Detoxification of Reactive Oxygen Species (Homo sapiens)

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7, 13, 17, 44, 56...15, 7686624, 36, 68, 815, 59, 8422, 281, 2527, 41, 47, 48, 64...5239, 7445, 55, 9426, 73, 80, 88, 95...4, 67, 813, 21, 31, 47, 79...19, 38, 9214, 45, 55, 61, 74...26, 73, 80, 83, 88...37, 65, 729, 12, 16, 46248, 8771, 10110, 69, 7718, 32, 85, 8620, 43, 53, 10250, 5111, 4252, 6826, 73, 80, 88, 95...629, 33, 35, 10057endoplasmic reticulum lumenperoxisomal matrixmitochondrionGolgi lumenmitochondrial matrixphagocytic vesiclecytosolH2ONADP+Cu1+ O2SOD2 tetramerFAD NCF2 CCS:Zn2+:2xCu1+:SOD1:Zn2+Zn2+ GPX5, (GPX6)GPX3 tetramerP4HBPRDX2 H2OH2OO2SOD1 H2OCCS:Zn2+:2xCu1+dimerferroheme NADP+AQP8 NCF1 Zn2+ PRDX5Cu2+ NADP+H+GP4GH+PRDX6 O2Zn2+ PRDX5-1H2O2Zn2+ CYBA L-selenoC49-GPX1 CCS Zn2+ GPX8 PRDX3 SOD1 O2.-O2SOD3 (19-227) Cu1+ CCS:Cu1+ dimerMn2+ L-selenoC73-GPX3 SOD3 tetramerZn2+PRDX1,2,5CCS dimerH2O2ferriheme Cu1+ CYBA GMPCYCS GSSGNitriteZn2+ GSHSOD1 dimerSOD3 H+ATPHC53,56-P4HBTXNRD1 Cu1+ GSR dimerGSSGPeroxynitriteCCS:SOD1 dimerCu2+ L-selenocysteine residue-GPX1 GPX2 tetramerNADPHERO1L:GPX7,8SOD1:Zn2+H+CCS:Zn2+:Cu1+ dimerFAD Zn2+ SOD3 H2O2H2O2SOD1 H2ONOCu1+ O2-PRDX5-1 2xHC-SOD1 Cytochrome c(oxidised)PRDX5 NUDT2TXNRD2 GPX1 tetramerATP7ATXNRD2 dimerGPX5 TNXRD1:FAD dimerH2ONADPH Zn2+ CYBB CAT H+GPX7 NOX4 GSHCu2+ 2xHC-SOD1:Zn2+:Cu2+dimerPeroxynitriteH+2xHC-SOD1 SOD1 NADP+PRDX6:GSTP1CCS 2xHC-TXN2NONADPHH2OCCS O2.-GSHCCS H2O2NADPHH2OH+2xHC-TXNCytochrome c(reduced)CAT tetramerH+H2OGSSGNOX2 complexH+TXN2CYBB H2OCu2+ FAD Zn2+ Zn2+ Cu1+ TXNO2FAD GPX1 tetramerGPX6 ATOX1 Cu1+ heme NOX5 NADPHNADPHERO1L CCS Zn2+ heme 2xSOD1:CCS:Zn2+:2xCu1+ dimerCYCS SOD3 tetramerZn2+ CCS NitritePiGSR-1 Zn2+ GTPNOX4, NOX5PRDX1 NCF4 CCS GSTP1 SOD3ATOX1ATOX1:Cu1+SOD1 SOD1:Zn2+ADPH2O2GSR-2 NADP+O2.-PRDX3,5Cu1+ AQP8 tetramerGSR-2:FAD dimerH2OGPX2 SOD2 FAD 19, 38, 50, 92165, 7870, 9029, 58, 89615059, 8470, 9061757226934230, 4959, 8419, 4023, 586949, 58, 9829, 5819, 38, 9250, 5459, 84


Reactive oxygen species such as superoxide (O2.-), peroxides (ROOR), singlet oxygen, peroxynitrite (ONOO-), and hydroxyl radical (OH.) are generated by cellular processes such as respiration (reviewed in Murphy 2009, Brand 2010) and redox enzymes and are required for signaling yet they are damaging due to their high reactivity (reviewed in Imlay 2008, Buettner 2011, Kavdia 2011, Birben et al. 2012, Ray et al. 2012). Aerobic cells have defenses that detoxify reactive oxygen species by converting them to less reactive products. Superoxide dismutases convert superoxide to hydrogen peroxide and oxygen (reviewed in Fukai and Ushio-Fukai 2011). Catalase and peroxidases then convert hydrogen peroxide to water.
Humans contain 3 superoxide dismutases: SOD1 is located in the cytosol and mitochondrial intermembrane space, SOD2 is located in the mitochondrial matrix, and SOD3 is located in the extracellular region. Superoxide, a negative ion, is unable to easily cross membranes and tends to remain in the compartment where it was produced. Hydrogen peroxide, one of the products of superoxide dismutase, is able to diffuse across membranes and pass through aquaporin channels. In most cells the primary source of hydrogen peroxide is mitochondria and, once in the cytosol, hydrogen peroxide serves as a signaling molecule to regulate redox-sensitive proteins such as transcription factors, kinases, phosphatases, ion channels, and others (reviewed in Veal and Day 2011, Ray et al. 2012). Hydrogen peroxide is decomposed to water by catalase, decomposed to water plus oxidized thioredoxin by peroxiredoxins, and decomposed to water plus oxidized glutathione by glutathione peroxidases (Presnell et al. 2013). View original pathway at:Reactome.


Pathway is converted from Reactome ID: 3299685
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101422view11:30, 1 November 2018ReactomeTeamreactome version 66
100960view21:07, 31 October 2018ReactomeTeamreactome version 65
100497view19:41, 31 October 2018ReactomeTeamreactome version 64
100042view16:24, 31 October 2018ReactomeTeamreactome version 63
99595view14:58, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99213view12:43, 31 October 2018ReactomeTeamreactome version 62
93829view13:39, 16 August 2017ReactomeTeamreactome version 61
93380view11:22, 9 August 2017ReactomeTeamreactome version 61
87468view14:17, 22 July 2016MkutmonOntology Term : 'stress response pathway' added !
86467view09:18, 11 July 2016ReactomeTeamreactome version 56
83117view10:01, 18 November 2015ReactomeTeamVersion54
81457view12:59, 21 August 2015ReactomeTeamVersion53
76144view16:05, 11 June 2014AnweshaNew pathway

External references


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NameTypeDatabase referenceComment
2xHC-SOD1 ProteinP00441 (Uniprot-TrEMBL)
2xHC-SOD1:Zn2+:Cu2+ dimerComplexR-HSA-3299679 (Reactome)
2xHC-TXN2ProteinQ99757 (Uniprot-TrEMBL)
2xHC-TXNProteinP10599 (Uniprot-TrEMBL)
2xSOD1:CCS:Zn2+:2xCu1+ dimerComplexR-HSA-8951722 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
AQP8 ProteinO94778 (Uniprot-TrEMBL)
AQP8 tetramerComplexR-HSA-3779353 (Reactome)
ATOX1 ProteinO00244 (Uniprot-TrEMBL)
ATOX1:Cu1+ComplexR-HSA-3697875 (Reactome)
ATOX1ProteinO00244 (Uniprot-TrEMBL)
ATP7AProteinQ04656 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
CAT ProteinP04040 (Uniprot-TrEMBL)
CAT tetramerComplexR-HSA-76028 (Reactome)
CCS ProteinO14618 (Uniprot-TrEMBL)
CCS dimerComplexR-HSA-3780978 (Reactome)
CCS:Cu1+ dimerComplexR-HSA-3780985 (Reactome)
CCS:SOD1 dimerComplexR-HSA-3780962 (Reactome)
CCS:Zn2+:2xCu1+ dimerComplexR-HSA-3697845 (Reactome)
CCS:Zn2+:2xCu1+:SOD1:Zn2+ComplexR-HSA-3299706 (Reactome)
CCS:Zn2+:Cu1+ dimerComplexR-HSA-3299731 (Reactome)
CYBA ProteinP13498 (Uniprot-TrEMBL)
CYBB ProteinP04839 (Uniprot-TrEMBL)
CYCS ProteinP99999 (Uniprot-TrEMBL)
Cu1+ MetaboliteCHEBI:49552 (ChEBI)
Cu2+ MetaboliteCHEBI:29036 (ChEBI)
Cytochrome c (oxidised)ComplexR-HSA-352607 (Reactome)
Cytochrome c (reduced)ComplexR-HSA-352609 (Reactome)
ERO1L ProteinQ96HE7 (Uniprot-TrEMBL)
ERO1L:GPX7,8ComplexR-HSA-3341375 (Reactome)
FAD MetaboliteCHEBI:16238 (ChEBI)
GMPMetaboliteCHEBI:17345 (ChEBI)
GP4GMetaboliteCHEBI:15883 (ChEBI)
GPX1 tetramerComplexR-HSA-3323016 (Reactome)
GPX1 tetramerComplexR-HSA-71674 (Reactome)
GPX2 ProteinP18283 (Uniprot-TrEMBL)
GPX2 tetramerComplexR-HSA-2142735 (Reactome)
GPX3 tetramerComplexR-HSA-3341349 (Reactome)
GPX5 ProteinO75715 (Uniprot-TrEMBL)
GPX5, (GPX6)ComplexR-HSA-6800144 (Reactome)
GPX6 ProteinP59796 (Uniprot-TrEMBL)
GPX7 ProteinQ96SL4 (Uniprot-TrEMBL)
GPX8 ProteinQ8TED1 (Uniprot-TrEMBL)
GSHMetaboliteCHEBI:16856 (ChEBI)
GSR dimerComplexR-HSA-3323075 (Reactome)
GSR-1 ProteinP00390-1 (Uniprot-TrEMBL)
GSR-2 ProteinP00390-2 (Uniprot-TrEMBL)
GSR-2:FAD dimerComplexR-HSA-71680 (Reactome)
GSSGMetaboliteCHEBI:17858 (ChEBI)
GSTP1 ProteinP09211 (Uniprot-TrEMBL)
GTPMetaboliteCHEBI:15996 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2O2MetaboliteCHEBI:16240 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HC53,56-P4HBProteinP07237 (Uniprot-TrEMBL)
L-selenoC49-GPX1 ProteinP07203 (Uniprot-TrEMBL)
L-selenoC73-GPX3 ProteinP22352 (Uniprot-TrEMBL)
L-selenocysteine residue-GPX1 ProteinP07203 (Uniprot-TrEMBL)
Mn2+ MetaboliteCHEBI:29035 (ChEBI)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPH MetaboliteCHEBI:16474 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NCF1 ProteinP14598 (Uniprot-TrEMBL)
NCF2 ProteinP19878 (Uniprot-TrEMBL)
NCF4 ProteinQ15080 (Uniprot-TrEMBL)
NOMetaboliteCHEBI:16480 (ChEBI)
NOX2 complexComplexR-HSA-1222368 (Reactome)
NOX4 ProteinQ9NPH5 (Uniprot-TrEMBL)
NOX4, NOX5ComplexR-HSA-6809211 (Reactome)
NOX5 ProteinQ96PH1 (Uniprot-TrEMBL)
NUDT2ProteinP50583 (Uniprot-TrEMBL)
NitriteMetaboliteCHEBI:16301 (ChEBI)
O2-MetaboliteCHEBI:18421 (ChEBI)
O2.-MetaboliteCHEBI:18421 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
P4HBProteinP07237 (Uniprot-TrEMBL)
PRDX1 ProteinQ06830 (Uniprot-TrEMBL)
PRDX1,2,5ComplexR-HSA-3341359 (Reactome)
PRDX2 ProteinP32119 (Uniprot-TrEMBL)
PRDX3 ProteinP30048 (Uniprot-TrEMBL)
PRDX3,5ComplexR-HSA-3323011 (Reactome)
PRDX5 ProteinP30044-2 (Uniprot-TrEMBL)
PRDX5-1 ProteinP30044-1 (Uniprot-TrEMBL)
PRDX5-1ProteinP30044-1 (Uniprot-TrEMBL)
PRDX5ProteinP30044-2 (Uniprot-TrEMBL)
PRDX6 ProteinP30041 (Uniprot-TrEMBL)
PRDX6:GSTP1ComplexR-HSA-3343687 (Reactome)
PeroxynitriteMetaboliteCHEBI:25941 (ChEBI)
PiMetaboliteCHEBI:18367 (ChEBI)
SOD1 ProteinP00441 (Uniprot-TrEMBL)
SOD1 dimerComplexR-HSA-3777109 (Reactome)
SOD1:Zn2+ComplexR-HSA-3299732 (Reactome)
SOD1:Zn2+ComplexR-HSA-3780986 (Reactome)
SOD2 ProteinP04179 (Uniprot-TrEMBL)
SOD2 tetramerComplexR-HSA-3299689 (Reactome)
SOD3 (19-227) ProteinP08294 (Uniprot-TrEMBL)
SOD3 ProteinP08294 (Uniprot-TrEMBL)
SOD3 tetramerComplexR-HSA-3299688 (Reactome)
SOD3 tetramerComplexR-HSA-3697840 (Reactome)
SOD3ProteinP08294 (Uniprot-TrEMBL)
TNXRD1:FAD dimerComplexR-HSA-73532 (Reactome)
TXN2ProteinQ99757 (Uniprot-TrEMBL)
TXNProteinP10599 (Uniprot-TrEMBL)
TXNRD1 ProteinQ16881 (Uniprot-TrEMBL)
TXNRD2 ProteinQ9NNW7 (Uniprot-TrEMBL)
TXNRD2 dimerComplexR-HSA-3323058 (Reactome)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
Zn2+MetaboliteCHEBI:29105 (ChEBI)
ferriheme MetaboliteCHEBI:38574 (ChEBI)
ferroheme MetaboliteCHEBI:38573 (ChEBI)
heme MetaboliteCHEBI:17627 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
2xHC-SOD1:Zn2+:Cu2+ dimerArrowR-HSA-3299753 (Reactome)
2xHC-SOD1:Zn2+:Cu2+ dimermim-catalysisR-HSA-3299691 (Reactome)
2xHC-TXN2ArrowR-HSA-3322995 (Reactome)
2xHC-TXN2ArrowR-HSA-3697894 (Reactome)
2xHC-TXN2R-HSA-3323050 (Reactome)
2xHC-TXNArrowR-HSA-3341343 (Reactome)
2xHC-TXNArrowR-HSA-3697882 (Reactome)
2xHC-TXNR-HSA-73646 (Reactome)
2xSOD1:CCS:Zn2+:2xCu1+ dimerArrowR-HSA-3697860 (Reactome)
2xSOD1:CCS:Zn2+:2xCu1+ dimerR-HSA-8951723 (Reactome)
ADPArrowR-HSA-3697838 (Reactome)
AQP8 tetramermim-catalysisR-HSA-3779381 (Reactome)
ATOX1:Cu1+R-HSA-3697838 (Reactome)
ATOX1ArrowR-HSA-3697838 (Reactome)
ATP7Amim-catalysisR-HSA-3697838 (Reactome)
ATPR-HSA-3697838 (Reactome)
CAT tetramermim-catalysisR-HSA-76031 (Reactome)
CCS dimerArrowR-HSA-3780979 (Reactome)
CCS:Cu1+ dimerR-HSA-3780958 (Reactome)
CCS:SOD1 dimerArrowR-HSA-3780958 (Reactome)
CCS:SOD1 dimerR-HSA-3780979 (Reactome)
CCS:Zn2+:2xCu1+ dimerR-HSA-3697860 (Reactome)
CCS:Zn2+:2xCu1+:SOD1:Zn2+ArrowR-HSA-8951723 (Reactome)
CCS:Zn2+:2xCu1+:SOD1:Zn2+R-HSA-3299753 (Reactome)
CCS:Zn2+:2xCu1+:SOD1:Zn2+mim-catalysisR-HSA-3299753 (Reactome)
CCS:Zn2+:Cu1+ dimerArrowR-HSA-3299753 (Reactome)
Cytochrome c (oxidised)R-HSA-3341294 (Reactome)
Cytochrome c (reduced)ArrowR-HSA-3341294 (Reactome)
ERO1L:GPX7,8mim-catalysisR-HSA-3341296 (Reactome)
GMPArrowR-HSA-5696197 (Reactome)
GP4GR-HSA-5696197 (Reactome)
GPX1 tetramermim-catalysisR-HSA-3323013 (Reactome)
GPX1 tetramermim-catalysisR-HSA-71676 (Reactome)
GPX2 tetramermim-catalysisR-HSA-3341277 (Reactome)
GPX3 tetramermim-catalysisR-HSA-3341397 (Reactome)
GPX5, (GPX6)mim-catalysisR-HSA-6799695 (Reactome)
GSHArrowR-HSA-3323079 (Reactome)
GSHArrowR-HSA-71682 (Reactome)
GSHR-HSA-3323013 (Reactome)
GSHR-HSA-3341277 (Reactome)
GSHR-HSA-3341397 (Reactome)
GSHR-HSA-3343700 (Reactome)
GSHR-HSA-6799695 (Reactome)
GSHR-HSA-71676 (Reactome)
GSR dimermim-catalysisR-HSA-3323079 (Reactome)
GSR-2:FAD dimermim-catalysisR-HSA-71682 (Reactome)
GSSGArrowR-HSA-3323013 (Reactome)
GSSGArrowR-HSA-3341277 (Reactome)
GSSGArrowR-HSA-3341397 (Reactome)
GSSGArrowR-HSA-3343700 (Reactome)
GSSGArrowR-HSA-6799695 (Reactome)
GSSGArrowR-HSA-71676 (Reactome)
GSSGR-HSA-3323079 (Reactome)
GSSGR-HSA-71682 (Reactome)
GTPArrowR-HSA-5696197 (Reactome)
H+ArrowR-HSA-1222376 (Reactome)
H+ArrowR-HSA-6807557 (Reactome)
H+R-HSA-3299680 (Reactome)
H+R-HSA-3299682 (Reactome)
H+R-HSA-3299691 (Reactome)
H+R-HSA-3323050 (Reactome)
H+R-HSA-3323079 (Reactome)
H+R-HSA-3777112 (Reactome)
H+R-HSA-71682 (Reactome)
H+R-HSA-73646 (Reactome)
H2O2ArrowR-HSA-3299680 (Reactome)
H2O2ArrowR-HSA-3299682 (Reactome)
H2O2ArrowR-HSA-3299691 (Reactome)
H2O2ArrowR-HSA-3777112 (Reactome)
H2O2ArrowR-HSA-3779381 (Reactome)
H2O2R-HSA-3322995 (Reactome)
H2O2R-HSA-3323013 (Reactome)
H2O2R-HSA-3341277 (Reactome)
H2O2R-HSA-3341296 (Reactome)
H2O2R-HSA-3341343 (Reactome)
H2O2R-HSA-3341397 (Reactome)
H2O2R-HSA-3343700 (Reactome)
H2O2R-HSA-3779381 (Reactome)
H2O2R-HSA-6799695 (Reactome)
H2O2R-HSA-71676 (Reactome)
H2O2R-HSA-76031 (Reactome)
H2OArrowR-HSA-3322995 (Reactome)
H2OArrowR-HSA-3323013 (Reactome)
H2OArrowR-HSA-3341277 (Reactome)
H2OArrowR-HSA-3341296 (Reactome)
H2OArrowR-HSA-3341343 (Reactome)
H2OArrowR-HSA-3341397 (Reactome)
H2OArrowR-HSA-3343700 (Reactome)
H2OArrowR-HSA-3697882 (Reactome)
H2OArrowR-HSA-3697894 (Reactome)
H2OArrowR-HSA-6799695 (Reactome)
H2OArrowR-HSA-71676 (Reactome)
H2OArrowR-HSA-76031 (Reactome)
H2OR-HSA-3697838 (Reactome)
H2OR-HSA-5696197 (Reactome)
HC53,56-P4HBArrowR-HSA-3341296 (Reactome)
NADP+ArrowR-HSA-1222376 (Reactome)
NADP+ArrowR-HSA-3323050 (Reactome)
NADP+ArrowR-HSA-3323079 (Reactome)
NADP+ArrowR-HSA-6807557 (Reactome)
NADP+ArrowR-HSA-71682 (Reactome)
NADP+ArrowR-HSA-73646 (Reactome)
NADPHR-HSA-1222376 (Reactome)
NADPHR-HSA-3323050 (Reactome)
NADPHR-HSA-3323079 (Reactome)
NADPHR-HSA-6807557 (Reactome)
NADPHR-HSA-71682 (Reactome)
NADPHR-HSA-73646 (Reactome)
NOR-HSA-1222407 (Reactome)
NOR-HSA-3697855 (Reactome)
NOX2 complexmim-catalysisR-HSA-1222376 (Reactome)
NOX4, NOX5mim-catalysisR-HSA-6807557 (Reactome)
NUDT2mim-catalysisR-HSA-5696197 (Reactome)
NitriteArrowR-HSA-3697882 (Reactome)
NitriteArrowR-HSA-3697894 (Reactome)
O2-R-HSA-3341294 (Reactome)
O2-R-HSA-3777112 (Reactome)
O2.-ArrowR-HSA-1222376 (Reactome)
O2.-ArrowR-HSA-6807557 (Reactome)
O2.-R-HSA-1222407 (Reactome)
O2.-R-HSA-3299680 (Reactome)
O2.-R-HSA-3299682 (Reactome)
O2.-R-HSA-3299691 (Reactome)
O2.-R-HSA-3697855 (Reactome)
O2ArrowR-HSA-3299680 (Reactome)
O2ArrowR-HSA-3299682 (Reactome)
O2ArrowR-HSA-3299691 (Reactome)
O2ArrowR-HSA-3341294 (Reactome)
O2ArrowR-HSA-3777112 (Reactome)
O2ArrowR-HSA-76031 (Reactome)
O2R-HSA-1222376 (Reactome)
O2R-HSA-6807557 (Reactome)
P4HBR-HSA-3341296 (Reactome)
PRDX1,2,5mim-catalysisR-HSA-3341343 (Reactome)
PRDX3,5mim-catalysisR-HSA-3322995 (Reactome)
PRDX5-1mim-catalysisR-HSA-3697894 (Reactome)
PRDX5mim-catalysisR-HSA-3697882 (Reactome)
PRDX6:GSTP1mim-catalysisR-HSA-3343700 (Reactome)
PeroxynitriteArrowR-HSA-1222407 (Reactome)
PeroxynitriteArrowR-HSA-3697855 (Reactome)
PeroxynitriteR-HSA-3697882 (Reactome)
PeroxynitriteR-HSA-3697894 (Reactome)
PiArrowR-HSA-3697838 (Reactome)
R-HSA-1222376 (Reactome) Macrophage NOX2 is a membrane complex that generates superoxide anions by reduction of oxygen with NADPH (Babior 1999, Dinauer et al. 1991).
R-HSA-1222407 (Reactome) Nitric oxide and superoxide rapidly combine to form peroxynitrite (Pryor & Squadrito 1995).
R-HSA-3299680 (Reactome) Mn superoxide dismutase (SOD2) is located in the mitochondrial matrix where it catalyzes the reaction of two molecules of superoxide (O2-.) to form one molecule of oxygen (O2) and one molecule of hydrogen peroxide (H2O2). Data from mouse liver indicate that respiratory complex I leaks superoxide into the matrix and respiratory complex III leaks superoxide into both the matrix and the intermembrane space (Muller et al. 2004). Because of its negative charge superoxide is unable to cross membranes, however hydrogen peroxide, a product of SOD2, is released from mitochondria to the cytosol in proportion to the proton potential (inferred from rat heart mitochondria in Boveris et al. 2006, Korshunov et al. 1997).
R-HSA-3299682 (Reactome) Extracellular Cu-Zn superoxide dismutase (SOD3) catalyzes the reaction of two molecules of superoxide (O2.-) to form one molecule of oxygen (O2) and one molecule of hydrogen peroxide (H2O2) (Marklund et al. 1982, Marklund 1982)
R-HSA-3299691 (Reactome) Cu-Zn superoxide dismutase (SOD1), originally known as erythrocuprein, catalyzes the reaction of two molecules of superoxide (O2.-) to yield one molecule of hydrogen peroxide (H2O2) and one molecule of oxygen (O2) (McCord and Fridovich 1969 assayed both bovine and human Cu-Zn superoxide dismutase, the human sample provided by Carrico and Deutsch). Diffusion of hydrogen peroxide, the product of SOD1, across the cytosol is limited (Mishina et al. 2011)
R-HSA-3299753 (Reactome) Copper chaperone of superoxide dismutase (CCS) transfers a copper(I) atom to a SOD1 monomer that already contains a Zn atom. After initial heterodimerization between SOD1 and CCS, the copper atom is transferred, intramolecular cysteine disulfide bonds are formed in SOD1, and SOD1 dimerizes (Banci et al. 2012, Casareno et al. 1998, Culotta et al. 1997, Rae et al. 2001, Brown et al. 2004, Carroll et al. 2006, Kawamata and Manfredi 2008). The transfer of copper to SOD1 requires oxygen but it is unknown at which step the oxygen acts (Brown et al. 2004). There is also a CCS-independent, oxygen-independent pathway of maturation of SOD1 (Leitch et al. 2009) whose molecular details and physiological role are not well characterized.
R-HSA-3322995 (Reactome) Peroxiredoxin 3 (PRDX3) and PRDX5 in the mitochondrial matrix reduce hydrogen peroxide (H2O2) with thioredoxin to yield oxidized thioredoxin and water (Yamashita et al. 1999, Knoops et al. 1999, Cao et al. 2007, Nagy et al. 2011). Reduced PRDX5 is a monomer (Declercq et al. 2001) and oxidized PRDX5 is a dimer (Evrard et al. 2004) therefore the enzyme may cycle between states.
R-HSA-3323013 (Reactome) Glutathione peroxidase 1 (GPX1) located in the mitochondrial matrix uses glutathione to reduce hydrogen peroxide (H2O2) to yield oxidized glutathione and water (Legault et al. 2000, Li et al. 2000, Faucher et al. 2003). As inferred from rat mitochondria, GPX1 is the major determinant of steady-state hydrogen peroxide levels (Antunes et al. 2002).
R-HSA-3323050 (Reactome) Thioredoxin reductase 2 (TXNRD2) in the mitochondrial matrix regenerates reduced thioredoxin (TXN) by reacting oxidized thioredoxin with NADPH (Gasdaska et al. 1999, Cao et al. 2007).
R-HSA-3323079 (Reactome) Glutathione reductase (GSR) in the mitochondrial matrix regenerates reduced glutathione from oxidized glutathione and NADPH (Berkholz et al. 2008).
R-HSA-3341277 (Reactome) GPX2 (located in the gastrointestinal tract, also called GSHPx-GI, GPX-GI, and GI-GPx), like glutathione peroxidase 1 (GPX1, ubiquitous), reduces one molecule of hydrogen peroxide (H2O2) with two molecules of glutathione to yield one molecule of oxidized glutathione (glutathione disulfide, GSSG) and two molecules of water (Chu et al. 1998).
R-HSA-3341294 (Reactome) Superoxide can reduce cytochrome c in the intermembrane space (Wegerich et al. 2013, and inferred from other mammals in Butler et al. 1975, Koppenol et al. 1976, Butler et al. 1982). Superoxide has been shown in rat and mouse mitochondria to be released into the intermembrane space by the complex III of the respiratory chain (Han et al. 2001, Muller et al. 2004).
R-HSA-3341296 (Reactome) Glutathione peroxidase 7 (GPX7) and GPX8 are atypical glutathione peroxidases that catalyze the peroxidation of protein disulfide isomerases, such as PDI (P4HB) (Nguyen et al. 2011 and inferred from mouse in Bosello-Travain et al. 2013). GPX7 and GPX8 are each able to form heterodimers with the sulfhydryl oxidase ERO1alpha (ERO1L) in the endoplasmic reticulum lumen. It is hypothesized that GPX7 and GPX8 use hydrogen peroxide produced by ERO1L.
R-HSA-3341343 (Reactome) Peroxiredoxin 1 (PRDX1), PRDX2, and PRDX5 in the cytosol reduce hydrogen peroxide (H2O2) with thioredoxin yielding oxidized thioredoxin and water (Yamashita et al. 1999, Lee et al. 2007, Nagy et al. 2011).
R-HSA-3341397 (Reactome) Glutathione peroxidase 3 (GPX3) in plasma reduces hydrogen peroxide (H2O2) with glutathione to yield oxidized glutathione and water (Maddipati and Marnett 1987, Takahashi et al. 1987, Chung et al. 2009, Ottaviano et al. 2009). Glutathione is synthesized in the liver and exported into the plasma.
R-HSA-3343700 (Reactome) Peroxiredoxin 6 (PRDX6) forms a heterodimer with GSTP1 (Pi Glutathione transferase) and catalyzes the reduction of hydrogen peroxide (H2O2) by glutathione to yield oxidized glutathione and water (Ralat et al. 2006, Ralat et al. 2008, Zhou et al. 2013).
R-HSA-3697838 (Reactome) As inferred from mouse, ATP7A (Menke's ATPase, MNK) transports copper from ATOX in the cytosol to SOD3 in the lumen of the trans golgi network. ATP7A and SOD3 directly interact. Mutations in ATP7A cause Menke's disease, a neurodegenerative condition.
R-HSA-3697855 (Reactome) Superoxide and nitric oxide react to form peroxynitrite within mitochondria (Huie and Padmaja 1993, Packer et al. 1996, reviewed in Radi et al. 2002).
R-HSA-3697860 (Reactome) Copper chaperone of superoxide dismutase (CCS) transfers a copper(I) atom to a SOD1 monomer that already contains a Zn atom (Culotta et al. 1997, Casareno et al. 1998, Rae et al. 2001, Brown et al. 2004, Banci et al. 2012). The reaction proceeds by a two step mechanism in which SOD1 first forms heterodimers with CCS (Rae et al. 2001, Banci et al. 2012).
R-HSA-3697882 (Reactome) Peroxiredoxin 5 (PRDX5) very efficiently reduces peroxynitrite using thioredoxin to yield nitrite (NO2-), water, and oxidized thioredoxin (Dubuisson et al. 2004). The N-terminal cysteine (Cys 47) of PRDX5 attacks the O-O peroxide bond of peroxynitrite.
R-HSA-3697894 (Reactome) Peroxiredoxin 5 (PRDX5) very efficiently reduces peroxynitrite using TXN2 in mitochodria to yield nitrite (NO2-), water, and oxidized TXN2 (Dubuisson et al. 2004). The N-terminal cysteine (Cys 47) of PRDX5 attacks the O-O peroxide bond of peroxynitrite.
R-HSA-3777112 (Reactome) A portion of SOD1 is located in the mitochondrial intermembrane space (IMS) where it catalyzes the formation of oxygen (O2) and hydrogen peroxide (H2O2) from superoxide (O2.-) (He et al. 2011, Higgins et al. 2002, inferred from rat in Okado-Matsumoto and Fridovich 2001).
R-HSA-3779381 (Reactome) As inferred from rat heart mitochondria, hydrogen peroxide is released from mitochondria at a rate that is dependent on the membrane potential. Knockdown of Aquaporin-8 (AQP8) in human cells indicates that hydrogen peroxide is able to transit through the water channel of AQP8 located in the inner mitochodrial membrane (Marchissio et al. 2012). The resulting level of cytosolic hydrogen peroxide is hypothesized to signal the state of the mitochondria to regulatory molecules in the cytosol and nucleus (reviewed in Antico Arciuch et al. 2012).
R-HSA-3780958 (Reactome) As inferred from the cytosolic reaction and from the mouse mitochondrial reaction, Copper chaperone of superoxide dismutase (CCS) transfers a copper(I) atom to a SOD1 monomer that already contains a Zn atom. The reaction proceeds by a two step mechanism in which SOD1 first forms heterodimers with CCS. The amounts of CCS and SOD1 in the intermembrane space appear to be regulated by the concentration of oxygen. Mutations in SOD1 are responsible for familial amyotrophic lateral sclerosis (fALS) and cause unregulated localization and aggregation of SOD1 in the intermembrane space (reviewed in Kawamata and Manfredi 2010).
R-HSA-3780979 (Reactome) As inferred from the cytosolic reaction and from the mitochondrial reaction in mouse, Copper chaperone of superoxide dismutase (CCS) transfers a copper(I) atom to a SOD1 monomer that already contains a Zn atom. After initial heterodimerization between SOD1 and CCS, the copper atom is transferred, intramolecular cysteine disulfide bonds are formed in SOD1, and SOD1 dimerizes.
R-HSA-4837364 (Reactome) SOD3 is secreted from cells into the extracellular region. Before secretion a portion of SOD3 molecules are cleaved near the C-terminus at glutamate-227 (glutamate-209 in the mature protein) (Olsen et al. 2004, Karlsson et al. 1993). Removal of the C-terminus prevents interaction with the extracellular matrix so cleaved molecules are soluble. Cleaved and uncleaved molecules are believed to be capable of forming mixed tetramers (Sandstrom et al. 1993).
R-HSA-5696197 (Reactome) Bis(5'-nucleosyl)-tetraphosphatase (asymmetrical) (NUDT2) mediates the asymmetrical hydrolysis of P(1),P(4)-bis(5'-guanosyl) tetraphosphate (GP4G) to yield AMP and ATP. GP4G is implicated in the regulation of cellular responses to stress and its hydrolysis could serve as a mechanism by which homeostasis is maintained by preventing its build-up (Thorne et al. 1995, Swarbrick et al. 2005).
R-HSA-6799695 (Reactome) Epididymal secretory glutathione peroxidase (GPX5), a secreted and selenium-independent isoform of glutathione peroxidases, is present in very low levels in human sperm ejaculate. GPX5 has the potential to reduce hydrogen peroxide (H2O2) using glutathione (GSH), based on activity observed in rat and pig forms of the enzyme but its role in human epidydimis is unknown (Hall et al. 1998). Glutathione peroxidase 6 (GPX6) is thought to have peroxidase activity based on sequence similarity to GPX5.
R-HSA-6807557 (Reactome) NADPH oxidases 4 and 5 (NOX4, 5) are ER membrane-bound proteins that generates superoxide (O2.-) in endothelial cells (BelAiba et al. 2007). NOX4 functions in association with cytochrome b heterodimer (CYBA:CYBB) on the ER (and nuclear) membrane (Martyn et al. 2006).
R-HSA-71676 (Reactome) Cytosolic glutathione peroxidase (GPX1) tetramer catalyzes the reaction of reduced glutathione and hydrogen peroxide to form reduced glutathione and water (Chu et al. 1993).
R-HSA-71682 (Reactome) Cytosolic glutathione reductase catalyzes the reaction of glutathione (oxidized) and NADPH + H+ to form two molecules of glutathione (reduced) and NADP+ (Scott et al. 1963, Loos et al. 1976). Deficiency of glutathione reductase can cause hemolytic anemia.
R-HSA-73646 (Reactome) Cytosolic thioredoxin reductase catalyzes the reaction of thioredoxin, oxidized and NADPH + H+ to form thioredoxin, reduced and NADP+ (Urig et al. 2006).
R-HSA-76031 (Reactome) Hydrogen peroxide is generated in the course of peroxisomal fatty acid oxidation and purine catabolism, and is rapidly converted to water and molecular oxygen by the enzyme catalase. This enzyme is widely distributed in the body, but is especially abundant in liver, kidney, and red blood cells.
R-HSA-8951723 (Reactome) Copper chaperone of superoxide dismutase (CCS) transfers a copper(I) atom to a SOD1 monomer that already contains a Zn atom (Culotta et al. 1997, Casareno et al. 1998, Rae et al. 2001, Brown et al. 2004, Banci et al. 2012). The reaction proceeds by a two step mechanism in which SOD1 first forms heterodimers with CCS (Rae et al. 2001, Banci et al. 2012).
SOD1 dimerArrowR-HSA-3780979 (Reactome)
SOD1 dimermim-catalysisR-HSA-3777112 (Reactome)
SOD1:Zn2+R-HSA-3697860 (Reactome)
SOD1:Zn2+R-HSA-3780958 (Reactome)
SOD2 tetramermim-catalysisR-HSA-3299680 (Reactome)
SOD3 tetramerArrowR-HSA-3697838 (Reactome)
SOD3 tetramerArrowR-HSA-4837364 (Reactome)
SOD3 tetramerR-HSA-4837364 (Reactome)
SOD3 tetramermim-catalysisR-HSA-3299682 (Reactome)
SOD3R-HSA-3697838 (Reactome)
TNXRD1:FAD dimermim-catalysisR-HSA-73646 (Reactome)
TXN2ArrowR-HSA-3323050 (Reactome)
TXN2R-HSA-3322995 (Reactome)
TXN2R-HSA-3697894 (Reactome)
TXNArrowR-HSA-73646 (Reactome)
TXNR-HSA-3341343 (Reactome)
TXNR-HSA-3697882 (Reactome)
TXNRD2 dimermim-catalysisR-HSA-3323050 (Reactome)
Zn2+R-HSA-3697838 (Reactome)
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