Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The selective inactivation by 17 beta-substituted steroids of rabbit and rat liver cytochromes P-450 involved in the 21-hydroxylation of progesterone has been investigated. Five derivatives each of pregnenolone and progesterone were prepared, in which the methylketo substituent of the 17 beta-position was replaced by a dichloromethylketo, chlorofluoromethylketo, difluoromethylketo, vinyl, or ethynyl group. The ability of the compounds to cause time-dependent (inactivation) and time-independent (inhibition) decreases in progesterone hydroxylase activity was assessed in vitro using intact liver microsomes as well as reconstituted systems containing the major forms of hepatic cytochrome P-450 responsible for progesterone 21-hydroxylation, P-450 1 in the rabbit and PB-C in the rat. In each species, one compound was identified that specifically inactivated the 21-hydroxylase, namely 21-chloro-21-fluoropregnenolone in the rabbit and pregn-4,20-diene-3-one in the rat, although both compounds inhibited several other hydroxylases as well. Moreover, the most effective and specific 21-hydroxylase inactivators were not necessarily the most effective or specific inhibitors. These results suggest that conversion of the enzyme-inhibitor complex to metabolites that inactivate the enzyme, rather than complex formation, is the crucial factor in determining the specificity of the compounds as cytochrome P-450 inactivators. The results indicate the feasibility of designing specific inactivators of hepatic cytochromes P-450 by utilizing the normal regioselectivity of the target enzyme towards steroids.
Mol Pharmacol 1989 Jan
PMID:Specific inactivation by 17 beta-substituted steroids of rabbit and rat liver cytochromes P-450 responsible for progesterone 21-hydroxylation. 278 20

The carboxyl-terminal 28 amino acids of rabbit cytochrome P450 2C2 are markedly different from those of other rabbit cytochrome P450 2C family members and, substitution of the equivalent amino acids of other cytochrome P450s can confer novel steroid hydroxylase activity to P450 2C2 while the normal lauric acid hydroxylase activity is retained. To determine the basis for the novel steroid hydroxylase activity, amino acids of cytochrome P450 2C1 were substituted for those of cytochrome P450 2C2 and the mutants were expressed in COS-1 cells. There are 13 differences between the sequences of cytochrome P450 2C2 and P450 2C1 in this region, including five nonconservative exchanges of charged and uncharged amino acids. However, only substitution of valine for Ser-473 increased steroid hydroxylase activity to the maximum level expected in a modified cytochrome P450 2C2, which contained additional substitutions in the 368-388 region to maximize progesterone hydroxylase activity. Introduction of this single substitution into cytochrome P450 2C2 resulted in 21-progesterone hydroxylase activity similar to that resulting from substitution of all 28 carboxyl-terminal cytochrome P450 2C1 amino acids. None of the substitutions, with one exception, substantially affected either lauric acid hydroxylase activity or the amount of immunologically reactive cytochrome P450 that was expressed. A glycine substitution for Val-477 reduced activity of both lauric acid hydroxylase and progesterone hydroxylase and altered the regioselectivity of the hydroxylation for both. Homology modeling of cytochrome P450 2C2, based on the cytochrome bacterial P450cam sequence, indicated that the side chains of residue 473 and the other five residues previously shown to affect substrate specificity face the substrate pocket. For four of the six residues, smaller and more hydrophobic residues increased progesterone relative to lauric acid hydroxylation.
Mol Pharmacol 1995 Sep
PMID:Substitution at residue 473 confers progesterone 21-hydroxylase activity to cytochrome P450 2C2. 756 21

Liver microsomal steroid hydroxylases and 5 alpha reductase activities were evaluated by quantitation of specific metabolites from 4-C14 progesterone after TLC separation. Each enzyme showed a different developmental profile depending on the gender of the rat. Dexamethasone induced both 6 beta and 16 alpha progesterone hydroxylase, being more potent for 6 beta (3 to 4 folds) than 16 alpha (1.2 to 1.6 folds). A comparison of the inducibility of 6 beta and 16 alpha hydroxylase by dexamethasone in rats from different age groups showed that for both enzymes, the degree of increase was higher in the younger than older groups. Thus there is a blunting in the responsiveness to dexamethasone induction of both 6 beta and 16 alpha hydroxylase with age particularly in female animals. This decrease in responsiveness in older females could potentially affect their capacity to metabolize endogenous and exogenous agents.
Biochem Mol Biol Int 1994 Nov
PMID:Age and gender effect on the inducibility of steroid metabolizing cytochrome P450 in rat liver. 770 3

Aromatase (CYP450(arom), CYP19) is an enzyme responsible for converting the aliphatic androgens androstenedione and testosterone to the aromatic estrogens estrone and estradiol, respectively. These endogenous hormones are a key factor in cancer tumor formation and proliferation through a cascade starting from estrogen binding to estrogen receptor. To interfere with the overproduction of estrogens especially in tumor tissue, it is possible to inhibit aromatase activity. This can be achieved using aromatase inhibitors. In order to design novel aromatase inhibitors, it is necessary to have an understanding of the active site of aromatase. As no crystal structure of the enzyme has yet been published, we built a homology model of aromatase using the first crystallized mammalian cytochrome enzyme, rabbit 21-progesterone hydroxylase 2C5, as a template structure. The initial model was validated with exhaustive molecular dynamics simulation with and without the natural substrate androstenedione. The resulting enzyme-substrate complex shows very good stability and only two of the residues are in disallowed regions in a Ramachandran plot.
J Steroid Biochem Mol Biol
PMID:A three-dimensional model of CYP19 aromatase for structure-based drug design. 1758 93