Leukotriene A4 hydrolase

The human malaria parasite Plasmodium falciparum expresses two neutral zinc-aminopeptidases, PfA-Ml and PfA-M17, which function in regulating the intracellular pool of amino acids required for parasite growth and development inside the red blood cell. These enzymes are essential for parasite viability and are validated therapeutic targets. As a result of the rapid emergence of drug-resistant parasites, blocking these peptidases with potent inhibitors has been proposed as a potential new antimalarial therapy. The simple phosphinic dipeptide 61 (Table 1) was reported to inhibit PfA-M17 with a Ki value of 80 nM [130]. 

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MA M1 M01.004 Leukotriene A4 hydrolase Drug target to control inflammation... 

Liang, A.M., Claret, E., Ouled-Diaf, J., Jean, A., Vogel, D., Light, D.R., Jones, S.W., Guilford, W.J., Parkinson, J.F., and Snider, R.M. (2007) Development of a homogeneous time-resolved fluorescence leukotriene B4 assay for determining the activity of Leukotriene A4 hydrolase. J. Biomol. Screen. 12, 536-545. 

The cytosolic enzyme leukotriene A4 hydrolase (EC 3.3.2.6), which ster-eoselectively converts leukotriene A4 (LTA4) to leukotriene B4 [56], This enzyme catalyzes the hydrolytic cleavage of the 5,6-epoxide ring in LTA4, but, in contrast to what happens with other EHs, the product is not a vicinal diol but a 5,12-diol. As a zinc metalloenzyme, LTA4 hydrolase does not appear to be related to any other epoxide hydrolase. 

M. J. Muller, B. Samuelsson, J. Z. Haeggstrom, Chemical Modification of Leukotriene A4 Hydrolase. Indications for Essential Tyrosyl and Arginyl Residues at the Active Site , Biochemistry 1995, 34, 3536 - 3543. 

LEUKOTRIENE Q SYNTHASE 5-LIPOXYCENASE LEUKOTRIENE A4 HYDROLASE Leukotriene A4 synthase, 5-LIPOXYCENASE Leukotriene 84,... 

PSSC based reanalysis of the development of leukotriene A4 hydrolase inhibitors... 

Helgadottir A, Manolescu A, Helgason A, et al. A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction. Nat Genet 2006 38 68-74. 

Leukotriene A4 hydrolase is a unique cytosolic epoxide hydrolase, structurally dissimilar to the cytosolic enzyme described above. Its substrate specificity is narrow, being restricted to leukotriene A4, (5(S)-trans-5,6-oxido-7,9-cis-ll,l4-trans-eicosatetraenoic acid), and related fatty acids. 

Enzyme-catalyzed epoxide ring opening including discussion of convergent families of epoxide hydrolases, the catalytic mechanism of microsomal epoxide hydrolases, epoxide hydrolases in metabolism, and the synthesis, structure, and mechanism of leukotriene A4 hydrolase, and glutathione transferase has been reviewed by Armstrong <1999CONAP(5)51>. 

Progress on probing the mechanism of action of leukotriene A4 hydrolase [EC 3.3.2.6.1 is elegantly summarized in a recent review by Haeggstrom and Wetterholm (185). This enzyme is a 70-kDa zinc-containing monomeric... 

Davies DR, Mamat B, Magnusson OT et al (2009) Discovery of leukotriene A4 hydrolase inhibitors using metabolomics biased fragment crystallography. J Med Chem 52 4694-4715... 

Sandanayaka V, Mamat B, Mishra RK et al (2010) Discovery of 4-[(2S)-2- [4-(4-chloro-phenoxy)phenoxy]methyl -l-pyrrolidinyl]butanoic acid (DG-051) as anovel leukotriene A4 hydrolase inhibitor of leukotriene B4 biosynthesis. J Med Chem 53 573-585... 

L. Orning, G. Krivi, F.A. Fitzpatrick, Leukotriene A4 hydrolase. Inhibition by bestatin and intrinsic aminopeptidase activity establish its functional resemblance to metallohydrolase enzymes, J. Biol. Chem. 1991, 266,1375-1378. 

Leukotriene A4 hydrolase Inflammatory diseases DS CATALYST Inhibitor (IC50 = 8 nM) [127]... 

Comparison of the ligands to Zn in human leukotriene A4 hydrolase with those in thermolysin allowed its classification as a thermolysin type (Table 1). Although the hydrolase reaction involved is different (Scheme 4), nucleophilic attack at the substrate by Zn -OH2 is a common feature. 

Zaitsu et al. [72] have studied the effect of IL-4 on A23187-stimulated synthesis of the potent chemotactic factor leukotriene B4 in human neutrophils. They found that IL-4 enhanced this response and increased mRNA expression and protein synthesis of leukotriene A4 hydrolase. More recently, it was reported that a single exposure of normal human skin to ultraviolet B radiation induced an infiltration of numerous IL-4+ cells that were identified as neutrophils [73], based on the observations that they coexpressed CDl 5 and CDl lb, showed a clear association with elastase, and had a multilobed nucleus. In one other study, the expression of CD23 (the low affinity receptor for IgE) on human neutrophils isolated from rheumatoid arthritis patients was monitored by immunofluorescence [74]. Results showed a strong association between the ability of neutrophils to express CD23 and rheumatoid arthritis, and that such expression may be regulated by GM-CSF, IFN-7 and IL-4. 

Yuan JH, Birkmeier J, Yang DC, Hribar JD, Liu N, Bible R, Hajdu E, Rock M, Schoenhard G. Isolation and identification of metabolites of leukotriene A4 hydrolase inhibitor SC-57461 in rats. Drug Metab Dispos 1996 24 1124-1133. 

Brock, T. G., Y. J. Lee et al. 2005. Nuclear localization of leukotriene A4 hydrolase in type II alveolar epithelial cells in normal and fibrotic lung. Am J Phvsiol 1ms Cell Mol Phv/siol 289(2) L224-232. 

Dalli, 1., M. Zhu et al. 2013. The novel 13S,14S-epoxy-maresin is converted hy human macrophages to maresin 1 (MaRl), inhihits leukotriene A4 hydrolase (LTA4H), and shifts macrophage phenotype. FASEB 27(7) 2573-2583. 

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