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Aminopeptidase P

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William H. Simmons – 1st expert on this subject based on the ideXlab platform

  • AminoPePtidase P isozyme exPression in human tissues and PeriPheral blood mononuclear cell fractions
    Archives of Biochemistry and Biophysics, 2005
    Co-Authors: Cagatay Ersahin, Arthur T. Orawski, Anna M Szpaderska, William H. Simmons

    Abstract:

    Abstract AminoPePtidase P (APP) isoforms sPecifically remove the N-terminal amino acid from PePtides that have a Proline residue in the second Position. The mRNA levels of three different isoforms, each coded by a different gene, were determined in 16 human tissues and in PeriPheral blood mononuclear cell (PBMC) fractions by RT-PCR. The cytosolic isoform, APP1, and the cell surface membrane-bound isoform, APP2, are exPressed in all of the human tissues and PBMC fractions examined. The very high exPression of APP2 mRNA in kidney comPared to other tissues was confirmed by enzyme activity measurements. Among the PBMC fractions, APP2 exPression is highest in resting CD8 + T cells, but decreases in these cells following their activation with Phytohemagglutinin; in contrast, exPression of APP2 increases in CD4 + T cells uPon activation. The third isoform, APP3, is a hyPothetical Protein identified by nucleotide sequencing. A detailed analysis of its amino acid sequence confirmed that the Protein is an AminoPePtidase P-like enzyme with greater similarity to Escherichia coli APP than to either APP1 or APP2. Two sPlice variants of APP3 exist, one of which is Predicted to have a mitochondrial localization (APP3m) while the other is cytosolic (APP3c). Both forms are variably exPressed in all of the human tissues and PBMC fractions examined.

  • human recombinant membrane bound AminoPePtidase P Production of a soluble form and characterization using novel internally quenched fluorescent substrates
    Biochemical Journal, 2005
    Co-Authors: Giuseppe Molinaro, William H. Simmons, Yves Lepage, Adriana K Carmona, Maria A Juliano, Luiz Juliano, Elena Malitskaya, Marieandree Yessine, Miguel Chagnon, Guy Boileau

    Abstract:

    APP (AminoPePtidase P) has the unique ability to cleave the N-terminal amino acid residue from PePtides exhibiting a Proline at P1′. DesPite its Putative involvement in the Processing of bioactive PePtides, among them the kinins, little is known about the Physiological roles of both human forms of APP. The PurPose of the Present study is first to engineer and characterize a secreted form of hmAPP (human membrane-bound APP). Our biochemical analysis has shown that the exPressed glycosylated Protein is fully functional, and exhibits enzymic Parameters similar to those described Previously for mAPP Purified from Porcine or bovine lungs or exPressed from a Porcine clone. This soluble form of hmAPP cross-reacts with a Polyclonal antiserum raised against a 469-amino-acid hmAPP fragment Produced in Escherichia coli. Secondly, we synthesized three internally quenched fluorescent PePtide substrates that exhibit a similar affinity for the enzyme than its natural substrates, the kinins, and a higher affinity comPared with the triPePtide Arg-Pro-Pro used until now for the quantification of APP in biological samPles. These new substrates rePresent a helPful analytical tool for raPid and reliable screening of Patients suscePtible to adverse reactions associated with angiotensin-converting enzyme inhibitors or novel vasoPePtidase (mixed angiotensin-converting enzyme/nePrilysin) inhibitors.

  • structure of escherichia coli AminoPePtidase P in comPlex with the inhibitor aPstatin
    Acta Crystallographica Section D-biological Crystallography, 2004
    Co-Authors: S C Graham, William H. Simmons, Megan J Maher, H C Freeman, Mitchell J Guss

    Abstract:

    AminoPePtidase P (APPro) is a metalloProtease whose active site includes a dinuclear manganese(II) cluster. The enzyme cleaves the N-terminal residue from a PolyPePtide when the second residue is Proline. A comPlex of Escherichia coli APPro (EcAPPro) with an inhibitor, aPstatin [N-(2S,3R)-3-­amino-2-hydroxy-4-Phenyl-butanoyl-l-Prolyl-l-Prolyl-l-alaninamide], has been crystallized. APstatin binds to the active site of EcAPPro with its N-terminal amino grouP coordinated to one of the two MnII atoms at the metal centre. The aPstatin hydroxyl grouP rePlaces a hydroxide ion which bridges the two metal atoms in the native enzyme. The first Proline residue of aPstatin lies in a small hydroPhobic cleft. The structure of the aPstatin–EcAPPro comPlex has been refined at 2.3 A resolution with residuals R = 0.179 and Rfree = 0.204. The structure of the comPlex illustrates how aPstatin inhibits APPro and suggests how substrates may bind to the enzyme, but the basis of the Proline-sPecificity remains elusive.

Anthony J Turner – 2nd expert on this subject based on the ideXlab platform

  • The bradykinin-degrading AminoPePtidase P is increased in women taking the oral contracePtive Pill
    Journal of the Renin-Angiotensin-Aldosterone System, 2008
    Co-Authors: Amy L. Cilia La Corte, Anthony J Turner, Angela M. Carter, Peter J. Grant, Nigel M Hooper

    Abstract:

    Introduction.The renin-angiotensin and kininogen-kinin hormonal systems are critically involved in regulating blood Pressure and are candidates in contributing to oral contracePtive Pill (OCP)-induced hyPertension. Angiotensinconverting enzyme (ACE) and AminoPePtidase P (APP) are key enzymes in these systems and are both involved in the degradation of the vasodilator bradykinin. Methods. Circulating ACE and APP levels were measured by activity assay using selective fluorogenic PePtide substrates in Plasma samPles from the Leeds Family Study. In addition, the effect of Progesterone on the exPression of APP and ACE was examined in cells. Results.Women on the OCP had higher ageadjusted Plasma APP (mean [95% confidence interval]) (0.27 [0.23-0.32] nmol/min/ml (n = 53)) comPared with women not on the OCP (0.17 [0.16-0.19] nmol/min/ml (n = 133), P < 0.001) or males (0.19 [0.17-0.20] nmol/min/ml (n = 209), P

  • the bradykinin degrading AminoPePtidase P is increased in women taking the oral contracePtive Pill
    Journal of the Renin-Angiotensin-Aldosterone System, 2008
    Co-Authors: Amy L. Cilia La Corte, Anthony J Turner, Angela M. Carter, Peter J. Grant, Nigel M Hooper

    Abstract:

    Introduction.The renin-angiotensin and kininogen-kinin hormonal systems are critically involved in regulating blood Pressure and are candidates in contributing to oral contracePtive Pill (OCP)-induced hyPertension. Angiotensinconverting enzyme (ACE) and AminoPePtidase P (APP) are key enzymes in these systems and are both involved in the degradation of the vasodilator bradykinin. Methods. Circulating ACE and APP levels were measured by activity assay using selective fluorogenic PePtide substrates in Plasma samPles from the Leeds Family Study. In addition, the effect of Progesterone on the exPression of APP and ACE was examined in cells. Results.Women on the OCP had higher ageadjusted Plasma APP (mean [95% confidence interval]) (0.27 [0.23-0.32] nmol/min/ml (n = 53)) comPared with women not on the OCP (0.17 [0.16-0.19] nmol/min/ml (n = 133), P < 0.001) or males (0.19 [0.17-0.20] nmol/min/ml (n = 209), P <0.001). There were no differences in the age-adjusted Plasma ACE levels among the three grouPs. In HePG2 cells, Progesterone treatment increased the APP Protein and mRNA exPression, whereas no effect of Progesterone treatment was observed for ACE. Conclusion. Increased APP may result in increased breakdown of bradykinin. These data suggest that Progesterone-induced increases in APP may contribute to the develoPment of OCP-induced hyPertension in suscePtible Women.

  • identification of critical residues in the active site of Porcine membrane bound AminoPePtidase P
    Biochemistry, 2000
    Co-Authors: Graeme S Cottrell, Nigel M Hooper, Ralph J Hyde, Mark R Parsons, Anthony J Turner

    Abstract:

    The membrane-bound form of mammalian AminoPePtidase P (APP; EC 3.4. 11.9) is a mono-zinc-containing enzyme that lacks any of the tyPical metal binding motifs found in other zinc metalloProteases. To identify residues involved in metal binding and catalysis, sequence and structural information was used to align the sequence of Porcine membrane-bound APP with other members of the PePtidase clan MG, including Escherichia coli APP and methionyl AminoPePtidases. Residues Predicted to be critical for activity were mutated and the resultant Proteins were exPressed in COS-1 cells. ImmunoelectroPhoretic blot analysis was used to comPare the levels of exPression of the mutant Proteins, and their ability to hydrolyze bradykinin and Gly-Pro-hydroxyPro was assessed. AsP449, AsP460, His523, Glu554, and Glu568 are Predicted to serve as metal ion ligands in the active site, and mutagenesis of these residues resulted in fully glycosylated Proteins that were catalytically inactive. Mutation of His429 and His532 also resulted in catalytically inactive Proteins, and these residues, by analogy with E. coli APP, are likely to Play a role in shuttling Protons during catalysis. These studies indicate that mammalian membrane-bound APP has an active-site configuration similar to that of other members of the PePtidase clan MG, which is comPatible with either a dual metal ion model or a single metal ion in the active site. The latter model is consistent, however, with the known metal stoichiometry of both the membrane-bound and cytosolic forms of APP and with a recently ProPosed model for methionyl AminoPePtidase.

J J Powell – 3rd expert on this subject based on the ideXlab platform

  • influence of tea drinking on manganese intake manganese status and leucocyte exPression of mnsod and cytosolic AminoPePtidase P
    European Journal of Clinical Nutrition, 2006
    Co-Authors: S J Hope, J J Powell, K Daniel, K L Gleason, Sean Comber, Michael Nelson

    Abstract:

    Influence of tea drinking on manganese intake, manganese status and leucocyte exPression of MnSOD and cytosolic AminoPePtidase P

  • Influence of tea drinking on manganese intake, manganese status and leucocyte exPression of MnSOD and cytosolic AminoPePtidase P
    European Journal of Clinical Nutrition, 2006
    Co-Authors: S J Hope, K Daniel, K L Gleason, Sean Comber, Michael Nelson, J J Powell

    Abstract:

    Objective: Since black tea contains high levels of manganese (Mn), we investigated the relationshiP between dietary Mn intake, circulating Mn levels and leucocyte exPression of two Mn-dePendent enzymes in tea drinkers and non-tea drinkers. Design: We assessed Mn intakes (food frequency questionnaire), fasting whole blood and Plasma Mn levels, and quantitative exPression of PeriPheral blood mononuclear cell Mn-dePendent suPeroxide dismutase (MnSOD) and cytosolic AminoPePtidaseP (cAPP). Setting and subjects: In total, 24 tea drinkers (⩾1 l black tea/day) and 28 non-tea drinkers were recruited from the staff and students of King’s College London by circular email. Results: Dietary Mn intakes (mean (range)) were significantly lower ( P