MINOR CREDIT SEMINARPeroxiredoxins: Guardians against oxidative stress and modulators of peroxide signalling

Submitted by: Arya Prakash PandaRoll no-M-5687

Animal Biochemistry

Peroxiredoxin

s

Glutathione peroxidase

O2 + e− → ·O2− (Reduction of molecular

oxygen) 2H+ + ·O2

− + ·O2− → H2O2 + O2 (Peroxidation)

H2O2 → HO · + ·OH (Partial Reduction)

H2O2 + H2O2 → H2O + H2O + O2 (Fully Reduced)

Chemistry of Peroxides…

-Peroxiredoxins (Prxs) :Ubiquitous enzymes that have emerged as most important and widespread peroxide scavenging enzymes in all of biology. -Cysteine based peroxidase enzymes that play a dominant role in regulating cell peroxide levels.

Karplus,P.A(2014)Free Radic. Biol,Med. 80, 183-190

-Thiol specific antioxidant proteins termed as thiol redoxin peroxidase.-Not only acts as antioxidants but also appear to regulate H2O2 mediated signal transduction.

Wood, Z.A. et al(2003) Science 300,650-653

What are Peroxiredoxins?

E.C-1.11.1.15 according to HGNC.Located primarily in cytosolRecently cellular roles include

modulation of H2O2 levels, which have been shown to mediate signaling cascades leading to cell Apoptosis.

Wood,Z.A.et al. Science 300,650-653

Additional informations…..

Prxs exist in six evolutionary subfamilies like Prx1, Prx5, Prx6,Tpx, PrxQ, and AhpE.

Prx1-highly expressed -0.1–1% of the soluble protein in the cell -typical 2-Cys Prxs (original type of ‘2-Cys Prx’having both a CP and CR In mammals, Prx1 subfamily enzymes divided into 6

groups( Prxs I-VI)PrxI and PrxII (cytosol and nucleus )PrxIII (mitochondria), PrxIV(ER), PrxV(peroxisomes, mitochondria, and cytosol)PrxVI, which is cytosolic .

PrxQ,Prx5-Bacteria, Plant Tpx & AhpE-Bacteria Prx(I-IV)-Typical 2-Cys, PrxV-Atypical 2-Cys, PrxVI-1 Cys

Rhee S, Chae H, Kim K (2005).   Free Radic .Biol Med 38 (12): 1543–52.

Classification

Wood ZA, et al.  Trends Biochem. Sci. 28 (1): 32–40.

Mechanism

Perkins A et al. Trends in Biochem. Sci. 40 (8): 435–445

Conformational changes

Wood ZA, Schröder E, Harris JR, Trends Biochem Sci. 2003; 28:32–40.

It is the state in which oxidation exceeds the antioxidant systems in the body secondary to a

loss of the balance between them. Imbalance between oxidants(ROS) and

antioxidants(Prx, catalase, Gpx)

Oxidative stress

OXIDATIVE STRESS

Reduce >90% of cellular peroxides. Can detect less concentration like 10 μM

H2O2 in cell. Some eukaryotic Prxs are inherent to

hyperoxidative inactivation by H2O2

Prxs in Stress…

Perkins A et al. Trends Biochem. Sci. 40 (8): 435–445

Not only oxidative stress defense enzymes but also regulators of peroxide levels in cells in stress response signaling.

Act as 2nd messenger in GF signalling, angiogenesis.

NADPH oxidase complex(Nox) are the source.

Localization of H2O2mediated Signaling process

Woojin Jeong, Tong-Shin Chang et al. Current Opinion in Cell Biology 2005, 17:183–189

Protein tyrosine phosphatase(PTP) and Phosphatase Tensin homolog lipid phosphatase (PTEN) which is regulated by Prxs.

PTPs-Proteins of low pKa of 4.7-5.4 Cysteine residues. It Undergoes H2O2 dependent inactivation in cells (Cys–S to Cys–SOH).

PTEN is a member of PTP family oxidised by H2O2 to intramolecular disulfide with Cys71 So oxidative inhibition of PTEN.

Target molecules

Sue Goo Rhee et al Current opinion in cell Bio. 17 (2): 183-189

PTP

www.fibrogenesis.com

PTEN

jcs.biologists.org

Reversible inactivation of PTPS & PTEN in cells

Kang W.S et al Current opinion in cell Bio. 17 (2): 183-189

Elimination of H2O2 by Prxs

Prxs ubiquitous group of antioxidant enzymes contain conserved Cys residues present in cytosol,mitochondria, ER as well as Nucleus.Plays important role in maintaining peroxide levels in cell as well as function as a guard against oxidative stress.Plays a key role in signaling.

Conclusion

Karplus,P.A, A primer on perxiredoxin biochemistryFree Radic. Biol,Med. 80, 183-190(2014)

Wood, Z.A, Peroxiredoxin evolution and the regulation of hydrogen peroxide signaling. Science 300, 650–653(2003)

Woo, H.A., Reversing the inactivation of peroxiredoxins caused by cysteine sulfinic acid formation. Science 300, 653–656 ( 2003)

Perkins A, Peroxiredoxins: guardians against oxidative stress and modulators of peroxide signaling Trends Biochem. Sci. 40 (8): 435–445(2015)

Rhee S.G., Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins, Current opinion in cell Bio. 17 (2): 183-189(2005)

REFERENCES

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