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At least 163 records · Page 9Linked to original sources
PubMed1995

Cloning and expression of the rat adrenal cytochrome P-450 11B3 (CYP11B3) enzyme cDNA: preferential 18-hydroxylation over 11 beta-hydroxylation of DOC.

The biosynthesis of glucocorticoids and mineralocorticoids in the rat adrenal cortex requires the action of two different cytochrome P450 11 beta-hydroxylases, CYP11B1 and CYP11B2, which are distributed in the zona fasciculata and glomerulosa, respectively. The existence of another cytochrome P450-11 beta gene, CYP11B3, was recently reported. Although CYP11B3 has similar gene structure and great homology to the CYP11B1 and -B2 genes, the CYP11B3 mRNA was not originally detected by reverse transcription-polymerase chain reaction (RT-PCR) and has only recently been cloned and detected from neonatal rat adrenals. Herein we demonstrate RT-PCR detection of CYP11B3 mRNA expressed in adult rat adrenal and brain tissues. The whole coding region of the CYP11B3 enzyme cDNA was cloned and sequenced. When transiently expressed in COS-7 cells the CYP11B3 converted deoxycorticosterone (DOC) to corticosterone and 18-hydroxydeoxycorticosterone, but not to 18-hydroxycorticosterone or aldosterone. It produced more 18-OH-DOC than corticosterone. A single mutation in CYP11B3 in which Gly-59 was replaced by Ser, reduced the enzymatic activity 5-6-fold. Furthermore, CYP11B3 mRNA expression is greater in neonatal, compared to adult rat adrenal glands.

Adrenal Glands↗
PubMed2005

Mechanistic pathways of the hydroxyl radical reactions of quinoline. 2. Computational analysis of hydroxyl radical attack at C atoms.

Density functional theory (DFT) calculations are employed to compare the mechanism of the *OH attacks at all carbon atoms in quinoline. The computational analysis of the energy surface for the reaction of *OH with quinoline reveals that the formation of OH adducts proceeds through exothermic formation of pi-complexes/H-bonded complexes. The gas-phase reactions have activation energies ranging from <1.3 kcal/mol for the attack at positions C3 through C8 to 8.6 kcal/mol for the attack at the C2 position. Solvation, as described by the CPCM cavity model, lowers these activation barriers so that the attack at all carbon atoms except C2 is effectively barrierless. The *OH attack at C2 in solution is significantly different than at all other quinoline positions because it involves the only transition structure with energy higher than that of the starting materials and with an energetic barrier of 5.1 kcal/mol. The specific solvation approach also corroborates this finding because the attack at C2 was shown to have an energy barrier of 2.3 kcal/mol compared to the barrierless attack at C5. These results are in agreement with our recent experimental studies but differ from literature reports on the degradation of quinoline using the photo-Fenton reaction.

Carbon↗
PubMed1996

Microsomal catalyzed N-hydroxylation of guanabenz and reduction of the N-hydroxylated metabolite: characterization of the two reactions and genotoxic potential of guanoxabenz.

The N-reduction of the centrally acting alpha 2-adrenoreceptor agonist guanoxabenz (Benzérial), an N-hydroxyamidinohydrazone, to the amidinohydrazone guanabenz (Wytensin, Hipten, Rexitene) by microsomal fractions from rabbits, pigs and humans has been detected in vitro. The conversion rates with rabbit microsomal fractions were markedly slower than those in the cases of fractions from humans and pigs. It was also possible to demonstrate the N-oxidation of guanabenz to guanoxabenz by the use of microsomal fractions from rabbits, pigs, and humans. Furthermore, the oxidation was also observed in reconstituted systems in the presence of enriched cytochrome P450 fractions, purified isoenzyme P450 2C3, and heterologously expressed P450 2C3 of the subforms 6 beta H and 6 beta L. The analyses were performed with a newly developed HPLC technique and were confirmed by LC-MS methods. The kinetic parameters determined for the metabolic cycle (bioreversible reactions) are indicative of a predominance of the reduction of guanoxabenz to guanabenz in vivo. Accordingly, guanoxabenz in part constitutes a prodrug of guanabenz. Examination of guanabenz and guanoxabenz for mutagenicity by means of the Ames test revealed that guanoxabenz has pronounced mutagenic effects in the strains TA 98 and TA 1537. Guanabenz did not exhibit mutagenicity so that the N-reduction of guanoxabenz has significance in terms of detoxification.

Adrenergic alpha-Agonists↗
PubMed2005

Convergent evolution of hydroxylation mechanisms in the fungal kingdom: molybdenum cofactor-independent hydroxylation of xanthine via alpha-ketoglutarate-dependent dioxygenases.

The xanthine oxidases and dehydrogenases are among the most conserved enzymes in all living kingdoms. They contain the molybdopterin cofactor Moco. We show here that in the fungi, in addition to xanthine dehydrogenase, a completely different enzyme is able to catalyse the oxidation of xanthine to uric acid. In Aspergillus nidulans this enzyme is coded by the xanA gene. We have cloned the xanA gene and determined its sequence. A deletion of the gene has the same phenotype as the previously known xanA1 miss-sense mutation. Homologues of xanA exist only in the fungal kingdom. We have inactivated the cognate gene of Schizosaccharomyces pombe and this results in strongly impaired xanthine utilization as a nitrogen source. We have shown that the Neurospora crassa homologue is functionally equivalent to xanA. The enzyme coded by xanA is an alpha-ketoglutarate- and Fe(II)-dependent dioxygenase which shares a number of properties with other enzymes of this group. This work shows that only in the fungal kingdom, an alternative mechanism of xanthine oxidation, not involving Moco, has evolved using the dioxygenase scaffold.

Amino Acid Sequence↗