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Information on EC 1.13.11.20 - cysteine dioxygenase and Organism(s) Homo sapiens and UniProt Accession Q16878
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1.13.11.20 cysteine dioxygenaseIUBMB Comments
Requires Fe2+ and NAD(P)H.
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Word Map
- 1.13.11.20
- taurine
-
sulfinic
-
non-heme
- hypotaurine
-
cysteinesulfinate
- cysteamine
- cystathionine
- 3-mercaptopropionate
-
cys-tyr
-
taut
-
adenosyltransferase
-
desulfhydration
-
2-his-1-carboxylate
-
gamma-lyase
-
cupins
- 2-aminoethanethiol
- medicine
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
cysteine dioxygenase, cysteine oxidase, cysteine dioxygenase type 1, bscdo, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
cysteine oxidase
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-
-
-
oxygenase, cysteine di-
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-
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
L-cysteine + O2 = 3-sulfinoalanine
reaction mechanism of cysteine oxygenation by CDO enzymes and reactivity of [TpMe,PhFe(CysOEt)] towards O2, detailed quantum mechanics/molecular mechanics calculations, overview
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
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-
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oxidation
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-
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reduction
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-
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PATHWAY SOURCE
PATHWAYS
BRENDA
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-, -
SYSTEMATIC NAME
IUBMB Comments
L-cysteine:oxygen oxidoreductase
Requires Fe2+ and NAD(P)H.
CAS REGISTRY NUMBER
COMMENTARY
37256-59-0
-
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
N-terminal Cys of RGS4 + O2
N-terminal Cys-sulfinic acid of RGS4
i.e. regulator of G-protein signalling
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-
?
N-terminal Cys of RGS5 + O2
N-terminal Cys-sulfinic acid of RGS5
i.e. regulator of G-protein signalling
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-
?
L-cysteine + O2
3-sulfinoalanine
structure of the sulfinato complex, overview
-
-
?
L-cysteine + O2
3-sulfino-L-alanine
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key enzyme in sulfate production, involved in the production of sulfate for the maintenance of a metabolic barrier against the entry of airborne xenobiotics and protein synthesis
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-
?
additional information
?
-
prediction of a h2-O,O-binding mode for synthetic as well as the natural enzyme, modeling of the cysteine sulfinic product complex in the active site
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-
?
additional information
?
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enzyme is able to cleave C-F bonds. The oxidants produced at the center of the non-heme ferrite effectively oxidize adjacent coordination residues and oxidize C-Cl and even C-F bonds during the formation of dihalogen-substituted cofactors, via four elementary steps: H-abstraction, C-S bond formation, F-transfer, and C-F bond cleavage. C-F bond cleavage is the rate-determining step with an energy barrier of 18.8 kcal/mol
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-
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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
L-cysteine + O2
3-sulfino-L-alanine
-
key enzyme in sulfate production, involved in the production of sulfate for the maintenance of a metabolic barrier against the entry of airborne xenobiotics and protein synthesis
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-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Cys-Tyr cofactor
a unique post-translational modification of human CDO consisting of a cross-link between cysteine 93 and tyrosine 157 (Cys-Tyr), which increases catalytic efficiency in a substrate-dependent manner. Production of a Cys-Tyr cofactor-saturated enzyme and analysis of the Cys-Tyr cofactor on kinetic properties, overview. The Cys-Tyr cofactor strongly contributes to efficient iron coordination in the active center of CDO
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NADH
enzyme uses NAD+/NADH as pharmacological chaperone. Presence of 0.1 mM NADH increase activity 1.3fold
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Fe2+
Mg
purified human cystein dioxygenase yields trace amounts of magnesium about 0.41%
Mn
purified human cystein dioxygenase yields trace amounts of manganese about 0.25%
Zn2+
purified human cystein dioxygenase yields a zinc incorporation of about 18.1%
Fe2+
-
mammalian cysteine dioxygenase is a non-heme iron protein, in its ferrous form [Fe(II)-CDO] it catalyzes the conversion of cysteine to cysteine sulfinic acid by incorporating both oxygen atoms of molecular oxygen to form the product. A Fe(III)-superoxo rather than a Fe(IV)-oxo intermediate facilitates substrate oxidation
Fe2+
purified human cystein dioxygenase yields a iron incorporation of about 68%
Fe2+
unsaturated distored tetragonal bipyramidal ferrous center with a vacant coordination site
Fe2+
non-heme iron enzyme. The enzyme contains an iron active site with an unusual 3-His ligation to the protein, which contrasts with the structural features of common nonheme iron dioxygenases
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
homocysteine
cysteine dioxygenase activity is reduced by 50% only when the molar ratio of homocysteine:cysteine dioxygenase reach about 30000:1
cytokine tumor necrosis factor-alpha
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also TNF-alpha, down-regulation observed in hepatic and brain cells
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transforming growth factor-beta
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also TGF-beta, down-regulation observed in hepatic and brain cells
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EDTA
an EDTA:cysteine dioxygenase molar ratio of about 1000:1 abolish`s cysteine oxidase activity
EDTA
enzyme activity is completely abolished at EDTA concentrations above 0.5 mM
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
NADH
enzyme uses NAD+/NADH as pharmacological chaperone. Presence of 0.1 mM NADH increase activity 1.3fold
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0715
N-terminal Cys of RGS5
pH not specified in the publication, 37°C
-
3.1
L-cysteine
under conditions where the second substrate oxygen is saturated
3.1
L-cysteine
pH 6.1, 37°C, recombinant wild-type enzyme, under iron saturation
0.0471
O2
cosubstrate N-terminal Cys of RGS5, pH not specified in the publication, 37°C
0.0551
O2
cosubstrate N-terminal Cys of RGS4, pH not specified in the publication, 37°C
additional information
additional information
Michaelis-Menten steady-state kinetics of wild-type and mutant enzymes, impact of the Cys-Tyr cofactor on kinetic properties, overview
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additional information
additional information
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Michaelis-Menten steady-state kinetics of wild-type and mutant enzymes, impact of the Cys-Tyr cofactor on kinetic properties, overview
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
41.2
O2
cosubstrate N-terminal Cys of RGS5, pH not specified in the publication, 37°C
56.6
O2
cosubstrate N-terminal Cys of RGS4, pH not specified in the publication, 37°C
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
-
hepatoblastoma cells, enzyme expression is up-regulated under hypertonic conditions
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alveolar epithelial cells, no enzyme detected in smooth muscle cells lining the alveoli or in blood vessels within the surrounding tissue
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
physiological function
physiological function
additional information
metabolism
active-site cluster models and comparison of CDO and 3-mercaptopropionate dioxygenase MDO, EC 1.13.11.91. The enzymes have different iron(III)-superoxo-bound structures due to differences in ligand coordination. The differences in the second-coordination sphere and the position of a positively charged Arg residue result in changes in substrate positioning, mobility and enzymatic turnover. For both enzymes, the second oxygen atom transfer has the highest barriers with magnitudes of 14.2 and 15.8 kcal/mol, respectively. In CDO with its 3-His ligand system, there are close-lying singlet, triplet and quintet spin-state surfaces along the mechanism, and the reaction will be influenced by the equilibration between these spin states and the ease of spin state change
metabolism
the first target to oxidize during the iron-assisted Cys-Tyr cofactor biogenesis is Cys93
physiological function
the enzyme is involved in the metabolism of L-cysteine in the body
physiological function
hepatic cytosolic fraction cysteine dioxygenase activity is not responsible for the S-oxidation of the substituted cysteine, S-carboxymethyl-L-cysteine
physiological function
transcription factor NRF2, i.e. nuclear factor-erythroid 2 p45-related factor two, promotes the accumulation of intracellular cysteine and engages the cysteine homeostatic control mechanism mediated by cysteine dioxygenase 1
physiological function
-
mammalian cysteine dioxygenase is a non-heme iron protein, in its ferrous form [Fe(II)-CDO] it catalyzes the conversion of cysteine to cysteine sulfinic acid by incorporating both oxygen atoms of molecular oxygen to form the product
physiological function
ADO catalyzes conversion of N-terminal cysteine to cysteine sulfinic acid and is related to the plant cysteine oxidases that mediate responses to hypoxia by an identical post-translational modification. In human cells ADO regulates the RGS4/5 (regulator of G-protein signalling) N-degron substrates, modulates G-protein coupled Ca2+ signals and MAPK activity, and acts on N-terminal cysteine proteins including the angiogenic cytokine IL-32. Inactivation of ADO leads to constitutive upregulation of endogenous and transfected RGS4 and RGS5 proteins irrespective of oxygen levels
additional information
structure and mechanism leading to formation of the cysteine sulfinate product complex of a biomimetic cysteine dioxygenase model, i.e. trispyrazolylborato iron(II) cysteinato complex, overview. The enzyme contains an iron active site with an unusual 3-His ligation to the protein, which contrasts with the structural features of common non-heme iron dioxygenases
additional information
-
cysteine dioxygenase crystal structures from pH 4-9: Cys binding is minimal at below pH 5 and persulfenate formation is consistently seen at pH values between pH 5.5 and pH 7. At above pH 8, the active-site iron shifts from 4- to 5-coordinate, and Cys is bound, while dioxygen is not
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). CDO1_HUMAN
200
0
22972
Swiss-Prot
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
a unique post-translational modification of human CDO consisting of a cross-link between cysteine 93 and tyrosine 157 (Cys-Tyr), which increases catalytic efficiency in a substrate-dependent manner
additional information
-
a unique post-translational modification of human CDO consisting of a cross-link between cysteine 93 and tyrosine 157 (Cys-Tyr), which increases catalytic efficiency in a substrate-dependent manner
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
co-crystallization of L-cysteine and purified wild-type cysteine dioxygenase by the hanging drop, vapor-diffusion method at 16°C, the crystals grow as rods up to 0.2 x 0.2 x 0.8 mm in 1 week. Refinement of the crystal stucture leads to a final model with a crystallographic R-factor of 18.1% and a free R-factor of 21.5% at 2.7 A resolution.
structures of both wild-type and engineered CDO variants containing unnatural tyrosines
structures of uncross-linked F2-Tyr157 CDO and mature wild-type CDO in complex with both L-cysteine and nitric oxide. The active site Cys93, rather than the Tyr157, is well-aligned to be oxidized should the normal oxidation reaction uncouple
enzyme with or without bound cysteine and formation of persulfenate, usage of crushed CDO crystals at 8 mg/mL in 10 mM Tris, pH 7.4, recrystallized by hanging drop vapour diffusion method, mixing of 0.0005 ml of crystal seed stock solution with 0.001 ml protein solution and 0.001 ml of reservoir solution containing 0.1 M trisodium citrate, pH 5.6, 24% PEG 4000, and 0.15 M ammonium acetate, final pH of 6.2, at room temperature, X-ray diffraction structure determination and analysis at pH 4.0-9.0 and 1.25-1.60 A resolution, overview
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C93A
C93S
C93 mutation reduces activity to 50%, zinc content of about 45%, specific activity of Cys-93 mutants is proportional to the measured iron content.
Y157F
in the gel-filtration chromatography Y157F shows an additional peak with an estimated molecular weight equivalent to a cysteine dioxygenase dimer. The results for monomer and dimer are similar. Activity reduced to 5% of the wild type activity. Zinc content of about 45%
additional information
C93A
C93 mutation reduces activity to 50%, zinc content of about 45%, specific activity of Cys-93 mutants is proportional to the measured iron content.
C93A
site-directed mutagenesis, CDO activity of the C93A variant increases with a much lower rate of iron supplementation and consequently a much higher concentration is required to approximate saturation, it has a 18fold higher Kd value
additional information
enzyme contains a posttranslationally generated Cys93-Tyr157 crosslinked cofactor. Incorporating unnatural tyrosines in place of Tyr157 via a genetic method gives catalytically active variants with a thioether bond between Cys93 and the halogen-substituted Tyr157. Crystal structures and data of both wild-type and engineered CDO variants in the purely uncrosslinked form and with a mature cofactor indicate that the enzyme can catalyze oxidative C-F or C-Cl bond cleavage, resulting in a substantial conformational change of both Cys93 and Tyr157 during cofactor assembly
additional information
-
enzyme contains a posttranslationally generated Cys93-Tyr157 crosslinked cofactor. Incorporating unnatural tyrosines in place of Tyr157 via a genetic method gives catalytically active variants with a thioether bond between Cys93 and the halogen-substituted Tyr157. Crystal structures and data of both wild-type and engineered CDO variants in the purely uncrosslinked form and with a mature cofactor indicate that the enzyme can catalyze oxidative C-F or C-Cl bond cleavage, resulting in a substantial conformational change of both Cys93 and Tyr157 during cofactor assembly
additional information
expression of purely uncross-linked human CDO due to site-specific incorporation of 3,5-difluoro-L-tyrosine Cys-Tyr at the cross-linking site through a genetic code expansion strategy
additional information
-
expression of purely uncross-linked human CDO due to site-specific incorporation of 3,5-difluoro-L-tyrosine Cys-Tyr at the cross-linking site through a genetic code expansion strategy
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
standard glutathione S-transferase fusion protein purification protocol, gel-filtration chromatography after removing the glutathione S-transferase tag
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
cloned into pGEX-6p-1 expression vector, expressed in Escherichia coli Bl21(DE3), glutathione S-transferase-fused CDO is purified and GTS tag is removed by cleavage with PreScission Protease
recombinant expression of wild-type and mutant enzymes in Escherichia coli strain BL21(DE3)
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
CDO1 is preferentially silenced by promoter methylation in human non-small cell lung cancers harboring mutations in KEAP1
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
CDO1 is preferentially silenced by promoter methylation in human non-small cell lung cancers harboring mutations in KEAP1, the negative regulator of transcription factor NRF2. CDO1 silencing promotes proliferation of non-small cell lung cancer cells by limiting the futile metabolism of cysteine to the wasteful and toxic byproducts CSA and sulfite, and depletion of cellular NADPH
synthesis
the mechanism of cysteine dioxygenase-catalyzed C-F bond cleavage of 3,5-difluoro-1-tyrosine contains four elementary steps: H-abstraction, C-S bond formation, F-transfer, and C-F bond cleavage. C-F bond cleavage is the rate-determining step with an energy barrier of 18.8 kcal/mol
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
McCann, K.P.; Akbari, M.T.; Williams, A.C.; Ramsden, D.B.
Human cysteine dioxygenase type I: primary structure derived from base sequencing of cDNA
Biochim. Biophys. Acta
1209
107-110
1994
Homo sapiens, Rattus norvegicus
Wilkinson, L.J.; Waring, R.H.
Cysteine dioxygenase: modulation of expression in human cell lines by cytokines and control of sulphate production
Toxicol. In Vitro
16
481-483
2002
Homo sapiens
Satsu, H.; Terasawa, E.; Hosokawa, Y.; Shimizu, M.
Functional characterization and regulation of the taurine transporter and cysteine dioxygenase in human hepatoblastoma HepG2 cells
Biochem. J.
375
441-447
2003
Homo sapiens
Millard, J.; Parsons, R.B.; Waring, R.H.; Williams, A.C.; Ramsden, D.B.
Expression of cysteine dioxygenase (EC 1.13.11.20) and sulfite oxidase in the human lung: a potential role for sulfate production in the protection from airborne xenobiotica
Mol. Pathol.
56
270-274
2003
Homo sapiens
Ye, S.; Wu, X.; Wei, L.; Tang, D.; Sun, P.; Bartlam, M.; Rao, Z.
An insight into the mechanism of human cysteine dioxygenase. Key roles of the thioether-bonded tyrosine-cysteine cofactor
J. Biol. Chem.
282
3391-3402
2007
Homo sapiens (Q16878), Homo sapiens
de Visser, S.
Elucidating enzyme mechanism and intrinsic chemical properties of short-lived intermediates in the catalytic cycles of cysteine dioxygenase and taurine/alpha-ketoglutarate dioxygenase
Coord. Chem. Rev.
253
754-768
2009
Homo sapiens (Q16878)
-
Driggers, C.M.; Cooley, R.B.; Sankaran, B.; Hirschberger, L.L.; Stipanuk, M.H.; Karplus, P.A.
Cysteine dioxygenase structures from pH 4 to 9: consistent Cys-persulfenate formation at intermediate pH and a Cys-bound enzyme at higher pH
J. Mol. Biol.
425
3121-3136
2013
Homo sapiens
Arjune, S.; Schwarz, G.; Belaidi, A.A.
Involvement of the Cys-Tyr cofactor on iron binding in the active site of human cysteine dioxygenase
Amino Acids
47
55-63
2015
Homo sapiens (Q16878), Homo sapiens
Sallmann, M.; Kumar, S.; Chernev, P.; Nehrkorn, J.; Schnegg, A.; Kumar, D.; Dau, H.; Limberg, C.; de Visser, S.P.
Structure and mechanism leading to formation of the cysteine sulfinate product complex of a biomimetic cysteine dioxygenase model
Chemistry
21
7470-7479
2015
Homo sapiens (Q16878)
Li, J.; Koto, T.; Davis, I.; Liu, A.
Probing the Cys-Tyr cofactor biogenesis in cysteine dioxygenase by the genetic incorporation of fluorotyrosine
Biochemistry
58
2218-2227
2019
Homo sapiens (Q16878), Homo sapiens
Song, Z.; Yue, Y.; Feng, S.; Sun, H.; Li, Y.; Xu, F.; Zhang, Q.; Wang, W.
Cysteine dioxygenase catalyzed C-F bond cleavage An in silico approach
Chem. Phys. Lett.
750
137449
2020
Homo sapiens (Q16878)
-
Yeh, C.G.; Pierides, C.; Jameson, G.N.L.; de Visser, S.P.
Structure and functional differences of cysteine and 3-mercaptopropionate dioxygenases A computational study
Chemistry
27
13793-13806
2021
Homo sapiens (Q16878)
Kang, Y.P.; Torrente, L.; Falzone, A.; Elkins, C.M.; Liu, M.; Asara, J.M.; Dibble, C.C.; DeNicola, G.
Correction Cysteine dioxygenase 1 is a metabolic liability for non-small cell lung cancer
eLife
8
e45572
2019
Mus musculus (P60334), Homo sapiens (Q16878)
Steventon, G.B.; Khan, S.; Mitchell, S.C.
Comparison of the sulfur-oxygenation of cysteine and S-carboxymethyl-l-cysteine in human hepatic cytosol and the role of cysteine dioxygenase
J. Pharm. Pharmacol.
70
1069-1077
2018
Homo sapiens (Q16878), Homo sapiens
Li, J.; Griffith, W.P.; Davis, I.; Shin, I.; Wang, J.; Li, F.; Wang, Y.; Wherritt, D.J.; Liu, A.
Cleavage of a carbon-fluorine bond by an engineered cysteine dioxygenase
Nat. Chem. Biol.
14
853-860
2018
Homo sapiens (Q16878), Homo sapiens
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