Hyperoxidation of mitochondrial peroxiredoxin limits H
            <sub>2</sub>
            O
            <sub>2</sub>
            ‐induced cell death in yeast

Calabrese, Gaetano; Peker, Esra; Amponsah, Prince Saforo; Hoehne, Martin; Riemer, Trine; Mai, Marie; Bienert, Gerd Patrick; Deponte, Marcel; Morgan, Bruce; Riemer, Jan

doi:10.15252/embj.2019101552

Cited by 67 publications

(60 citation statements)

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“…fluorescent protein have previously been used to gain mechansitic insight into glutaredoxin catalysis in vitro 18 , as well as to dynamically monitor the redox state of the intracellular glutathione pool 44,45 . Recently, we successfully established fusion constructs between redox-sensitive green-fluorescent protein 2 (roGFP2) and peroxidases for monitoring their catalytic mechanism and inactivation in living cells 46,47 . We thus asked if roGFP2 fusion constructs could also be adapted for the noninvasive assessment of Grx structure-function relationships inside living cells.…”

Section: Resultsmentioning

confidence: 99%

“…In our roGFP2 assays we choose to use H 2 O 2 to initiate GSSG formation. Whilst yeast do not harbor any bona fide glutathione peroxidase, it was recently shown that GSH and/or Grx can reduce both 1-Cys and typical 2-Cys peroxiredoxins thereby leading to GSSG production 42,46,47,49,50 . Furthermore, GSSG was shown to readily accumulate in Δglr1 cells following H 2 O 2 treatment 45 .…”

Section: Discussionmentioning

confidence: 99%

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Quantitative assessment of the determinant structural differences between redox-active and inactive glutaredoxins

et al. 2020

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Class I glutaredoxins are enzymatically active, glutathione-dependent oxidoreductases, whilst class II glutaredoxins are typically enzymatically inactive, Fe-S cluster-binding proteins. Enzymatically active glutaredoxins harbor both a glutathione-scaffold site for reacting with glutathionylated disulfide substrates and a glutathione-activator site for reacting with reduced glutathione. Here, using yeast ScGrx7 as a model protein, we comprehensively identified and characterized key residues from four distinct protein regions, as well as the covalently bound glutathione moiety, and quantified their contribution to both interaction sites. Additionally, we developed a redox-sensitive GFP2-based assay, which allowed the realtime assessment of glutaredoxin structure-function relationships inside living cells. Finally, we employed this assay to rapidly screen multiple glutaredoxin mutants, ultimately enabling us to convert enzymatically active and inactive glutaredoxins into each other. In summary, we have gained a comprehensive understanding of the mechanistic underpinnings of glutaredoxin catalysis and have elucidated the determinant structural differences between the two main classes of glutaredoxins.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Quantitative assessment of the determinant structural differences between redox-active and inactive glutaredoxins

et al. 2020

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“…In addition, knockdown of TOPK inhibits Prx1 (Ser-32) phosphorylation and thereby induces apoptosis that benefits skin cancer therapy [ 62 ]; indeed, knockout or mutation of TOPK leads to the phosphorylation of Prx1 and significantly increases H2O2. The ability of cells to tolerate oxidative stress is ultimately decreased, and this triggers apoptosis [ 63 ]. Taken together, these findings indicate that targeting TOPK is efficacious for cancer drugs resistance and, therefore, induces cell apoptosis.…”

Section: Topk Induces Apoptosis Resistance In Tumor Cellsmentioning

confidence: 99%

PBK/TOPK: An Effective Drug Target with Diverse Therapeutic Potential

Huang

Lee

Liu

et al. 2021

Cancers

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T-lymphokine-activated killer cell-originated protein kinase (TOPK, also known as PDZ-binding kinase or PBK) plays a crucial role in cell cycle regulation and mitotic progression. Abnormal overexpression or activation of TOPK has been observed in many cancers, including colorectal cancer, triple-negative breast cancer, and melanoma, and it is associated with increased development, dissemination, and poor clinical outcomes and prognosis in cancer. Moreover, TOPK phosphorylates p38, JNK, ERK, and AKT, which are involved in many cellular functions, and participates in the activation of multiple signaling pathways related to MAPK, PI3K/PTEN/AKT, and NOTCH1; thus, the direct or indirect interactions of TOPK make it a highly attractive yet elusive target for cancer therapy. Small molecule inhibitors targeting TOPK have shown great therapeutic potential in the treatment of cancer both in vitro and in vivo, even in combination with chemotherapy or radiotherapy. Therefore, targeting TOPK could be an important approach for cancer prevention and therapy. Thus, the purpose of the present review was to consider and analyze the role of TOPK as a drug target in cancer therapy and describe the recent findings related to its role in tumor development. Moreover, this review provides an overview of the current progress in the discovery and development of TOPK inhibitors, considering future clinical applications.

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“…Recently, it was reported that as human PRXD6, targeted to the yeast mitochondrial matrix, elicited glutathione disulfide (GSSG) formation upon treatment of cells with H 2 O 2 [32]. Because yeast lack GSTP1, it was suggested that other enzymes may re-activate the peroxidase activity of PRDX6.…”

Section: Discussionmentioning

confidence: 99%

Protective Role of Peroxiredoxins against Reactive Oxygen Species in Neonatal Rat Testicular Gonocytes

et al. 2019

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Peroxiredoxins (PRDXs) are antioxidant enzymes that protect cells from oxidative stress and play a role in reactive oxygen species (ROS)-mediated signaling. We reported that PRDXs are critical for human fertility by maintaining sperm viability and regulating ROS levels during capacitation. Moreover, studies on Prdx6 −/− mice revealed the essential role of PRDX6 in the viability, motility, and fertility competence of spermatozoa. Although PRDXs are abundant in the testis and spermatozoa, their potential role at different phases of spermatogenesis and in perinatal germ cells is unknown. Here, we examined the expression and role of PRDXs in isolated rat neonatal gonocytes, the precursors of spermatogonia, including spermatogonial stem cells. Gene array, qPCR analyses showed that PRDX1, 2, 3, 5, and 6 transcripts are among the most abundant antioxidant genes in postnatal day (PND) 3 gonocytes, while immunofluorescence confirmed the expression of PRDX1, 2, and 6 proteins. The role of PRDXs in gonocyte viability was examined using PRDX inhibitors, revealing that the 2-Cys PRDXs and PRDX6 peroxidases activities are critical for gonocytes viability in basal condition, likely preventing an excessive accumulation of endogenous ROS in the cells. In contrast to its crucial role in spermatozoa, PRDX6 independent phospholipase A 2 (iPLA 2 ) activity was not critical in gonocytes in basal conditions. However, under conditions of H 2 O 2 -induced oxidative stress, all these enzymatic activities were critical to maintain gonocyte viability. The inhibition of PRDXs promoted a two-fold increase in lipid peroxidation and prevented gonocyte differentiation. These results suggest that ROS are produced in neonatal gonocytes, where they are maintained by PRDXs at levels that are non-toxic and permissive for cell differentiation. These findings show that PRDXs play a major role in the antioxidant machinery of gonocytes, to maintain cell viability and allow for differentiation.PRDXs are classified depending on the cysteine residues (Cys) in their active site, that will react with peroxides. They comprise the 2-Cys PRDX1 to 4, the atypical 2-Cys PRDX5, and the 1-Cys PRDX6, which has the particularity of being bifunctional, with both peroxidase and calcium-independent phospholipase A 2 (iPLA 2 ) activities [4]. The 2-Cys PRDX1 to 4 are homodimers in which the thiol of a cysteine residue of one PRDX subunit gets oxidized, then further reacts with the thiol group of the catalytic cysteine of the other subunit, forming a disulfide bond between the two subunits. By contrast, in the atypical PRDX5, 2 Cys of the same chain react upon oxidation to form an intrasubunit disulfide bond. Inactive PRDXs are then reactivated by a reduction of the disulfide bonds by thioredoxin (TRX), itself further reactivated by TRX reductase (TRD), using NADPH as a reducing equivalent. In the case of PRDX6, since the enzyme has only one catalytic Cys, the oxidized thiol will be reduced by the glutathione-GSH-transferase P1 (GSTP1) system [4][5][6].Studies in PRDXs kno...

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Hyperoxidation of mitochondrial peroxiredoxin limits H ₂ O ₂ ‐induced cell death in yeast

Cited by 67 publications

References 68 publications

Quantitative assessment of the determinant structural differences between redox-active and inactive glutaredoxins

Quantitative assessment of the determinant structural differences between redox-active and inactive glutaredoxins

PBK/TOPK: An Effective Drug Target with Diverse Therapeutic Potential

Protective Role of Peroxiredoxins against Reactive Oxygen Species in Neonatal Rat Testicular Gonocytes

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Hyperoxidation of mitochondrial peroxiredoxin limits H 2 O 2 ‐induced cell death in yeast

Cited by 67 publications

References 68 publications

Quantitative assessment of the determinant structural differences between redox-active and inactive glutaredoxins

Quantitative assessment of the determinant structural differences between redox-active and inactive glutaredoxins

PBK/TOPK: An Effective Drug Target with Diverse Therapeutic Potential

Protective Role of Peroxiredoxins against Reactive Oxygen Species in Neonatal Rat Testicular Gonocytes

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Product

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Hyperoxidation of mitochondrial peroxiredoxin limits H ₂ O ₂ ‐induced cell death in yeast