Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol.
CYP11B1 (11beta-hydroxylase) and CYP11B2 (aldosterone synthase) are 93% identical mitochondrial enzymes that both catalyze 11beta-hydroxylation of steroid hormones. CYP11B2 has the additional 18-hydroxylase and 18-oxidase activities required for conversion of 11-deoxycorticosterone to aldosterone. These two additional C18 conversions can be catalyzed by CYP11B1 if serine-288 and valine-320 are replaced by the corresponding CYP11B2 residues, glycine and alanine. Here we show that such a hybrid enzyme also catalyzes conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol. These latter two steroids are present at elevated levels in individuals with glucocorticoid suppressible hyperaldosteronism (GSH) and some forms of primary aldosteronism. Their production by the recombinant CYP11B enzyme is enhanced by substitution of further amino acids encoded in exons 4, 5, and 6 of CYP11B2. A converted CYP11B1 gene, containing these exons from CYP11B2, would be regulated like CYP11B1, yet encode an enzyme with the activities of CYP11B2, thus causing GSH or essential hypertension. In a sample of 103 low renin hypertensive patients, 218 patients with primary aldosteronism, and 90 normotensive individuals, we found a high level of conversion of CYP11B genes and four cases of GSH caused by unequal crossing over but no gene conversions of the type expected to cause GSH.
Mulatero
P
P
INSERM U36, Collège de France, Paris.
Curnow
K M
KM
Aupetit-Faisant
B
B
Foekling
M
M
Gomez-Sanchez
C
C
Veglio
F
F
Jeunemaitre
X
X
Corvol
P
P
Pascoe
L
L
D016022:Case-Control Studies; D002384:Catalysis; D003350:Cortodoxone / Q000378:metabolism; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics*; D005785:Gene Conversion; D005815:Genetic Code; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000378:metabolism*; D006929:Hyperaldosteronism / Q000235:genetics; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism; D012083:Renin / Q000378:metabolism; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics*
C038135:18-oxocortisol; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase; D012083:Renin; C033689:18-hydroxycortisol; D003350:Cortodoxone; D006854:Hydrocortisone