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Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Leukotriene A4 (LTA4), produced by 5-LOX activity, and lipoxins may be subject to further oxidative metabolism; ω-hydroxylation is mediated by CYP4F2 and CYP4F3, while β-oxidation in mitochondria and peroxisomes proceeds in a manner dependent on coenzyme A conjugation. Conjugation of LTA4 at the 6 position with reduced glutathione to generate LTC4 occurs under the influence of leukotriene C4 synthase, with the subsequent formation of LTD4 and LTE4, all three of which are agonists at CysLT receptors. LTD4 formation is catalysed by γ-glutamyltransferase, and subsequently dipeptidase 2 removes the terminal glycine from LTD4 to generate LTE4. Leukotriene A4 hydrolase converts the 5,6-epoxide LTA4 to the 5-hydroxylated LTB4, an agonist for BLT receptors. LTA4 is also acted upon by 12S-LOX to produce the trihydroxyeicosatetraenoic acids lipoxins LXA4 and LXB4. Treatment with a LTA4 hydrolase inhibitor in a murine model of allergic airway inflammation increased LXA4 levels, in addition to reducing LTB4, in lung lavage fluid .
LTA4 hydrolase is also involved in biosynthesis of resolvin Es. Aspirin has been reported to increase endogenous formation of 18S-hydroxyeicosapentaenoate (18S-HEPE) compared with 18R-HEPE, a resolvin precursor. Both enantiomers may be metabolised by human recombinant 5-LOX; recombinant LTA4 hydrolase converted chiral 5S(6)-epoxide-containing intermediates to resolvin E1 and 18S-resolvin E1 .
1. Graham DW, Ashton WT, Barash L, Brown JE, Brown RD, Canning LF, Chen A, Springer JP, Rogers EF. (1987) Inhibition of the mammalian beta-lactamase renal dipeptidase (dehydropeptidase-I) by (Z)-2-(acylamino)-3-substituted-propenoic acids. J. Med. Chem., 30 (6): 1074-90. [PMID:3495664]
2. Oh SF, Pillai PS, Recchiuti A, Yang R, Serhan CN. (2011) Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation. J. Clin. Invest., 121 (2): 569-81. [PMID:21206090]
3. Orning L, Krivi G, Fitzpatrick FA. (1991) Leukotriene A4 hydrolase. Inhibition by bestatin and intrinsic aminopeptidase activity establish its functional resemblance to metallohydrolase enzymes. J. Biol. Chem., 266 (3): 1375-8. [PMID:1846352]
4. Rao NL, Riley JP, Banie H, Xue X, Sun B, Crawford S, Lundeen KA, Yu F, Karlsson L, Fourie AM et al.. (2010) Leukotriene A(4) hydrolase inhibition attenuates allergic airway inflammation and hyperresponsiveness. Am. J. Respir. Crit. Care Med., 181 (9): 899-907. [PMID:20110560]
5. Shiro T, Kakiguchi K, Takahashi H, Nagata H, Tobe M. (2013) 7-Phenyl-imidazoquinolin-4(5H)-one derivatives as selective and orally available mPGES-1 inhibitors. Bioorg. Med. Chem., 21 (11): 2868-78. [PMID:23623673]
Database page citation:
Leukotriene and lipoxin metabolism. Accessed on 28/04/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=272.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Fabbro D, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Southan C, Davies JA and CGTP Collaborators (2015) The Concise Guide to PHARMACOLOGY 2015/16: Enzymes. Br J Pharmacol. 172: 6024-6109.