Physiological and pathological views of peroxiredoxin 4

Peroxiredoxin 4 (PRDX4): Its Critical <em>In Vivo</em> Roles in Animal Models of Metabolic Syndrome Using Our Unique PRDX4 Transgenic Mice

“…Cys [41][42][43][44][45][46][47], PRDX4 might be a weak antioxidative enzyme compared to other thiol-dependent antioxidants in the context of metabolic syndrome-related diseases. On the other hand, PRDX4 is the only known secretory form located in not only the intracellular (especially the ER) but also the extracellular space, in contrast to the intracellular localization of other family members (PRDX1, 2 and 6 are located in the cytoplasm, and PRDX3 and 5 in mitochondria) [41][42][43][44]48,49].…”

“…Peroxiredoxin (PRDX), a new family of antioxidant enzymes, is ubiquitously synthesized and has been abundantly identified in various organisms [41][42][43][44]. At least six distinct PRDX genes expressed in mammals possess high similarities in their molecular structures and contain a reactive cysteine (Cys) in a conserved region near the N-terminus that forms Cys-sulfenic acid as an intermediate reaction during the reduction of H2O2 [44][45][46].…”

“…At least six distinct PRDX genes expressed in mammals possess high similarities in their molecular structures and contain a reactive cysteine (Cys) in a conserved region near the N-terminus that forms Cys-sulfenic acid as an intermediate reaction during the reduction of H2O2 [44][45][46]. As shown in Figure 1, PRDXs regulate the H2O2 levels using thioredoxin (TRX) as an electron donor, and their functional peroxidase activity is dependent on the reduced forms of TRX (redTRX) and/or glutathione (GSH) [41][42][43][44][45][46]. Figure 1 summarizes the pathway of the detoxification of ROS by PRDXs.…”

“…Figure 1 summarizes the pathway of the detoxification of ROS by PRDXs. Within the PRDX family, PRDX4 is a member of the 2-Cys-type PRDX family and homologous to typical 2-Cys PRDX1 and 2, thus serving as a TRX-dependent peroxidase via a similar catalytic mechanism to PRDX1/2 [44,47]. On one hand, since PRDX4 could be highly susceptible to hyperoxidation/inactivation due to H2O2-mediated sulfonic acid formation on its peroxidatic…”

“…On the other hand, PRDX4 is the only known secretory form located in not only the intracellular (especially the ER) but also the extracellular space, in contrast to the intracellular localization of other family members (PRDX1, 2 and 6 are located in the cytoplasm, and PRDX3 and 5 in mitochondria) [41][42][43][44]48,49]. PRDX4 has an additional N-terminal region, which is unique to this enzyme, following a signal peptide that allows translocation across 9 the ER membrane and is thereafter cleaved [41][42][43][44]. Several previous studies have focused on the molecular regulatory roles of PRDX4 in the nuclear factor κB (NF-κB) [ We hypothesized that PRDX4 locally (intracellularly) and systemically (extracellularly) plays a critical, diverse role in vivo in the protection against the initiation and development of metabolic syndrome manifesting as visceral obesity, DM, atherosclerosis and/or NAFLD (i.e.…”