BRENDA - Enzyme Database show
show all sequences of 1.14.14.16

Why human cytochrome P450c21 is a progesterone 21-hydroxylase

Mizrachi, D.; Wang, Z.; Sharma, K.K.; Gupta, M.K.; Xu, K.; Dwyer, C.R.; Auchus, R.J.; Biochemistry 50, 3968-3974 (2011)

Data extracted from this reference:

Engineering
Amino acid exchange
Commentary
Organism
I471A
site-directed mutagenesis, the mutant shows activity similar to the wild-type enzyme
Homo sapiens
I471G
site-directed mutagenesis, the mutant shows activity similar to the wild-type enzyme
Homo sapiens
L107X
site-directed mutagenesis, inactive mutant
Homo sapiens
L109X
site-directed mutagenesis, inactive mutant
Homo sapiens
V359A
site-directed mutagenesis, the mutant shows 60% reduced activity compared to the wild-type enzyme
Homo sapiens
V359G
site-directed mutagenesis, the mutant shows 10% reduced activity compared to the wild-type enzyme
Homo sapiens
V470A
site-directed mutagenesis, the mutant shows activity similar to the wild-type enzyme
Homo sapiens
V470A/I471A
site-directed mutagenesis, the mutant shows activity similar to the wild-type enzyme
Homo sapiens
V470G
site-directed mutagenesis, the mutant shows activity similar to the wild-type enzyme
Homo sapiens
Inhibitors
Inhibitors
Commentary
Organism
Structure
additional information
no inhibition of progesterone 21-hydroxylation by the wild-type enzyme by pregnenolone, 17alpha-hydroxypregnenolone, and 5alpha-pregnane-3alpha-ol-20-one (allopregnanolone)
Homo sapiens
KM Value [mM]
KM Value [mM]
KM Value Maximum [mM]
Substrate
Commentary
Organism
Structure
0.00048
-
progesterone
pH 7.4, 37C, mutant V359A
Homo sapiens
0.00061
-
17alpha-hydroxyprogesterone
pH 7.4, 37C, mutant V359G
Homo sapiens
0.00082
-
17alpha-hydroxyprogesterone
pH 7.4, 37C, mutant V359A
Homo sapiens
0.001
-
progesterone
pH 7.4, 37C, mutant V470A
Homo sapiens
0.0011
-
progesterone
pH 7.4, 37C, wild-type enzyme
Homo sapiens
0.0015
-
progesterone
pH 7.4, 37C, mutant V470A/I471A
Homo sapiens
0.0016
-
17alpha-hydroxyprogesterone
pH 7.4, 37C, mutant V470A/I471A; pH 7.4, 37C, wild-type enzyme
Homo sapiens
0.0025
-
17alpha-hydroxyprogesterone
pH 7.4, 37C, mutant V470A
Homo sapiens
0.0032
-
progesterone
pH 7.4, 37C, mutant V359G
Homo sapiens
Metals/Ions
Metals/Ions
Commentary
Organism
Structure
Fe2+
heme enzyme
Homo sapiens
Natural Substrates/ Products (Substrates)
Natural Substrates
Organism
Commentary (Nat. Sub.)
Natural Products
Commentary (Nat. Pro.)
Organism (Nat. Pro.)
Reversibility
progesterone + [reduced NADPH-hemoprotein reductase] + O2
Homo sapiens
-
11-deoxycorticosterone + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
?
Organism
Organism
Primary Accession No. (UniProt)
Commentary
Textmining
Homo sapiens
P08686
-
-
Substrates and Products (Substrate)
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
17alpha-hydroxyprogesterone + [reduced NADPH-hemoprotein reductase] + O2
preferred substrate. The 17alpha-hydroxyprogesterone metabolites formed by mutants of V470 and I471 include a second, unidentified product. Both mutants V359A and V359G also metabolize 17alpha-hydroxyprogesterone to 11-deoxycortisol and this second product, and for mutation V359G, the unidentified compound is the major product. The second compound is not androstenedione and is neither the 16alpha- nor 6beta-hydroxylation products (pregn-4-ene-16alpha,17alpha-diol-3,20-dione and pregn-4-ene-6beta,17alpha-diol-3,20-dione, respectively)
726962
Homo sapiens
11-deoxycortisol + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
additional information
17alpha-hydroxyprogesterone is hydroxylated 28times faster than progesterone by the wild-type enzyme. No activity of the wild-type enzyme with pregnenolone, 17alpha-hydroxypregnenolone, and 5alpha-pregnane-3alpha-ol-20-one (allopregnanolone)
726962
Homo sapiens
?
-
-
-
-
progesterone + [reduced NADPH-hemoprotein reductase] + O2
-
726962
Homo sapiens
11-deoxycorticosterone + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
progesterone + [reduced NADPH-hemoprotein reductase] + O2
mutants V359A and V359G both produce an additional metabolite, 16alpha-hydroxyprogesterone
726962
Homo sapiens
16alpha-hydroxyprogesterone + [oxidized NADPH-hemoprotein reductase] + H2O
product identification by TLC
-
-
?
Temperature Optimum [C]
Temperature Optimum [C]
Temperature Optimum Maximum [C]
Commentary
Organism
37
-
assay at
Homo sapiens
pH Optimum
pH Optimum Minimum
pH Optimum Maximum
Commentary
Organism
7.4
-
assay at
Homo sapiens
Cofactor
Cofactor
Commentary
Organism
Structure
heme
-
Homo sapiens
Cofactor (protein specific)
Cofactor
Commentary
Organism
Structure
heme
-
Homo sapiens
Engineering (protein specific)
Amino acid exchange
Commentary
Organism
I471A
site-directed mutagenesis, the mutant shows activity similar to the wild-type enzyme
Homo sapiens
I471G
site-directed mutagenesis, the mutant shows activity similar to the wild-type enzyme
Homo sapiens
L107X
site-directed mutagenesis, inactive mutant
Homo sapiens
L109X
site-directed mutagenesis, inactive mutant
Homo sapiens
V359A
site-directed mutagenesis, the mutant shows 60% reduced activity compared to the wild-type enzyme
Homo sapiens
V359G
site-directed mutagenesis, the mutant shows 10% reduced activity compared to the wild-type enzyme
Homo sapiens
V470A
site-directed mutagenesis, the mutant shows activity similar to the wild-type enzyme
Homo sapiens
V470A/I471A
site-directed mutagenesis, the mutant shows activity similar to the wild-type enzyme
Homo sapiens
V470G
site-directed mutagenesis, the mutant shows activity similar to the wild-type enzyme
Homo sapiens
Inhibitors (protein specific)
Inhibitors
Commentary
Organism
Structure
additional information
no inhibition of progesterone 21-hydroxylation by the wild-type enzyme by pregnenolone, 17alpha-hydroxypregnenolone, and 5alpha-pregnane-3alpha-ol-20-one (allopregnanolone)
Homo sapiens
KM Value [mM] (protein specific)
KM Value [mM]
KM Value Maximum [mM]
Substrate
Commentary
Organism
Structure
0.00048
-
progesterone
pH 7.4, 37C, mutant V359A
Homo sapiens
0.00061
-
17alpha-hydroxyprogesterone
pH 7.4, 37C, mutant V359G
Homo sapiens
0.00082
-
17alpha-hydroxyprogesterone
pH 7.4, 37C, mutant V359A
Homo sapiens
0.001
-
progesterone
pH 7.4, 37C, mutant V470A
Homo sapiens
0.0011
-
progesterone
pH 7.4, 37C, wild-type enzyme
Homo sapiens
0.0015
-
progesterone
pH 7.4, 37C, mutant V470A/I471A
Homo sapiens
0.0016
-
17alpha-hydroxyprogesterone
pH 7.4, 37C, mutant V470A/I471A; pH 7.4, 37C, wild-type enzyme
Homo sapiens
0.0025
-
17alpha-hydroxyprogesterone
pH 7.4, 37C, mutant V470A
Homo sapiens
0.0032
-
progesterone
pH 7.4, 37C, mutant V359G
Homo sapiens
Metals/Ions (protein specific)
Metals/Ions
Commentary
Organism
Structure
Fe2+
heme enzyme
Homo sapiens
Natural Substrates/ Products (Substrates) (protein specific)
Natural Substrates
Organism
Commentary (Nat. Sub.)
Natural Products
Commentary (Nat. Pro.)
Organism (Nat. Pro.)
Reversibility
progesterone + [reduced NADPH-hemoprotein reductase] + O2
Homo sapiens
-
11-deoxycorticosterone + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
?
Substrates and Products (Substrate) (protein specific)
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
17alpha-hydroxyprogesterone + [reduced NADPH-hemoprotein reductase] + O2
preferred substrate. The 17alpha-hydroxyprogesterone metabolites formed by mutants of V470 and I471 include a second, unidentified product. Both mutants V359A and V359G also metabolize 17alpha-hydroxyprogesterone to 11-deoxycortisol and this second product, and for mutation V359G, the unidentified compound is the major product. The second compound is not androstenedione and is neither the 16alpha- nor 6beta-hydroxylation products (pregn-4-ene-16alpha,17alpha-diol-3,20-dione and pregn-4-ene-6beta,17alpha-diol-3,20-dione, respectively)
726962
Homo sapiens
11-deoxycortisol + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
additional information
17alpha-hydroxyprogesterone is hydroxylated 28times faster than progesterone by the wild-type enzyme. No activity of the wild-type enzyme with pregnenolone, 17alpha-hydroxypregnenolone, and 5alpha-pregnane-3alpha-ol-20-one (allopregnanolone)
726962
Homo sapiens
?
-
-
-
-
progesterone + [reduced NADPH-hemoprotein reductase] + O2
-
726962
Homo sapiens
11-deoxycorticosterone + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
progesterone + [reduced NADPH-hemoprotein reductase] + O2
mutants V359A and V359G both produce an additional metabolite, 16alpha-hydroxyprogesterone
726962
Homo sapiens
16alpha-hydroxyprogesterone + [oxidized NADPH-hemoprotein reductase] + H2O
product identification by TLC
-
-
?
Temperature Optimum [C] (protein specific)
Temperature Optimum [C]
Temperature Optimum Maximum [C]
Commentary
Organism
37
-
assay at
Homo sapiens
pH Optimum (protein specific)
pH Optimum Minimum
pH Optimum Maximum
Commentary
Organism
7.4
-
assay at
Homo sapiens
General Information
General Information
Commentary
Organism
additional information
residues L107, L109, V470, I471, and V359 contribute to the CYP21A2 substate-binding pocket. Progesterone binds to CYP21A2 in a fundamentally different orientation than to CYP17A1, EC 1.14.99.9, expansion of the CYP21A2 substrate-binding pocket allows additional substrate trajectories and metabolic switching. CYP21A2 structure modelling, overview
Homo sapiens
physiological function
CYP21A2 activities are required for cortisol and aldosterone biosynthesis, and involve the formation of energetically disfavored primary carbon radicals
Homo sapiens
General Information (protein specific)
General Information
Commentary
Organism
additional information
residues L107, L109, V470, I471, and V359 contribute to the CYP21A2 substate-binding pocket. Progesterone binds to CYP21A2 in a fundamentally different orientation than to CYP17A1, EC 1.14.99.9, expansion of the CYP21A2 substrate-binding pocket allows additional substrate trajectories and metabolic switching. CYP21A2 structure modelling, overview
Homo sapiens
physiological function
CYP21A2 activities are required for cortisol and aldosterone biosynthesis, and involve the formation of energetically disfavored primary carbon radicals
Homo sapiens
Other publictions for EC 1.14.14.16
No.
1st author
Pub Med
title
organims
journal
volume
pages
year
Activating Compound
Application
Cloned(Commentary)
Crystallization (Commentary)
Engineering
General Stability
Inhibitors
KM Value [mM]
Localization
Metals/Ions
Molecular Weight [Da]
Natural Substrates/ Products (Substrates)
Organic Solvent Stability
Organism
Oxidation Stability
Posttranslational Modification
Purification (Commentary)
Reaction
Renatured (Commentary)
Source Tissue
Specific Activity [micromol/min/mg]
Storage Stability
Substrates and Products (Substrate)
Subunits
Temperature Optimum [C]
Temperature Range [C]
Temperature Stability [C]
Turnover Number [1/s]
pH Optimum
pH Range
pH Stability
Cofactor
Ki Value [mM]
pI Value
IC50 Value
Activating Compound (protein specific)
Application (protein specific)
Cloned(Commentary) (protein specific)
Cofactor (protein specific)
Crystallization (Commentary) (protein specific)
Engineering (protein specific)
General Stability (protein specific)
IC50 Value (protein specific)
Inhibitors (protein specific)
Ki Value [mM] (protein specific)
KM Value [mM] (protein specific)
Localization (protein specific)
Metals/Ions (protein specific)
Molecular Weight [Da] (protein specific)
Natural Substrates/ Products (Substrates) (protein specific)
Organic Solvent Stability (protein specific)
Oxidation Stability (protein specific)
Posttranslational Modification (protein specific)
Purification (Commentary) (protein specific)
Renatured (Commentary) (protein specific)
Source Tissue (protein specific)
Specific Activity [micromol/min/mg] (protein specific)
Storage Stability (protein specific)
Substrates and Products (Substrate) (protein specific)
Subunits (protein specific)
Temperature Optimum [C] (protein specific)
Temperature Range [C] (protein specific)
Temperature Stability [C] (protein specific)
Turnover Number [1/s] (protein specific)
pH Optimum (protein specific)
pH Range (protein specific)
pH Stability (protein specific)
pI Value (protein specific)
Expression
General Information
General Information (protein specific)
Expression (protein specific)
KCat/KM [mM/s]
KCat/KM [mM/s] (protein specific)
745363
Wang
Functional analysis of human ...
Homo sapiens
J. Biol. Chem.
292
10767-10778
2017
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24
24
734302
Pallan
Human cytochrome P450 21A2, th ...
Bos taurus, Homo sapiens
J. Biol. Chem.
290
13128-13143
2015
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2
1
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4
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1
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4
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2
2
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4
4
745776
Pallan
Research Resource Correlating ...
Homo sapiens
Mol. Endocrinol.
29
1375-1384
2015
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1
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2
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6
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6
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2
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6
-
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6
6
735122
Doleschall
Common genetic variants of the ...
Homo sapiens
PLoS ONE
9
e107244
2014
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1
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2
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2
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1
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744331
Yoshimoto
Epoxidation activities of hum ...
Homo sapiens
Biochemistry
53
7531-7540
2014
-
-
-
-
1
-
-
-
-
-
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2
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1
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1
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1
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728691
Haider
Structure-phenotype correlatio ...
Homo sapiens
Proc. Natl. Acad. Sci. USA
110
2605-2610
2013
-
-
-
-
75
-
-
-
1
1
-
-
-
3
-
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1
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1
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1
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75
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1
1
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1
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2
2
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726923
Sushko
Mechanism of intermolecular in ...
Homo sapiens
Biochemistry (Moscow)
77
585-592
2012
-
-
1
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1
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2
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2
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1
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2
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1
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1
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1
1
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726997
Yoshimoto
Minor activities and transitio ...
Homo sapiens
Biochemistry
51
7064-7077
2012
-
-
1
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1
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1
1
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2
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2
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1
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4
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1
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1
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1
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1
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4
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1
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727898
Zhao
Three-dimensional structure of ...
Bos taurus, Homo sapiens
J. Biol. Chem.
287
10613-10622
2012
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1
1
2
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5
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5
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1
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2
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728213
Yoshimoto
Synthesis of halogenated pregn ...
Homo sapiens
J. Steroid Biochem. Mol. Biol.
128
38-50
2012
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1
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728828
Parr
Unexpected contribution of cyt ...
Homo sapiens
Toxicol. Lett.
213
381-391
2012
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716052
Gaffney
Functional characterisation of ...
Homo sapiens
J. Steroid Biochem. Mol. Biol.
123
109-114
2011
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4
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1
1
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726962
Mizrachi
Why human cytochrome P450c21 i ...
Homo sapiens
Biochemistry
50
3968-3974
2011
-
-
-
-
9
-
1
9
-
1
-
1
-
2
-
-
-
-
-
-
-
-
4
-
1
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1
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1
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1
-
9
-
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1
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9
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1
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1
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4
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1
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1
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2
2
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697794
Marques
Mutational characterization of ...
Homo sapiens
Exp. Clin. Endocrinol. Diabetes
118
505-512
2010
-
-
-
-
6
-
-
-
-
-
-
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2
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1
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6
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1
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715325
Rottembourg
21-Hydroxylase epitopes are ta ...
Homo sapiens
J. Autoimmun.
35
309-315
2010
-
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2
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-
-
-
-
-
-
-
-
1
-
2
-
-
-
-
1
-
-
2
-
2
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
285440
Hiwatashi
Purification and reconstitutio ...
Bos taurus
Biochim. Biophys. Acta
664
33-48
1981
6
-
-
-
-
-
5
-
1
-
1
-
-
2
-
1
1
-
-
1
3
1
4
1
-
-
-
-
1
-
-
1
-
-
-
6
-
-
1
-
-
-
-
5
-
-
1
-
1
-
-
-
1
1
-
1
3
1
4
1
-
-
-
-
1
-
-
-
-
-
-
-
-
-
285441
Greenfield
Activation and Inhibition of t ...
Bos taurus
Arch. Biochem. Biophys.
200
232-244
1980
8
-
-
-
-
-
2
-
1
-
-
-
-
1
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
8
-
-
-
-
-
-
-
2
-
-
1
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
285447
Kominami
Studies on the steroid hydroxy ...
Bos taurus
J. Biol. Chem.
255
3386-3394
1980
-
-
-
-
-
-
-
-
1
-
1
-
-
1
-
-
1
-
-
-
-
2
2
-
-
-
-
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
1
-
-
-
-
1
-
-
-
2
2
-
-
-
-
2
-
-
-
-
-
-
-
-
-
-
285439
Ryan
Hydroxylation of steroids at c ...
Bos taurus
J. Biol. Chem.
225
103-114
1957
-
-
-
-
-
-
12
-
1
-
-
1
-
1
-
-
-
-
-
1
-
-
7
-
-
-
-
-
1
1
-
2
-
-
-
-
-
-
2
-
-
-
-
12
-
-
1
-
-
1
-
-
-
-
-
1
-
-
7
-
-
-
-
-
1
1
-
-
-
-
-
-
-
-