Aminopeptidase B from the rat testis is a bifunctional enzyme structurally related to leukotriene-A<sub>4 </sub>hydrolase

Cadel, Sandrine; Foulon, Thierry; Viron, A.; Balogh, Agnès; Midol-Monnet, Stéphanie; Noel, Nadine; Cohen, Paul A.

doi:10.1073/pnas.94.7.2963

Cited by 78 publications

(65 citation statements)

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“…AP-B generates mature (Met)enkephalin (ME) from Arg-ME and Lys-ME peptide intermediates [6]. Sequence analyses of bovine and rat AP-B cDNAs [6][7][8] illustrate the presence of the metal-binding HEXXH motif which is typical of members of metalloprotease families [9,10]. Most metalloproteases are regulated by zinc metal ion, but a few metalloproteases, such as methionyl aminopeptidase in Escherichia coli (M24 family of metalloprotease) and aminopeptidase T from thermus aquaticus (M29 family) utilize cobalt for activity [10].…”

Section: Introductionmentioning

confidence: 99%

Zinc regulation of aminopeptidase B involved in neuropeptide production

Hwang

Hook

2008

FEBS Letters

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Aminopeptidase B (AP-B) is a metallopeptidase that removes basic residues from the N-termini of neuropeptide substrates in secretory vesicles. This study assessed zinc regulation of AP-B activity, since secretory vesicles contain endogenous zinc. AP-B was inhibited by zinc at concentrations typically present in secretory vesicles. Zinc effects were dependent on concentration, incubation time, and the molar ratio of zinc to enzyme. AP-B activity was recovered upon removal of zinc. AP-B with zinc became susceptible to degradation by trypsin, suggesting that zinc alters enzyme conformation. Zinc regulation demonstrates the metallopeptidase property of AP-B.

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Section: Introductionmentioning

confidence: 99%

Zinc regulation of aminopeptidase B involved in neuropeptide production

Hwang

Hook

2008

FEBS Letters

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“…However, the epoxide hydrolase activity appears to be unique for LTA4H and has not been detected with certainty in any human homologue, although conflicting data have been reported for aminopeptidase B (38,39). LTA4H is present in several lower vertebrates including fish and frogs but not in lower species (40,41).…”

Section: Molecular Evolution Of Lta 4 Hydrolasementioning

confidence: 99%

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

Haeggström

2004

Journal of Biological Chemistry

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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“…Thus, mammalian LTA 4 hydrolases may have originated from aminopeptidases like AP-1, retaining their aminopeptidase activity and developing a LTA 4 hydrolase function in higher eukaryotes. In support of this hypothesis, an aminopeptidase B has recently been cloned from rat testes (46) that shows highest homology to mammalian leukotriene A 4 hydrolases (44%), intermediate homology to C. elegans AP-1 (38%), and lowest homology to mammalian N-type aminopeptidases (21-24%) (Table II) and can catalyze the conversion of LTA 4 to LTB 4 (46).…”

mentioning

confidence: 95%

Molecular Cloning and Functional Expression of aCaenorhabditis elegans Aminopeptidase Structurally Related to Mammalian Leukotriene A4 Hydrolases

Baset

Ford‐Hutchinson

O’Neill

1998

Journal of Biological Chemistry

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In a search of the Caenorhabditis elegans DNA data base, an expressed sequence tag of 327 base pairs (termed cm01c7) with strong homology to the human leukotriene A 4 (LTA 4 ) hydrolase was found. The use of cm01c7 as a probe, together with conventional hybridization screening and anchored polymerase chain reaction techniques resulted in the cloning of the full-length 2.1 kilobase pair C. elegans LTA 4 hydrolase-like homologue, termed aminopeptidase-1 (AP-1). The AP-1 cDNA was expressed transiently as an epitope-tagged recombinant protein in COS-7 mammalian cells, purified using an anti-epitope antibody affinity resin, and tested for LTA 4 hydrolase and aminopeptidase activities. Despite the strong homology between the human LTA 4 hydrolase and C. elegans AP-1(63% similarity and 45% identity at the amino acid level), reverse-phase high pressure liquid chromatography and radioimmunoassay for LTB 4 production revealed the inability of the C. elegans AP-1 to use LTA 4 as a substrate. In contrast, the C. elegans AP-1 was an efficient aminopeptidase, as demonstrated by its ability to hydrolyze a variety of amino acid pnitroanilide derivatives. The aminopeptidase activity of C. elegans AP-1 resembled that of the human LTA 4 hydrolase/aminopeptidase enzyme with a preference for arginyl-p-nitroanilide as a substrate. Hydrolysis of the amide bond of arginyl-p-nitroanilide was inhibited by bestatin with an IC 50 of 2.6 ؎ 1.2 M. The bifunctionality of the mammalian LTA 4 hydrolase is still poorly understood, as the physiological substrate for its aminopeptidase activity is yet to be discovered. Our results support the idea that the enzyme originally functioned as an aminopeptidase in lower metazoa and then developed LTA 4 hydrolase activity in more evolved organisms.

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Aminopeptidase B from the rat testis is a bifunctional enzyme structurally related to leukotriene-A₄hydrolase

Cited by 78 publications

References 51 publications

Zinc regulation of aminopeptidase B involved in neuropeptide production

Zinc regulation of aminopeptidase B involved in neuropeptide production

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

Molecular Cloning and Functional Expression of aCaenorhabditis elegans Aminopeptidase Structurally Related to Mammalian Leukotriene A4 Hydrolases

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Aminopeptidase B from the rat testis is a bifunctional enzyme structurally related to leukotriene-A4 hydrolase

Cited by 78 publications

References 51 publications

Zinc regulation of aminopeptidase B involved in neuropeptide production

Zinc regulation of aminopeptidase B involved in neuropeptide production

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

Molecular Cloning and Functional Expression of aCaenorhabditis elegans Aminopeptidase Structurally Related to Mammalian Leukotriene A4 Hydrolases

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Aminopeptidase B from the rat testis is a bifunctional enzyme structurally related to leukotriene-A₄hydrolase