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 [7].

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 [5].

LTA4H is a member of a family of arginyl aminopeptidases (ENSFM00250000001675), which also includes aminopeptidase B (RNPEP, 9H4A4) and aminopeptidase B-like 1 (RNPEPL1, Q9HAU8). Dipeptidase 1 and 2 are members of a family of membrane dipeptidases, which also includes (DPEP3, Q9H4B8) for which LTD₄ appears not to be a substrate.

1. Allen L, Meck R, Yunis A. (1980) The inhibition of gamma-glutamyl transpeptidase from human pancreatic carcinoma cells by (alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125; NSC-163501). Res Commun Chem Pathol Pharmacol, 27 (1): 175-82. [PMID:6102405]

2. 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]

3. Han L, Hiratake J, Kamiyama A, Sakata K. (2007) Design, synthesis, and evaluation of gamma-phosphono diester analogues of glutamate as highly potent inhibitors and active site probes of gamma-glutamyl transpeptidase. Biochemistry, 46 (5): 1432-47. [PMID:17260973]

4. Munck Af Rosenschöld M, Johannesson P, Nikitidis A, Tyrchan C, Chang HF, Rönn R, Chapman D, Ullah V, Nikitidis G, Glader P et al.. (2019) Discovery of the Oral Leukotriene C4 Synthase Inhibitor (1S,2S)-2-({5-[(5-Chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic Acid (AZD9898) as a New Treatment for Asthma. J Med Chem, 62 (17): 7769-7787. [PMID:31415176]

5. 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]

6. 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]

7. 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]

8. Ronn R, Lindh CJ, Ringberg E, Andersson EHB, Nilsson P, Schall WR, Munk af RM, Nikitidis A, Nikitidis G, Johannesson PJ et al.. (2016) Cyclopropane carboxylic acid derivatives and pharmaceutical uses thereof. Patent number: WO2016177845. Assignee: Astrazeneca Ab. Priority date: 06/05/2015. Publication date: 10/11/2016.