Disease relevance of CPM

• The high CPM activity may stem from its induction and release in acute lung disease [1].
• In this review, we emphasize neuropathologic and neurobehavioral aspects of central pontine and extrapontine myelinolysis (CPM/EPM), also known as the osmotic demyelination syndrome [2].
• In patients with Pneumocystis carinii pneumonia, CPM activity was elevated to 26.00 (+/- 4.85) (p < 0.01) and in patients with lung cancer, to 30.95 (+/- 4.12) (p < 0.01) [1].
• The degree of renal insufficiency was directly correlated to the CPM/image (an index of whole-body retention) on all 3 days of imaging and the slower clearance of radioactivity from the blood [3].
• Central pontine myelinolysis (CPM, osmotic demyelination syndrome) and acquired chronic hepatocerebral degeneration (ACHD) both occur in patients with liver failure, but are not thought to be caused by similar etiopathogenic mechanisms despite the fact that occasional patients exhibit both disorders [4].

Psychiatry related information on CPM

• Ninety-six children and adolescents with spinal muscular atrophy I-III, aged 6.0-18.11 years, 45 non-affected siblings and 59 healthy, matched controls were examined with one- (CPM/SPM), as well as multi-dimensional intelligence tests (Kaufman-ABC; Wechsler tests) [5].
• The patients showed a significant memory deficit, both in Recognition Memory for Words (RMW) and Recognition Memory for Faces (RMF), even when the scores were corrected for verbal intelligence score (WAIS Vocabulary) or a measure of visuoperceptual ability (Raven's Coloured Progressive Matrices, CPM) [6].
• It was observed that CPM caused little or no pain and elicited excellent patient compliance [7].

High impact information on CPM

• This CPM induction was specifically enhanced by CD19 or CD40 ligation [8].
• CD40 + BCR stimulation of resting B cells with CD40 ligand-transfected fibroblastic cells in the presence of cross-linked anti-BCR monoclonal antibodies resulted in the coexpression of CD38, CD95, and CPM [8].
• In the present study, we report that the platelet-derived alpha-chemokine platelet factor 4 (PF4) induces the differentiation of monocytes into macrophages, as is evident from morphological changes as well as from the up-regulation of differentiation markers (carboxypeptidase M/MAX1 and CD71) [9].
• RA suppressed the expression of the maturation-associated antigen carboxypeptidase M (CPM)/MAX.1 at both the protein and mRNA levels and modulated the lipopolysaccharide-stimulated cytokine secretion of MO/MAC [10].
• Thus, the hydrolysis of hemoglobin by CPM and CPN demonstrated the contribution of the alpha-Arg141 residue to sustaining the tetrameric structure of hemoglobin and its normal oxygen affinity and vasoactivity [11].

Chemical compound and disease context of CPM

• Case>We describe here a case of CPM that occurred in a young patient after correction of hyponatremia, its treatment by intravenous thyrotropin-releasing hormone, and its outcome [12].
• As determined by MICs, the resistance to tested antibiotics in E. coli O157 isolates was found to AMS (90.9%), CLZ (81.8%), CRX (63.6%), CXT (72.7%), CPM (72.7%), TET (81.8%), SAM (59.1%), COT (9.1%), COL (63.61%), AZT (9%) and GEN (4.5%) [13].

Biological context of CPM

• This locus, however, does not appear to correspond to the PTPRR or CPM, although a contribution of mutations in regulatory regions cannot be excluded at this time [14].
• Modelling of the C-terminal part of the natural substrate Arg(6)-Met-enkephalin into the active site shows that the S1' pocket of CPM is particularly well designed to accommodate P1'-Arg residues, in agreement with the preference of CPM for cleaving C-terminal Arg [15].
• Both forms had lower molecular masses (50 kDa) than native placental CPM (62 kDa), indicating minimal glycosylation [16].
• The identity of the basic carboxypeptidase activity with CPM was shown by similarities in subcellular localization, membrane attachment, substrate hydrolysis, inhibition by a specific basic carboxypeptidase inhibitor, and cross-reaction with anti-human CPM antiserum [17].
• Physical map location of the human carboxypeptidase M gene (CPM) distal to D12S375 and proximal to D12S8 at chromosome 12q15 [18].

Anatomical context of CPM

• Immunostaining localized CPD primarily in a perinuclear/Golgi region, whereas CPM was on the cell membrane [19].
• In addition, CPM was found on granulocytes and monocytes, but not on their progenitors [20].
• CPM was also expressed on mature T cells, mainly after activation [20].
• Using M27 antibody, CPM was detected only at discrete B lymphocyte developmental stages, namely on committed precursors and on germinal center cells [20].
• CPM co-purified with myelin extracted from the brain [17].

Associations of CPM with chemical compounds

• Of interest, CPM displayed a largely overlapping distribution with the CD10 and CD13 peptidases, with which it shares common substrates (enkephalins, bradykinin) [20].
• Carboxypeptidase M (CPM), an extracellular glycosylphosphatidyl-inositol(GPI)-anchored membrane glycoprotein belonging to the CPN/E subfamily of "regulatory" metallo-carboxypeptidases, specifically removes C-terminal basic residues from peptides and proteins [15].
• Consistent with results obtained in placenta and cultured kidney cells, CPM in the brain appears to be membrane-bound via a phosphatidylinositol glycan anchor [17].
• The released CPM contained ethanolamine, indicating liberation by a phospholipase [21].
• This was demonstrated by [3H)ethanolamine labeling of Madin Darby canine kidney (MDCK) cells which resulted in labeling of the membrane anchor of CPM as shown by immunoprecipitation, polyacrylamide gel electrophoresis and autoradiography [22].

Enzymatic interactions of CPM

• CPM was also found in soluble form in biological fluids such as urine and amniotic fluid where it is the primary enzyme that hydrolyzes epidermal growth factor (EGF), producing des-Arg53-EGF [22].

Regulatory relationships of CPM

• We found the known macrophage differentiation marker Carboxypeptidase M to be suppressed while CD14, HLA-DR, and CD16 were up-regulated [23].
• A monoclonal antibody to the C-terminal beta-sheet domain of CPM reduced the B1R response to B2R agonists without inhibiting CPM [24].

Other interactions of CPM

• However, if cells are activated by the lectins PWM or ConA or by double-stranded RNA (polyinosinic-polycytidylic acid, pI:C), normal MAC maturation is suppressed: MO stay small and do not acquire MAC maturation-associated surface molecules like carboxypeptidase M (CPM, determined by antibody MAX.1) or CD84 (determined by antibody MAX.3) [25].
• In this study, purified carboxypeptidase M efficiently released the COOH-terminal arginine residue from EGF with a Km = 56 microM, kcat = 388 min-1, and kcat/Km = 6.9 microM-1 min-1 [26].
• Although CPM belongs to the same metallocarboxypeptidase subfamily as CPE, their intron/exon structures differ significantly [27].
• CPM as detected by MAX [28].
• 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 [29].

Analytical, diagnostic and therapeutic context of CPM

• Northern blot analysis revealed the presence of mRNA coding for CPM in the brain, showing that the enzyme is indeed synthesized there [17].
• The roles of Glu(260) and Glu(264) in CPM were investigated by site-directed mutagenesis [16].
• The released enzyme is a soluble form of CPM as shown by Triton X-114 partitioning, immunoprecipitation, Western blotting, inhibition studies and its neutral pH optimum [22].
• Molecular cloning and sequencing of the cDNA for human membrane-bound carboxypeptidase M. Comparison with carboxypeptidases A, B, H, and N [30].
• Finally, immunohistochemistry, employing purified antibody to the enzyme, revealed in fluorescent light microscopy that carboxypeptidase M is present in alveolar type I pneumocytes and in macrophages in apparently lower concentration [31].

References