Inactivation of Thyrotropin Releasing Hormone (TRH). The TRH-Degrading Enzyme as a Regulator and/or Terminator of TRH-Signals?
Gerard O’Cuinn in Metabolism of Brain Peptides, 2020
For the enzymatic inactivation of the peptidergic signal the minimal condition is that the enzyme is localized on the plasma membrane with its active site orientated towards the extracellular space. Subcellular fractionation studies first demonstrated that the particulate TRH-degrading enzyme is located in synaptosomal12,14,15 and adenohypophyseal13 plasma membranes. To investigate whether the enzyme is indeed located on the cell surface, the degradation of TRH by murine brain and pituitary cell cultures was studied.24,25 As expected, TRH added to the culture medium was not taken up by these cells but rapid degradation was observed with neuronal cell cultures and low but significant activities of the TRH-degrading enzyme were found on adenohypophyseal cells. Interestingly, glial cells were almost devoid of this peptidase activity. These findings were confirmed and extended by the detailed studies reported by Cruz et al.26 and corroborated that the membrane-bound enzyme is indeed a true ectoenzyme.27
Enzymatic Degradation of Bradykinin
Sami I. Said in Proinflammatory and Antiinflammatory Peptides, 2020
Because membrane-bound carboxypeptidase M is a widely distributed ectoenzyme, it is well situated to metabolize Bk at the cell surface. After its release from cell membranes it also can function as a soluble enzyme. As with carboxypeptidase N, des-Arg9-Bk, the agonist for the B1 receptor, is produced by carboxypeptidase M (Fig. 1). However, because of its location on plasma membranes, carboxypeptidase M can carry out this role in a local environment outside the circulation, for example, at sites of inflammation where the B1 receptor may be upregulated (Skidgel, 1992, 1996; Bhoola et al., 1992).
Platelet Function in Hemostasis
Genesio Murano, Rodger L. Bick in Basic Concepts of Hemostasis and Thrombosis, 2019
Another ectoenzyme of special interest is “ecto-ATPase”. Since it is inhibited by ADP, it may participate in platelet aggregation induced by ADP.35 The ecto-ATPase may be necessary to maintain the platelet in a nonadhesive state. In addition, ecto-ATPase has antithrombosthenin properties and may function in preventing surface responses of this contractile protein.36 However, antibodies to thrombosthenin do not prevent platelet aggregation by various inducers.37
Screening models combining maternal characteristics and multiple markers for the early prediction of preeclampsia in pregnancy: a nested case–control study
Published in Journal of Obstetrics and Gynaecology, 2022
Li Chen, Yan Pi, Kai Chang, Sifu Luo, Zhuyun Peng, Ming Chen, Lili Yu
5′-Nucleotidase (5′-ribonucleotide phosphohydrolase; 5′NT), an intrinsic membrane glycoprotein that acts as an ectoenzyme in a wide variety of mammalian cells, catalyses adenosine 5′-monophosphate (AMP) to adenosine (Sunderman 1990). Serum concentrations of 5′-nucleotidase show changes in hepatobiliary disease with considerable specificity (Phelan et al. 1971). Serum concentrations of 5′-nucleotidase are reported to increase (Bacq et al. 1996) or remain unchanged (Alvi et al. 1988) in normal pregnancy. In our present study, the concentration of 5′-nucleotidase was significantly elevated in the maternal serum of PE patients at 11–13 wks of gestation. This is the first report to identify 5′-nucleotidase as an independent risk factor for PE. The elevation of 5′-nucleotidase levels is suggestive of enhanced dephosphorylation from AMP to adenosine in PE. Previous studies found that placental adenosine represents a causative factor for the induction of maternal features associated with PE (Iriyama et al. 2015). One potentially detrimental role for adenosine signalling in PE is that adenosine stimulates the increased production of fms-like tyrosine kinase 1 (George et al. 2010). Furthermore, vascular endothelial ecto-5′nucleotidase also plays a role in controlling the circulating levels of adenosine in microvascular beds (Zukowska et al. 2015). In view of these results, we considered that 5′-nucleotidase may represent a potential marker and play an important role in the pathophysiology of PE.
Daratumumab induces CD38 internalization and impairs myeloma cell adhesion
Published in OncoImmunology, 2018
Jayeeta Ghose, Domenico Viola, Cesar Terrazas, Enrico Caserta, Estelle Troadec, Jihane Khalife, Emine Gulsen Gunes, James Sanchez, Tinisha McDonald, Guido Marcucci, Balveen Kaur, Michael Rosenzweig, Jonathan Keats, Steven Rosen, Amrita Krishnan, Abhay R Satoskar, Craig C Hofmeister, Flavia Pichiorri
Daratumumab (Dara) is a human anti-CD38 IgG1 (ĸ subclass) antibody against the receptor CD38, which is highly expressed on the surface of MM cells.8 CD38 participates in a number of enzymatic activities, including breaking down extracellular nicotinamide adenine dinucleotide (NAD+)9 and regulating calcium homeostasis,10 which influences immune cell functions.11–13 It is present in large amounts in the marrow of MM patients.14 In support of its function as an ectoenzyme, it has been previously reported that a fraction of the entire CD38 surface molecule can be internalized by endocytosis in a number of leukemia- and lymphoma-derived cell lines.15,16 CD38 also interacts with its known ligand CD31, which is expressed on microenvironmental endothelial cells, stromal cells and macrophages.17 Dara and other CD38 antibodies in turn exhibit various mechanisms, including recruitment of effector cells, removal of CD38+ immune-suppressor cells, and direct apoptotic activity.18
Monoclonal antibodies in newly diagnosed and smoldering multiple myeloma: an updated review of current clinical evidence
Published in Expert Review of Hematology, 2020
Pellegrino Musto, Francesco La Rocca
Isatuximab (SAR650984) is a chimeric IgG1 MoAb targeting a unique epitope on CD38, which exhibits some relevant differences from daratumumab concerning its mechanism of action [55]. Isatuximab anti-neoplastic activity appears to be mainly mediated by ADCC, with a minor involvement of CDC. Furthermore, crosslinking induced by isatuximab maybe not necessary for triggering apoptosis processes in neoplastic cells. Isatuximab also induces significant immune cell depletion and inhibition of immune-suppressive cells, i.e. T-regs. Lastly, isatuximab has greater inhibitory effects on ectoenzyme activity. Isatuximab is generally considered better tolerated than daratumumab as it requires shorter duration of infusion. It has been successfully investigated in the RRMM setting as single agent or in combination with pomalidomide and dexamethasone, receiving recently approval from FDA and preliminary positive opinion form EMA for this last indication.