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Enzyme Nomenclature
Information on EC 1.8.1.15 - mycothione reductase
for references in articles please use BRENDA:EC1.8.1.15
Word Map on EC 1.8.1.15
- 1.8.1.15
- tuberculosis
- thiols
- mycobacteria
- mycoredoxins
- actinobacteria
-
corynebacterium
-
dithiolic
- glutamicum
-
small-angle
-
oxidized-reduced
- natalensis
-
mycothiol-dependent
-
nadph-binding
-
antituberculosis
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ms-based
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monothiolic
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low-molecular
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antimycobacterial
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peroxidatic
-
sulfenic
- isoniazid
- peroxidases
- medicine
- analysis
- molecular biology
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The enzyme appears in viruses and cellular organisms
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EC NUMBER 
COMMENTARY 
1.8.1.15
-
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RECOMMENDED NAME
GeneOntology No.
mycothione reductase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
2 mycothiol + NAD(P)+ = mycothione + NAD(P)H + H+
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-
-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oxidation
-
-
-
-
redox reaction
-
-
-
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reduction
-
-
-
-
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
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SYSTEMATIC NAME
IUBMB Comments
mycothiol:NAD(P)+ oxidoreductase
Contains FAD. No activity with glutathione, trypanothione or coenzyme A as substrate.
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
-
in vivo Mtr knockout strain shows that the enzyme is involved in arsenate (As(V)) resistance suggesting a possible relation with the arsenate reductase activities
metabolism
-
cellular mycothiol metabolism, overview. Under stress conditions, proteins are oxidized to mixed disulfides with MSH to form S-mycothiolated proteins that is reversed by the Mrx1/Mtr/MSH pathway
physiological function
additional information
physiological function
-
in a mycothione disulfide reductase mutant, mycothiol levels decrease only upon treatment with peroxide
physiological function
-
in Mycobacterium tuberculosis, the enzyme is part of a versatile machinery of the mycothiol-dependent system, containing the proteins mycothiol disulfide reductase (Mtr), the oxido-reductase mycoredoxin-1 (Mrx-1) and the alkyl-hydroperoxide subunit E (AhpE), system overview. 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 uponexposure to oxidative stress
physiological function
-
the enzyme maintains intracellular redox homeostasis. The physiological roles of Mtr in resistance to oxidative stresses are corroborated by decreased reactive oxygen species levels, reduced carbonylation damage, decreased loss of reduced protein thiols, and a massive increase in the levels of reversible protein thiols in Mtr-overexpressing cells exposed to stressful conditions
physiological function
Mycobacterium smegmatis mc(2)155 / ATCC 700084
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in a mycothione disulfide reductase mutant, mycothiol levels decrease only upon treatment with peroxide
-
physiological function
-
in Mycobacterium tuberculosis, the enzyme is part of a versatile machinery of the mycothiol-dependent system, containing the proteins mycothiol disulfide reductase (Mtr), the oxido-reductase mycoredoxin-1 (Mrx-1) and the alkyl-hydroperoxide subunit E (AhpE), system overview. 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 uponexposure to oxidative stress
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additional information
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MtMtr is predicted to undergo a mono-to-dimeric equilibrium in solution during catalysis. Enzyme homology structure modelling
additional information
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MtMtr is predicted to undergo a mono-to-dimeric equilibrium in solution during catalysis. Enzyme homology structure modelling
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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
2-(-N-acetyl-L-cysteinyl) amino-2-deoxy-alpha-D-glucopyranoside disulfide + NADPH
?
-
-
-
-
?
5-(benzyl 2-(-N-acetyl-L-cysteinyl) amino-2-deoxy-alpha-D-glucopyranoside)-dithio-2-nitrobenzoate + NADPH
?
-
a 5,5'-dithiobis-2-nitrobenzoic acid (DTNB)-coupled assay is developed. The mixed disulfide substrate liberates one molecule of TNB on NADPH-dependent reduction by Mycobacterium tubercolosis reductase. The liberated mycothiol analogue then reacts with DTNB to regenerate the mixed disulfide substrate and another molecule of TNB. Reaction progress can be measured by the increase in absorbance (412 nm) from the two molecules of TNB produced per turn of this catalytic cycle
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-
?
8-chloro-5-methoxy-7-methyl-1,4-naphthoquinone + NADPH
?
-
-
-
-
?
benzyl 2-(-N-acetyl-L-cysteinyl) amino-2-deoxy-alpha-D-glucopyranoside disulfide + NADPH
?
-
-
-
-
?
benzyl 2-(N-acetyl-L-cysteinyl)amino-2-deoxy-alpha-D-glucopyranoside disulfide + NADPH
?
-
-
-
-
?
des-myo-inositol mycothione + reduced beta-nicotinamide hypoxanthine dinucleotide
?
-
-
-
?
des-myo-inositol mycothione + reduced beta-nicotinamide hypoxanthine dinucleotide phosphate
?
-
-
-
?
methyl 2-(-N-acetyl-L-cysteinyl) amino-2-deoxy-alpha-D-glucopyranoside disulfide + NADPH
?
-
-
-
-
?
mycothione + NADPH
mycothiol + NADP+
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the enzyme is involved in mycothiol metabolism. Mycothiol may play an important role in the survival and adaption of mycobacteria to oxidative stress caused by normal metabolism, ir induced by the action of anti-tubercular drugs
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-
?
additional information
?
-
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many naphthoquinones operate as subversive substrates. The native functions of these enzyme involves the NADPH-dependent reduction of disulfide bonds in the substrate. The enzyme-mediated toxicity of quinones/naphthoquinones is a consequence of their enzymatic reduction to semiquinone radicals. The naphthoquinone is then regenerated via the concomitant reduction of oxygen to toxic superoxide anion radicals. In this manner the naphthoquinone substrate is regenerated and the futile redox cycle continues
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additional information
?
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mycothiol disulfide reductase (Mtr) interacts with the oxido-reductase Mycoredoxin-1 (Mrx-1). the MtMtr-MtMrx-1 interaction is characterized by a fast exchange regime, critical residues by NMR spectroscopy and docking studies, overview
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additional information
?
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mycothiol disulfide reductase (Mtr) interacts with the oxido-reductase Mycoredoxin-1 (Mrx-1). the MtMtr-MtMrx-1 interaction is characterized by a fast exchange regime, critical residues by NMR spectroscopy and docking studies, overview
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NATURAL SUBSTRATES
NATURAL PRODUCTS
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
mycothione + NADPH
mycothiol + NADP+
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the enzyme is involved in mycothiol metabolism. Mycothiol may play an important role in the survival and adaption of mycobacteria to oxidative stress caused by normal metabolism, ir induced by the action of anti-tubercular drugs
-
-
?
additional information
?
-
-
mycothiol disulfide reductase (Mtr) interacts with the oxido-reductase Mycoredoxin-1 (Mrx-1). the MtMtr-MtMrx-1 interaction is characterized by a fast exchange regime, critical residues by NMR spectroscopy and docking studies, overview
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-
-
additional information
?
-
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mycothiol disulfide reductase (Mtr) interacts with the oxido-reductase Mycoredoxin-1 (Mrx-1). the MtMtr-MtMrx-1 interaction is characterized by a fast exchange regime, critical residues by NMR spectroscopy and docking studies, overview
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-
-
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
FAD
-
the FAD-binding- and interface domain participate in the dimer formation
NADPH
-
structure analysis of the two NADPH-binding domains inside the dimeric MtMtr in different conformations
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INHIBITORS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2-(5-bromo-2-methoxyphenyl)acrylonitrile
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time-dependent inhibitor
DMSO
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in the presence of 4% (v/v) DMSO, Mycobacterium tubercolosis reductase activity is reduced by only 10%. It is recommended that the DMSO content in sets of inhibition assays should be kept at a constant with 4% (v/v) DMSO as the upper limit
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.463
2-(-N-acetyl-L-cysteinyl) amino-2-deoxy-alpha-D-glucopyranoside disulfide
-
30°C, pH 7.5
0.268
5-(benzyl 2-(N-acetyl-L-cysteinyl) amino-2-deoxy-alpha-D-glucopyranoside)-dithio-2-nitrobenzoate
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-
0.142
8-chloro-5-methoxy-7-methyl-1,4-naphthoquinone
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pH 7.6, 30°C
0.055
alpha-NADPH
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des-myo-inositol mycothione as second substrate
0.438
benzyl 2-(-N-acetyl-L-cysteinyl) amino-2-deoxy-alpha-D-glucopyranoside disulfide
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30°C, pH 7.5
0.438
benzyl 2-(N-acetyl-L-cysteinyl) amino-2-deoxy-alpha-D-glucopyranoside disulfide
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-
0.008
beta-NADPH
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des-myo-inositol mycothione as second substrate
0.61
methyl 2-(-N-acetyl-L-cysteinyl) amino-2-deoxy-alpha-D-glucopyranoside disulfide
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30°C, pH 7.5
0.2
reduced beta-nicotinamide hypoxanthine dinucleotide
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des-myo-inositol mycothione as second substrate
0.023
reduced beta-nicotinamide hypoxanthine dinucleotide phosphate
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des-myo-inositol mycothione as second substrate
0.001
thio-NADPH
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des-myo-inositol mycothione as second substrate
additional information
additional information
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stopped-flow kinetics
-
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
70.05
2-(-N-acetyl-L-cysteinyl) amino-2-deoxy-alpha-D-glucopyranoside disulfide
-
30°C, pH 7.5
115
5-(benzyl 2-(N-acetyl-L-cysteinyl) amino-2-deoxy-alpha-D-glucopyranoside)-dithio-2-nitrobenzoate
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-
0.435
8-chloro-5-methoxy-7-methyl-1,4-naphthoquinone
-
pH 7.6, 30°C
36.99
benzyl 2-(-N-acetyl-L-cysteinyl) amino-2-deoxy-alpha-D-glucopyranoside disulfide
-
30°C, pH 7.5
37
benzyl 2-(N-acetyl-L-cysteinyl) amino-2-deoxy-alpha-D-glucopyranoside disulfide
-
-
25.54
methyl 2-(-N-acetyl-L-cysteinyl) amino-2-deoxy-alpha-D-glucopyranoside disulfide
-
30°C, pH 7.5
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.427
5-(benzyl 2-(N-acetyl-L-cysteinyl) amino-2-deoxy-alpha-D-glucopyranoside)-dithio-2-nitrobenzoate
-
-
0.09
benzyl 2-(N-acetyl-L-cysteinyl) amino-2-deoxy-alpha-D-glucopyranoside disulfide
-
-
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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SUBUNITS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
additional information
dimer
-
2 * 49800, about, sequence calculation, spectroscopic and dynamic light scattering structure analysis, modelling
dimer
-
2 * 49800, about, sequence calculation, spectroscopic and dynamic light scattering structure analysis, modelling
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additional information
-
MtMtr is predicted to undergo a mono-to-dimeric equilibrium in solution during catalysis. Enzyme homology structure modelling, the FAD-binding- and interface domain participate in the dimer formation
additional information
-
MtMtr is predicted to undergo a mono-to-dimeric equilibrium in solution during catalysis. Enzyme homology structure modelling, the FAD-binding- and interface domain participate in the dimer formation
-
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
recombinant tagged enzyme by affinity chromatography and gel filtration
-
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
overexpression of His6-tagged enzyme from expression vector pXMJ19 in Corynebacterium glutamicum. Transfected cells show increased tolerance to reactive oxygen species induced by oxidants, bactericidal antibiotics, alkylating agents, and heavy metals
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
enzyme expression is positively regulated by SigH, the stress-responsive extracytoplasmic function-sigma (ECF-sigma) factor
-
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
overexpression of mycothiol disulfide reductase enhances Corynebacterium glutamicum robustness by modulating cellular redox homeostasis and antioxidant proteins under oxidative stress. Overexpression of Mtr causes a marked increase in the ratio of reduced to oxidized mycothiol (MSH:MSSM), and significantly enhances the activities of a variety of antioxidant enzymes, including mycothiol peroxidase (MPx), mycoredoxin 1 (Mrx1), thioredoxin 1 (Trx1), and methionine sulfoxide reductase A (MsrA). The mycothione levels of enzyme expressing cells are lower than those of untransfectde cells under H2O2, ciprofloxacin, CdCl2, N-ethylmaleimide, iodoacetamide, methylglyoxal, and 1-chloro-2,4-dinitrobenzene stresses, no significant difference in MSH or MSSM levels when both cells are exposed to formaldehyde and rifamycin SV
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
analysis
medicine
-
the enzyme is sensitive to free radical generating antituberculosis drugs and may be useful target for new drug development
molecular biology
-
a DTNB-coupled assay is developed for time-dependent inhibition of Mycobacterium tubercolosis reductase employing a benzyl glycoside analogue of MSH, from which an efficient mixed disulfide substrate is chemically recycled in situ, thereby greatly reducing the substrate quantities needed for such assays
analysis
-
rapid method for the relative quantification of mycothiol using high-sensitivity mass spectrometry with selected ion monitoring. The method uses only minimal sample cleanup, and does not require advanced chromatographic equipment or fluorescent compounds
analysis
Mycobacterium smegmatis mc(2)155 / ATCC 700084
-
rapid method for the relative quantification of mycothiol using high-sensitivity mass spectrometry with selected ion monitoring. The method uses only minimal sample cleanup, and does not require advanced chromatographic equipment or fluorescent compounds
-
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LINKS TO OTHER DATABASES (specific for EC-Number 1.8.1.15)
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