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Catalytic Site Atlas

CSA LITERATURE entry for 1l1d

E.C. namepeptide-methionine (S)-S-oxide reductase
SpeciesNeisseria gonorrhoeae (strain ATCC 700825 / FA 1090)
E.C. Number (IntEnz) 1.8.4.11
CSA Homologues of 1l1d
CSA Entries With UniProtID P14930
CSA Entries With EC Number 1.8.4.11
PDBe Entry 1l1d
PDBSum Entry 1l1d
MACiE Entry 1l1d

Literature Report

IntroductionThe oxidation of methionine residues to methionine sulfoxide is implicated in ageing processes; the reduction of methionine sulfoxide protein residues is similarly implicated in antioxidant repair activity, but also the virulence of pathogenic organisms, such as Neisseria gonorrhoeae which secretes pilB. The modular pilB contains three domains; one is a methionine sulfoxide reductase (Msr) A which reduces S-methionine sulfoxide (S-chiral at sulphur), and another an MsrB which reduces R-methionine sulfoxide. The two domains have no sequence homology but use the same mechanism - an example of the fusion of two convergently evoluted enzymes.
Mechansim1) Cys 495 exists as a thiolate due to the conserved interactions with Arg 493 and Asp 484. Attack of Cys 495 on the sulphur of methionine sulfoxide leads to a 1,3-sigmatropic rearrangement involving the sulphur of Cys 495, and the S=O atoms of the substrate.
2) The trigonal bipyramid transition state (one equatorial position occupied by the substrate sulphur lone pair) is stabilised by hydrogen bonding to His 480 and a fixed water molecule.
3) The transition state collapses to yield methionine and a sulfenic acid intermediate, with Cys 495 hydroxylated as Cys 495-SOH .
4) Cys 440 is also a thiolate and forms a disulfide bond with Cys 495, releasing the hydroxyl group as water.
5) The disulfide bond is reduced by thioredoxin to regenerate the free thiolates.
Reaction

Catalytic Sites for 1l1d

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
HisA480480macie:sideChainHis 480 is the oxyanion hole, stabilising the trigonal bipyramid transition state via hydrogen bonding to the negative charge on the substrate oxygen.
ArgA493493macie:sideChainArg 493 hydrogen bonds to the Cys 495 thiolate, stabilising the negative charge (i.e. lowers the pKa of the neutral form).
CysA495495macie:sideChainThe Cys 495 thiolate attacks the sulphur of the methionine sulfoxide residue, leading to a 1,3-sigmatropic rearrangement with the sulfoxide group. The oxygen of the sulfoxide is therefore transferred to Cys 495 to give a sulfenic acid intermediate.
CysA440440macie:sideChainCys 440 attacks the sulfenic acid intermediate of Cys 495, forming a disulfide bond and displacing the hydroxyl as water.
AspA484484macie:sideChainAsp 484 hydrogen bonds to Arg 493, making Arg 493 a better stabiliser of the thiolate charge.

Annotated By Reference To The Literature - Site 2 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
HisB480480macie:sideChainHis 480 is the oxyanion hole, stabilising the trigonal bipyramid transition state via hydrogen bonding to the negative charge on the substrate oxygen.
ArgB493493macie:sideChainArg 493 hydrogen bonds to the Cys 495 thiolate, stabilising the negative charge (i.e. lowers the pKa of the neutral form).
CysB495495macie:sideChainThe Cys 495 thiolate attacks the sulphur of the methionine sulfoxide residue, leading to a 1,3-sigmatropic rearrangement with the sulfoxide group. The oxygen of the sulfoxide is therefore transferred to Cys 495 to give a sulfenic acid intermediate.
CysB440440macie:sideChainCys 440 attacks the sulfenic acid intermediate of Cys 495, forming a disulfide bond and displacing the hydroxyl as water.
AspB484484macie:sideChainAsp 484 hydrogen bonds to Arg 493, making Arg 493 a better stabiliser of the thiolate charge.

Literature References

Notes:
Lowther WT
The mirrored methionine sulfoxide reductases of Neisseria gonorrhoeae pilB.
Nat Struct Biol 2002 9 348-352
PubMed: 11938352
Olry A
Characterization of the methionine sulfoxide reductase activities of PILB, a probable virulence factor from Neisseria meningitidis.
J Biol Chem 2002 277 12016-12022
PubMed: 11812798
Olry A
Kinetic characterization of the catalytic mechanism of methionine sulfoxide reductase B from Neisseria meningitidis.
Biochemistry 2004 43 11616-11622
PubMed: 15350148
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