Disease relevance of CPA1

• The cysteine proteinases CPA and CPB from Leishmania major induced Th1 responses in patients with leishmaniasis due to Leishmania guyanensis [1].
• In addition, 54% of individuals tested, who had recovered from cutaneous leishmaniasis, produced more than 50 pg/ml IFN-gamma, in response to the CPA/B hybrid protein in an in vitro assay, demonstrating the importance of cysteine proteinases as targets of immune response in humans [2].
• PURPOSE: We studied high-dose cyclophosphamide, cisplatin, and carmustine (CPA/cDDP/BCNU) with autologous bone marrow support (ABMS) as consolidation after standard-dose adjuvant chemotherapy treatment of primary breast cancer involving 10 or more axillary lymph nodes [3].
• Successfully, radically treated cancer patients with no detectable residues or metastases for at least 1 year had values (186 +/- 39; 76 +/-24) almost within the normal ranges (93 to 250 mg pectin equivalents per liter for CPA and 35 to 120 mg pectin equivalents per liter for SPA) [4].
• The amount of CPA required to make MTX-Phe equitoxic with MTX, when tested against UCLA-P3 human lung adenocarcinoma cells in vitro, was more than 10-fold lower than that required to achieve the same result with MTX-alpha-alanine [5].

Psychiatry related information on CPA1

• Without CPAP, alcohol produced a small non-significant decrease in the percentage of rapid eye movement (REM) sleep (control 11+/-2 vs alcohol 8+/-1% (mean+/-SEM)), but with CPAP there was no such effect (control 15+/-2 vs 17+/-2%; CPA x alcohol interaction p=0.015) [6].
• Re: CPA position statement: "The Role of Mental Health Legislation" [7].
• Furthermore, CPA is associated with loss of libido and erectile dysfunction [8].
• All patients who had a panic attack during the breath-holding test also had a panic attack during the CO(2)test (n = 40; CPA group) [9].
• The purpose of this study was to examine comparatively the use of an atypical, noncognitive predictor of academic achievement, the Problem Solving Inventory (PSI), with the traditional cognitive measures of American College Testing (ACT) score and grade point average (CPA) [10].

High impact information on CPA1

• MC-CPA is unique among carboxypeptidases in having a CPA-like substrate-binding pocket and enzymatic activity despite overall protein and gene structures more similar to CPB [11].
• Effects on ADP- and collagen-induced ex vivo platelet aggregation (APA or CPA) and template bleeding time (TBT) were evaluated [12].
• Finally, a conditioned medium from COS-1 cells containing PlGF is capable of stimulating specifically the growth of CPA, a line of endothelial cells, in vitro [13].
• The presence of a codon for isoleucine at the residues corresponding to codon 255 of rat CPA1 cDNA strongly suggests that the A form of human carboxypeptidase has been isolated [14].
• This compound was designed rationally based on the knowledge of the active site topology and the reported stereospecific proton exchange on ketonic substrate analogue (R)-3-(p-methoxybenzoyl)-2-benzylpropanoic acid [Sugimoto, T. & Kaiser, E. T. (1978) J. Am. Chem. Soc. 100, 7750-7751] by CPA [15].

Chemical compound and disease context of CPA1

• CONCLUSION: High-dose consolidation with CPA/cDDP/BCNU and ABMS after standard-dose CAF results in a decreased frequency of relapse in patients with high-risk primary breast cancer compared with historical series at the median follow-up of 2.5 years [3].
• Acute CPA-induced control of NHE3 was blocked by antagonists of A1 adenosine receptors and inhibition of phospholipase C, pretreatment with BAPTA-AM (chelator of cellular calcium), and exposure to pertussis toxin [16].
• After pertussis toxin treatment, the agonist NECA produced a stimulation of cAMP production, whereas CPA and (R)-N(6)-(2-phenylisopropyl)adenosine were ineffective [17].
• The relative intrinsic activity of NECA in stimulating inositol phosphate accumulation, compared to CPA (100%), was much greater in the presence of pertussis toxin (289.6%) than in the absence of pertussis toxin (155.2%) [17].
• The A(1)R agonist N(6)-cyclopentyladenosine (CPA), the A(2A)R agonist CGS21680 [2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine], and the A(3)R agonist N(6)-(3-iodobenzyl)adenosine-5'-methyluronamide (IB-MECA) all prevented PE-induced hypertrophy [18].

Biological context of CPA1

• The active site of CPA5 is predicted to cleave substrates with C-terminal hydrophobic residues, as do CPA1, -2, and -3 [19].
• The deduced amino acid sequence of human CPA5 has highest amino acid sequence identity (60%) to CPA1 [19].
• Hybridization screening of a human pancreatic cDNA library with cDNA probes that encoded either rat carboxypeptidase A1 (rCPA1) or carboxypeptidase A2 (rCPA2) was used to clone the human prepro-CPA homologs [20].
• Thus, in the carboxypeptidase gene family, MC-CPA displays a unique genealogy and several amino acid replacements in its S1' binding pocket that result in substrate specificity quite similar to bovine CPA [21].
• We noted two consensus N-linked glycosylation sites in human MC-CPA that are not found in rat and mouse MC-CPA, or in bovine CPA; that at least one of these sites is glycosylated in vivo was verified by N-glycosidase F treatment, lentil lectin binding, and Concanavalin A-Sepharose chromatography [21].

Anatomical context of CPA1

• A rat cDNA probe for preprocarboxypeptidase A was used to follow the segregation of the human gene for carboxypeptidase A (CPA) in 49 human X mouse somatic cell hybrids using Southern filter hybridization techniques [22].
• Location and size of cells in two groups of serotonin-immunoreactive neurons in the cerebral ganglia appeared to be similar to those of CPA1 and CPB1 neurons [23].
• Activation of a CPA1 by current injection resulted in speeding up of the locomotor rhythm and intensification of the firing of the locomotor motor neurons [23].
• These data reveal that CPA can directly or indirectly process CPB(C25G) and suggest that cysteine proteases are targeted to lysosomes via the flagellar pocket [24].
• However, in contrast to the basophils in normal individuals, many of the metachromatic cells in the three patient groups expressed c-kit, Try, Chy, and/or CPA [25].

Associations of CPA1 with chemical compounds

• Purified hCPA1 and hCPA2 migrate as a single protein band with M(r) 34,000 when subjected to gel electrophoresis in the presence of sodium dodecyl sulfate under reducing conditions [20].
• This antigenic determinant is located on one of the four cyanogen bromide fragments of CPA [26].
• The mAbs also readily detect both conformational alterations of CPA on treatment with urea and subtle, reversible conformational alterations on removal of zinc from the active site of the enzyme [26].
• The binding of the mAbs to CPA adsorbed onto a polystyrene plate is characterized by apparent binding constants higher by 1 or 2 orders of magnitude than those characterizing the interaction of the mAbs with CPA in solution [26].
• However, both CPB and CPA degraded the des-Arg derivatives to remove the C-terminal phenylalanine [27].

Physical interactions of CPA1

• The kinetic data show that hCPA2 has a larger substrate binding site than the hCPA1 enzyme [20].

Other interactions of CPA1

• These experiments indicate that hCPA1 and hCPA2 are potential candidates for use in a human-based ADEPT approach [20].
• One hundred kilobases proximal to MEST lies a group of four carboxypeptidase A (CPA) genes [28].
• Even at high concentrations, they do not recognize carboxypeptidase B (CPB) in spite of the similar tertiary structure and the 50% homology in amino acid sequence with CPA [26].

Analytical, diagnostic and therapeutic context of CPA1

• This is corroborated by the lack of antibody additivity in the ELISA assay carried out in the presence of pairs of mAbs, the similarity in molecular weight of the immunocomplex formed between CPA and one of the mAbs in the presence of another, and also a competition experiment in which one of the mAbs was labeled enzymatically [26].
• The expression of the CPA/B hybrid protein (60 kDa) was verified using rabbit anti-CPA and anti-CPB antibodies by SDS-PAGE and immunoblotting [2].
• Site-directed mutagenesis has been used to identify key residues in the PCI tail and estimate the contribution of their chemical groups to the binding to CPA [29].
• No cyclical changes in HDL-C were found in the group receiving continuously combined hormone replacement therapy (E/CPA) [30].
• EE/CPA did not modify responses to OGTT of glucose, insulin, C peptide, or C peptide/insulin ratio [31].

References