P450 hydroxylase enzymes

Further Structural Modifications P450 Hydroxylase Enzymes... 

A report (1991) may lead to the ultimate solution of the acid instability problem the production of 6-deoxyerythromycin A by the use of a mutant strain of Saccharopolyspora erythrea. This was accomplished by a targeted disruption of the gene ery F, believed to code for the P450 hydroxylase enzyme, which normally produces the C-6 OH function. This new mutant antibiotic was found to be acid stable and as effective as EM-A in mice (orally) against several pathogenic bacteria. 

The precursor, 7-dehydrocholesterol is converted by a non-enzymatic reaction to cholecalciferol (calciol). This reaction occurs in skin exposed to sunlight due to irradiation by UV-B light at a wavelength of about 300 nm. Cholecalciferol is transported via carrier proteins to the liver where hydroxylation at carbon-25 occurs in a reaction catalysed by a microsomal cytochrome P450 hydroxylase to form calcidiol. This compound travels to the kidney attached to specific binding proteins, where another cytochrome P450 enzyme, mitochondrial 1-a-hydroxylase, introduces a second hydroxyl group in to the molecule to form the active calcitriol. 

Pearce R, Greenway D, Parkinson A (1992) Species differences and interindividual variahon in liver microsomal cytochrome P450 2A enzymes effects on coumarin, dicumarol, and testosterone oxidation. Arch Biochem Biophys 298 211-225 Pelkonen O, Sotaniemi EA, Ahokas JT (1985) Coumarin 7-hydroxylase activity in human hver microsomes. Properties of the enzyme and interspedes comparisons. Br J Clin Pharmacol 19 59-66... 

The monooxygenase group of enzymes includes the non-P450 hydroxylases which catalyze the insertion of a hydroxyl group to replace a hydrogen atom at a saturated carbon [6-8] and the non-heme-dependent oxygenases such as the flavin-molybdenum-cobalt-dependent xanthine oxidase and aldehyde oxidase... 

Within the adrenal cortex (the outer portion of the adrenal glands) progesterone is converted into two groups of hormones of which cortisol and aldosterone are representative.263 Two different cytochrome P450 hydroxylases, found in the ER and specific for C-21 and C-17a, respectively, together with a mitochondrial cytochrome P450 specific for C-lip (Eq. 18-55) participate in formation of cortisol.264 Two of the same enzymes together with additional hydroxylases are required to form aldosterone. 

Various studies have shown that ketoconazole interferes with 17- and 20-hydroxylases and inhibits mitochondrial 11-a-hydroxylase and cytochrome P450-dependent steroid hydroxylase enzymes (SED-12, 677 SEDA-12, 228 SEDA-14, 234) (584). 

Metabolites of PCBs also exert biological effects. The Ah-receptor mediated responses, however, are probably caused by the parent compounds only. The effects of hydroxylated PCBs include inhibition of cytochrome P450-dependent enzyme activities and competitive interference with thyroid hormone and vitamin A metabolism.89,90 Methylsulfonyl-PCBs have been shown to inhibit aryl hydrocarbon hydroxylase activity91 and to elicit phenobarbital-type toxicity and may in fact be responsible for the observed effect presumed to be caused by the parent compound.92... 

SCHRODER, G., UNTERBUSCH, E KALTENBACH, M SCHMIDT, J., STRACK, D., DE LUCA, V., SCHRODER, J., Light induced cytochrome P450-dependent enzyme in indole alkaloid biosynthesis tabersonine 16 hydroxylase., FEBSLett., 1999,458,97-102. 

Cholesterol 7a-hydroxylase, a cytochrome P450-dependent enzyme, catalyzes the first and rate-limiting step in the biosynthesis of bile acids from cholesterol. Potential mechanisms for regulation of the enzyme have been extensively studied. 

Cholecalciferol 25-hydroxylase is not restricted to the liver kidneys, skin, and gut microsomes also have a cytochrome P450 -dependent enzyme that catalyzes the 25-hydroxylation of cholecalciferol and la-hydroxycholecalciferol, hut not ergocalciferol. Although there is some evidence that calcitriol can reduce the activity of calciferol 25-hydroxylase, it is not known whether this is physiologically important the major factor controlling 25-hydroxylation is the rate of uptake of cholecalciferol into the liver. It is the fate of calcidiol in the kidneys that provides the most important regulation of vitamin D metabolism (Wikvall, 2001). 

The active metabolite of vitamin D, calcitriol, is formed in the proximal tubules of the kidneys from calcidiol. There are three cytochrome P450-dependent enzymes in kidneys that catalyze 1-hydroxylation of calcidiol CYP27A and CYP27 in mitochondria and a microsomal la-hydroxylase, which is ferredoxin-dependent. It is likely that the microsomal enzyme is the most important its synthesis is induced by cAMP in response to parathyroid hormone (Section 3.2.8.2) and repressed by calcitriol (Omdahl et al., 2001 Wikvall, 2001). 

Petersen, M., Seitz, H., Alfermann, A. and Reinhard, E. (1987) Immobilization of digitoxin 12p-hydroxylase, a cytochrome P450-dependent enzyme, from cell cultures of Digitalis lanata EHRH. Plant Cell Rep., 6, 200-3. 

Schroeder, G., E. Unterbusch, M. Kaltenbach, J. Schmidt, D. Strack, V. De Luca et al. (1999). Light-induced cytochrome P450-dependent enzyme in indole alkaloid biosynthesis Tabersonine 6-hydroxylase. FEBS Lett. 458, 97-102. 

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