API

Relationship: 1765

Title

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Binding, SH/SeH proteins involved in protection against oxidative stress leads to Protection against oxidative stress, decreased

Upstream event

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Binding, SH/SeH proteins involved in protection against oxidative stress

Downstream event

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Protection against oxidative stress, decreased

Key Event Relationship Overview

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AOPs Referencing Relationship

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Taxonomic Applicability

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Term Scientific Term Evidence Link
rat Rattus norvegicus NCBI
mouse Mus musculus NCBI
human Homo sapiens NCBI

Sex Applicability

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Sex Evidence
Male
Female

Life Stage Applicability

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Term Evidence
All life stages High

Key Event Relationship Description

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Thiol (SH) and selenol (SeH) compounds exhibit reactivity toward electrophiles and oxidants and have high binding affinities for metals (Higdon, 2012; Nagy, 2013; Winterbourn, 2008; Winther, 2014). Glutathione is a thiol-containing tripeptide acting as a cofactor for the enzyme peroxidase and thus serving as an indirect antioxidant donating the electrons necessary for its decomposition of H2O2, and is also involved in many other cellular functions (Kohen, 2002). Selenoproteins contain selenocysteine amino acid residues. The selenoprotein family is composed of proteins exerting diverse functions, among them several are oxidoreductases classified as antioxidant enzymes (Labunskyy, 2014; Reeves, 2009). Relevant for this KER there are two well-studied selenoprotein families which are described to be expressed in the brain; (i) the Glutathione Peroxidase (GPx) family, involved in detoxification of hydroperoxides; (ii) the Thioredoxin Reductase (TrxR) family, involved in the regeneration of reduced thioredoxin (Pillai, 2014), but also the less studied SelH, K, S, R, W, and P selenoproteins (Pisoschi, 2015; Reeves, 2009).

As summarized in the table 1, binding to the thiol/selenol groups of the selenoproteins cited above can result in structural modifications of these proteins, which in turn inhibits their catalytic activity and thereby reduces or blocks their metabolic capacity to neutralize reactive oxygen species (Fernandes, 1996; Rajanna, 1995). Similarly, binding to the thiol group of glutathione will decrease its anti-oxidant capacity.

 

Figure (Poole, 2015) Structures of cysteinyl and selenocysteinyl residues within proteins. The aminoacyl groups are shown to the left, with dotted lines representing peptide bonds to the next residue on either side. Both protonated (left) and deprotonated (right) forms of these amino acids are depicted with average pKa values.

 

 

 

 

Evidence Supporting this KER

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Biological Plausibility

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GPx family

GPxs are tetrameric enzymes, except GPx4 which is a monomer. Their thiol groups can either act directly as a reductant, or catalyze reduction of hydrogen peroxide and/or phospholipid hydroperoxides through glutathione co-factors (Hanschmann, 2013; Labunskyy, 2014).

TrxR family

TxRs are asymmetric homodimeric flavoenzymes, which mediate the reduction of oxidized Trx at the expense of NADPH (Birben, 2012). Inhibition of TrxR enzymes has been shown to lead to oxidative stress (Carvalho, 2008).

SelP

Downregulation of intracellular SelP by use of small interfering RNA (siRNA) impaired the viability of human astrocytes and made them more susceptible to hydroperoxide-induced oxidative stress, pointing to a direct contribution of SeP to ROS clearance (Steinbrenner, 2006).

GPx family

GPxs are tetrameric enzymes. Their thiol groups can either act directly as a reductant, or catalyze reduction of hydrogen peroxide and/or phospholipid hydroperoxides through glutathione co-factors (Hanschmann, 2013, Labunskyy, 2014).

TrxR family

TxRs are homodimeric flavoenzymes, which mediate the reduction of oxidized Txn at the expense of NADPH (Birben, 2012). Inhibition of TrxR enzymes has been shown to lead to oxidative stress (Carvalho, 2008).

SelP

Downregulation of intracellular SelP by use of small interfering RNA (siRNA) impaired the viability of human astrocytes and made them more susceptible to hydroperoxide-induced oxidative stress, pointing to a direct contribution of SeP to ROS clearance (Steinbrenner, 2006).

Table 1

Selenoprotein family

Protein name

Normal brain function

Disruption leading to oxidative stress

Reference

Glutathione

GSH

GSH is a major endogenous antioxidant functioning directly in neutralization of free radicals and reactive oxygen compounds. GSH is the reduced form of glutathione and its SH group of cysteine is able to reduce and/or maintain reduced form of other molecules.

Disruptions leads to increased oxidative stress and apoptosis.

(Dringen, 2000)

(Hall, 1999)

Glutathione Peroxidase (GPx) Family

GPx1

Peroxide/ROS reduction

(Promotes neuroprotection in response to oxidative challenge).

 

Brain expression levels are highest in microglia and lower levels detected in neurons.

Brains of GPx1−/− mice are more vulnerable to mitochondrial toxin treatment, ischemia/ reperfusion, and cold-induced brain injury.

Cultured neurons from GPx1−/− mice were reported to be more susceptible to Aβ-induced oxidative stress, and addition of ebselen reversed this.

(Lindenau, 1998)

(Crack, 2001, Flentjar, 2002, Klivenyi, 2000)

(Crack, 2006)

GPx4

Reduction of phospholipid

Hydroperoxides.

Only in neurons during normal conditions.

Brains of GPx4+/− mice were shown to have increased lipid peroxidation (a sign of oxidative stress).

Injury-induced GPx4 expression in astrocytes.

In vivo over expression of GPx4 protects against oxidative stress-induced apoptosis.

(Chen, 2008)

(Borchert, 2006, Ran, 2004, Savaskan, 2007)

Thioredoxin Reductase (TrxR) Family

TrxR1

Cytocsolic localization. Contributes to the reduction of hydrogen peroxide and oxidative stress, and regulates redox-sensitive

transcription factors that

control cellular transcription

mechanisms.

TrxR-1 regulates the induction of the antioxidant enzyme heme oxygenase 1 (HO-1).

Overexpression of human Trx1 and Trx2 protects retinal ganglion cells against oxidative stress-induced neurodegeneration.

(Pitts, 2014)

(Zhong, 2000)

 

(Burk, 2013)

(Arbogast, 2010, Trigona, 2006)

(Munemasa, 2008)

TrxR2

Mitochondrial localization. Contribute to the reduction of hydrogen peroxide and

oxidative stress, and regulates redox sensitive

transcription factors that

control cellular transcription

mechanisms.

Exogenously administered human rTrx ameliorates neuronal damage after transient middle cerebral artery occlusion in mice, reduces oxidative/nitrative stress and neuronal apoptosis after cerebral ischemia/reperfusion injury in mice

(Arbogast, 2010, Gladyshev, 1996, Papp, 2007, Pitts, 2014)

(Hattori, 2004, Ma, 2012)

Other relevant seleno- proteins

SelH

Nuclear localization. Redox sensing.

Hypersensitivity of SelH shRNA HeLa cells to paraquat- and H2O2-induced oxidative stress.

 

(Novoselov, 2007, Panee, 2007, Wu, 2014)

SelK

Transmembrane protein

localized to the ER membrane.

ER homeostasis and oxidative stress response.

Protects HepG2 cells from ER stress agent-induced apoptosis.

Overexpression of SelK attenuated the intracellular reactive oxygen species level and protected cells from oxidative stress-induced toxicity in cardiomyocytes

(Shchedrina, 2011)

(Du, 2010)

(Lu, 2006)

SelS

Transmembrane protein

localized to the ER membrane. Catalyze the reduction of disulfide bonds and peroxides.

SelS overexpression increased astrocyte resistance to ER-stress and inflammatory stimuli, and suppression of SelS compromised astrocyte viability.

(Liu, 2013)

(Fradejas, 2011)

(Fradejas, 2008)

(Gao, 2007)

MSRB1, SelR, SelX

Function in reduction of oxidized methionine residues, and actin polymerization.

Induce expression of MSRB1 protects neurons from amyloid β-protein insults in vitro and in vivo.

(Lee, 2013)

(Moskovitz, 2011, Pillai, 2014)

SelW

Expressed in synapses. Plays an antioxidant role in cells.

Rat in vivo overexpression of SelW was shown to protect glial cells against oxidative stress caused by heavy metals and 2,20-Azobis.

Silencing of SelW made neurons more sensitive to oxidative stress.

(Chung, 2009, Loflin, 2006, Raman, 2013, Reeves, 2009, Sun, 2001)

SelP

Is important for selenium transport, distribution and retention within the brain.

Acts as a ROS-detoxifying enzyme.

Protects human astrocytes from induced oxidative.

SelP-/- mice show neurological dysfunction and that Se content and GPx activity were reduced within brain, Se supplementation to diet attenuated neurological dysfunctions.

SelP-/- mice have reported deficits in PV-interneurons due to diminished antioxidant defense capabilities. Decreased neuronal selenoprotein synthesis may be a functional outcome of SelP

Colocalization of Sel P with amyloid plaques

SelP can function as an antioxidant enzyme against reactive lipid intermediates

(Arbogast, 2010, Steinbrenner, 2009, Zhang, 2008)

(Hill, 2003, Hill, 2004)

(Cabungcal, 2006)

(Pitts, 2012)

(Byrns, 2014)

(Schomburg, 2003)

(Rock, 2010)

Empirical Evidence

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Mercury

Thiol- and selenol containing proteins have a high affinity for binding metals which contributes to the target site – brain – distribution of such toxicants (Farina, 2011).

The selenol group (-SeH) of selenocysteines is generally more reactive than thiols (-SH) towards mercury (Sugiura 1976, Khan, 2009). Methyl mercury (MeHg) can target both the GPx and TrxR proteins thereby decreasing protection against oxidative stress and therefore causing increased oxidative stress and neurotoxicity (Branco, 2017, Carvalho, 2008, Farina, 2011).

 

Table 2

KEup

Interference with SH/SeH

KEdown

Decreased protection against oxidative stress

species; in vivo / in vitro

Stressor

Dose/ conc. +

Duration of exp.

Protective/ aggravating evidence

Reference

Post-transcriptional effects on GPx1 and TrxR1 expression and activity.

 

TrxR1 – 2-fold

GPx1 – 0.6-fold

Disturbance of redox-response and induction of oxidative stress.

 

 

SOD – 2-fold

ROS – increased

Mouse myoblast C2C12,

 

MeHg

0.4 µM

 

9 h

Treatment with ebselen suppressed MeHg-induced oxidative

stress

(Usuki, 2011)

Inhibition of TrxR and GSH activities.

 

 

TrxR1&2 – 0.6-fold

GSH – 0.7-fold

Oxidative stress shown by shift in GSSG/GSH ratio.

 

GSSG/GSH – 1.5-fold

Human neuroblastoma cells (SH-SY5Y)

MeHg

1 µM

 

 

Se supplementation gave some extent of oxidative stress protection.

(Branco, 2017)

Depletion of GSH levels.

 

 

 

 

 

 

 

 

 

 

 

GSH-activity:

10µM – 0.75-fold

30µM – 0.6-fold

100µM – 0,5-fold

Increased glutathione oxidation, hydroperoxide formation (xylenol orange assay) and lipid peroxidation

end-products (thiobarbituric acid reactive substances, TBARS).

 

Mitochondrial viability:

10µM – 0.75-fold

30µM – 0.6-fold

100µM – 0,5-fold

Total hydroperoxidases:

10µM – 1.0-fold

30µM – 1.2-fold

100µM – 1.75-fold

Mouse brain mito-chondrial-enriched

fractions

MeHg

10, 30, and 100 μM

 

30 minutes

The co-incubation with diphenyl diselenide (100 μM)

completely prevented the disruption of mitochondrial activity as well as the increase in TBARS levels. thiol peroxidase activity of organoselenium compounds accounts for their protective actions against methylmercury-induced oxidative stress

(Meinerz, 2011)

Depleted GSH levels.

Antioxidant imbalance and lipid peroxidation.

Adult male Wistar rats

mercuricchloride

30ppm in drinking water

 

(Agrawal, 2015)

 

Acrylamide (acrylamide is a common food contaminant generated by heat processing)

No literature supporting the link “SH/SeH binding leads to decreased protection against oxidative stress” for acrylamide as stressor in brain/neural tissue can be found.

Uncertainties and Inconsistencies

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Another important group of thiol-containing proteins are the metal-binging detoxifying metallothioneins. This protein family bind mercury and lead, and this binding thus serves as a protective mechanism and also protects against metal toxicity and oxidative stress (Aschner, 2006).

Lactational exposure to methylmercury (10 mg/L in drinking water) significantly increased cerebellar GSH level and GR activity. Possibly a compensatory response to mercury-induced oxidative stress (Franco, 2006).

Quantitative Understanding of the Linkage

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See Table 2

Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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Experimental evidences has been observed in rat, mice and human cells (Agrawal, 2015; Meinerz, 2011; Branco, 2017)

References

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Birben, E. et al. (2012) Oxidative stress and antioxidant defense. World Allergy Organ J 5, 9-19.

Borchert, A. et al. (2006) The role of phospholipid hydroperoxide glutathione peroxidase isoforms in murine embryogenesis. J Biol Chem 281, 19655-19664.

Branco, V. et al. (2017) Impaired cross-talk between the thioredoxin and glutathione systems is related to ASK-1 mediated apoptosis in neuronal cells exposed to mercury. Redox Biol 13, 278-287.

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