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1.14.14.19: steroid 17alpha-monooxygenase

This is an abbreviated version!
For detailed information about steroid 17alpha-monooxygenase, go to the full flat file.

Word Map on EC 1.14.14.19

Reaction

a C21-steroid
+
[reduced NADPH-hemoprotein reductase]
 +
O2
=
a 17alpha-hydroxy-C21-steroid
 +
[oxidized NADPH-hemoprotein reductase]
 +
H2O

Synonyms

17 alpha-hydroxylase/C17,20-lyase, 17,20-lyase, 17-alpha-hydroxylase/C17-20 lyase, 17-hydroxylase/17,20-lyase, 17-hydroxylase/C17,20-lyase, 17alphahydroxylase, 17alpha-hydroxylase, 17alpha-hydroxylase 17,20 lyase, 17alpha-hydroxylase-17,20-lyase, 17alpha-hydroxylase-C17,20 lyase, 17alpha-hydroxylase-C17,20-lyase, 17alpha-hydroxylase/17,20 lyase, 17alpha-hydroxylase/17,20-lyase, 17alpha-hydroxylase/C(17,20)-lyase, 17alpha-OHase, 17OHD, CYP 17, CYP17, CYP17A1, CYPXVII, cytochrome P-450 (P45017alpha,lyase), cytochrome P-45017alpha, cytochrome P450 17, cytochrome P450 17A1, cytochrome P450 17A2, cytochrome P450 17alpha-hydroxylase, cytochrome P450 17alpha-hydroxylase-17,20-lyase, cytochrome P450 17alpha-hydroxylase/17,20 lyase, cytochrome P450 17alpha-hydroxylase/17,20-lyase, cytochrome p450 17alpha-hydroxylase/C(17,20)-lyase, cytochrome P450 17alpha-hydroxylase/C17,20-lyase, cytochrome P450 17alpha-hydroxylase/c17-20 lyase, cytochrome P45017alpha, cytochrome P450c17, cytochrome P450c17alpha, cytochromeP450 17alpha-hydroxylase/C17-20 lyase, EC 1.14.1.7, EC 1.14.99.9, EC 1.99.1.9, P450 17, P450 17A1, P450(17alpha), P450-17alpha, P450-C17, P45017alpha, P450c17, P450c17-I, Steroid 17-alpha-hydroxylase/17,20 lyase, steroid 17alpha-hydroxylase, steroidogenic cytochrome P450 17A1

ECTree

     1 Oxidoreductases
         1.14 Acting on paired donors, with incorporation or reduction of molecular oxygen
             1.14.14 With reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen into the other donor
                1.14.14.19 steroid 17alpha-monooxygenase

Engineering

Engineering on EC 1.14.14.19 - steroid 17alpha-monooxygenase

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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
L105A
R200N
-
increased reactivity towards pregnenolone, converts pregnenolone to 17alpha-hydroxypregnenolone and dehydroepiandrosterone, at the expense of 17,20-lyase activity towards 17alpha-hydroxyprogesterone
A105L
A174E/K388X
-
naturally occuring mutation leading to CYP17A1 deficiency and adrenal hyperplasia, phenotype, overview
D216H
natural genetic variant. Cells transiently expressing D216H demonstrate a selective impairment of 16alpha-hydroxyprogesterone synthesis by 2.1fold compared to wild-type CYP17A1, no effect on 17alpha-hydroxyprogesterone synthesis is observed
E305G
-
naturally occuring mutation, the active site mutant shows lack of 17,20-lyase activity and reduced 17alpha-hydroxylase activity compared to the wild-type, males homozygous show a phenotype with severe micropenis, perineal hypospadias, chordae, and bifid scrotum, while females show normal genitalia, genotyping of two families, overview
G162R
natural genetic variant. Mutation leads to decreased CYP17A1 protein stability with a near 70% reduction in protein levels compared to wild-type. Mutant is preferentially ubiquitinated and degraded prematurely, with an enzyme half-life of about 2.5 h, proteasome inhibitor treatment recovers G162R protein expression
H373L
-
the replacement causes complete loss of both 17alpha-hydroxylase and 17,20-lyase activities with a defect in heme binding due to a global alteration of P450c17 structure. The mutation is combined with another mutation, a deletion of codon 53 or 54 encoding Phe, TTC, in exon 1, DELTAF54, on a maternal allele. Both mutations together partially abolish both 17alpha-hydroxylase and 17,20-lyase activities. Enzyme deficiency causes clitoromegaly, phenotype, overview
H373N
-
the substitution results in markedly reduced production of 17alpha-hydroxyprogesterone at 0.2% of the wild-type P450c17 and no production of androstenedione
K89N
78% loss of 17,20-lyase activity and 20% loss of 17alpha-hydroxylase activity
L465P
-
naturally occuring mutation leading to CYP17A1 deficiency and adrenal hyperplasia, phenotype, overview
R239Q
-
naturally occuring mutation leading to loss of function of CYP17A1 and to enzyme deficiency resulting in failure in synthesizing cortisol, andrenal androgens, and gonadal steroids, phenotype, detailed overview
R347A
-
site-directed mutagenesis, the mutant shows abolished activation by cytochrome b5 for the hydroxylase activity and overall highly reduced lyase activityindependently of cytochrome b5
R347H
R347K
the mutant exhibits similar 17-hydroxylase and b5-stimulated 17,20-lyase activity as the wild type enzyme
R358A
-
site-directed mutagenesis, the mutant shows abolished activation by cytochrome b5 for the hydroxylase activity and overall highly reduced lyase activityindependently of cytochrome b5
R358K
the mutant exhibits similar 17-hydroxylase and b5-stimulated 17,20-lyase activity as the wild type enzyme
R358Q
R449A
-
site-directed mutagenesis, the mutant shows abolished activation by cytochrome b5 for the hydroxylase activity and overall highly reduced lyase activityindependently of cytochrome b5
R449L
site-directed mutagenesis, the mutant shows no cytochrome b5-CYP17A1 complex formation
R96Q
-
mutation identified in a female patient with a malignant mixed germ cell tumor. Mutation affects a key substrate-binding region and results in complete inactivity of enzyme
S258A
-
significant decrease in both 17alpha-hydroxylase and 17,20-lyase activity
S258D
-
significant decrease in both 17alpha-hydroxylase and 17,20-lyase activity
S427A
site-directed mutagenesis
S427D
site-directed mutagenesis
S427E
site-directed mutagenesis
T260D
-
significant decrease in both 17alpha-hydroxylase and 17,20-lyase activity
T306A
site-directed mutagenesis, the mutant shows highly reduced hydroxylation activity compared to the wild-type enzyme. due to a high degree of uncoupling in which reducing equivalents and protons are funneled into non-productive pathways. The catalysis of carbon-carbon bond scission by the T306A mutant is largely unimpeded by disruption of the CYP17A1 acid-alcohol pair
T341A
site-directed mutagenesis
T341A/S427A
site-directed mutagenesis
T341D
site-directed mutagenesis
T341E
site-directed mutagenesis
V178D/R440C
-
naturally occuring mutation leading to CYP17A1 deficiency and adrenal hyperplasia, phenotype, overview
L105A
additional information