Substrate specificities of Cl−-activated arginine aminopeptidases from human and rat origin

Söderling, Eva

doi:10.1016/0003-9861(83)90380-6

Cited by 30 publications

(12 citation statements)

References 22 publications

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“…This hypothesis agrees well with earlier work with human and rat APB, showing that di-and tripeptides are good substrates, whereas oligopeptides are not hydrolyzed (57). In any event, our data suggest that evolution has developed Arg 563 and Lys 565 to carry out a fundamental function in carboxylate recognition as well as catalytic turnover of both lipid and peptide substrates, in the common active center of LTA4H.…”

supporting

confidence: 82%

Leukotriene A4 Hydrolase

Rudberg

Tholander

Andberg

et al. 2004

Journal of Biological Chemistry

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Leukotriene (LT) A 4 hydrolase is a bifunctional zinc metalloenzyme, which converts LTA 4 into the neutrophil chemoattractant LTB 4 and also exhibits an anion-dependent aminopeptidase activity. In the x-ray crystal structure of LTA 4 The leukotrienes (LTs) 1 are a class of structurally related lipid mediators involved in the development and maintenance of inflammatory and allergic reactions (1, 2). In the biosynthesis of LTs, 5-lipoxygenase converts arachidonic acid into the unstable epoxide LTA 4 . This intermediate may in turn be conjugated with glutathione to form the spasmogenic LTC 4 , or hydrolyzed into the proinflammatory lipid mediator LTB 4 , in a reaction catalyzed by LTA 4 hydrolase (LTA4H). Leukotriene B 4 is a classical chemoattractant of human neutrophils and triggers adherence and aggregation of leukocytes to vascular endothelium at only nanomolar concentrations (3). In addition, LTB 4 modulates immune responses (4, 5) and recent studies show that this lipid mediator is involved in early effector CD4 ϩ and CD8ϩ T cell recruitment to sites of inflammation (6 -8). Moreover, LTB 4 participates in the host-defense against infections (9, 10) and is a key mediator of platelet activating factorinduced lethal shock (11-13). These effects are signaled via specific, G protein-coupled receptors for LTB 4 (BLT 1 and BLT 2 ) (14, 15). The relative contributions of these two receptors to signaling and bioactivity are presently not clear.LTA4H (EC 3.3.2.6) is a bifunctional zinc metalloenzyme, exhibiting an anion-dependant aminopeptidase activity in addition to its epoxide hydrolase activity, i.e.

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supporting

confidence: 82%

Leukotriene A4 Hydrolase

Rudberg

Tholander

Andberg

et al. 2004

Journal of Biological Chemistry

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“…How ever, Södering [24] concluded that AP-B from human fetal liver does not seem to be connected to the metabolism of kinins and the other biologically active peptides such as angiotensin III. The nature of the natural substrate(s) will be required for understand ing the physiological significance of placen tal AP-B during pregnancy.…”

Section: Properties Of the Enzymementioning

confidence: 99%

“…Södering [24] showed that AP-Bs from the human erythrocyte and fetal liver show a narrow substrate specificity: L-Arg-ß-NA was the best and L-lysyl-ß-NA the second-…”

Section: Al [4] Pointed Out Is Probably Aminopeptidase Mmentioning

confidence: 99%

Purification and Properties of Human Placental Aminopeptidase B

Nagata

Mizutani²,

Nomura³

et al. 1991

Enzyme

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Aminopeptidase B (EC 3.4.11.6; L-arginyl-β-naphthylamidase) was purified 1,800-fold from human placental cytoplasm and characterized. The enzyme was subjected to ammonium sulfate fractionation and a series of chromatographies on DE-52, hydroxylapatite, Bio-gel A 0.5 m and L-arginine-Sepharose. The native molecular mass of the enzyme was estimated to be 220,000 by gel filtration. The molecular mass was estimated to be about 83,000 by SDS/PAGE in the absence of 2-mercaptoethanol, suggesting that the enzyme exists in a polymeric form. The isoelectric point of the enzyme was 5.4. The purified enzyme was most active at pH 7.2 with L-arginyl-β-naphthylamide as substrate and the K(m) value for this enzyme was 0.3 mmol/1. Human placental aminopeptidase B was markedly activity by CL. Bestatin and arphamenin, low molecular weight peptides, showed appreciable inhibition of this enzyme. However, amastatin and purymycin did not inhibit the enzyme. Bacitracin markedly activated this enzyme.

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“…In contrast to APA and APB, which specifically cleave N-terminal acidic and basic residues from peptide substrates, respectively [16, 17, 18], APN has a wide substrate specificity, directed against N-terminal neutral and basic amino acids [19, 20]. In vitro, APA hydrolyzes the N-terminal aspartate of AngII (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) to generate AngIII (Arg-Val-Tyr-Ile-His-Pro-Phe) [17, 21]whereas APN and APB hydrolyze the N-terminal arginine of AngIII to generate AngIV (Val-Tyr-Ile-His-Pro-Phe) [22, 23]. The in vivo involvement of APN in AngIII metabolism [5]was previously demonstrated by using EC27 (2-amino-pentan-1,5-dithiol), a specific APN inhibitor (K i = 0.032 ± 0.004 µ M ) 100 times less active on APA, but its inhibitory potency on APB was not evaluated [24].…”

Section: Introductionmentioning

confidence: 99%

PC18, a Specific Aminopeptidase N Inhibitor, Induces Vasopressin Release by Increasing the Half-Life of Brain Angiotensin III

et al. 1999

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Angiotensin III (AngIII), which is metabolized in vivo by aminopeptidase N (APN), was previously shown to be one of the main effector peptides of the brain renin-angiotensin system (RAS) in the control of vasopressin release. Recently, a potent APN inhibitor, PC18 (2-amino-4-methylsulfonyl butane thiol, methionine thiol), has been developed. In this study, we first checked the in vitro selectivity of PC18 towards APN, aminopeptidase A (APA) and aminopeptidase B (APB), three zinc metalloproteases with significant identity between their amino acid sequences. The K_i values of this compound on APN were found to be in the nanomolar range (K_i = 8.0 ± 1.7 nM) but it was 2,150 and 125 times less active on APA and APB, respectively. Secondly, we evaluated in vivo the effect of brain APN inhibition with PC18 on the inactivation of brain AngIII and on vasopressin secretion in mice. For this purpose, mice received [³H]AngII intracerebroventricularly in the presence or absence of the APN inhibitor PC18 (30 µg). At different times after the injection, [³H]AngIII levels were evaluated from hypothalamus homogenates after separation by cation-exchange chromatography. PC18 induced an accumulation of [³H]AngIII, increasing its half-life 3.9 times as compared with control values. In addition, the effect of PC18 on vasopressin release was studied in mice. PC18 (10–100 µg) was injected intracerebroventricularly, and plasma vasopressin levels were estimated by radioimmunoassay. PC18 increased vasopressin levels in a dose-dependent manner. The maximal increase in vasopressin release (+220%) is observed for a dose of PC18 of 100 µg and was inhibited 75% by the coadministration of the AngII receptor antagonist (Sar¹–Ala⁸)-AngII (0.5 µg). These results indicate that in vivo, in the mouse brain, APN inhibition by PC18 increases the half-life of endogenous AngIII, resulting in an enhanced vasopressin release.

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Substrate specificities of Cl−-activated arginine aminopeptidases from human and rat origin

Cited by 30 publications

References 22 publications

Leukotriene A4 Hydrolase

Leukotriene A4 Hydrolase

Purification and Properties of Human Placental Aminopeptidase B

PC18, a Specific Aminopeptidase N Inhibitor, Induces Vasopressin Release by Increasing the Half-Life of Brain Angiotensin III

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