User:Eduarda Franco Marcolino/Sandbox 2
From Proteopedia
Contents |
Peroxiredoxin 3 (Prx3), Human
Peroxiredoxin 3 (Prx3) is a crucial antioxidant enzyme primarily found in the mitochondria, where it plays a vital role in protecting cells from oxidative stress. It belongs to the 2-Cys peroxiredoxin family, characterized by two key cysteine residues essential for its function. Prx3 reduces harmful hydrogen peroxide (H₂O₂) and organic hydroperoxides to water and alcohol, respectively, thereby maintaining cellular redox balance and influencing processes like apoptosis. Its unique mitochondrial localization makes it a key player in managing reactive oxygen species (ROS) produced during cellular respiration.
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Function
The active site is a peroxidatic cysteine (C(P)), which is the name given to a conserved redox-active cysteine residue. The catalysis is initiated by the nucleophilic attack on the peroxide substrate performed by this residue. Upon oxidation, the C(P)-SH site is converted to cysteine sulfenic acid (C(P)-SOH), which reacts with the resolving cysteine (C(R)), another residue usually located on the opposing subunit in the dimeric 2-Cys peroxiredoxins, forming a disulfide bridge. Finally, the catalytic cycle is completed when thioredoxin reduces this disulfide and, furthermore, regenerates the active site. The peroxidatic cysteine is C47 and the resolving cysteine is residue C168. The global reaction of the catalytic activity can be represented by a hydroperoxide + [thioredoxin]-dithiol = an alcohol + [thioredoxin]-disulfide + H2O. The peroxidatic N-terminal cysteine (C47) of mammalian Prdxs present a high susceptibility to inactivation by overoxidation. It is important to note the uncertainty on whether the cleavage of the transit peptide occurs after His-61 or Ala-62, since peptides have been found for both N-termini.
Disease
Cancer
Serum peroxiredoxin 3 has been identified as a valuable biomarker for early diagnosis and prognosis assessment of hepatocellular carcinoma in patients, probably due to its regulation of redox-sensitive signaling pathways related to cell proliferation. Additionally, in breast cancer, peroxiredoxin proteins play a protective role by shielding MCF-7 cells from doxorubicin-induced cytotoxicity, becoming a hindrance to chemotherapy by inducing mitochondrial reactive oxygen species (ROS). Furthermore, Prdx3 is overexpressed in prostate cancer, where it enhances cancer cell survival by mitigating oxidative stress damage.
Corneal dystrophy
In relation to Prdx3, it’s natural variant c.568G>C (p.Asp190His) has shown to be the genetic basis of punctiform and polychromatic pre-descement corneal dystrophy (PPPCD). As the name suggests, this variant changes the aspartate residue at position 190 (A190) to a histidine residue, which in biochemical terms means changing a medium size and acidic residue to a medium size and polar. The molecular interactions between the variant protein that leads to the formation of punctiform, multicolored opacities in the eye’s posterior strome are yet unclear.
Spinocerebellar ataxia
Spinocerebellar ataxia (SCA) is a clinically and genetically (i. e. inherited) heterogenous group of progressive, neurodegenerative cerebellar disorders which can be related to the brainstem and spinal cord. Specifically biallelic loss-of-function variants of Prdx3 have been shown to be associated with SCAR32, an autosomal recessive form of SCA due to reduced glutathione peroxidase activity.
Structural highlights
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References
1. Cao ZB, Bhella D, Lindsay JO. Reconstitution of the Mitochondrial PrxIII Antioxidant Defence Pathway: General Properties and Factors Affecting PrxIII Activity and Oligomeric State. 2007 Sep 28;372(4):1022–33.
2. Radyuk SN, Klichko VI, Spinola B, Sohal RS, Orr WC. The peroxiredoxin gene family in drosophila melanogaster. Free Radical Biology and Medicine. 2001 Nov 1;31(9):1090–100.
3. Yewdall NA, Peskin AV, Hampton MB, Goldstone DC, Pearce FG, Gerrard JA. Quaternary structure influences the peroxidase activity of peroxiredoxin 3. Biochemical and Biophysical Research Communications. 2018 Mar;497(2):558–63.
4. De Simoni S, Goemaere J, Knoops B. Silencing of peroxiredoxin 3 and peroxiredoxin 5 reveals the role of mitochondrial peroxiredoxins in the protection of human neuroblastoma SH-SY5Y cells toward MPP+. Neuroscience Letters. 2008 Mar;433(3):219–24.
5. PRDX3 peroxiredoxin 3 [Homo sapiens (human)] - Gene - NCBI [Internet]. Nih.gov. 2025 [cited 2025 Jun 14]. Available from: https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=10935
6. Cox AG, Peskin AV, Paton LN, Winterbourn CC, Hampton MB. Redox Potential and Peroxide Reactivity of Human Peroxiredoxin 3. Biochemistry. 2009 May 22;48(27):6495–501.
7. Rhea - reaction knowledgebase [Internet]. Rhea-db.org. 2025 [cited 2025 Jun 14]. Available from: https://www.rhea-db.org/rhea/62620
8. Wood ZA, Schröder E, Robin Harris J, Poole LB. Structure, mechanism and regulation of peroxiredoxins. Trends in Biochemical Sciences. 2003 Jan;28(1):32–40.
9. Cao Z, Lindsay JG, Isaacs NW. Mitochondrial peroxiredoxins. In: Flohé L, Harris JR, editors. Peroxiredoxin systems. Dordrecht: Springer; 2007. p. (Subcellular Biochemistry; vol. 44). doi: 10.1007/978-1-4020-6051-9_14.
10. Gourlay LJ, Bhella D, Kelly SM, Price NC, J. Gordon Lindsay. Structure-Function Analysis of Recombinant Substrate Protein 22 kDa (SP-22). Journal of Biological Chemistry. 2003 Aug 1;278(35):32631–7.
11. Cao Z, Roszak AW, Gourlay LJ, Lindsay JG, Isaacs NW. Bovine Mitochondrial Peroxiredoxin III Forms a Two-Ring Catenane. Structure. 2005 Nov;13(11):1661–4.
12. UniProt [Internet]. UniProt. 2025 [cited 2025 Jun 14]. Available from: https://www.uniprot.org/uniprotkb/P30048/entry#structure
13. Choo CH, Boto A, Chung DD, Aldave AJ. Confirmation of PRDX3 c.568G>C as the Genetic Basis of Punctiform and Polychromatic Pre-Descemet Corneal Dystrophy. Cornea. 2021 Aug 5;41(6):779–81.
14. Rebelo AP, Eidhof I, Cintra VP, Léna Guillot-Noel, Pereira CV, Timmann D, et al. Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia. Brain. 2021 Mar 3;144(5):1467–81.
15. Bhandari J, Thada PK, Samanta D. Spinocerebellar Ataxia [Internet]. Translate.goog. StatPearls Publishing; 2023 [cited 2025 Jun 15]. Available from: https://www-ncbi-nlm-nih-gov.translate.goog/books/NBK557816/?_x_tr_sl=en&_x_tr_tl=pt&_x_tr_hl=pt&_x_tr_pto=tc
16. UniProtKB/SwissProt variant VAR_087331 [Internet]. Expasy.org. 2020 [cited 2025 Jun 15]. Available from: https://web.expasy.org/variant_pages/VAR_087331.html#
17. Shi L, Wu LL, Yang JR, Chen XF, Zhang Y, Chen ZQ, et al. Serum Peroxiredoxin3 is a Useful Biomarker for Early Diagnosis and Assessment of Prognosis of Hepatocellular Carcinoma in Chinese Patients. Asian Pacific Journal of Cancer Prevention. 2014 Apr 1;15(7):2979–86.
18. McDONALD C, MUHLBAUER J, PERLMUTTER G, TAPARRA K, PHELAN SA. Peroxiredoxin proteins protect MCF-7 breast cancer cells from doxorubicin-induced toxicity. International Journal of Oncology. 2014 Apr 24;45(1):219–26.
19. Whitaker HC, Patel D, Howat WJ, Warren AY, Kay JD, T Sangan, et al. Peroxiredoxin-3 is overexpressed in prostate cancer and promotes cancer cell survival by protecting cells from oxidative stress. 2013 Jul 23;109(4):983–93.
20. Yewdall NA, Venugopal H, Desfosses A, Abrishami V, Yosaatmadja Y, Hampton MB, et al. Structures of Human Peroxiredoxin 3 Suggest Self-Chaperoning Assembly that Maintains Catalytic State. Structure (London, England: 1993) [Internet]. 2016 Jul 6 [cited 2022 May 30];24(7):1120–9.
