Figure 1. Pathways and chemical structures for leukotriene and lipoxin biosynthesis. Enzymes responsible for known catalytic steps are noted in italics. AA, arachidonicacid.5-, 15-LOX, 5-, 15-lipoxygenase. 5-, 15-HETE, 5(5 )-, 15(5)-hydroxyeicosatetraenoicacid.5-, 15-HPETE, 5(5 )-, 15(5 )-hydroperoxyeicosatetraenoic acid. 5(6)-Epoxytetraene, 15(5)-hydroxy-5(6)-epoxy-7,9,13- ra. -ll-c/5-eicosatetraenoic acid. LTA, leukotriene A 5(6)-epoxy-7,9- rafZ5-ll,14-cw-eicosatetraenoic acid. LTB, leukotriene 5(5 ),12(/ )-dihydroxy-6,14-cw-8,10- rfl .y-eicosatetraenoic acid. LTC, peptido-leukotriene C 5(5)-hydroxy-6(/ )-5 -glutathione-7,9-fra 5-ll,14-cw-eicosatetraenoic acid. LTD, peptido-leukotriene D 5(5)-hydroxy-6(/ )-( S-cysteinylglycinyl)-7,9-rra 5-11,14-cA-eicosatetraenoic acid. LTE, peptido-leukotriene E 5(5)-hydroxy-6(/ )-( S-cysteinyl)-7,9-rra 5-ll,14-cw-eicosatetraenoic acid. LXA, lipoxin A 5(5 ),6(/ ), 15(5)-trihydroxy-7,9, 3-trans-11 -cA-eicosatetraenoic acid.

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