API

Event: 1487

Key Event Title

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Binding, SH/seleno proteins

Short name

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Binding, SH/seleno proteins

Biological Context

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Level of Biological Organization
Molecular

Cell term

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Organ term

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Key Event Components

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Process Object Action

Key Event Overview


AOPs Including This Key Event

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AOP Name Role of event in AOP
Oxidative stress and Developmental Neurotoxicity MolecularInitiatingEvent

Stressors

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Taxonomic Applicability

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Term Scientific Term Evidence Link
rat Rattus norvegicus NCBI
mouse Mus musculus NCBI
zebra fish Danio rerio NCBI
human Homo sapiens NCBI
Gallus gallus Gallus gallus NCBI

Life Stages

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Life stage Evidence
During brain development, adulthood and aging High

Sex Applicability

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Term Evidence
Unspecific High

Key Event Description

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Thiol (SH)- and seleno-containing proteins are located in different organelles and in the cytoplasm of the different neural cell types (Comini, 2016; Hoppe et al. 2008; Barbosa et al. 2017; Zhu et al. 2017). Binding of chemicals to these proteins induces either their inactivation or favor their degradation and/or inhibition of their synthesis (Farina et al. 2009; Zemolin et al. 2012). Therefore, we will directly include in the description of this MIE and of the protein of interest the main chemicals (mercury, acrylamide and acrolein) able to bind and to interfere with these proteins. (See Evidences for perturbations of this MIE by stressors)

 


How It Is Measured or Detected

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Domain of Applicability

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Evidence for Perturbation by Stressor


Overview for Molecular Initiating Event

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Interferences of the chemical initiators with SH-/seleno-containing proteins

Mercury

MeHg can interact with different functional groups found abundantly in biomolecules (e.g., carboxylate, primary and secondary amine groups, etc; Rabestein 1978a); however, its affinity for thiol and selenol groups are 6 to 12 orders of magnitude superior to that for hard nucleophile centers found in biomolecules (Table 1). The constants described in Table 1 indicate that MeHg behaves as a strong soft electrophile, i.e., it has much higher affinity for the soft nucleophiles centers of thiol- and selenol-containing molecules (Pearson, 1963; Rabestein 1978; Arnold et al. 1986; Sugiura et al., 1976; 1978), than for hard nucleophiles centers found in the functional groups of proteins, RNA, DNA, carbohydrates and lipids (Rabeinstein, 1978a).  Furthermore, the rate constant for the reaction of MeHg with thiol/thiolate (R-SH/R-S-) has been estimated to be about 6 x 108 M-1.sec-1, which indicates a very fast reaction (Rabenstein and Fairhurst, 1975).  As corollary, the occurrence of free MeHg or bound to other ligands such as carboxylates, amines, chloride or hydroxyl anions in the physiological media of living cells is insignificant or nonexistent (George et al. 2008). The binding of MeHg to abundant low molecular mass thiols or LMM-SH (e.g., cysteine and reduced glutathione-GSH) and high molecular thiol-containing proteins or HMM-SH (e.g., albumin, hemoglobin, etc) is critical for the MeHg distribution from non-target to target organs and cells (Farina et al. 2017).

Table 1 - Affinity constants of methylmercury for important chemical groups found in biomolecules (adapted from a Rabestein, 1978, Rabestein and Bravob using different thiol-containing molecules with the arylmercurial para-mercurybenzenosulfonate,  and cIsab 1991; and from dArnold et al. 1986 taking into consideration that the calculated formation constant of –Se-MeHg conjugates was 0.1 to 1.2 order greater than that of –S-MeHg). The values represent the Log of the constants.

 

Functional Group

 

Occurrence

Formation constant

Carboxyl/Carboxylate (-COOH/-COO-)

Amino acids, proteins, fatty acid

≈2.5-3.0a

Amino or primary amine (-NH2/-NH3+)

Amino acids, proteins, nitrogenous bases, nucleosides, nucleotides

≈7.0-8.0 a

Secundary amine

(-NH)

Amino acids, proteins, nitrogenous bases, nucleosides, nucleotides

≈7.0-9.0 a

Thioester (-S-)

Methionine

≈2.0 a

Thiol/thiolate (-SH/-S-)

Cysteine, glutathione, proteins

≈14-18 a,b

Thiol/thiolate (-SH/-S-)

Captopril

≈16-17c

Selenol/selenolate  (-SeH/Se-)

Selenocysteinyl residues in selenoproteins

≈ 16-18d

   

 

Here we will not discuss factors that can modify MeHg distribution, specifically, we will assume that MeHg-S conjugates reach the mitochondria, where MeHg will bind to thiol- and selenol-containing proteins via the exchange reactions of MeHg from one –SH to another –SH or –SeH groups  (Figure 1; Rabenstein 1978b; Rabenstein and Fairhurst, 1975; Rabenstein et al., 1974; 1982; Rabenstein and Reid, 1984; Farina et al. 2011, 2017; Dórea et al. 2013). But we have to emphasize that what we call of binding to –SH or –SeH groups is, in fact, an exchange reaction of MeHg from MeHg-S conjugates (e.g., MeHg-cysteine or MeHg-Cys and MeHg-glutathione or MeHg-SG conjugates; Figure 1) to  a free thiol- or selenol-group from non-target or target proteins (Figure 1). Thus, the interaction of MeHg with its target proteins in the brain usually involves the exchange of MeHg from LMM-S-conjugate to a thiol or selenol group in different types of proteins. The Molecular Initiating Event  (MIE) of targeting thiol- or selenol-groups in mitochondrial brain proteins is expected to start a cascade of related events, which will culminate in mitochondrial failure, oxidative stress, thiol depletion, glutamate dyshomeostasis, inflammation, cell death and learning disabilities (Wormser et al. 2012; Roos et al. 2012; Ciccatelli et al. 2010; Montgomery et al. 2008, Stringari et al. 208)

Figure 1 – Binding of MeHg (CH3Hg+) to target thiol- (HMM-SH) or selenol-containing proteins (HMM-SeH). Note that, in fact, the binding of MeHg to their high molecular mass target proteins is mediated by exchange reactions of MeHg from low molecular mass thiol (LMM-SH) molecules to HMM-SH (represented by Prot-SH) or HMM-SeH (represented by Prot-SeH). The scheme also demonstrated that MeHg conjugated with one LMM-SH (here represented by either Cys1-SHgCH3 or G1SHgCH3) can exchange with others LMM-SH (here represented by Cys2-SH or G2SH). After one exchange reaction, the conjugated Cys1-SHgCH3 and G1SHgCH3 release the free LMM-SH molecules Cys1-SH or G1SH. This type of exchange reaction can also occur in the extracellular space.

In view of the strong affinity of MeHg for thiol-groups and the relative high abundance of LMM-SH molecules over HMM-SH and high molecular mass selenol containing proteins (HMM-SeH) (Table 2), the probability of finding MeHg molecules bound to LMM-SH molecules is high. In fact, at physiological pH, the affinity (constant formation) of MeHg with GSH or hemoglobin was higher for GSH than hemoglobin  (about 1 order of magnitude, Reid and Rabestein, 1982). However, the studies performed by professor Dallas Rabestein have clearly demonstrated that MeHg can migrate rapidly/easily from one LMM-SH to either other LMM-SH or HMM-SH groups and vice and verse (Rabenstein 1978b; Rabenstein and Fairhurst, 1975; Rabenstein et al., 1974; 1982; Rabenstein and Reid, 1984; Arnold et al. 1986; Farina et al. 2011, 2017; Dórea et al. 2013).  The studies of Rabenstein and others have also pointed out that the affinity of MeHg for –SeH groups is higher than for analog –SH groups (Sugira et al. 1976; 1978; Arnold et al. 1986). Thus, one would guess that –SeH-containing molecules (i.e., selenoproteins) should be the preferential targets for MeHg (Farina et al. 2011). Although this can be the case, the great abundance of –SH-containing molecules over the very limited occurrence of selenoproteins (-SeH groups) and the potential change in the reactivity of specific –SH groups at the microenvironment of thiol-containing proteins, made the picture a little more complicate. Despite of this, several studies have demonstrate that the selenoenzymes glutathione peroxidase (GPx), thioredoxin reductase (TrxR) and 5′-deiodinase (DIO) can be inhibited after in vitro and in vivo exposure to MeHg (Li et al. 2008; Carvalho et al., 2008; 2011, Farina et al.,  2009; Franco et al., 2009; Wagner et al., 2010; Branco et al., 2011; 2012; 2014, 2017; Dalla Corte et al., 2013; Meinerz et al., 2017)

Table 2 – Occurrence of Soft Nucleophilic Centers (SNC) that can bind the Soft Electrophile Methylmercury (MeHg) with high affinity. The thiol (-SH) groups can be found in thousands of proteins and in a few low molecular mass molecules. In constrast, the selenol (-SeH) group is found only in a few number of selenoproteins.

 

Thiol-containing proteins - High molecular mass thiol molecules

 

–Cysteinyl residues (Cys)

Occurrence                                          

Concentration

in thousands of proteins

pmol/L-mmol/La

 

Selenoproteins - High molecular mass selenol molecules

 

–Selenocysteinyl residues (Sec)

Occurrence

Concentration

in few dozens of proteins

fmol/L-µmol/Lb

 

Low molecular mass thiol molecules (-SH)

Occurrence

Concentration

Cysteine

glutathione (GSH)

homocysteine

 

µmol/L-mmol/L

 

Low molecular mass selenol molecules (-SeH)

Occurrence

 

Selenocysteine/selenocystine

negligible

aThe exact concentration of thiol-containing proteins is not well characterized (except for hemoglobin and albumin, which have reactive cysteinyl residues in the mmol/L range.) The pmol/L is an estimation. bThe actual concentrations of selenoproteins have not been well characterized and the presented range is an estimation.

The binding of MeHg to the –SH or –SeH groups of proteins can directly inactivate their function or can indirectly facilitate the denaturation of the proteins even after the exchanging or transference of MeHg to another LMM-SH, HMM-SH or HMM-SeH  molecules (Farina et al. 2011; Farina et al. 2017). The hypothetical types of interactions between LMM-S-MeHg conjugates with thiol- and selenol-containing proteins (HMM-SH or HMM-SeH molecules) is depicted in Figure 2.   As commented above, the binding of MeHg to redox sensitive thiol- or selenol-groups can disrupt the activity of enzymes or the biochemical role of non-enzymatic brain proteins. Some examples of thiol- and selenol-containing brain enzymes that have been reported to be disrupted after MeHg exposure are presented in Tables 3 and 4Table 5 shows some of the mitochondrial processes that can be disturbed by MeHg.

Figure 2 – Hypothetical Binding of MeHg to different types of target proteins. The binding of MeHg to proteins can cause either a transitory inhibition of the protein fucntion (first line, the yellow protein was reactivated by interacting with LMM-SH or R-SH). The pink protein is an example of protein that after the binding of MeHg suffered a change in the structure in a such way that it cannot be reactivated by LMM-SH or R-SH.  The third protein (blue) is an example of protein that was permanently denaturated after MeHg binding and even after the removal of MeHg the activity was not recovered. The same type of interactions can be applied to the selenol-containing proteins (i.e., the selenoproteins). Here we have not included the non-targets proteins or thiol-containing proteins that can bind MeHg without interfering in the protein function.

 

Table 3 – Examples of thiol- and selenol-containing proteins that are inhibited by MeHg

Protein (complex) activity inhibited by MeHg

 

exposure

Functional group

 

organism

 

 

Creatine Kinase (CK)

 

in vitro

-SH

 

Adult mice cerebral cortex

C6 glioma cells

 

50-1500 µM -IC50=87 µM

1-50 µM -IC50≈50 µM

 

Glasser et al. 2010b

 

Total GPx

 

 

 

 

 

in vitro

 

 

-SeH

 

 

SH-SY5Y cells

 

0.5-2.0 µM Max. Inh.≈40%

 

Franco et al. 2009

Mouse  neuroblastoma

2.5 - 5.0  µM (24h)   Max. Inh.≈15-40%

Kromidas et al. 1990

PC12 cells

1.0-7.5 µM (24h) –  Max. Inh.≈7%

Li et al. 2008

Rat Fetal Telenchepalic cells

Aggregating immature and mature cells  (Cu2+ +ascorbate) + 1-100 nM MeHg

Sorg et al. 1998

 

Cytoplasmic TrxR

 

 

 

 

 

Nuclear TrxR

 

 

 

 

 

 

 

Cytoplasmic Gpx

 

 

in vivo

 

 

mice (gestacional and lactacional)

 

22 days-old C57BL/6J mice – 5 mg/L

cerebrum- male ¯

cerebrum- female ­

cerebellum- male ¯

cerebrum- female =

 

cerebrum- female =

cerebrum- male ¯

 

cerebellum- female =

cerebellum male  ¯

 

 

 

cerebrum- male ¯

cerebrum- female ­

cerebellum- male =

cerebellum- female =

 

 

Ruszkiewicz et al. 2016

 

GPx1

 

 

 

 

GPx4

 

 

 

TrxR

 

in vivo

 

-SeH

 

Adult Swiss male  mice-

 

 

21 days - 40 mg/L water

 

Cerebellum (immunocontent and activity) ¯

Cortex (activity) ¯

 

Cerebellum (immunocontent and activity) ¯

Cortex (immunocontent and activity) ¯

 

 

Cerebellum (activity)¯

Cortex (activity)¯

 

 

Zemolin et al. 2012

Total GPx

 

in vivo

 

 

-SeH

 

Adult Swiss mice-cerebellum

21 days - 40 mg/L water

male ¯

female=

Malagutti et al. 2009

1-, 11-, 21-day old mice (brain)

gestational exposure (1,3 or 10 mg/L water)

≈29, 84 or280 µg MeHg/day/dam

 

Stringari et al. 2008

Adult rat brain

5 or 10 mg/kg MeHg – 7 days

Cheng et al. 2005

Thioredoxin Reductase (TrxR)

 

in vivo

-SeH  and –SH

 

 

Adult rat brain

 

21 days - 5 mg/kg

 

Dalla Corte et al. 2012

in vitro

-SeH  and –SH

Adult mice brain

50-1.000 nM-IC50≈100 nM

Wagner et al. 2010

 

 

 

 

 

 

Type 2 5′-deiodinase (DIO2)

 

in vitro

-SeH

NB41A3 neuroblastoma cells

10-100 nM -IC50≈30 nM

Mori et al. 2006

in vitro

-SeH

Pituitary tumors GH3 cells

0.3-3 µM -IC50≈0.3-1.0  µM

Mori et al. 2007

Glutamine synthetase

in vitro

 

 

 

 

in vivo

-SH

Hypocampus  6-wk-old male ICR mice

Adult male Sprague/Dawley rats

Frontal cortex (0.1-100 µM -IC50≈50 µM)

Hippocampus  (0.1-100 µM -IC50≈50 µM)

Cerebellum  (0.1-100 µM -IC50≈20 µM)

 

6-wk-old ICR mice (2,4 and 10 mg/kg, i.p., once)

Hippocampus -  inhibition (12,17 and 21%)

 

 

 

Kwon and Park 2003[FT1] 

 

Ca2+-ATPase

 

in vitro

 

-SH

 

Adult rat brain microsomes

 

0.5-10 µM-IC50≈4 µM (Ca2+-uptake and ATP hydrolysis)

 

Freitas et al. 1996

 

Table 4 – Some mitochondrial thiol- or selenol-containing proteins that are inhibited by MeHg

Mitochondrial creatine kinase (mtCK)

in vivo

-SH

Adult Swiss male mice

21 days - 40 mg/L water

Glasser et al. 2010a; 2014

Complex I      

in vivo

-SH

Adult Swiss male mice, cerebral cortex

21 days - 40 mg/L water

Glasser et al. 2010a; 2013

Complex II

in vivo

-SH

Adult Swiss male mice, cerebral cortex

 

Adult male rats

21 days - 40 mg/L water

 

5 days, 10 mg/kg, p.o., cerebellum

Glasser et al. 2010a; 2013

Mori et al. 2011

Succinate dehydratase

in vivo

-SH

Adult Swiss male mice

Brain and spinal cord, 7 days, 1 mg/kg, s.c.

Bapu et al. 2003

Complex III

in vivo

-SH

Adult Swiss male mice, cerebral cortex  

21 days - 40 mg/L water

Glasser et al. 2010a; 2013

Complex IV

in vivo

-SH

Adult Swiss male mice, cerebral cortex  

21 days - 40 mg/L water

Glasser et al. 2010a; 2013

Mitochondrial total GPx

in vivo

-SeH

Adult rats

5 days – 10 mg/kg, p.o., cerebellum and cerebrum

Mori et al. 2007

Mitochondrial total GPx

in vivo

-SeH

Adult Swiss male mice brain

21 days - 40 mg/L water

Franco et al. 2009

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 5– Mitochondrial processes that are disrupted by MeHg exposure and can be associated with over-production of reactive oxygen species (ROS) and oxidative stress (OS).

Process

disrupted

 

 

Functional group

 

organism-preparation

 

 

MTT reduction

 

in vitro

-SH

Stratiatal synaptosomes male rats

 

7 day-old (0.5-10 µM -IC50≈5 µM)

14 day-old (0.5-10 µM -IC50≈5 µM)

21 day-old (0.5-10 µM -IC50≈5 µM)

2-3 month-old (0.5-10 µM -IC50≈8 µM)

 

Dreiem et al. 2005

 

 

2-3 month old (1-10 µM -IC50≈7.5 µM)

 

Dreiem & Seegal, 2007

 

C6 glioma cells

 

 

IC50 between 1-10 µM (3-24 h exposure)

 

Belletti et al. 2002

 

in vivo

Adult male rat (brain)

 

21 days, 5 mg/kg; i.p.

 

Dalla Corte et al. 2013

 

DYm (mitochondrial membrane potential)

in vitro

-SH

Stratiatal synaptosomes male rats

7 day-old (0.5-2.5 µM -IC50≈0.3 µM)

14 day-old (0.5-2.5 µM -IC50≈0.4 µM)

21 day-old (0.5-2.5 µM -IC50≈0.6 µM)

2-3 month-old (0.5-2.5 µM -IC50≈0.6 µM)

 

 

Dreiem et al. 2005

 

Cerebellar granule cells  (Marty and Atchison, 1997).

 

7-day-old Sprague–Dawley rats (0.5 µM – total collapse of DYm in 25 min

 

Limke and Atchison, 2002

 

Astrocytes

 

1,5 and 10  µM – 15-40% collapse of DYm (1-6h)

 

Yin et al. 2007

 

P19 murine embryonal carcinoma (EC) cells

 

1.5  µM –50% DYm collapse after 50 min

 

Polunas et al. 2011

Day 5 P19-derived neurons

1.5  µM –50% DYm collapse after 20 min

Ultrastructural changes consistent with an inhibition of

mitochondrial respiration

in vivo

 

 

in vivo

 

 

-SH and –SeH

 

 

-SH and     –SeH

 

Sprague-Dawley rats cerebral cortex

1.5 mg/kg day 2 to 50 (each 48h)

O’Kusky (1983)

Number of Mitochondria

and ultrastructure

Adult Swiss male mice

21 days-40 mg/L water         

Glasser et al. 2014

Oxygen consumption

Adult rats

5 days – 10 mg/kg, p.o., cerebellum

Mori et al. 2007

 

In short, the stable or transitory interaction (binding) of MeHg with critical thiol and selenol groups in target enzymes can disrupt the biological function of different types of enzymes (Table 3). In addition to enzymes, MeHg can disrupt the physiological activity of transporters and receptors.  As indicated in Table 3, mitochondrial and non-mitochondrial  oxidoreductases containing thiol and selenol redox centers have been reported to be disrupted by MeHg.  The dysregulation of cerebral glutathione (GSH and GSSG) and thioredoxin [Trx(SH)2]  systems by MeHg (Farina et al. 2011; Branco et al. 2017) can impair the fine cellular redox balance via disruption of sensitive cysteinyl- or thiol-containing proteins (Go and Jones, 2013; Go et al. 2015; Jones 2015).

 

Acrylamide and Acrolein

         Acrylamide and acrolein are a,β-unsaturated (conjugated) reactive molecule, which can react with thiol (-SH) and amino (-NH2) groups in proteins proteins (LoPachin, 2004; LoPachin et al. 2007; 2009; 2011;  Friedman, 2003; Bent et al. 2016; Martyniuk et al.2011; LoPachin and Gavin, 2014 ). However, the rate constant for the reaction between acrylamide with thiol/thiolate groups are much lower than that for MeHg (Table x).  The rate of reaction of these compounds with HMM-SH and LMM-SH is slow but can occur under physiological conditions (Tong et al. 2004; LoPachin, 2004). The inhibition of brain enzyme by acrylamide have been studied and the inhibition caused by acrylamide in some HMM-SH can be reversible  (Howland et al. 1980 ). Despite of this, we can infer that some targets of MeHg and acrylamide and acrolein can overlap.  Accordingly, some targets reported in Table 3 for MeHg have also been shown to be inhibited after exposure to acrylamide (Yousef and Demerdash, 2006; Lapadula et al. 1989; Kopańska et al. 2015). Of particular toxicological significance, both MeHg, acrylamide and acrolein have been reported to change the normal dynamic of synaptic function via interaction with specific HMM-SH (LoPachin et al. 2004 ; Farina et al. 2017).  Acrylamide can also be metabolized to an epoxide intermediate (glycidamide), which can also form adducts with cysteinyl residues in HMM-SH target proteins (Bergmark et al. 1991).

Table 6-Second order rate constants for the reaction of MeHg Acrylamide and acrolein with thiol/thiolate groups of biomolecules

Electrophile

Thiol/thiolate source

Rate constant

 

MeHg

GSH

≈6.0 x 108 M-1.sec-1

 

Acrylamide

Human serum albumin

≈5.4 x 10-3 M-1.sec-1

 

 

GSH

≈0.15-2.1 x 10-2 M-1.sec-1

 

 

N-acetylcysteine

≈0.2-3.2 x 10-3 M-1.sec-1

 

 

GADPH (Cys152)

≈5.3 x 10-2M-1.sec-1

 

Acrolein

GADPH (Cys152)

≈3.0 x 102 M-1.sec-1

 

 

N-acetylcysteine

≈2.15 M-1.sec-1

 

 

 

 

 

   

GADPH-glyceraldehyde 3-phosphate dehydrogenase



References

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