Journal of Energy Bioscience 2025, Vol.16, No.1, 31-41 http://bioscipublisher.com/index.php/jeb 37 includes gp91phox and p22phox on the membrane, as well as p47phox, p67phox, p40phox and Rac1/2 in the cytoplasm. These components assemble when activated and then generate reactive oxygen species (El-Benna et al., 2005; El-Benna et al., 2009; Nunes et al., 2013). The entire process is strictly controlled to avoid excessive reactive oxygen species that damage tissues while ensuring a bactericidal effect (Mcphail et al., 1985; Edwards, 1996) (see Figure 3). Figure 3 Activation and assembly of mammalian NOX2. NOX2 consists of the cytosolic components p67phox, p47phox, p40phox, Rac2, and the integral membrane subunits gp91phox and p22phox. Upon cell stimulation, the cytosolic subunits translocate to the membranes to form an active complex with gp91phox and p22phox. Meanwhile, Rac exchanges GDP to GTP, and dissociates from Rho-GDI. In the resting state, the p47phox-SH3 tandem domain interacts with AIR keeping p47phox in an inactive conformation (Belambri et al., 2018). Cell stimulation induces phosphorylation of AIR, releasing the interactive domains, i.e., SH3, PX, and PRR, which mediate oxidase assembly. The PRR of p47phox binds to the SH3 region of p67phox, while p67phox links with p40phox through their PB1 domains. The p47phox-SH3 regions then bind to the p22phox-PRR domains promoting p67phox interaction with gp91phox and moving p40phox-PX domains in close proximity to the membrane. Activated NOX2 uses cytosolic NADPH to induce oxygen reduction and superoxide anion (O2 -) generation. Abbreviations: SH3, Src homology 3 (SH3);, PX, phox homology (PX); AIR, auto-inhibitory region (AIR);, PRR, proline-rich region (PRR);, TPR, tetratricopeptide-rich regions; PB1, phox and Bem1 domain; and AD, activation domain (Adopted from Moghadam et al., 2021) 7.2 Contribution of NADPH to the respiratory burst and microbial defense The respiratory burst is a fast reaction that rapidly releases a large number of ROS, such as superoxide anions and hydrogen peroxide. These reactive oxygen species are generated by NADPH oxidase. Once NADPH oxidase is activated, it transfers electrons from NADPH to oxygen molecules to produce superoxide anions. These reactive oxygen species are then converted into other ROS (Kotsias et al., 2013; Nunes et al., 2013; Thomas, 2017). These ROS are lethal to the engulfed microorganisms, which can be completely killed in the phagosome. Chronic granulomatous disease illustrates the importance of this process. This disease is caused by a malfunction of part of the NADPH oxidase, which makes it difficult for the patient's immune system to kill bacteria, resulting in repeated infections (El-Benna et al., 2005; Glennon-Alty et al., 2018).
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