Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P50583 (asymmetrical)
 12,197 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The metabolic dealkylation of nine nitrosodialkylamines, including five symmetrical (nitrosodimethylamine, nitrosodiethylamine, nitrosodipropylamine, nitrosodibutylamine and nitrosodiamylamine) and four asymmetrical nitrosodialkylamines (nitrosomethylethylamine, nitrosomethylpropylamine, nitrosomethylbutylamine and nitrosomethylamylamine), was investigated in 14 samples of human liver microsomes. All these nitrosodialkylamines were dealkytated to aldehydes that were separated by reversed phase HPLC and UV detected as dinitrophenylhydrazones. As the length of the alkyl chain increased from methyl to pentyl, dealkylation of symmetrical nitrosodialkylamines became less efficiently catalyzed by cytochrome P450. Conversely, oxidation of the methyl moiety of asymmetrical nitrosomethylalkylamines increased with the size of the alkyl moiety, while dealkylation of the longer alkyl group decreased. N-Dealkylase activities were significantly correlated with P450 activities measured in human liver microsomes. These catalytic activities involve CYP2A6 (coumarin 7-hydroxylation), CYP2C (mephenytoin 4-hydroxylation and tolbutamide hydroxylation), CYP2D6 (dextromethorphan O-demethylation), CYP2E1 (chlorzoxazone and p-nitrophenol hydroxylation) and CYP3A4 (nifedipine oxidation). By using 10 heterologously expressed P450s, it was shown that nitrosodimethylamine was mainly demethylated by CYP2E1. However, such enzyme specificity was lost with increasing size of the alkyl group. Therefore, the chain length of the alkyl group of nitrosodialkylamines determined the P450 involved in its oxidation. All these results emphasize that the catalytic site of P450 2EI has a geometric configuration such that only small molecules like nitrosodimethylamine fit favorably within the putative active site of the enzyme. Furthermore, there is good evidence that P450s other than P450 2E1, such as P450 2A6, 2C8/2C9/2C19 and 3A4, are involved in the metabolism of nitrosodialkylamines bearing bulky alkyl chains.
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PMID:Cytochrome P450 metabolic dealkylation of nine N-nitrosodialkylamines by human liver microsomes. 882 31

Abscisic acid (ABA), a plant stress hormone, has a chiral center (C1') in its molecule, yielding the enantiomers (1'S)-(+)-ABA and (1'R)-(-)-ABA during chemical synthesis. ABA 8'-hydroxylase (CYP707A), which is the major and key P450 enzyme in ABA catabolism in plants, catalyzes naturally occurring (1'S)-(+)-enantiomer, whereas it does not recognize naturally not occurring (1'R)-(-)-enantiomer as either a substrate or an inhibitor. Here we report a structural ABA analogue (AHI1), whose both enantiomers bind to recombinant Arabidopsis CYP707A3, in spite of stereo-structural similarity to ABA. The difference of AHI1 from ABA is the absence of the side-chain methyl group (C6) and lack of the alpha,beta-unsaturated carbonyl (C2'C3'-C4'O) in the six-membered ring. To explore which moiety is responsible for asymmetrical binding by CYP707A3, we synthesized and tested ABA analogues that lacked each moiety. Competitive inhibition was observed for the (1'R) enantiomers of these analogues in the potency order of (1'R,2'R)-(-)-2',3'-dihydro-4'-deoxo-ABA (K(I)=0.45 microM)>(1'R)-(-)-4'-oxo-ABA (K(I)=27 microM)>(1'R)-(-)-6-nor-ABA and (1'R,2'R)-(-)-2',3'-dihydro-ABA (no inhibition). In contrast to the (1'R)-enantiomers, the inhibition potency of the (1'S)-analogues declined with the saturation of the C2',C3'-double bond or with the elimination of the C4'-oxo moiety. These findings suggest that the C4'-oxo moiety coupled with the C2',C3'-double bond is the significant key functional group by which ABA 8'-hydroxylase distinguishes (1'S)-(+)-ABA from (1'R)-(-)-ABA.
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PMID:Asymmetrical ligand binding by abscisic acid 8'-hydroxylase. 1758 74