Protein repair (Homo sapiens)
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Reactive oxygen species (ROS) such as H2O2, superoxide anions and hydroxyl radicals interact with molecules in the cell causing damage that impairs cellular functions. Although cells have mechanisms to destroy ROS and repair the damage caused by ROS, it is considered to be a major factor in age-related diseases and the ageing process (Zhang & Weissbach 2008, Kim et al. 2014). ROS-scavenging systems include enzymes such as peroxiredoxins, superoxide dismutases, catalases and glutathione peroxidases exist to minimise the potential damage.
ROS reactions can also cause specific modifications to amino acid side chains that result in structural changes to proteins/enzymes. Methionine (Met) and cysteine (Cys) can be oxidised by ROS to sulfoxide and further oxidised to sulfone derivatives. Both free Met and protein-based Met are readily oxidized to form methionine sulphoxide (MetO) (Brot & Weissbach 1991). Many proteins have been demonstrated to undergo such oxidation and as a consequence have altered function (Levine et al. 2000). Sulphoxide formation can be reversed by the action of the methionine sulphoxide reductase system (MSR) which catalyses the reduction of MetO to Met (Brot et al. 1981). This repair uses one ROS equivalent, so MSR proteins can act as catalytic antioxidants, removing ROS (Levine et al. 1996). Methionine oxidation results in a mixture of methionine (S)-S- and (R)-S-oxides of methionine, diastereomers which are reduced by MSRA and MSRB, respectively. MSRA can reduce both free and protein-based methionine-(S)-S-oxide, whereas MSRB is specific for protein-based methionine-(R)-S-oxide. Mammals typically have only one gene encoding MSRA, but at least three genes encoding MSRBs (Hansel et al. 2005). Although structurally distinct, MRSA and MRSB share a common three-step catalytic mechanism. In the first step, the MSR catalytic cysteine residue interacts with the MetO substrate, which leads to product release and formation of the sulfenic acid. In the second step, an intramolecular disulfide bridge is formed between the catalytic cysteine and the regenerating cysteine. In the final step, the disulfide bridge is reduced by an electron donor, the NADPH-dependent thioredoxin/TR system, leading to the regeneration of the MSR active site (Boschi-Muller et al. 2008).
Beta-linked isoaspartyl (isoAsp) peptide bonds can arise spontaneously via succinimide-linked deamidation of asparagine (Asn) or dehydration of aspartate (Asp). Protein-L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1, PIMT EC 2.1.1.77) transfers the methyl group from S-adenosyl-L-methionine (AdoMet) to the alpha side-chain carboxyl group of L-isoaspartyl and D-aspartatyl amino acids. The resulting methyl ester undergoes spontaneous transformation to L-succinimide, which spontaneously hydrolyses to generates L-aspartyl residues or L-isoaspartyl residues (Knorre et al. 2009). This repair process helps to maintain overall protein integrity. View original pathway at:Reactome.
ROS reactions can also cause specific modifications to amino acid side chains that result in structural changes to proteins/enzymes. Methionine (Met) and cysteine (Cys) can be oxidised by ROS to sulfoxide and further oxidised to sulfone derivatives. Both free Met and protein-based Met are readily oxidized to form methionine sulphoxide (MetO) (Brot & Weissbach 1991). Many proteins have been demonstrated to undergo such oxidation and as a consequence have altered function (Levine et al. 2000). Sulphoxide formation can be reversed by the action of the methionine sulphoxide reductase system (MSR) which catalyses the reduction of MetO to Met (Brot et al. 1981). This repair uses one ROS equivalent, so MSR proteins can act as catalytic antioxidants, removing ROS (Levine et al. 1996). Methionine oxidation results in a mixture of methionine (S)-S- and (R)-S-oxides of methionine, diastereomers which are reduced by MSRA and MSRB, respectively. MSRA can reduce both free and protein-based methionine-(S)-S-oxide, whereas MSRB is specific for protein-based methionine-(R)-S-oxide. Mammals typically have only one gene encoding MSRA, but at least three genes encoding MSRBs (Hansel et al. 2005). Although structurally distinct, MRSA and MRSB share a common three-step catalytic mechanism. In the first step, the MSR catalytic cysteine residue interacts with the MetO substrate, which leads to product release and formation of the sulfenic acid. In the second step, an intramolecular disulfide bridge is formed between the catalytic cysteine and the regenerating cysteine. In the final step, the disulfide bridge is reduced by an electron donor, the NADPH-dependent thioredoxin/TR system, leading to the regeneration of the MSR active site (Boschi-Muller et al. 2008).
Beta-linked isoaspartyl (isoAsp) peptide bonds can arise spontaneously via succinimide-linked deamidation of asparagine (Asn) or dehydration of aspartate (Asp). Protein-L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1, PIMT EC 2.1.1.77) transfers the methyl group from S-adenosyl-L-methionine (AdoMet) to the alpha side-chain carboxyl group of L-isoaspartyl and D-aspartatyl amino acids. The resulting methyl ester undergoes spontaneous transformation to L-succinimide, which spontaneously hydrolyses to generates L-aspartyl residues or L-isoaspartyl residues (Knorre et al. 2009). This repair process helps to maintain overall protein integrity. View original pathway at:Reactome.
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These reactions are a significant source of protein damage under physiological conditions and represent both a mechanism that can usefully determine the lifetime of a protein (Robinson et al. 1970) and a component of the pathological process of ageing (Clarke 2003).