Leukotriene A4 Hydrolase

Rudberg, Peter; Tholander, Fredrik; Andberg, Martina; Thunnissen, Marjolein M.G.M.; Haeggström, Jesper Z.

doi:10.1074/jbc.m401031200

Cited by 48 publications

(38 citation statements)

References 56 publications

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“…Thus, ERAP1 does not bind the C-terminal residue by interacting with the carboxyl group but instead associates with its hydrophobic side chain (Table 1). This substrate-recognition mechanism contrasts with that of certain related M1 aminopeptidases (e.g., leukotriene A4 hydrolase) that cleave di-and tripeptides by binding their carboxyl group through conserved Arg and Lys residues (42). ERAP1, accordingly, lacks these conserved basic residues.…”

Section: Discussionmentioning

confidence: 64%

The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism

Chang

Momburg

Bhutani

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

300

336

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Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an IFN-␥-induced aminopeptidase in the endoplasmic reticulum that trims longer precursors to the antigenic peptides presented on MHC class I molecules. We recently reported that purified ERAP1 trimmed N-extended precursors but spared peptides of 8 -9 residues, the length required for binding to MHC class I molecules. Here, we show another remarkable property of ERAP1: that it strongly prefers substrates 9 -16 residues long, the lengths of peptides transported efficiently into the ER by the transporter associated with antigen processing (TAP) transporter. This aminopeptidase rapidly degraded a model 13-mer to a 9-mer and then stopped, even though the substrate and the product had identical N-and C-terminal sequences. No other aminopeptidase, including the closely related ER-aminopeptidase ERAP2, showed a similar length preference. Unlike other aminopeptidases, the activity of ERAP1 depended on the C-terminal residue of the substrate. ERAP1, like most MHC class I molecules, prefers peptides with hydrophobic C termini and shows low affinity for peptides with charged C termini. Thus, ERAP1 is specialized to process precursors transported by TAP to peptides that can serve as MHC class I epitopes. Its ''molecular ruler'' mechanism involves binding the hydrophobic C terminus of the substrate 9 -16 residues away from the active site.antigen presentation ͉ antigen processing ͉ proteases M HC class I molecules bind tightly and display on the cell surface antigenic peptides that are derived from peptides generated during the degradation of intracellular proteins. If nonnative peptides (e.g., from viral proteins) are presented, they are recognized by circulating cytotoxic T lymphocytes (1-4). To fit in the groove in most MHC class I molecules, these antigenic peptides must have a length of 8-10 residues (5, 6), although certain class I molecules can admit peptides up to 11 residues (7). It is now firmly established that the proteasome pathway is responsible for the generation of the great majority of antigenic peptides (8-10). Proteasomes generally degrade proteins to peptide fragments ranging from 2-25 residues long (11), but most are too short (Ͻ8 residues) for antigen presentation. Several studies using proteasome inhibitors have further shown that cleavages within proteasomes define the C-terminal residues of MHC class I-presented peptides (12). However, their N termini often are generated by aminopeptidases, which trim longer N-extended proteasome products to the mature epitopes (13). In fact, proteasomes, and especially immunoproteasomes (1), the forms found in immune tissues and induced by IFN-␥ elsewhere, seem to preferentially generate such longer precursors (14), whose presentation requires Nterminal processing. Several cytosolic peptidases, including tripeptidyl peptidase II (TPPII) (15), bleomycin hydrolase and puromycin-sensitive aminopeptidase (16), and the IFN-␥-inducible enzyme leucine aminopeptidase (17), may play a role in trimming some precursors to antige...

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Section: Discussionmentioning

confidence: 64%

The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism

Chang

Momburg

Bhutani

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

300

336

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“…Furthermore, the C-1 carboxylate can make direct electrostatic interactions with the positive charge of Arg-563. This crucial interaction will also ensure perfect substrate alignment required for catalysis (31), in agreement with the fact that the free carboxylic acid of LTA 4 is required for catalysis (19,36). Furthermore, the catalytic zinc as well as Glu-271 will be proximal to the labile allylic epoxide, suggesting that they will polarize a water molecule and promote an acid-induced activation and opening of the epoxide ring (Fig.…”

Section: Proposed Mechanism Of the Epoxide Hydrolase Reactionmentioning

confidence: 70%

Leukotriene A4 Hydrolase/Aminopeptidase, the Gatekeeper of Chemotactic Leukotriene B4 Biosynthesis

Haeggström

2004

Journal of Biological Chemistry

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171

181

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The leukotrienes (LTs) 1 are a family of lipid mediators that play important roles in a variety of allergic and inflammatory reactions (1, 2). These molecules are formed by leukocytes and are divided into two classes, the spasmogenic cysteinyl leukotrienes and LTB 4 , which is a classical chemoattractant that triggers adherence and aggregation of leukocytes to the endothelium at nanomolar concentrations. Recent data also indicate that LTB 4 is a chemoattractant for T-cells, creating a functional link between early innate and late adaptive immune responses to inflammation (3-5). In addition, LTB 4 participates in the host defense against infections (6) and is a key mediator of platelet-activating factor-induced lethal shock (7). Because of these powerful biological effects, LTB 4 is regarded as an important chemical mediator in a variety of acute and chronic inflammatory diseases, e.g. nephritis, arthritis, dermatitis, and chronic obstructive pulmonary disease (8). Moreover, only recently, several lines of pharmacological, morphological, biochemical, and genetic evidence have been gathered implicating LTs, in particular LTB 4 , as a mediator of vascular inflammation and arteriosclerosis (9). This article gives an overview of the biochemical, structural, and catalytic properties of LTA 4 hydrolase (LTA4H), which catalyzes the final and committed step in LTB 4 biosynthesis. LTA 4 Hydrolase Is a Key Enzyme in the 5-Lipoxygenase PathwayIn cellular biosynthesis of LTs, 5-lipoxygenase, assisted by 5-lipoxygenase-activating protein, converts arachidonic acid into the unstable epoxide LTA 4 , which in turn may be enzymatically conjugated with GSH to form LTC 4 , the parent compound of the cysteinyl leukotrienes, or hydrolyzed into LTB 4 by LTA4H (Fig. 1). Leukotrienes can also be formed via transcellular routes, where LTA 4 is donated from an activated leukocyte to a recipient cell for further metabolism by downstream enzymes, a process that was recently shown to occur in vivo (10). LTB 4 signals via a specific, high affinity, G-protein-coupled receptor (BLT 1 ) (11). In addition, a second receptor for LTB 4 (BLT 2 ) has been discovered, the functional role of which is presently not known (12). Interestingly, LTB 4 is also a natural ligand of the peroxisome proliferator-activated receptor ␣ class of nuclear receptors and has been suggested to play a role in lipid homeostasis (13). Leukotriene A 4 Hydrolase Is a Zinc-dependent Epoxide Hydrolase and AminopeptidaseLTA4H is a monomeric soluble protein that is widely distributed and has been purified from several mammalian sources (14). It resides in the cytosol, although nuclear localization has also been reported recently (15). The cDNAs encoding the human, mouse, rat, and guinea pig enzymes have been cloned and sequenced. The proteins contain 610 amino acids, excluding the first Met, and the calculated molecular mass of the human enzyme is 69,153 Da. The primary, secondary, and tertiary structures of LTA4H bear no resemblance to soluble xenobiotic epoxide hydrolase, alth...

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“…Aminopeptidase activity was determined by a modification of the procedure of Rudberg et al (2004). Recombinant human LTA 4 H (375 ng) was preincubated for 15 min at room temperature in assay buffer (50 mM Tris-HCl, pH 8.0, 100 mM KCl) in the presence of different concentrations of JNJ-26993135 (0.2% final DMSO concentration).…”

Section: Methodsmentioning

confidence: 99%

Anti-Inflammatory Activity of a Potent, Selective Leukotriene A4 Hydrolase Inhibitor in Comparison with the 5-Lipoxygenase Inhibitor Zileuton

Rao

Dunford²,

Xue³

et al. 2007

The Journal of Pharmacology and Experimental Therapeutics

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Leukotriene A 4 hydrolase (LTA 4 H) catalyzes production of the proinflammatory lipid mediator, leukotriene (LT) B 4 , which is implicated in a number of inflammatory diseases. We have identified a potent and selective inhibitor of both the epoxide hydrolase and aminopeptidase activities of recombinant human LTA 4 H (IC 50 , approximately 10 nM). In a murine model of arachidonic acid-induced ear inflammation, the LTA 4 H inhibitor, JNJ-26993135 (1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidine-4-carboxylic acid), dose-dependently inhibited ex vivo LTB 4 production in blood, in parallel with dose-dependent inhibition of neutrophil influx (ED 50 , 1-3 mg/kg) and ear edema. In murine whole blood and in zymosan-induced peritonitis, JNJ-26993135 selectively inhibited LTB 4 production, without affecting cysteinyl leukotriene production, while maintaining or increasing production of the anti-inflammatory mediator, lipoxin (LX) A 4 . The 5-lipoxygenase (5-LO) inhibitor zileuton showed inhibition of LTB 4 , LTC 4 , and LXA 4 production. Although zileuton inhibited LTB 4 production in the peritonitis model more effectively than the LTA 4 H inhibitor, the influx of neutrophils into the peritoneum after 1 and 2 h was significantly higher in zileuton-versus JNJ-26993135-treated animals. This difference may have been mediated by the increased LXA 4 levels in the presence of the LTA 4 H inhibitor. The selective inhibition of LTB 4 production by JNJ-26993135, while increasing levels of the anti-inflammatory mediator, LXA 4 , may translate to superior therapeutic efficacy versus 5-LO or 5-LO-activating protein inhibitors in LTB 4 -mediated inflammatory diseases.

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Leukotriene A4 Hydrolase

Cited by 48 publications

References 56 publications

The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism

The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism

Leukotriene A4 Hydrolase/Aminopeptidase, the Gatekeeper of Chemotactic Leukotriene B4 Biosynthesis

Anti-Inflammatory Activity of a Potent, Selective Leukotriene A4 Hydrolase Inhibitor in Comparison with the 5-Lipoxygenase Inhibitor Zileuton

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