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Protein repair
Stable Identifier
R-HSA-5676934
DOI
10.3180/r-hsa-5676934.1
Type
Pathway
Species
Homo sapiens
ReviewStatus
5/5
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Metabolism of proteins (Homo sapiens)
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.
Literature References
PubMed ID
Title
Journal
Year
23648414
Methionine oxidation and reduction in proteins
Levine, RL
,
Kim, G
,
Weiss, SJ
Biochim. Biophys. Acta
2014
Participants
Events
Methionine is oxidised to methionine sulfoxide
(Homo sapiens)
MSRA reduces L-methyl-(S)-S-oxide to L-Methionine
(Homo sapiens)
MRSBs reduce L-methyl-(R)-S-oxide to L-methionine
(Homo sapiens)
Methionine sulfoxide is oxidised to methionine sulfone
(Homo sapiens)
Formation of isoAsp
(Homo sapiens)
PCMT1 transfers CH3 from AdoMet to isoAsp to form MetAsp
(Homo sapiens)
MetAsp transforms to L-Asp,isoAsp
(Homo sapiens)
Participates
as an event of
Metabolism of proteins (Homo sapiens)
Event Information
Go Biological Process
protein repair (0030091)
Orthologous Events
Protein repair (Bos taurus)
Protein repair (Caenorhabditis elegans)
Protein repair (Canis familiaris)
Protein repair (Danio rerio)
Protein repair (Dictyostelium discoideum)
Protein repair (Drosophila melanogaster)
Protein repair (Gallus gallus)
Protein repair (Mus musculus)
Protein repair (Plasmodium falciparum)
Protein repair (Rattus norvegicus)
Protein repair (Schizosaccharomyces pombe)
Protein repair (Sus scrofa)
Authored
Jupe, S (2015-01-05)
Reviewed
Meldal, BH (2015-10-05)
Created
Jupe, S (2015-02-20)
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