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Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Elotuzumab and daratumumab are two relatively new mAbs approved by the FDA in 2015 for treatment of patients with relapsed or refractory MM. Elotuzumab targets directly the glycoprotein receptor SLAMF7 (Signalling Lymphocyte Activation Molecule Family Member 7) that is overexpressed on the surface of myeloma and NK cells but is not found on normal cells. It exerts a dual effect in that it activates NK cells directly and also mediates antibody-dependent cell-mediated cytotoxicity (ADCC) by recruiting activated NK cells on MM cells (Lonial et al., 2015). Daratumumab is a human anti-CD38 IgG1 (κ subclass) antibody. It targets the protein CD38 (also an enzyme that catalyzes the metabolism of cyclic adenosine diphosphate ribose and nicotinic acid adenine dinucleotide phosphate) that is overexpressed on multiple myeloma cells and also expressed on many types of immune cells. Its antimyeloma effect mainly relies on its prominent ADCC and complement-dependent cytotoxicity (CDC) activities (Phipps et al., 2015). This topic is discussed in more detail in Section 21.2.3.4.3.
Lysosomal Ion Channels and Human Diseases
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Peng Huang, Mengnan Xu, Yi Wu, Xian-Ping Dong
The activation mechanism and ion selectivity of TPCs have been debated for a long time. Early studies suggest that TPC1 and TPC2 are implicated in lysosomal Ca2+ release in response to nicotinic acid adenine dinucleotide phosphate (NAADP) (Brailoiu et al., 2009; Brailoiu et al., 2010a; Calcraft et al., 2009; Grimm et al., 2017; Jha et al., 2014; Patel et al., 2017; Pitt et al., 2010; Ruas et al., 2010, 2015; Rybalchenko et al., 2012; Schieder et al., 2010a). However, later studies suggest that TPCs are Na+-selective channels activated by PI(3,5)P2 (Bellono et al., 2016; Cang et al., 2013, 2014b; Gerndt et al., 2020; Guo et al., 2017; Jha et al., 2014; Kirsch et al., 2018; She et al., 2018, 2019; Wang et al., 2012; Zhang et al., 2019). Although both views have received support in the proceeding years (Gerndt et al., 2020; Grimm et al., 2014; Guo et al., 2017; Jha et al., 2014; Kirsch et al., 2018; Lagostena et al., 2017; Moccia et al., 2020; Ogunbayo et al., 2018; Patel et al., 2017; Ruas et al., 2015; Rybalchenko et al., 2012), increasing evidence suggests that NAADP may indirectly activate TPC1/2 via an accessory protein (Krogsaeter et al., 2019; Lin-Moshier et al., 2012; Pitt et al., 2010; Ruas et al., 2015; She et al., 2019; Walseth et al., 2012; Wang et al., 2012; Xu and Ren, 2015). High-resolution structural studies combined with functional analysis have suggested that the opening of animal TPC1 is dependent on both ligand PI(3,5)P2 and voltage, and the VSD from the second 6-TM domain confers voltage dependence on TPC1 (She et al., 2018). In contrast, TPC2 is simply a PI(3,5)P2-activated channel (She et al., 2019). The binding site of PI(3,5)P2 is located at the first 6-TM domain for both TPC1 (She et al., 2018) and TPC2 (She et al., 2019). Similar to TPC1, the second VSD of TPC3 is involved in sensing changes in the membrane potential to open the channel (Dickinson et al., 2020). Distinct from animal TPC1 and TPC2, animal TPC3 is sensitive to PI(3,4)P2 but not PI(3,5)P2 when recorded at extracellular pH of 7.4, suggesting that TPC3 may function as a PI(3,4)P2-sensitive Na+ channel in the PM (Cang et al., 2014a; Dickinson et al., 2020; Shimomura and Kubo, 2019). In spite of the high sequence similarity in the filter region, plant TPC1 functions as a nonselective cation channel on the vacuole membrane, with higher selectivity for Ca2+ over Na+, but without selectivity among monovalent cations (Li+, Na+, and K+) (Guo et al., 2017). Plant TPC1 activation requires both voltage and cytosolic Ca2+ (Guo et al., 2016) but not PI(3,5)P2 (Boccaccio et al., 2014).
Investigating the Role of Two-Pore Channel 2 (TPC2) in Zebrafish Neuromuscular Development
Published in Bruno Gasnier, Michael X. Zhu, Ion and Molecule Transport in Lysosomes, 2020
Sarah E. Webb, Jeffrey J. Kelu, Andrew L. Miller
Over the last decade, the rapid progress in the development, improvement and/or commercialization of a range of different techniques, including molecular and genetic methodologies (Cong et al., 2013; Jinek et al., 2013) and imaging strategies (Carroni and Saibil, 2016; Meyer et al., 2008), as well as the development of novel pharmacological agents (Naylor et al., 2009), has encouraged the discovery of new proteins and advanced our knowledge of their function in cells, tissues and whole organisms. A key example is the identification and subsequent characterization of the two-pore channel (TPC) family (Calcraft et al., 2009). TPCs were identified during a search for a nicotinic acid adenine dinucleotide phosphate (NAADP) receptor. NAADP at concentrations as low as nanomolar amounts were known to stimulate the release of significant amounts of Ca2+ in a highly localized manner in sea urchin (Strongylocentrotus purpuratus and Lytechinus pictus) egg homogenate (Lee and Aarhus, 1995) and in live sea urchin eggs (Aarhus et al., 1996), in starfish (Asterina pectinifera) oocytes (Santella et al., 2000) and in various mammalian cell types, including mouse pancreatic acinar cells (Cancela et al., 1999) and human Jurkat T-lymphocytes (Berg et al., 2000). The intracellular Ca2+ stores involved in generating these highly localized signals were reported to be distinct from the endoplasmic reticulum (ER) (Genazzani and Galione, 1996; Lee and Aarhus, 1995; Patel et al., 2001), and they were identified as being lysosome-related acidic organelles (Churchill et al., 2002; Kinnear et al., 2004). At this time, it was also reported that in rat arterial smooth muscle cells, lysosomal Ca2+ stores are closely associated with regions of the sarcoplasmic reticulum (SR) expressing ryanodine receptors (RyR), and it was suggested that localized Ca2+ signals from the lysosomes might stimulate or “trigger” long-range Ca2+ signalling by Ca2+-induced Ca2+ release (CICR) via RyR in the SR (Kinnear et al., 2004). The molecular identity of the NAADP receptor was subsequently identified as being a voltage-gated cation channel, and it was called the two-pore channel or TPC (Calcraft et al., 2009; Galione et al., 2009). Since then, it has been reported that there is bidirectional Ca2+ signalling between the ER and acidic organelles. Thus, in addition to Ca2+ released from acidic organelles triggering the release of Ca2+ from the ER via inositol 1,4,5-trisphosphate (IP3) receptors (IP3R) and RyR (Morgan et al., 2011), Ca2+ released from the ER can also activate and/or modulate NAADP-regulated channels (Morgan et al., 2013).
CD38 as an immunotherapeutic target in multiple myeloma
Published in Expert Opinion on Biological Therapy, 2018
Francesca Bonello, Mattia D’Agostino, Maria Moscvin, Chiara Cerrato, Mario Boccadoro, Francesca Gay
Next to its receptor function, CD38 was recently described as part of the leukocyte ectonucleotidases family, characterized by two main substrates: nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NADP+). CD38 converts NAD+ to ADP ribose (ADPR) directly (hydrolase activity) or through formation and degradation of cyclic ADP ribose to ADPR (cyclase activity). Furthermore, in acidic conditions, CD38 catalyzes the generation of nicotinic acid-adenine dinucleotide phosphate (NAADP) from NADP+. Overall, the final result of these catalytic reactions is the generation of potent intracellular Ca2+ mobilizing compounds (cADPR, ADPR, and NAADP) followed by activation of signaling pathways that control various biological processes, such as lymphocyte proliferation [19]. Interestingly, recent studies suggest a pivotal role for CD38 involved in the production of adenosine, which has immunosuppressive effects [20]. Thus, this enzyme is suggested to function as an ‘immunological switch’ capable of converting a proinflammatory extracellular environment into an adenosine-rich, anti-inflammatory niche, suppressing antitumor immunity and promoting tumor progression.
Artificial oocyte activation: physiological, pathophysiological and ethical aspects
Published in Systems Biology in Reproductive Medicine, 2019
George Anifandis, Alexandros Michopoulos, Alexandros Daponte, Katerina Chatzimeletiou, Mara Simopoulou, Christina I. Messini, Nikolas P. Polyzos, Katerina Vassiou, Konstantinos Dafopoulos, Dimitrios G. Goulis
In most species, the Ca+2 increases during fertilization are predominately caused by IP3-mediated Ca+2 release from the endoplasmic reticulum. Apart from IP3, additional agents, such as cyclic GMP (cGMP), cyclic ADP-ribose (cADP ribose), nicotinic acid adenine dinucleotide phosphate (NADP) and nitric oxide (NO) can also cause Ca+2 release (Whalley et al. 1992; Galione 1994; Galione and Churchill 2000; Willmott et al. 2000). It is possible that the primary role of IP3 as an initiator of intracellular Ca+2 release during fertilization is accompanied by the supporting action of these additional agents to regulate the increases in Ca +2 (Jaffe 1993).
Targeting calcium-mediated inter-organellar crosstalk in cardiac diseases
Published in Expert Opinion on Therapeutic Targets, 2022
Mohit M. Hulsurkar, Satadru K. Lahiri, Jason Karch, Meng C. Wang, Xander H.T. Wehrens
Beyond its known function in SR Ca2+ handling, multiple studies have suggested an additional role of RyR2 in overall cellular Ca2+ homeostasis by regulating mitochondrial and lysosomal Ca2+ transport [46,47]. A recent study showed a strong correlation between increased SR Ca2+ leak due to RyR2 hyperglycation and mitochondrial damage in aged hearts [46] suggesting a role of RyR2 in mitochondrial bioenergetics. Another study revealed an interesting feedback loop where RyR2-mediated SR Ca2+ leak increases mitochondrial ROS, which further oxidizes RyR2 in AF [48]. This RyR2-redox feedback loop was validated in a myocardial infarction model where impeding RyR2-mediated Ca2+ leak reduced mitochondrial Ca2+ overload and damage [49]. Further mechanistic studies may reveal if RyR2 directly affects mitochondrial Ca2+ signaling and function by either residing in the mitochondrial membrane or by interacting with mitochondrial proteins across SR-mitochondria contact sites. Indeed, a recent proteomics study revealed that several of the most abundant RyR2-binding proteins are mitochondrial proteins, including Aifm1, Cpt1b, and Idh3b [50]. The role of RyR2 in lysosomes has not been studied in detail although the identification of SR-lysosomes microdomains [47] suggests that RyR2 is involved in lysosomal Ca2+ regulation as well. One study in arterial smooth muscle cells revealed that lysosomal nicotinic acid adenine dinucleotide phosphate (NAADP) binds RyR3 to mediate Ca2+ regulation [51]. Taken together, mechanistic studies dissecting RyR2 gene regulation, epigenetic modifications, post-translation regulations, sub-cellular localization, and organelle-specific Ca2+ handling could establish RyR2 inhibitory therapies as a primary treatment for various heart diseases.