- Identification of new substrates for the CYP106A1-mediated 11-oxidation and investigation of the reaction mechanism
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Abstract CYP106A1 from Bacillus megaterium DSM319 was recently shown to catalyze steroid and terpene hydroxylations. Besides producing hydroxylated steroid metabolites at positions 6β, 7β, 9α and 15β, the enzyme displayed previously unknown 11-oxidase activity towards 11β-hydroxysteroids. Novel examples for 11-oxidation were identified and confirmed by 1H and 13C NMR for prednisolone, dexamethasone and 11β-hydroxyandrostenedione. However, only 11β-hydroxyandrostenedione formed a single 11-keto product. The latter reaction was chosen to investigate the kinetic solvent isotope effect on the steady-state turnover of the CYP106A1-mediated 11-oxidation. Our results reveal a large inverse kinetic isotope effect (~0.44) suggesting the involvement of the ferric peroxoanion as a reactive intermediate.
- Kiss, Flora Marta,Khatri, Yogan,Zapp, Josef,Bernhardt, Rita
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- CORRELATION BETWEEN METABOLISM OF BETAMETHASONE 17,21-DIPROPIONATE AND ADRENAL HYPERTROPHY IN RAT FETUSES
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The effects of metabolites of betamethasone 17,21-dipropionate (BMDP) on the hypothalamo-pituitary-adrenocortical axis were assessed by measurements of adrenal weights, after studying the metabolism of BMDP in vivo and in vitro in pregnant rats and mice.After BMDP was injected intravenously at a dose of 5mg/kg into rats and mice in late stages of pregnancy, it disappeared rapidly from the plasma and brain in both mothers and fetuses while betamethasone 17-propionate (BMP) was detected as the main metabolite followed by betamethasone (BM).In vitro studies demonstrated that BMDP was metabolized to BMP in maternal and fetal tissues (plasma, liver, brain and placenta) of both species.The subcutaneous administration of BMP to rats in the late stages of pregnancy induced adrenal hypertrophy in fetuses, though the adrenals of the mothers became atrophic.In the case of mice, both maternal and fetal adrenals became atrophic.Administration of BM produced adrenal atrophy in mothers and fetuses of both species.The subcutaneous administration of 6β-hydroxybetamethasone 17-propionate (6β-OH-BMP) to rat fetuses in utero produced adrenal hypertrophy and 6β-hydroxybetamethasone (6β-OH-BM) showed no effect.These data suggest that BMP is transferred across the placental barrier to produce marked adrenal hypertrophy in rat fetuses.
- Nakano, Masayuki,Nishiuchi, Masanori,Takeuchi, Masaharu,Yamada, Hideo
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p. 511 - 526
(2007/10/02)
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