ChemInform Abstract: Mechanistic Aspects of CYP74 Allene Oxide Synthases and Related Cytochrome P450 Enzymes

ChemInform ◽  
2010 ◽  
Vol 41 (7) ◽  
Author(s):  
Alan R. Brash
Keyword(s):  
Cytochrome P450 ◽  
Allene Oxide ◽  
Cytochrome P450 Enzymes

CYP74C3 and CYP74A1, plant cytochrome P450 enzymes whose activity is regulated by detergent micelle association, and proposed new rules for the classification of CYP74 enzymes

2006 ◽  
Vol 34 (6) ◽  
pp. 1223-1227 ◽  
Author(s):  
R.K. Hughes ◽  
E.J. Belfield ◽  
R. Casey
Keyword(s):  
Cytochrome P450 ◽  
Major Effect ◽  
Hydroperoxide Lyase ◽  
Allene Oxide ◽  
Cytochrome P450 Enzymes ◽  
Oligomeric State ◽  
Product Specificity ◽  
Detergent Micelle ◽  
Sequence Relatedness ◽  
Monomeric Proteins

CYP74C3 (cytochrome P450 subfamily 74C3), an HPL (hydroperoxide lyase) from Medicago truncatula (barrel medic), and CYP74A1, an AOS (allene oxide synthase) from Arabidopsis thaliana, are key membrane-associated P450 enzymes in plant oxylipin metabolism. Both recombinant detergent-free enzymes are monomeric proteins with dual specificity and very low enzyme activity that can be massively activated with detergent. This effect is a result of the formation of a complex between the protein monomer and a single detergent micelle and, in the case of CYP74A1, has a major effect on the substrate specificity of the enzyme. Association with a detergent micelle without an effect on protein oligomeric state represents a new mechanism of activation for membrane-associated P450 enzymes. This may represent a second unifying feature of CYP74 enzymes, in addition to their known differences in reaction mechanism, which separates them functionally from more classical P450 enzymes. Highly concentrated and monodispersed samples of detergent-free CYP74C3 and CYP74A1 proteins should be suitable for structural resolution. On the basis of recent evidence for incorrect assignment of CYP74 function, using the current rules for CYP74 classification based on sequence relatedness, we propose an alternative based on substrate and product specificity for debate and discussion.

Pharmacogenomics of Cytochrome P450 Enzymes in Tumours

2004 ◽  
Vol 2 (3) ◽  
pp. 243-254 ◽  
Author(s):  
Diane Downie ◽  
Patrick Rooney ◽  
Morag McFadyen ◽  
Graeme Murray
Keyword(s):  
Cytochrome P450 ◽  
Cytochrome P450 Enzymes

Engineering Cytochrome P450 Enzymes

2008 ◽  
Vol 21 (1) ◽  
pp. 220-231 ◽  
Author(s):  
Elizabeth M. J. Gillam
Keyword(s):  
Cytochrome P450 ◽  
Cytochrome P450 Enzymes

scholarly journals Exploring the effect of khat (Catha edulis) chewing on the pharmacokinetics of the antiplatelet drug clopidogrel in rats using the newly developed LC-MS/MS technique

2020 ◽  
Vol 18 (1) ◽  
pp. 681-690
Author(s):  
Hassan A. Alhazmi ◽  
Adnan A. Kadi ◽  
Mohamed W. Attwa ◽  
Waquar Ahsan ◽  
Manal Mohamed Elhassan Taha ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Active Metabolite ◽  
Dose Adjustment ◽  
Internal Standard ◽  
Cardiovascular Complications ◽  
Antiplatelet Drug ◽  
Peak Ratio ◽  
Cytochrome P450 Enzymes ◽  
Time Intervals ◽  
Addictive Substance

AbstractClopidogrel (CLOP) is widely used worldwide for cardiovascular complications. CLOP is highly metabolized in the liver to its active metabolite by cytochrome P450 enzymes. Studies have shown that khat, an addictive substance, is a powerful inhibitor of cytochrome P450 enzymes and can influence the metabolism of drugs that are concomitantly used. Therefore, this study was designed to evaluate the effects of khat on the pharmacokinetics of CLOP in rats. In this study, rats were administered either CLOP alone or CLOP combined with khat and their plasma were obtained at different time intervals and analyzed using the newly developed and validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method using foretinib (FTB) as the internal standard. The corresponding peak area of the analyte versus FTB was used for calculating the peak ratio. The validated LC-MS/MS method resulted in the separation of the well-defined quantifiable peaks of CLOP, FTB, and CLOP metabolite within 7 min. Results showed a significant influence of khat on the peak ratio of CLOP metabolite, which was found to be significantly decreased (P < 0.05) in comparison to CLOP alone, suggesting significant decrease in the conversion of CLOP to its active metabolite due to the inhibition of CYP450 enzymes by khat. Therefore, there might be a need for dose adjustment for regular khat chewers using CLOP.

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