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Information on EC 1.14.14.16 - steroid 21-monooxygenase and Organism(s) Homo sapiens

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IUBMB Comments
A P-450 heme-thiolate protein responsible for the conversion of progesterone and 17alpha-hydroxyprogesterone to their respective 21-hydroxylated derivatives, 11-deoxycorticosterone and 11-deoxycortisol. Involved in the biosynthesis of the hormones aldosterone and cortisol. The electron donor is EC 1.6.2.4, NADPH---hemoprotein reductase.
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Homo sapiens
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Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
Synonyms
21-hydroxylase, cyp21a2, cyp21, cyp2d, steroid 21-hydroxylase, p450c21, progesterone 21-hydroxylase, cytochrome p450c21, p-450(c21), 21-hydroxylase cytochrome p-450, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
17alpha-hydroxyprogesterone 21-hydrolase
-
-
-
-
21-hydroxylase
21-hydroxylase cytochrome P-450
-
-
-
-
CYP21
CYP21A2
Cytochrome P-450 specific for steroid C-21 hydroxylation
-
-
-
-
cytochrome P-450-linked mixed function oxidase system
-
-
-
-
cytochrome P-450C-21
-
-
-
-
cytochrome p450 21A2
-
cytochrome P450c21
-
P-450(C21)
-
-
-
-
P450 oxidoreductase-21-hydroxylase
-
-
P450-C21
-
-
-
-
P450-C21B
-
-
-
-
P450c21
Progesterone 21-hydroxylase
-
Steroid 21-hydroxylase
steroid 21-hydroxylase system
-
-
-
-
steroid 21-hydroxylation system
-
-
-
-
steroid cytochrome P450 21-hydroxylase
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
hydroxylation
-
-
-
-
oxidation
-
-
-
-
redox reaction
-
-
-
-
reduction
-
-
-
-
PATHWAY SOURCE
PATHWAYS
-
-, -
SYSTEMATIC NAME
IUBMB Comments
steroid,NADPH-hemoprotein reductase:oxygen oxidoreductase (21-hydroxylating)
A P-450 heme-thiolate protein responsible for the conversion of progesterone and 17alpha-hydroxyprogesterone to their respective 21-hydroxylated derivatives, 11-deoxycorticosterone and 11-deoxycortisol. Involved in the biosynthesis of the hormones aldosterone and cortisol. The electron donor is EC 1.6.2.4, NADPH---hemoprotein reductase.
CAS REGISTRY NUMBER
COMMENTARY hide
9029-68-9
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
16,17-dehydroprogesterone + NADPH + O2
16,17-dehydro-21-hydroxyprogesterone + NADP+ + H2O
show the reaction diagram
-
-
-
?
17,17-dimethyl-18-norandrosta-1,4,13-trien-3-one + [reduced NADPH-hemoprotein reductase] + O2
16beta-hydroxy-17,17-dimethyl-18-norandrosta-1,4,13-trien-3-one + 16alpha-hydroxy-17,17-dimethyl-18-norandrosta-1,4,13-trien-3-one + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
-
i.e. metandienone
product identification by GC-EI-MS analysis
-
?
17,17-dimethyl-18-norandrosta-1,4,13-trien-3-one + [reduced NADPH-hemoprotein reductase] + O2
20beta-hydroxy-17,17-dimethyl-18-norandrosta-1,4,13-trien-3-one + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
-
i.e. metandienone
product identification by GC-EI-MS analysis
-
?
17-fluoro-progesterone + [reduced NADPH-P450 reductase] + O2
17-fluoro-11-deoxycorticosterone + [oxidized NADPH-P450 reductase] + H2O
show the reaction diagram
-
-
-
-
?
17-hydroxy-progesterone + NADH + O2
17-hydroxy-11-deoxy-corticosterone + NAD+ + H2O
show the reaction diagram
-
-
-
-
?
17-hydroxyprogesterone + NADPH + H+ + O2
11-deoxycortisol + NADP+ + H2O
show the reaction diagram
17-hydroxyprogesterone + [reduced NADPH-hemoprotein reductase] + O2
11-deoxycortisol + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
-
-
-
?
17alpha-hydroxyprogesterone + AH2 + O2
11-deoxycortisol + A + H2O
show the reaction diagram
-
-
-
-
?
17alpha-hydroxyprogesterone + NADPH + H+ + O2
11-deoxycortisol + NADP+ + H2O
show the reaction diagram
-
-
-
-
?
17alpha-hydroxyprogesterone + NADPH + H+ + O2
17,21-dihydroxyprogesterone + NADP+ + H2O
show the reaction diagram
17alpha-hydroxyprogesterone + [reduced NADPH-hemoprotein reductase] + O2
11-deoxycortisol + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
17alpha-hydroxyprogesterone + [reduced NADPH-P450 reductase] + O2
11-deoxycortisol + [oxidized NADPH-P450 reductase] + H2O
show the reaction diagram
progesterone + AH2 + O2
deoxycorticosterone + A + H2O
show the reaction diagram
-
-
-
-
?
progesterone + NADH + O2
deoxycorticosterone + NAD+ + H2O
show the reaction diagram
-
-
-
-
?
progesterone + NADPH + H+ + O2
11-deoxycorticosterone + NADP+ + H2O
show the reaction diagram
progesterone + NADPH + H+ + O2
deoxycorticosterone + NADP+ + H2O
show the reaction diagram
progesterone + [reduced NADPH-hemoprotein reductase] + O2
11-deoxycorticosterone + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
progesterone + [reduced NADPH-hemoprotein reductase] + O2
16alpha-hydroxy-progesterone + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
-
mutant V359A produces an additional metabolite, 16alpha-hydroxyprogesterone of progesterone, very low activity with the wild-type enzyme
product identification by TLC
-
?
progesterone + [reduced NADPH-hemoprotein reductase] + O2
16alpha-hydroxyprogesterone + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
mutants V359A and V359G both produce an additional metabolite, 16alpha-hydroxyprogesterone
product identification by TLC
-
?
progesterone + [reduced NADPH-P450 reductase] + O2
11-deoxycorticosterone + [oxidized NADPH-P450 reductase] + H2O
show the reaction diagram
additional information
?
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
17-hydroxyprogesterone + NADPH + H+ + O2
11-deoxycortisol + NADP+ + H2O
show the reaction diagram
17-hydroxyprogesterone + [reduced NADPH-hemoprotein reductase] + O2
11-deoxycortisol + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
-
-
-
?
17alpha-hydroxyprogesterone + [reduced NADPH-hemoprotein reductase] + O2
11-deoxycortisol + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
17alpha-hydroxyprogesterone + [reduced NADPH-P450 reductase] + O2
11-deoxycortisol + [oxidized NADPH-P450 reductase] + H2O
show the reaction diagram
progesterone + NADPH + H+ + O2
11-deoxycorticosterone + NADP+ + H2O
show the reaction diagram
-
-
-
-
?
progesterone + [reduced NADPH-hemoprotein reductase] + O2
11-deoxycorticosterone + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
progesterone + [reduced NADPH-P450 reductase] + O2
11-deoxycorticosterone + [oxidized NADPH-P450 reductase] + H2O
show the reaction diagram
additional information
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
cytochrome P450
-
NADPH
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
17alpha-hydroxyprogesterone
inhibits above 0.2mM
cytochrome b5
-
-
ketoconazole
-
inhibits hydroxylation activity with progesterone and 17-fluoroprogesterone to the same amount
additional information
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2.3 - 9.2
17-hydroxy-progesterone
0.00044 - 0.022
17alpha-hydroxyprogesterone
0.00021 - 9.2
progesterone
additional information
additional information
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00003 - 4
17alpha-hydroxyprogesterone
0.0001 - 2.8
progesterone
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.016 - 2667
17alpha-hydroxyprogesterone
0.012 - 13333
progesterone
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.00027
-
37°C, mutant P482S, substrate 17-hydroxy-progesterone
0.00038
-
37°C, mutant P482S, substrate progesterone
0.00117
-
37°C, wild-type, substrate progesterone
0.00122
-
37°C, wild-type, substrate 17-hydroxy-progesterone
0.00129
-
37°C, mutant A15T, substrate 17-hydroxy-progesterone
0.00148
-
37°C, mutant A15T, substrate progesterone
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.2
-
assay at
7.5
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
30
assay at
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
physiological function
additional information
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
CP21A_HUMAN
494
0
55887
Swiss-Prot
Secretory Pathway (Reliability: 1)
E9M5C7_HUMAN
51
0
5812
TrEMBL
other Location (Reliability: 2)
Q16755_HUMAN
97
0
11069
TrEMBL
Secretory Pathway (Reliability: 1)
Q2UVX5_HUMAN
494
0
55918
TrEMBL
Secretory Pathway (Reliability: 1)
Q8TE42_HUMAN
77
0
8364
TrEMBL
Secretory Pathway (Reliability: 1)
E9M5D1_HUMAN
87
0
9447
TrEMBL
Mitochondrion (Reliability: 3)
E9M5C9_HUMAN
67
0
7275
TrEMBL
other Location (Reliability: 1)
Q2UVX6_HUMAN
494
0
55872
TrEMBL
Secretory Pathway (Reliability: 1)
A0A0H4CUT2_HUMAN
59
0
6575
TrEMBL
other Location (Reliability: 2)
B2D081_HUMAN
34
0
3857
TrEMBL
other Location (Reliability: 1)
A0A023J7R6_HUMAN
29
0
3586
TrEMBL
other Location (Reliability: 4)
E9M5C8_HUMAN
34
0
3778
TrEMBL
other Location (Reliability: 3)
Q1EM52_HUMAN
494
0
55835
TrEMBL
Secretory Pathway (Reliability: 1)
A5HSJ6_HUMAN
67
0
7259
TrEMBL
other Location (Reliability: 1)
B8YJC6_HUMAN
66
0
7557
TrEMBL
Secretory Pathway (Reliability: 1)
A0A1U9IMX4_HUMAN
91
0
9406
TrEMBL
other Location (Reliability: 3)
A0A1P8SW43_HUMAN
59
0
6650
TrEMBL
other Location (Reliability: 2)
Q1H8Y4_HUMAN
494
0
55941
TrEMBL
Secretory Pathway (Reliability: 1)
A0A1P8SW53_HUMAN
51
0
5874
TrEMBL
other Location (Reliability: 2)
V5WC48_HUMAN
58
0
6505
TrEMBL
other Location (Reliability: 3)
Q1H8Y3_HUMAN
494
0
55789
TrEMBL
Secretory Pathway (Reliability: 1)
A0A1P8SW42_HUMAN
51
0
5908
TrEMBL
other Location (Reliability: 2)
Q1H8Y2_HUMAN
494
0
55901
TrEMBL
Secretory Pathway (Reliability: 1)
Q1EM51_HUMAN
494
0
55870
TrEMBL
Secretory Pathway (Reliability: 1)
Q1H8Y5_HUMAN
494
0
55918
TrEMBL
Secretory Pathway (Reliability: 1)
Q1EM53_HUMAN
494
0
55922
TrEMBL
Secretory Pathway (Reliability: 1)
Q16748_HUMAN
371
0
42370
TrEMBL
Secretory Pathway (Reliability: 1)
A0A2U7NZY9_HUMAN
67
0
7406
TrEMBL
other Location (Reliability: 1)
E9M5D0_HUMAN
113
0
11328
TrEMBL
Mitochondrion (Reliability: 2)
Q16746_HUMAN
371
0
42343
TrEMBL
Secretory Pathway (Reliability: 1)
Q7KYP0_HUMAN
372
0
42483
TrEMBL
Secretory Pathway (Reliability: 1)
U5YU50_HUMAN
57
0
6368
TrEMBL
other Location (Reliability: 3)
A0A1P8SW33_HUMAN
51
0
5880
TrEMBL
other Location (Reliability: 2)
C7DTU9_HUMAN
495
0
55957
TrEMBL
Secretory Pathway (Reliability: 1)
B2YHV7_HUMAN
87
0
9376
TrEMBL
Mitochondrion (Reliability: 4)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
50000
x * 50000, SDS-PAGE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
x * 50000, SDS-PAGE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
in complex with progesterone, sitting drop vapor diffusion method, using 0.1 M sodium HEPES (pH 7.5) containing 0.2 M ammonium sulfate and 25% (w/v) polyethylene glycol 3350
in omplex with 17alpha-hydroxyprogesterone, to 3.3 A resolution
modeling of mutant structures connected with congenital adrenal hyperplasia
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
A15T
-
natural mutation found in patients with classical congenital adrenal hyperplasia, no significant difference in activity compared to wild-type
A265C
naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues
A265V
A391T
naturally occuring mutation, the mutation disrupts the hydrophobicity of the region
A434V
naturally occuring mutation, the mutation causes steric clashes with the heme rendering the enzyme almost inactive
C169R
naturally occuring mutation, the mutation alters the region's hydrophobicity, conserved residue C169 makes hydrophobic interactions with the loop between E-F helices and F-helix
D322G
D407N
naturally occuring mutation, the mutation prevents salt bridge formation resulting in a localized, as opposed to global, destabilization of tertiary structure
E320K
naturally occuring mutation, the mutation of E320, which is a highly conserved residue on a negatively charged Glu-Glu-Leu-Asp (EELD) motif, alters the charge on the motif
E351K
-
rare missense mutation located in the ERR triad and found in a patient with virilizing congenital hyperplasia. Residual activity is about 1% of wild-type for both 17-hydroxyprogesterone and progesterone
E431K
naturally occuring mutation, the mutation prevents salt bridge formation resulting in a localized, as opposed to global, destabilization of tertiary structure
F404S
naturally occuring mutation, the mutation prevents stable packing interactions resulting in salt-wasting congenital adrenal hyperplasia
G178A
naturally occuring mutation, the mutation causes reduced structural flexibility of the sharp fold between the E- and F-helices
G291C
naturally occuring mutation, the mutation abolishes substrate binding causing salt-wasting congenital adrenal hyperplasia
G291R
naturally occuring mutation, the mutation abolishes substrate binding causing salt-wasting congenital adrenal hyperplasia
G291S
naturally occuring mutation, the mutation abolishes substrate binding causing salt-wasting congenital adrenal hyperplasia
G292C
0.32% of wild-type efficiency with substrate progesterone
G292D
naturally occuring mutation, the mutation abolishes substrate binding causing salt-wasting congenital adrenal hyperplasia
G292S
0.0005% of wild-type efficiency with substrate progesterone
G424S
naturally occuring mutation, the mutation imparts rigidity to the loop between K'- and L-helix
G56R
naturally occuring mutation, P57 and G56 form the hinge between the membrane interacting N-terminus and rest of the protein. The substitution of G56 with a polar and rigid Arg residue disrupts the hinge affecting the interactions of CYP21A2 with the membrane
G90V
naturally occuring mutation, mutation of G90 to valine affects the ability of R91 to hydrogen bond with heme, causing salt-wasting congenital adrenal hyperplasia
H119R
naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues
H365W
-
the naturally occuring CYP21A2 mutant exhibits minimal 21-hydroxylase activity to convert 17-hydroxyprogesterone to 11-deoxycortisol or progesterone to 11-deoxycorticosterone compared to the wild-type
H365Y
H365Y/R356W
H62L
naturally occuring mutation, the mutation may disrupt hydrogen bonding to reduce, but not eliminate, enzyme activity
I171N
-
mutation identified in Italian patient with congenital adrenal hyperplasia, less than 1% of wild-type enzyme activity
I172N
I194N
naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues
I230T
naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues
I236N/V237E/M239K
-
naturally occuring mutant, no enzymic activity, dominant negative effect over wild-type with 35% decrease in activity
I471A
site-directed mutagenesis, the mutant shows activity similar to the wild-type enzyme
I471G
site-directed mutagenesis, the mutant shows activity similar to the wild-type enzyme
I77T
naturally occuring mutation, the mutation disrupts the hydrophobic environment
K121Q
naturally occuring mutation, the mutation impairs the interaction with the P450 oxidoreductase
K122Q
-
missense mutation causing nonclassical 21-hydroxylase deficiency, shows reduced activity of 14% for the conversion of 17alpha-hydroxyprogesterone and 19% for the conversion of progesterone compared to wild type
L107R
naturally occuring mutation, the mutation abolishes heme binding and causes salt-wasting congenital adrenal hyperplasia
L107X
site-directed mutagenesis, inactive mutant
L108R
0.0003% of wild-type efficiency with substrate progesterone
L109X
site-directed mutagenesis, inactive mutant
L142P
naturally occuring mutation, the mutation of the D-helix causes helical disruption and destabilization of secondary structures
L166P
naturally occuring mutation, the mutation of the E-helix causes helical disruption and destabilization of secondary structures
L167P
naturally occuring mutation, the mutation of the E-helix causes helical disruption and destabilization of secondary structures
L236N/V237E/M239K
the mutation is associated with congenital adrenal hyperplasia
L261P
naturally occuring mutation, the mutation of the H-helix causes helical disruption and destabilization of secondary structures
L300F
naturally occuring mutation, the mutation causes localized destabilization of secondary structure
L307M
naturally occuring mutation, the mutation disrupts the optimal packing of side chains but does not alter the hydrophobic environment
L307V
naturally occuring mutation, the mutation disrupts the optimal packing of side chains but does not alter the hydrophobic environment
L308F
naturally occuring mutation, the mutation causes localized destabilization of secondary structure
L353R
naturally occuring mutation, the mutation abolishes heme binding and causes salt-wasting congenital adrenal hyperplasia
L363W
naturally occuring mutation, the mutation causes steric clashes with the heme rendering the enzyme almost inactive
L446P
N387K
naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues
P30E
naturally occuring mutation causing disruption of the interaction between the carbon of P30 in the N-terminal loop and the side chain of Y376 within the beta5-beta6 hairpin loop resuting in the salt-wasting disease
P31L
2.4% of wild-type efficiency with substrate progesterone
P31Q
0.0001% of wild-type efficiency with substrate progesterone
P432L
naturally occuring mutation, the mutation makes the structure more flexible and prevents cysteine from being presented to heme
P453S
P459H
naturally occuring mutation, the mutation disrupts the hydrophobicity of the region
P463L
naturally occuring mutation, the mutation interferes with the conformation of the beta8-beta9 loop with the subsequent closure of substrate entrance channel
P482S
-
natural mutation found in patients with nonclassical congenital adrenal hyperplasia, precocious pubarche, menstrual irregularities or hypertrichosis, about 70% of activity compared to wild-type
Q318X
the mutation is associated with congenital adrenal hyperplasia
Q481P
naturally occuring mutation, the mutation destabilizes the structure rendering the protein inactive
R124H
naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues
R132C
naturally occuring mutation, the mutation impairs the interaction with the P450 oxidoreductase
R149C
naturally occuring mutation, the mutation prevents salt bridge formation resulting in a localized, as opposed to global, destabilization of tertiary structure
R233G
naturally occuring mutation, the mutation may prevent R233 from binding to the 3-keto oxygen of the proximal 17OHP in the proper orientation, it does not influence protein activity significantly, resulting in minimal phenotype
R233K
naturally occuring mutation, the mutation may prevent R233 from binding to the 3-keto oxygen of the proximal 17OHP in the proper orientation, it does not influence protein activity significantly, resulting in minimal phenotype
R339H
naturally occuring mutation, the mutation impairs the interaction with the P450 oxidoreductase
R341P
R341W
naturally occuring mutation, the mutation impairs the interaction with the P450 oxidoreductase
R356P
naturally occuring mutation, the mutation disrupts the interaction of R356 with Q389 rendering the enzyme inactive and causing salt-wasting congenital adrenal hyperplasia
R356W
R357W
0.01% of wild-type efficiency with substrate progesterone
R369Q
naturally occuring mutation, the mutation impairs the interaction with the P450 oxidoreductase
R408C/L
naturally occuring mutation, the mutation destabilizes structural elements because of the extensive loss of hydrogen bonds
R408H
naturally occuring mutation, the mutation prevents normal hydrogen bonding with E351 and R354
R409C
0.4% of wild-type efficiency with substrate progesterone
R426C
naturally occuring mutation, the mutation disrupts the interaction of residues R91 and R426 rendering the protein nonfunctional and causing salt-wasting congenital adrenal hyperplasia
R426H
-
mutation identified in Italian patient with congenital adrenal hyperplasia, less than 1% of wild-type enzyme activity
R435C
naturally occuring mutation, the mutation prevents salt bridge formation resulting in a localized, as opposed to global, destabilization of tertiary structure
R479L
naturally occuring mutation, the mutation prevents salt bridge formation resulting in a localized, as opposed to global, destabilization of tertiary structure
R483P
naturally occuring mutation, the mutation prevents salt bridge formation resulting in a localized, as opposed to global, destabilization of tertiary structure
R483Q
S301Y
naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues
T168N
naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues
T295X
naturally occuring mutation, the mutation abolishes substrate binding and causes salt-wasting congenital adrenal hyperplasia
T296N
T450P
naturally occuring mutation, the mutation reduces flexibility of beta8-sheet, which helps stabilize the very long C-terminal loop
V139E
naturally occuring mutation, mutation to glutamate disrupts the interaction with residues V440 and L436 on the L-helix causing instability of the enzyme, charge repulsions between the side chain of mutated V139E and E437 of the E-helix render the protein unstable and inactive causing salt-wasting congenital adrenal hyperplasia
V249A
naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues
V281G
naturally occuring mutation, the mutation causes a loss of the hydrophobic pocket
V281L
V282L
2% of wild-type efficiency with substrate progesterone
V304M
naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues
V359A
V359G
site-directed mutagenesis, the mutant shows 10% reduced activity compared to the wild-type enzyme
V470A
site-directed mutagenesis, the mutant shows activity similar to the wild-type enzyme
V470A/I471A
site-directed mutagenesis, the mutant shows activity similar to the wild-type enzyme
V470G
site-directed mutagenesis, the mutant shows activity similar to the wild-type enzyme
W302R
naturally occuring mutation, the mutation prevents stable packing interactions resulting in salt-wasting congenital adrenal hyperplasia
W302S
W303R
0.0001% of wild-type efficiency with substrate progesterone
Y47C
naturally occuring mutation, the mutation disables hydrogen bonding with H38, the interaction is compensated by a weak His-Cys interaction
Y47L
naturally occuring mutation, the mutation disrupts hydrogen bonds and causes salt-wasting congenital adrenal hyperplasia
Y59N
naturally occuring mutation, the mutation disrupts the hydrophobicity of the region resulting in loss of function
additional information
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
HisTrap HP column chromatography (using Ni2+ ions immobilized onto a metal-chelating column)
Ni-NTA agarose column chromatography, and SP Fast-Flow Sepharose column chromatography
recombinant His-tagged enzyme from Escherichia coli strain JM109 by nickel affinity chromatography
-
recombinant wild-type and mutant enzymes from yeast microsomes
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in COS-1 cells
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expressed in Escherichia coli BL21-Gold DE(3) cells
expressed in Sf9 insect cell microsomes
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expressed in Spodoptera frugiperda insect cell microsomes using a baculovirus expression system
expression of His-tagged enzyme in Escherichia coli strain JM109, coexpression with molecular chaperones GroES and GroEL
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expression of wild-type and mutant enzymes in yeast microsomes
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gene CYP11B!, DNA and amino acid sequence determination and analysis, genotyping
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gene CYP21, expression in Schizosaccharomyces pombe strain CAD18, method optimization and evaluation, and quantification of the intracellular redox cofactor pool in transformed cells, overview
gene CYP21A2, DNA and amino acid sequence determination and analysis, genotyping. Recombinant expression of mutant H365Y/R356W in HEK-293T cells
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gene CYP21A2, genotyping, expression of wild-type and mutant enzymes in HEK-293T and hepatoblastoma C3A cells, the H365Y enzyme is produced in more variable amounts than wild-type CYP21A2
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mutant enzymes are expressed in COS-7 cells
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mutant enzymes are expressed in Saccharomyces cerevisiae strain W303B
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recombinant expression in yeast microsomes
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
biotechnology
the CYP21 expression model system using resting Schizosaccharomyces pombe cells can be used for biotransformations
medicine
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Higashi, Y; Yoshioka, H.; Yamane, M.; Gotoh, O.; Fuji-Kuriyama, Y.
complete nucleotide sequence of two steroid 21-hydroxylase genes tandemly arranged in human chromosomes: a pseudogene and a genuine gene
Proc. Natl. Acad. Sci. USA
83
2841-2845
1986
Homo sapiens
Manually annotated by BRENDA team
Barbaro, M.; Lajic, S.; Baldazzi, L.; Balsamo, A.; Pirazzoli, P.; Cicognani, A.; Wedell, A.; Cacciari, E.
Functional analysis of two recurrent amino acid substitutions in the CYP21 gene from Italian patients with congenital adrenal hyperplasia
J. Clin. Endocrinol. Metab.
89
2402-2407
2004
Homo sapiens
Manually annotated by BRENDA team
Felix-Lopez, X.; Riba, L.; Ordonez-Sanchez, M.L.; Ramirez-Jimenez, S.; Ventura-Gallegos, J.L.; Zentella-Dehesa, A.; Tusie-Luna, M.T.
Steroid 21-hydroxylase (P450c21) naturally occurring mutants I172N, V281L and I236N/V237E/M239K exert a dominant negative effect on enzymatic activity when co-expressed with the wild-type protein
J. Pediatr. Endocrinol. Metab.
16
1017-1024
2003
Homo sapiens
Manually annotated by BRENDA team
Miguel, R.N.; Chen, S.; Nikfarjam, L.; Kominami, S.; Carpenter, B.; Dal Pra, C.; Betterle, C.; Zanchetta, R.; Nakamatsu, T.; Powell, M.; Hewer, R.; Blundell, T.L.; Smith, B.R.; Furmaniak, J.
Analysis of the interaction between human steroid 21-hydroxylase and various monoclonal antibodies using comparative structural modelling
Eur. J. Endocrinol.
153
949-961
2005
Homo sapiens
Manually annotated by BRENDA team
Dolzan, V.; Solyom, J.; Fekete, G.; Kovacs, J.; Rakosnikova, V.; Votava, F.; Lebl, J.; Pribilincova, Z.; Baumgartner-Parzer, S.M.; Riedl, S.; Waldhauser, F.; Frisch, H.; Stopar-Obreza, M.; Krzisnik, C.; Battelino, T.
Mutational spectrum of steroid 21-hydroxylase and the genotype-phenotype association in Middle European patients with congenital adrenal hyperplasia
Eur. J. Endocrinol.
153
99-106
2005
Homo sapiens
Manually annotated by BRENDA team
Krone, N.; Riepe, F.G.; Groetzinger, J.; Partsch, C.; Braemswig, J.; Sippell, W.G.
The residue E351 is essential for the activity of human 21-hydroxylase: evidence from a naturally occurring novel point mutation compared with artificial mutants generated by single amino acid substitutions
J. Mol. Med.
83
561-568
2005
Homo sapiens
Manually annotated by BRENDA team
Barbaro, M.; Baldazzi, L.; Balsamo, A.; Lajic, S.; Robins, T.; Barp, L.; Pirazzoli, P.; Cacciari, E.; Cicognani, A.; Wedell, A.
Functional studies of two novel and two rare mutations in the 21-hydroxylase gene
J. Mol. Med.
84
521-528
2006
Homo sapiens
Manually annotated by BRENDA team
Trinh, L.; Nimkarn, S.; New, M.I.; Lin-Su, K.
Growth and pubertal characteristics in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency
J. Pediatr. Endocrinol. Metab.
20
883-891
2007
Homo sapiens
Manually annotated by BRENDA team
Soardi, F.C.; Lemos-Marini, S.H.; Coeli, F.B.; Maturana, V.G.; Silva, M.D.; Bernardi, R.D.; Justo, G.Z.; de-Mello, M.P.
Heterozygosis for CYP21A2 mutation considered as 21-hydroxylase deficiency in neonatal screening
Arq. Bras. Endocrinol. Metabol.
52
1388-1392
2008
Homo sapiens
Manually annotated by BRENDA team
Concolino, P.; Mello, E.; Minucci, A.; Giardina, E.; Zuppi, C.; Toscano, V.; Capoluongo, E.
A new CYP21A1P/CYP21A2 chimeric gene identified in an Italian woman suffering from classical congenital adrenal hyperplasia form
BMC Med. Genet.
10
72
2009
Homo sapiens (P08686), Homo sapiens
Manually annotated by BRENDA team
Ono, M.; Kashimada, K.; Miyai, K.; Onishi, T.; Takagi, M.; Honma, S.; Mizutani, S.
In vitro enzyme assay of CYP21A2 mutation (R483Q) by a novel method using liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS)
Clin. Pediatr. Endocrinol.
17
49-56
2008
Homo sapiens
Manually annotated by BRENDA team
Marques, C.J.; Pignatelli, D.; Carvalho, B.; Barcelo, J.; Almeida, A.C.; Fernandes, S.; Witchel, S.F.; Sousa, M.; Oliveira, M.J.; Freitas, P.; Fontoura, M.; Carvalho, D.; Barros, A.; Carvalho, F.
Mutational characterization of steroid 21-hydroxylase gene in Portuguese patients with congenital adrenal hyperplasia
Exp. Clin. Endocrinol. Diabetes
118
505-512
2010
Homo sapiens (P08686), Homo sapiens
Manually annotated by BRENDA team
Bleicken, C.; Loidi, L.; Dhir, V.; Parajes, S.; Quinteiro, C.; Dominguez, F.; Groetzinger, J.; Sippell, W.G.; Riepe, F.G.; Arlt, W.; Krone, N.
Functional characterization of three CYP21A2 sequence variants (p.A265V, p.W302S, p.D322G) employing a yeast co-expression system
Hum. Mutat.
30
E443-E450
2009
Homo sapiens
Manually annotated by BRENDA team
Bratland, E.; Bredholt, G.; Mellgren, G.; Knappskog, P.M.; Mozes, E.; Husebye, E.S.
The purification and application of biologically active recombinant steroid cytochrome P450 21-hydroxylase: the major autoantigen in autoimmune Addisons disease
J. Autoimmun.
33
58-67
2009
Homo sapiens (P08686), Homo sapiens
Manually annotated by BRENDA team
Dubey, S.; Idicula-Thomas, S.; Anwaruddin, M.; Saravanan, C.; Varma, R.R.; Maitra, A.
A novel 9-bp insertion detected in steroid 21-hydroxylase gene (CYP21A2): prediction of its structural and functional implications by computational methods
J. Biomed. Sci.
16
3-3
2009
Homo sapiens (P08686), Homo sapiens
Manually annotated by BRENDA team
Riepe, F.G.; Hiort, O.; Groetzinger, J.; Sippell, W.G.; Krone, N.; Holterhus, P.M.
Functional and structural consequences of a novel point mutation in the CYP21A2 gene causing congenital adrenal hyperplasia: potential relevance of helix C for P450 oxidoreductase-21-hydroxylase interaction
J. Clin. Endocrinol. Metab.
93
2891-2895
2008
Homo sapiens
Manually annotated by BRENDA team
Bratland, E.; Skinningsrud, B.; Undlien, D.E.; Mozes, E.; Husebye, E.S.
T cell responses to steroid cytochrome P450 21-hydroxylase in patients with autoimmune primary adrenal insufficiency
J. Clin. Endocrinol. Metab.
94
5117-5124
2009
Homo sapiens
Manually annotated by BRENDA team
Rottembourg, D.; Deal, C.; Lambert, M.; Mallone, R.; Carel, J.C.; Lacroix, A.; Caillat-Zucman, S.; le Deist, F.
21-Hydroxylase epitopes are targeted by CD8 T cells in autoimmune Addisons disease
J. Autoimmun.
35
309-315
2010
Homo sapiens (P08686), Homo sapiens
Manually annotated by BRENDA team
Zehentgruber, D.; Dragan, C.A.; Bureik, M.; Luetz, S.
Challenges of steroid biotransformation with human cytochrome P450 monooxygenase CYP21 using resting cells of recombinant Schizosaccharomyces pombe
J. Biotechnol.
146
179-185
2010
Homo sapiens (P08686), Homo sapiens
Manually annotated by BRENDA team
Gaffney, D.; Howie, A.; Bakkush, A.; Hoffmann, T.; Mason, J.; Wallace, A.; Donaldson, M.
Functional characterisation of the H365Y mutation of the 21-hydroxylase gene in congenital adrenal hyperplasia
J. Steroid Biochem. Mol. Biol.
123
109-114
2011
Homo sapiens
Manually annotated by BRENDA team
Sushko, T.A.; Gilep, A.A.; Usanov, S.A.
Mechanism of intermolecular interactions of microsomal cytochrome P450s CYP17 and CYP21 involved in steroid hormone biosynthesis
Biochemistry (Moscow)
77
585-592
2012
Homo sapiens
Manually annotated by BRENDA team
Mizrachi, D.; Wang, Z.; Sharma, K.K.; Gupta, M.K.; Xu, K.; Dwyer, C.R.; Auchus, R.J.
Why human cytochrome P450c21 is a progesterone 21-hydroxylase
Biochemistry
50
3968-3974
2011
Homo sapiens (P08686), Homo sapiens
Manually annotated by BRENDA team
Yoshimoto, F.K.; Zhou, Y.; Peng, H.M.; Stidd, D.; Yoshimoto, J.A.; Sharma, K.K.; Matthew, S.; Auchus, R.J.
Minor activities and transition state properties of the human steroid hydroxylases cytochromes P450c17 and P450c21, from reactions observed with deuterium-labeled substrates
Biochemistry
51
7064-7077
2012
Homo sapiens
Manually annotated by BRENDA team
Zhao, B.; Lei, L.; Kagawa, N.; Sundaramoorthy, M.; Banerjee, S.; Nagy, L.D.; Guengerich, F.P.; Waterman, M.R.
Three-dimensional structure of steroid 21-hydroxylase (cytochrome P450 21A2) with two substrates reveals locations of disease-associated variants
J. Biol. Chem.
287
10613-10622
2012
Bos taurus (P00191), Bos taurus, Homo sapiens (P08686)
Manually annotated by BRENDA team
Yoshimoto, F.K.; Desilets, M.C.; Auchus, R.J.
Synthesis of halogenated pregnanes, mechanistic probes of steroid hydroxylases CYP17A1 and CYP21A2
J. Steroid Biochem. Mol. Biol.
128
38-50
2012
Homo sapiens
Manually annotated by BRENDA team
Haider, S.; Islam, B.; DAtri, V.; Sgobba, M.; Poojari, C.; Sun, L.; Yuen, T.; Zaidi, M.; New, M.I.
Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia
Proc. Natl. Acad. Sci. USA
110
2605-2610
2013
Homo sapiens (P08686), Homo sapiens
Manually annotated by BRENDA team
Parr, M.K.; Zoellner, A.; Fusshoeller, G.; Opfermann, G.; Schloerer, N.; Zorio, M.; Bureik, M.; Schaenzer, W.
Unexpected contribution of cytochrome P450 enzymes CYP11B2 and CYP21, as well as CYP3A4 in xenobiotic androgen elimination - insights from metandienone metabolism
Toxicol. Lett.
213
381-391
2012
Homo sapiens
Manually annotated by BRENDA team
Pallan, P.S.; Wang, C.; Lei, L.; Yoshimoto, F.K.; Auchus, R.J.; Waterman, M.R.; Guengerich, F.P.; Egli, M.
Human cytochrome P450 21A2, the major steroid 21-hydroxylase: structure of the enzyme-progesterone substrate complex and rate-limiting C-H bond cleavage
J. Biol. Chem.
290
13128-13143
2015
Bos taurus (P00191), Bos taurus, Homo sapiens (P08686), Homo sapiens
Manually annotated by BRENDA team
Doleschall, M.; Szabo, J.A.; Pazmandi, J.; Szilagyi, A.; Koncz, K.; Farkas, H.; Toth, M.; Igaz, P.; Glaz, E.; Prohaszka, Z.; Korbonits, M.; Racz, K.; Fuest, G.; Patocs, A.
Common genetic variants of the human steroid 21-hydroxylase gene (CYP21A2) are related to differences in circulating hormone levels
PLoS ONE
9
e107244
2014
Homo sapiens (P08686), Homo sapiens
Manually annotated by BRENDA team
Yoshimoto, F.K.; Peng, H.M.; Zhang, H.; Anderson, S.M.; Auchus, R.J.
Epoxidation activities of human cytochromes P450c17 and P450c21
Biochemistry
53
7531-7540
2014
Homo sapiens (P08686), Homo sapiens
Manually annotated by BRENDA team
Wang, C.; Pallan, P.S.; Zhang, W.; Lei, L.; Yoshimoto, F.K.; Waterman, M.R.; Egli, M.; Guengerich, F.P.
Functional analysis of human cytochrome P450 21A2 variants involved in congenital adrenal hyperplasia
J. Biol. Chem.
292
10767-10778
2017
Homo sapiens (P08686), Homo sapiens
Manually annotated by BRENDA team
Pallan, P.S.; Lei, L.; Wang, C.; Waterman, M.R.; Guengerich, F.P.; Egli, M.
Research Resource Correlating human cytochrome P450 21A2 crystal structure and phenotypes of mutations in congenital adrenal hyperplasia
Mol. Endocrinol.
29
1375-1384
2015
Homo sapiens (P08686), Homo sapiens
Manually annotated by BRENDA team