1. Identification of Peroxiredoxins As Antioxidant Enzymes

1. Identification of peroxiredoxins as antioxidant enzymes

Peroxiredoxin was first identified in yeast Saccharomyces cerevisiae as a sulfur radical scavenger in 1987 [1]. As this new antioxidant enzyme required thiol for its activity thus named as thiol-specific antioxidant (TSA) at that time [1]. There are several characteristics different from the classical antioxidant enzymes. Firstly, this novel antioxidant enzyme does not require any redox cofactors (such as copper/zinc for superoxide dismutase and heme for cytochrome c peroxidase). Secondly, unique peroxidatic cysteine in the catalytic center of peroxiredoxins responses for their basic functions in oxidant defense [2]. Thirdly, these antioxidant enzymes can reduce broad spectrum of oxidants [including both reactive oxygen species (ROS) and reactive nitrogen species (RNS)] via its evolutionarily highly conserved redox-active cysteines ^[3][4][3, 4]. These newly found thiol-dependent peroxidases can be found in all organisms, and multiple isoenzymes are commonly found in one species. In 2016, this large and highly conserved family of peroxidases is now the named as peroxiredoxin by the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology.

2. Classification of Peroxiredoxins

2. Classification of peroxiredoxins

As the amino acid sequences of the active sites of peroxiredoxins are highly conserved from bacteria to humans, based on the sequence homology, more new family members were identified in last decade [5]. A systematic classification system is required for these huge number of peroxiredoxins. The current classification is based on the number and location of highly conserved redox-sensitive cysteine residues in the peroxiredoxin [6]. Most peroxiredoxins have two conserved redox-sensitive cysteine residues - a peroxidatic cysteine that directly reduces various peroxide substrates and a resolving cysteine that can regenerate the peroxide reduction activity of their peroxidatic cysteine [7]. The peroxidase reaction between peroxidatic and resolving cysteines are usually on two individual peroxiredoxins [8]. That is why usually homodimers of typical 2-Cys peroxiredoxins are formed after the condensation reaction via a stable inter-subunit disulfide bond. This class of peroxiredoxins is named as typical two cysteine (2-Cys) peroxiredoxin. In contrast, for atypical peroxiredoxins, both peroxidatic and resolving cysteines for the peroxidase reaction are on the same peroxiredoxin via formation of intramolecular disulfide bond. It explains why atypical peroxiredoxins usually function monomerically. The third class of peroxiredoxins is one cysteine (1-Cys) peroxiredoxins that only contain the peroxidatic cysteine, but no resolving cysteine [9]. In addition, most of the peroxiredoxins use thioredoxin as their main electron donor. The disulfide bridge formed after oxidation can be reduced by electron donors such as thioredoxin to restore its peroxidatic activity. Glutaredoxins, cyclophilins, glutathione, and ascorbic acid are used as their electron donors for particular isoenzymes of peroxiredoxin were also reported ^{[10][11][12][13]}[10-13].

3. Multiple Peroxiredoxins Are Commonly Found in An Organism

3. Multiple peroxiredoxins are commonly found in an organism

The importance of peroxiredoxins can be reflected by their ubiquity and abundance. In budding yeast, there are five different peroxiredoxin [14], and in human and mouse, there are six different peroxiredoxins [15]. All of them with distinct but overlapping properties. Knockout or knockdown individual peroxiredoxins in cells are often viable and showed relative mile or even no phenotype under standard growth conditions [16]. Increase in the amount of oxidized DNA and carbonylated protein; and reduce in the growth and survival rates of the cells after oxidative insults were usually observed [17]. The effects of peroxiredoxin deficiency became more obvious for deletion of multiple peroxiredoxin and more prominent under stress conditions ^[14][18][14, 18]. For example, the amino acid sequence of mouse PRX1 and PRX2 proteins share 74% identity and 89% similarity and compensatory effects among peroxiredoxins are suggested. PRX1 KO mice have shorter lifespan, developed age-dependent hemolytic anemias and various cancers [19]. PRX2 KO mice also have hemolytic anemia [20], but no cancer phenotype was reported. PRX1/PRX2 double knockout mice showed many novel abnormalities in addition to an aggravation of individual single knockout mice [21].

4. From An Antioxidant Enzyme to A Redox Signaling Regulator

4. From an antioxidant enzyme to a redox signaling regulator

It is generally agreed that the main function of peroxiredoxins is in defending against oxidative stress. The evidence mainly based on the laboratory experiments with cells lacking peroxiredoxins [14]. However, the antioxidant activity of peroxiredoxins is relatively weak [22]. Very low concentration of hydrogen peroxide (~100 μM) already can inactivate human PRX1 [23]. Indeed, the peroxidase activity of peroxiredoxin can be easily inactivated by hyperoxidation of their peroxidatic cysteine under mild oxidative stress. To restore the peroxidase activity of a hyperoxidized peroxiredoxin, a special oxidoreductase sulfiredoxin is required [24]. ATP is required for sulfiredoxin to reduce sulfinic acid of peroxiredoxin back to thiol [25]. Therefore, it was proposed that peroxiredoxins mainly function as redox sensors for regulating signaling pathways via the local concentration of free radical messengers [26]. For example, it has been demonstrated that PRX1 can bind to and preserve its tumor-suppressive function of PTEN by preventing oxidation [27]. Mechanistically, the intramolecular disulfide bond in PTEN is required for its function in inhibiting cell growth and proliferation by downregulating PI3K/AKT signaling pathway via dephosphorylating phosphatidylinositol (3, 4, 5)-trisphosphate (PIP3) to phosphatidylinositol (4, 5)-bisphosphate (PIP2). Peroxiredoxins can preserve the activity of PTEN by preventing oxidation of intramolecular disulfide bond of PTEN [27]. Therefore, peroxiredoxins can regulate the activities of different redox sensitive proteins by similar mechanisms.

5. Role of Peroxiredoxin in Cell Cycle Regulation

5. Role of peroxiredoxin in cell cycle regulation

The basic cell cycle machine is dependent on the sequential expression of cyclins and activation of cyclin-dependent kinases (CDKs) that drives the cell cycle transitions from one to the next phase{Burhans, 2009 #32261}, and many cell-cycle regulatory proteins have also redox-sensitive motifs [28]. It raises the feasibility to regulate cell cycle by redox dependent signaling pathways. It was demonstrated that intracellular concentration of H₂O₂ increases at G1–S phase transition, peak at mitosis, and then decrease during mitotic exit. At late G1–S phase transition and during mitosis, peroxidase activity of PRX1 is inactivated by cell cycle-dependent kinase 1 (Cdk1) through phosphorylation at  on its Tyr194 that leads to increased endogenous ROS for the inhibition of APC/C–Cdh1 activity{Heo, 2020 #32262}. In addition, phosphorylated PRX1 can associate with centrosome that is required for proper mitotic progression in mammalian cells ^[29] [29]{Lim, 2015 #32263}{Lim, 2015 #32263}. Mechanistically, phosphorylated PRX1 indirectly inactivate centrosome-bound phosphatases by oxidation [29]. Knockdown PRX1 leads to G2/M blockade in pancreatic ductal adenocarcinoma (PDAC) cells [30]. This is an example to demonstrate how to fine-tune intercellular free radical levels by phosphorylation of peroxiredoxins through signaling pathway. Interestingly, knockdown other peroxiredoxins such as PRX2, PRX3 and PRX6 also can induce cell cycle arrest in different mammalian cells ^[31][32][33][31-33]. However, knockout PRX2 in primary dermal mesenchymal stem cells (DMSC) exhibited significant accumulation of G₀/G₁ cell [31] and knockdown PRX3 in trophoblast cells exhibited prolonged G₀/G₁ phase [32], and knockout of PRX6 induced cell cycle arrest at G2/M in HepG2 hepatocarcinoma cells [33]. It remains to be explored the cell cycle arrests are peroxiredoxin and/or cell type specific.

6. Moonlighting Function as Chaperone

6. Moonlighting function as chaperone

As mentioned above, homodimer of peroxiredoxins is formed via formation of intersubunit disulfide bridge upon oxidation. Interestingly, homodimers assemble to form a toroidal complex of 8, 10, or 12 subunits. The change in their quaternary structure regulates their functional switch from peroxidase to chaperone [34]. These toroid structures can stack with one another to form high molecular weight (HMW) nanotube-like structures or dodecahedron [35]. The oligomeric states of peroxiredoxin are dependent on many factors such as redox state, pH and post-transitional modifications.

The first in vivo evidence to support peroxiredoxin functions as chaperone under physiological relevance condition also by yeast peroxiredoxin named as TSA1 and TSA2 [36]. Both TSA1 and TSA2 can protect the thermal aggregation of citrate synthase and from DTT-induced insulin β chain precipitation ^[36] [36]. For the first in vivo evidence function as chaperone, overexpressing peroxidase inactive TSA1 mutant lacking the functional resolving cysteine still able to rescue the zinc deficiency induced protein aggregation phenotype in yeast [37]. Mechanistically, hyperoxidated TSA1 is required for the recruitment of cytosolic molecular chaperone HSP70 and disaggregase HSP104 to aggregates [38]. The aggregate resolution will be triggered by the ATP-dependent peroxiredoxin sulfinic acid reductase SRX1 and TSA1 will also be reduced by SRX1 [38]. Chaperones such as heat shock proteins (HSPs) are thought to plays an essential role in preventing aging [39], but progression and aggressiveness of various cancers [40]. It remains to be explored whether the chaperone function of peroxiredoxins plays any role in senescence and tumorigenesis.

7. From Tumor Suppressor to Oncoprotein

7. From tumor suppressor to oncoprotein

Peroxiredoxins is firstly suggested as tumor suppressor by inhibiting the oncoprotein c-Abl in 1997. The mechanism of the cytostatic effect of PRX1 is inhibits tyrosine tyrosine kinase activity of proto-oncoprotein c-Abl by binding with the Src Homology 3 (SH3) domain of c-Abl [41]. It was also reported that PRX1 also binds to transactivation domain of oncoprotein c-Myc and hence inhibits the expression of c-Myc target genes [42]. In addition, several malignant cancers are observed in the first PRX1 knockout (KO) mice [19]. The high malignancy phenotype of PRX1 KO shall be due to increased sensitivity to oxidative DNA damage and abnormalities in their natural killer (NK) cells [19]. Later study demonstrated that PRX1 as the one of the most prominently induced mRNAs in activated human NK cells [43]. PRX1 supports the survival and antitumor activity of NK Cells especially under oxidative stress condition [44]. Therefore, on one hand, increased sensitivity to DNA oxidative damage in PRX1 KO mice increase the risk of many types of cancer. On the other hand, the NK cells in PRX1 KO mice fail to perform their antitumor immunity.

In addition, there are evidence indicating that peroxiredoxins suppress mutations by oxidant-mediated DNA damage independent mechanism. Loss of peroxiredoxin TSA1 enhances mutation rates induces genome instability through elevation of deoxyribonucleotide triphosphate (dNTP) levels in yeast [45], and over-expression of TSA1 can rescuing the mutator phenotype [46]. Mechanistically, constitutively high dNTPs concentration leads to mutagenesis by promote polymerase slippage and/or impairing the polymerase proofreading activity ^[47][48][47, 48]. TSA1 and TSA2 may require for the limitation in dNTPs synthesis by inhibiting overall ribonucleotide reductase activity ^[46][49][46, 49]. It remains to be explored whether high eukaryotic peroxiredoxins play any role in maintaining dNTPs pool.

Interestingly, human PRX2 can protect genome integrity by coupling of fluctuations of dNTP biogenesis with DNA replication fork speed [50]. Mechanistically, PRX2 binds the fork accelerator TIMELESS and prevents the displacement of TIMELESS from the replisome [50]. Ribonucleotide reductase (RNR) is an essential enzyme that produces dNTPs for genome replication. When RNR catalyzes the reduction of ribonucleoside 5′-diphosphates (NDPs) into 2′-deoxyribonucleoside 5′-diphosphates (dNDPs) via redox reactions [51], perturbation of RNR elevates ROS in the micro-environment that can slow down replication fork progression by disruption the association TIMELESS from chromatin via PRX2 [50]. Recent study demonstrated that decrease in genomic stability in PRX5 knockdown mouse inner medullary collecting duct 3 (IMCD3) cells by the increased centrosome amplification and multi-polar spindle formation [52]. The functions of PRXs in nucleus remain largely unclarified.

However, in most circumstances, cancer cells are known to contain high expression levels of peroxiredoxins [53]. Many mechanisms of peroxiredoxin in tumorigenesis are proposed. In brief, peroxiredoxins mainly act as a general cell survival enhancer not only for normal cells but also cancer cells. Knockdown the expression levels of peroxiredoxins suppresses their tumorigenic, metastatic, migrating and invasion capacities. Overexpression of peroxiredoxins enhances tumorigenicity and associates with development of chemoresistance [54] and poor prognosis in cancer patient [55]. The early observations include PRX3 is required for Myc-mediated proliferation and transformation of R1a-myc cells in nude mice [56]. Other mechanisms include PRX1 promotes carcinogenesis via induction of vascular endothelial growth factor (VEGF) expression [57]. That is why the approach is using inhibitors against peroxiredoxins for treatment of cancers were suggested [58].

8. Peroxiredoxins as Damage-Associated Molecular Patterns (DAMPs) and Pathogen Associated Molecular Patterns (PAMPs)

8. Peroxiredoxins as damage-associated molecular patterns (DAMPs) and pathogen associated molecular patterns (PAMPs)

In response to stress and injury, certain endogenous molecules can be released or secreted from cells or those exposed on the cell surface. These molecules are named as damage-associated molecular patterns (DAMPs). Efficient clearance of DAMPs is required to resolve inflammation. DAMPs can trigger of sterile inflammation via various innate immune receptors for tissue repair and regeneration. However, DAMPs can also lead to the development of many inflammation-related diseases, such as metabolic disorders, neurodegenerative diseases, autoimmune diseases, and cancer resulting from dysregulated sterile inflammation [59]. According to the “DAMP hypothesis” of aging and cancer published on Ageing Res Rev in 2015, increased stressors, especially oxidative stress, lead to DAMPs translocating and releasing into the extracellular space [60]. Loss of intracellular DAMPs increases genomic instability, epigenetic alteration, telomere attrition, reprogrammed metabolism, and impaired degradation system, whereas increased extracellular DAMPs cause excessive inflammation and immune injury [60]. Extracellular peroxiredoxins are now recognized as one of the pro-inflammatory factors, as they function as DAMPs for nervous system injury [61] and liver damages [62]. Mechanistically, in general, peroxiredoxins released from necrotic cells binds to and TLR2 and/or TLR4 to increase secretion of inflammatory cytokines by immune cells that aggravates ischemic stroke [61] and liver injury [62].

Indeed, previous studies showed that peroxiredoxins from parasites act as pathogen associated molecular patterns (PAMPs) by triggering a pro-inflammatory response via binding to TLR4 receptor. The peroxiredoxins from parasites also protect the parasites against ROS/RNS produced by the host immune system [63]. Therefore, it seems only the intracellular peroxiredoxins have protective functions and extracellular peroxiredoxins are potential harmful. It is further confirmed by intraventricular injection of PRX2 alone caused hydrocephalus, ventricular wall damage, activation of macrophages, and an accumulation of neutrophils in rats [64]. 

9. Pros and Cons of Peroxiredoxin Inhibitors

9. Pros and Cons of peroxiredoxin inhibitors

Peroxiredoxins are multifunctional enzymes that function as redox signaling regulators, chaperones, and pro-inflammatory factors. By changing redox states of their unique active center cysteine and switch between low and high molecular weight species for regulating their peroxidase and chaperone activities that is not only crucial for survival of normal cells, but also senescence and cancer cells. Various inhibitors against peroxiredoxins developed for the treatment diseases related to overexpression of peroxiredoxins, such as cancers. As multiple peroxiredoxins are expressed in high level in most cells in peopleur body, the potential side effects such as inducing apoptosis and impairing genome integrity to normal cells shall be considered.

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