Peroxiredoxins (Prxs) are a ubiquitous family of antioxidant proteins. They can be divided into three classes: typical 2-Cys, atypical 2-Cys and 1-Cys peroxiredoxins . The peroxidase reaction comprises two steps centred around a redox-active cysteine called the peroxidatic cysteine. All three peroxiredoxin classes have the first step in common, in which the peroxidatic cysteine attacks the peroxide substrate and is oxidized to S-hydroxycysteine (a sulfenic acid) (see {single/111115a::mechanism}). The second step of the peroxidase reaction, the regeneration of cysteine from S-hydroxycysteine, distinguishes the three peroxiredoxin classes. For typical 2-Cys Prxs, in the second step, the peroxidatic S-hydroxycysteine from one subunit is attacked by the 'resolving' cysteine located in the C-terminus of the second subunit, to form an intersubunit disulfide bond, which is then reduced by one of several cell-specific thiol-containing reductants completing the catalytic cycle. In the atypical 2-Cys Prxs, both the peroxidatic cysteine and its resolving cysteine are in the same polypeptide, so their reaction forms an intrachain disulfide bond. The 1-Cys Prxs conserve only the peroxidatic cysteine, so its regeneration involves direct interaction with a reductant molecule. Mycoredoxin-dependent enzymes are found in Mycobacteria. Following the reduction of the substrate, the sulfenic acid derivative of the peroxidatic cysteine forms a protein mixed disulfide with the N-terminal cysteine of mycoredoxin, which is then reduced by the C-terminal cysteine of mycoredoxin, restoring the peroxiredoxin to active state and resulting in an intra-protein disulfide in mycoredoxin. The disulfide is eventually reduced by mycothiol.
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SYSTEMATIC NAME
IUBMB Comments
mycoredoxin:hydroperoxide oxidoreductase
Peroxiredoxins (Prxs) are a ubiquitous family of antioxidant proteins. They can be divided into three classes: typical 2-Cys, atypical 2-Cys and 1-Cys peroxiredoxins [1]. The peroxidase reaction comprises two steps centred around a redox-active cysteine called the peroxidatic cysteine. All three peroxiredoxin classes have the first step in common, in which the peroxidatic cysteine attacks the peroxide substrate and is oxidized to S-hydroxycysteine (a sulfenic acid) (see {single/111115a::mechanism}). The second step of the peroxidase reaction, the regeneration of cysteine from S-hydroxycysteine, distinguishes the three peroxiredoxin classes. For typical 2-Cys Prxs, in the second step, the peroxidatic S-hydroxycysteine from one subunit is attacked by the 'resolving' cysteine located in the C-terminus of the second subunit, to form an intersubunit disulfide bond, which is then reduced by one of several cell-specific thiol-containing reductants completing the catalytic cycle. In the atypical 2-Cys Prxs, both the peroxidatic cysteine and its resolving cysteine are in the same polypeptide, so their reaction forms an intrachain disulfide bond. The 1-Cys Prxs conserve only the peroxidatic cysteine, so its regeneration involves direct interaction with a reductant molecule. Mycoredoxin-dependent enzymes are found in Mycobacteria. Following the reduction of the substrate, the sulfenic acid derivative of the peroxidatic cysteine forms a protein mixed disulfide with the N-terminal cysteine of mycoredoxin, which is then reduced by the C-terminal cysteine of mycoredoxin, restoring the peroxiredoxin to active state and resulting in an intra-protein disulfide in mycoredoxin. The disulfide is eventually reduced by mycothiol.
Mycobacteria employ a versatile machinery of the mycothiol-dependent system, containing the proteins mycothiol disulfide reductase, the oxido-reductase Mycoredoxin-1 and the alkyl-hydroperoxide subunit E (AhpE). The mycothiol-dependent protein ensemble regulates the balance of oxidized-reduced mycothiol, to ensure a reductive intracellular environment for optimal functioning of its proteins even upon exposure to oxidative stress. The epitopes of MtMrx-1 and MtAhpE interaction are described
mycoredoxin-1 (MtMrx1), a glutaredoxin-like, mycothiol-dependent oxidoreductase, directly reduces the oxidized form of the enzyme (MtAhpE), through a protein mixed disulfide with the N-terminal cysteine of MtMrx1 and the sulfenic acid derivative of the peroxidatic cysteine of MtAhpE. This disulfide is then reduced by the C-terminal cysteine in MtMrx1. Accordingly, MtAhpE catalyzes the oxidation of wild-type MtMrx1 by hydrogen peroxide but not of MtMrx1 lacking the C-terminal cysteine, confirming a dithiolic mechanism
mycoredoxin-1 (MtMrx1), a glutaredoxin-like, mycothiol-dependent oxidoreductase, directly reduces the oxidized form of the enzyme (MtAhpE), through a protein mixed disulfide with the N-terminal cysteine of MtMrx1 and the sulfenic acid derivative of the peroxidatic cysteine of MtAhpE. This disulfide is then reduced by the C-terminal cysteine in MtMrx1. Accordingly, MtAhpE catalyzes the oxidation of wild-type MtMrx1 by hydrogen peroxide but not of MtMrx1 lacking the C-terminal cysteine, confirming a dithiolic mechanism
Mycobacteria employ a versatile machinery of the mycothiol-dependent system, containing the proteins mycothiol disulfide reductase, the oxido-reductase Mycoredoxin-1 and the alkyl-hydroperoxide subunit E (AhpE). The mycothiol-dependent protein ensemble regulates the balance of oxidized-reduced mycothiol, to ensure a reductive intracellular environment for optimal functioning of its proteins even upon exposure to oxidative stress. The epitopes of MtMrx-1 and MtAhpE interaction are described
Thiol and sulfenic acid oxidation of AhpE, the one-cysteine peroxiredoxin from mycobacterium tuberculosis: kinetics, acidity constants, and conformational dynamics.
the essential residue of oxido-reductase Mycoredoxin-1 (MtMrx-1) identified in the interaction with mycothiol disulfide reductase (MtMtr) and MtAhpE form a platform for structure-guided drug design against the versatile enzyme machinery of the mycothiol-dependent system inside Mycobacterium tuberculosis
Mycobacteria employ a versatile machinery of the mycothiol-dependent system, containing the proteins mycothiol disulfide reductase, the oxido-reductase Mycoredoxin-1 (Mrx-1) and the alkyl-hydroperoxide subunit E (AhpE). The mycothiol-dependent protein ensemble regulates the balance of oxidized-reduced mycothiol, to ensure a reductive intracellular environment for optimal functioning of its proteins even upon exposure to oxidative stress
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
X-ray crystal structures of the MtAhpE mutants R116A and F37H at high resolution (1.74 A for R116A and 1.38 A for F37H). It is not possible to obtain the crystal structure of the T42V variant
Kumar, A.; Nartey, W.; Shin, J.; Manimekalai, M.S.S.; Grueber, G.
Structural and mechanistic insights into mycothiol disulphide reductase and the mycoredoxin-1-alkylhydroperoxide reductase E assembly of Mycobacterium tuberculosis
Kumar, A.; Balakrishna, A.M.; Nartey, W.; Manimekalai, M.SS.; Gruber, G.
Redox chemistry of Mycobacterium tuberculosis alkylhydroperoxide reductase E (AhpE) Structural and mechanistic insight into a mycoredoxin-1 independent reductive pathway of AhpE via mycothiol