Disease relevance of CPN1

• Pharmacologic intervention with angiotensin II and kininase inhibitor enhanced efficacy of radioimmunotherapy in human colon cancer xenografts [1].
• Previous studies identified a deficient subject afflicted with frequent episodes of angioedema, and other family members also had SCPN deficiency [2].
• The highest values for kallikrein, kininogen and kininase activity were found in patients in whom acute pancreatitis was accompanied by hemodynamic changes [3].
• PURPOSE: We investigated whether the kallikrein kinin system is activated in interstitial cystitis by measuring urinary excretion rates of kinin peptides, active and total kallikrein, and the kininase neutral endopeptidase in women with interstitial cystitis [4].
• The arginine carboxypeptidase involved in the proteolytic cleavage of the haemagglutinin of influenza A virus has been analysed by an assay employing a Sepharose-bound peptide containing radioactive arginine as a substrate [5].

Psychiatry related information on CPN1

• This paper outlines the development and piloting of a measure of professional stress for community mental health nurses, the CPN Stress Questionnaire (Revised) [6].
• The measures used included the Maslach Human Services Survey, the CPN Stress Questionnaire, the Psychnurse Methods of Coping Questionnaire, the Rosenberg Self-Esteem Scale and the General Health Questionnaire GHQ-12 [7].
• The CPN and eating disorders [8].
• This paper is based on the author's experience of using the Q sort technique with BA Social Sciences (BASS) students, and the community psychiatric nursing (CPN, ENB No 811 course) [9].

High impact information on CPN1

• VPE activity induced by RGP-1 was augmented by kininase inhibitors, inhibited by a kallikrein inhibitor and unaffected by an antihistamine drug [10].
• The kininase activity of endothelial cells was partially inhibited by antibody to human lung converting enzyme [11].
• The chemotactic factor inactivator (CFI) isolated from human serum contains a kininase activity that causes extensive hydrolysis of bradykinin [12].
• Using a new biochemical assay for measuring the carboxy-terminal cleavage activity, we purified from serum and plasma a peptidase that specifically removes the carboxy-terminal lysine from SDF-1alpha and identified it as carboxypeptidase N (CPN, also known as kininase I, arginine carboxypeptidase, and anaphylotoxin inactivator) [13].
• We tested the hypothesis that the copper present in bile--the major route of elimination of the metal from the body--is derived exclusively from hepatocytes by administering radiocopper (64Cu or 67Cu)-labeled ionic Cu, desialylated (AsCPN) or intact human ceruloplasmin (CPN), intravenously, to rats with cannulated bile ducts [14].

Chemical compound and disease context of CPN1

• In contrast, when kininase I and II inhibitors (DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid and enalaprilat, each 1 microM) were used to prevent the degradation of endogenous BK, NE overflow and reperfusion arrhythmias were enhanced [15].
• To shed light on the role of bradykinin in preeclampsia in addition to acute hypoxia, we measured the activity of kininase I, the enzyme responsible for its degradation, in umbilical plasma [16].
• Aldosterone, kallikrein, kininase I and II in normal and hypertension complicated pregnancy [17].

Biological context of CPN1

• We have prepared and crystallized the recombinant C-terminally truncated catalytic domain of human CPN1, and have determined and refined its 2.1 A crystal structure [18].
• Modeling of the Pro-Phe-Arg C-terminal end of the natural substrate bradykinin into the active site shows that the S1' pocket of CPN1 might better accommodate P1'-Lys than Arg residues, in agreement with CPN's preference for cleaving off C-terminal Lys residues [18].
• In tetrameric CPN, each CPN1 subunit might interact with the central leucine-rich repeat tandem of the cognate CPN2 subunit via a unique hydrophobic surface patch wrapping around the catalytic domain-TT interface, exposing the two active centers [18].
• In an in-vivo complement activation model in guinea pigs, BX 528 showed minimal inhibition of plasma CPN activity up to 60 mg/kg with peak plasma concentrations up to 250 micro M [19].
• The third level of control of eosinophil chemotaxis is composed of inactivators and inhibitors of chemotactic stimuli and is exemplified by degradation of C5a by anaphylatoxin inactivator or chemotactic factor inactivator and of ECF-A by carboxypeptidase-A or aminopeptidases [20].

Anatomical context of CPN1

• Normally, CPN circulates in blood plasma as a hetero-tetramer consisting of two 83 kDa (CPN2) domains each flanked by a 48 to 55 kDa catalytic (CPN1) domain [18].
• Kininase I-type carboxypeptidases enhance nitric oxide production in endothelial cells by generating bradykinin B1 receptor agonists [21].
• Accordingly, the authors investigated the effect of hemodialysis on circulating neutrophil counts and serum levels of AI and CFI activity in 10 patients [22].
• In radioimmunoassay (bradykinin 10 nmol/l), 46 and 55% of kininase in rat and dog skeletal muscle P3, respectively, was due to ACE; 36 and 28%, respectively, was due to NEP [23].
• Potential sources of CPN in human nasal mucosa were identified by immunohistochemistry [24].

Associations of CPN1 with chemical compounds

• Three Thr residues at the distal TT edge of CPN1 are O-linked to N-acetyl glucosamine sugars; equivalent sites in the membrane-anchored CPM are occupied by basic residues probably involved in membrane interaction [18].
• Human carboxypeptidase N (CPN), a member of the CPN/E subfamily of "regulatory" metallo-carboxypeptidases, is an extracellular glycoprotein synthesized in the liver and secreted into the blood, where it controls the activity of vasoactive peptide hormones, growth factors and cytokines by specifically removing C-terminal basic residues [18].
• CPN is a member of a larger family of carboxypeptidases, many of which also cleave arginine and lysine [25].
• The C5a degradation product, C5a des Arg, is rapidly formed after exposure of C5a to serum carboxypeptidase N and may represent the relevant C5-derived inflammatory peptide in vivo [26].
• Endothelial cells also possess enzymatic activities, in particular ACE/kininase activity, which can alter local levels of angiotensin II and bradykinin [27].

Regulatory relationships of CPN1

• The kinin activity from incubated HAE plasma was susceptible to kininase inactivation and was blocked by a Bk2 receptor antagonist [28].

Other interactions of CPN1

• Chromosomal localization of the genes for human carboxypeptidase D (CPD) and the active 50-kilodalton subunit of human carboxypeptidase N (CPN1) [29].
• Characterization of a prolyl endopeptidase (kininase) from human urine using fluorogenic quenched substrates [30].
• The activities of ACE, aminopeptidase P (APP), and kininase I were respectively 44 +/- 12, 22 +/- 9, and 62 +/- 10 nmol x min(-1) x ml(-1) [31].
• Our investigations started when synthetic bradykinin became available and we could characterize two enzymes that cleaved it: kininase I or plasma carboxypeptidase N and kininase II, a peptidyl dipeptide hydrolase that we later found to be identical with the angiotensin I converting enzyme (ACE) [32].
• Kallikrein-like esteroprotease activity and kininase activity in submandibular gland from a mutant mouse with human cystic fibrosis like alterations [33].

Analytical, diagnostic and therapeutic context of CPN1

• Alterations in activities of anaphylatoxin inactivator and chemotactic factor inactivator during hemodialysis [22].
• Ninety-nine neurotic patients from a controlled trial of CPN v. psychiatric out-patient aftercare were followed up seven years later [34].
• TETR-PCR for C. pneumoniae with primer set CPN 90-CPN 91 was 90% sensitive and 93.3% specific compared with a nested PCR with primer set CP1/2-CPC/D for clinical respiratory samples [35].
• Arginine carboxypeptidase (CPR) is a labile enzyme present in human serum which is unrelated to carboxypeptidase N. In this study we demonstrate that CPR exists in a precursor form in plasma and can be converted to the active form by trypsin and presumable trypsin-like enzymes [36].
• Treatment of rat plasma with an excess of trypsin in the presence of a kininase inhibitor generated T-kinin immunoreactivity equivalent to 455 +/- 71 pmol/ml (mean +/- S.E.M.; n = 9) and this immunoreactivity was eluted from a reversed-phase HPLC column as a single peak with the same retention time as synthetic T-kinin [37].

References