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Information on EC 1.8.4.11 - peptide-methionine (S)-S-oxide reductase and Organism(s) Bos taurus and UniProt Accession P54149
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1.8.4.11 peptide-methionine (S)-S-oxide reductaseIUBMB Comments
The reaction occurs in the reverse direction to that shown above. The enzyme exhibits high specificity for the reduction of the S-form of L-methionine S-oxide, acting faster on the residue in a peptide than on the free amino acid . On the free amino acid, it can also reduce D-methionine (S)-S-oxide but more slowly . The enzyme plays a role in preventing oxidative-stress damage caused by reactive oxygen species by reducing the oxidized form of methionine back to methionine and thereby reactivating peptides that had been damaged. In some species, e.g. Neisseria meningitidis, both this enzyme and EC 1.8.4.12, peptide-methionine (R)-S-oxide reductase, are found within the same protein whereas, in other species, they are separate proteins [1,4]. The reaction proceeds via a sulfenic-acid intermediate [5,10].
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The taxonomic range for the selected organisms is: Bos taurus
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
Synonyms
methionine sulfoxide reductase a, msra1, msra2, methionine sulfoxide reductases a, msra-1, methionine-s-sulfoxide reductase, peptide methionine sulphoxide reductase, methionine sulphoxide reductase a, peptide methionine sulfoxide reductase a, protein-methionine-s-oxide reductase, 
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topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
methionine S-oxide reductase (S-form oxidizing)
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-
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
L-methionine (S)-sulfoxide + thioredoxin = L-methionine + thioredoxin disulfide + H2O
catalytic mechanism and structural features, roles of cysteine residues, active site structure
L-methionine (S)-sulfoxide + thioredoxin = L-methionine + thioredoxin disulfide + H2O
catalytic mechanism involving the formation of a sulfenic acid intermediate, Cys72, Cys218 and Cys228 are involved
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peptide-L-methionine + thioredoxin disulfide + H2O = peptide-L-methionine (S)-S-oxide + thioredoxin
catalytic mechanism, Cys72 is essential for activity forming disulfide bonds with either Cys218 or Cys227
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SYSTEMATIC NAME
IUBMB Comments
peptide-L-methionine:thioredoxin-disulfide S-oxidoreductase [L-methionine (S)-S-oxide-forming]
The reaction occurs in the reverse direction to that shown above. The enzyme exhibits high specificity for the reduction of the S-form of L-methionine S-oxide, acting faster on the residue in a peptide than on the free amino acid [9]. On the free amino acid, it can also reduce D-methionine (S)-S-oxide but more slowly [9]. The enzyme plays a role in preventing oxidative-stress damage caused by reactive oxygen species by reducing the oxidized form of methionine back to methionine and thereby reactivating peptides that had been damaged. In some species, e.g. Neisseria meningitidis, both this enzyme and EC 1.8.4.12, peptide-methionine (R)-S-oxide reductase, are found within the same protein whereas, in other species, they are separate proteins [1,4]. The reaction proceeds via a sulfenic-acid intermediate [5,10].
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
alpha-synuclein-L-methionine (S)-S-oxide + thioredoxin
alpha-synuclein-L-methionine + thioredoxin disulfide + H2O
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-
-
?
peptide-L-methionine (S)-S-oxide + thioredoxin
peptide-L-methionine + thioredoxin disulfide + H2O
MsrA suppresses dopaminergic cell death and protein aggregation induced by the complex I inhibitor rotenone or mutant alpha-synuclein, but not by the proteasome inhibitor MG132. MsrA protects against Parkinson's disease-related stresses primarily via methionine sulfoxide repair rather than by scavenging reactive oxygen species
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-
?
L-methionine (S)-sulfoxide + thioredoxin
L-methionine + thioredoxin disulfide + H2O
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MsrA is specific for the S-form, enzyme variants with specificities for either free or protein-bound methionine
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-
?
N-acetyl-L-methionine-(S)-S-oxide + DTT
N-acetyl-L-methionine + DTT disulfide + H2O
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stereospecific reduction
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-
?
N-acetyl-L-methionine-(S)-S-oxide + thioredoxin
N-acetyl-L-methionine + thioredoxin disulfide + H2O
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stereospecific reduction
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-
?
peptide-L-methionine-(S)-S-oxide + thioredoxin
peptide-L-methionine + thioredoxin disulfide + H2O
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stereospecific reduction
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-
?
sulindac + thioredoxin
sulindac sulfide + thioredoxin disulfide
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activation of a methionine sulfoxide-containing prodrug, activity with membrane-bound enzyme form Mem-R,S-Msr
activated drug which inhibits cyclooxygenase 1 and 2 and exhibiting anti-inflammatory activity
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?
sulindac + thioredoxin
sulindac sulfide + thioredoxin disulfide
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activity with membrane-bound enzyme form Mem-R,S-Msr and MsrA
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-
?
additional information
?
-
-
the enzyme protects cells against oxidative damage and plays a role in age-related diseases
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-
?
additional information
?
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MsrA protects neuronal cells against brief hypoxia/reoxygenation, the enzyme is involved in oxidized protein repair and protects cells against reactive oxygen species and oxidative damage preventing apoptosis, overview
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-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
peptide-L-methionine (S)-S-oxide + thioredoxin
peptide-L-methionine + thioredoxin disulfide + H2O
MsrA suppresses dopaminergic cell death and protein aggregation induced by the complex I inhibitor rotenone or mutant alpha-synuclein, but not by the proteasome inhibitor MG132. MsrA protects against Parkinson's disease-related stresses primarily via methionine sulfoxide repair rather than by scavenging reactive oxygen species
-
-
?
L-methionine (S)-sulfoxide + thioredoxin
L-methionine + thioredoxin disulfide + H2O
-
MsrA is specific for the S-form, enzyme variants with specificities for either free or protein-bound methionine
-
-
?
peptide-L-methionine-(S)-S-oxide + thioredoxin
peptide-L-methionine + thioredoxin disulfide + H2O
-
stereospecific reduction
-
-
?
sulindac + thioredoxin
sulindac sulfide + thioredoxin disulfide
-
activation of a methionine sulfoxide-containing prodrug, activity with membrane-bound enzyme form Mem-R,S-Msr
activated drug which inhibits cyclooxygenase 1 and 2 and exhibiting anti-inflammatory activity
-
?
additional information
?
-
-
the enzyme protects cells against oxidative damage and plays a role in age-related diseases
-
-
?
additional information
?
-
-
MsrA protects neuronal cells against brief hypoxia/reoxygenation, the enzyme is involved in oxidized protein repair and protects cells against reactive oxygen species and oxidative damage preventing apoptosis, overview
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-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
the enzyme does not require meal ions for activity, free sulfhydryl content and disulfide bond numbers in wild-type and mutant enzymes, overview
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
-
subcellular sulindac reducing activity distribution in calf liver
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UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). MSRA_BOVIN
233
0
25818
Swiss-Prot
Mitochondrion (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
amino acid sequence comparison, analysis of three-dimensional structures, structure comparison to enzymes from other species
additional information
-
the Cys residue within the conserved sequence motif GCFWG at the N-terminus is essential for catalytic activity
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C107S
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site-directed mutagenesis, the mutant shows 14% increased activity with DTT and 4% with thioredoxin compared to the wild-type enzyme
C107S/C218S
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site-directed mutagenesis, the mutant shows 78% reduced activity with DTT and 94% with thioredoxin compared to the wild-type enzyme
C107S/C218S/C227S
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site-directed mutagenesis, the mutant shows 61% reduced activity with DTT and 92% with thioredoxin compared to the wild-type enzyme
C107S/C227S
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site-directed mutagenesis, the mutant shows 4% reduced activity with DTT and 86% with thioredoxin compared to the wild-type enzyme
C218S
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site-directed mutagenesis, the mutant shows 65% reduced activity with DTT and 78% with thioredoxin compared to the wild-type enzyme
C218S/C227S
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site-directed mutagenesis, the mutant shows 58% reduced activity with DTT and 96% with thioredoxin compared to the wild-type enzyme
C227S
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site-directed mutagenesis, the mutant shows 11% reduced activity with DTT and 81% with thioredoxin compared to the wild-type enzyme
C72S
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site-directed mutagenesis, inactive mutant, no disulfide bond in the mutant enzyme
additional information
additional information
-
expression of GFP-tagged MsrA in syncytial blastoderm-stage embryos of Drosophila melanogaster leads to a phenotype with extended lifespan of the mutant fruit flies, resistance to paraquat-induced oxidative stress, and to deleyed senescence-induced decline in general activity and reproductive capacity, overview
additional information
-
free sulfhydryl content and disulfide bond numbers in wild-type and mutant enzymes, overview
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant N-terminally His-tagged wild-type and mutant MsrAs from Escherichia coli by nickel affinity chromatography and dialysis
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
functional overexpression of EGFP-tagged MSRA in PC-12 cells using adenovirus-mediated gene transfer protecting the cells against apoptosis caused by hyperoxia, overview
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gene bmsrA, expression of GFP-tagged enzyme in syncytial blastoderm-stage embryos of Drosophila melanogaster
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gene msrA, DNA and amino acid sequence determination and analysis, recombinant expression, overexpression of MsrA leads to increased resistance to reactive oxygen species
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overexpression of bovine MsrA in Drosophila extends lifespan by 70%, as well as increased resistance to paraquat-induced oxidative stress
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overexpression of N-terminally His-tagged wild-type and mutant MsrAs in Escherichia coli
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
MsrA efficiently reduces oxidized methionine residues in recombinant alpha-synuclein. Enhancing MsrA function may be a reasonable therapeutic strategy in Parkinson's disease
synthesis
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enzyme can be useful in the development and action of anti-cancer and anti-inflammation drugs
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Lowther, W.T.; Brot, N.; Weissbach, H.; Honek, J.F.; Matthews, B.W.
Thiol-disulfide exchange is involved in the catalytic mechanism of peptide methionine sulfoxide reductase
Proc. Natl. Acad. Sci. USA
97
6463-6468
2000
Bos taurus
Ruan, H.; Tang, X.D.; Chen, M.L.; Joiner, M.A.; Sun, G.; Brot, N.; Weissbach, H.; Heinemann, S.H.; Iverson, L.; Wu, C.F.; Hoshi, T.
High-quality life extension by the enzyme peptide methionine sulfoxide reductase
Proc. Natl. Acad. Sci. USA
99
2748-2753
2002
Bos taurus
Etienne, F.; Resnick, L.; Sagher, D.; Brot, N.; Weissbach, H.
Reduction of Sulindac to its active metabolite, sulindac sulfide: assay and role of the methionine sulfoxide reductase system
Biochem. Biophys. Res. Commun.
312
1005-1010
2003
Bos taurus, Escherichia coli
Weissbach, H.; Resnick, L.; Brot, N.
Methionine sulfoxide reductases: history and cellular role in protecting against oxidative damage
Biochim. Biophys. Acta
1703
203-212
2005
Bos taurus, Dickeya chrysanthemi, Drosophila melanogaster, Escherichia coli, Haemophilus influenzae, Helicobacter pylori, Homo sapiens, Mus musculus, Neisseria gonorrhoeae, Neisseria meningitidis, Saccharomyces cerevisiae, Streptococcus gordonii, Streptococcus pneumoniae
Kauffmann, B.; Aubry, A.; Favier, F.
The three-dimensional structures of peptide methionine sulfoxide reductases: current knowledge and open questions
Biochim. Biophys. Acta
1703
249-260
2005
Bacillus subtilis, Bos taurus (P54149), Deinococcus radiodurans, Escherichia coli (P0A744), Mycobacterium tuberculosis (P9WJM5), Mycobacterium tuberculosis H37Rv (P9WJM5), Neisseria gonorrhoeae (P14930), Neisseria meningitidis, Solanum lycopersicum
Yermolaieva, O.; Xu, R.; Schinstock, C.; Brot, N.; Weissbach, H.; Heinemann, S.H.; Hoshi, T.
Methionine sulfoxide reductase A protects neuronal cells against brief hypoxia/reoxygenation
Proc. Natl. Acad. Sci. USA
101
1159-1164
2004
Bos taurus
Kim, H.Y.; Gladyshev, V.N.
Methionine sulfoxide reductases: selenoprotein forms and roles in antioxidant protein repair in mammals
Biochem. J.
407
321-329
2007
Bos taurus, Escherichia coli, Homo sapiens, Mycobacterium tuberculosis, Neisseria gonorrhoeae, Neisseria meningitidis, Populus trichocarpa, Mus musculus (Q9D6Y7)
Liu, F.; Hindupur, J.; Nguyen, J.L.; Ruf, K.J.; Zhu, J.; Schieler, J.L.; Bonham, C.C.; Wood, K.V.; Davisson, V.J.; Rochet, J.C.
Methionine sulfoxide reductase A protects dopaminergic cells from Parkinsons disease-related insults
Free Radic. Biol. Med.
45
242-255
2008
Bos taurus (P54149)
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