A Bioorganometallic Chemistry Overview: From Cytochrome P450 Enzyme Metabolism of Organotin Compounds to Organorhodium-Hydroxytamoxifen Complexes with Potential Anti-Cancer Properties; A 37 Year Perspective at the Interface of Organometallic Chemistry and Biology

2010 ◽  
Vol 63 (11) ◽  
pp. 1505 ◽  
Author(s):  
Richard H. Fish
Keyword(s):  
Cytochrome P450 ◽  
Organotin Compounds ◽  
Cytochrome P450 Enzyme ◽  
Oxidation Reactions ◽  
Tandem Catalysis ◽  
Cytochrome P450 Enzymes ◽  
Exciting Field ◽  
Bioorganometallic Chemistry ◽  
Hydride Reduction ◽  
P450 Enzyme

A 37 year perspective on bioorganometallic chemistry studies, which included metabolism of organotin compounds with cytochrome P450 enzymes, and their biomimics; reactions of organorhodium aqua complexes with nucleobases, nucleosides, and nucleotides; supramolecular organorhodium-nucleobase complexes as hosts for aromatic amino acid and aromatic carboxylic acid guests; regioselective reduction of NAD+ biomimics with an organorhodium hydride; tandem catalysis of an organorhodium hydride reduction to provide a 1,4-NADH biomimic for horse liver dehydrogenase stereoselective reduction of achiral ketones to chiral alcohols, and oxidation reactions with cytochrome P450 enzymes; and organorhodium-hydroxytamoxifen pharmaceuticals, will be presented. Each of these areas of bioorganometallic chemistry will be briefly discussed in this personal synopsis of the new, important, and exciting field of bioorganometallic chemistry, and its impact on metal-based drug research.

Drug Interactions of Macrolides: Emphasis on Dirithromycin

1997 ◽  
Vol 31 (3) ◽  
pp. 349-356 ◽  
Author(s):  
Vish S Watkins ◽  
Ron E Polk ◽  
Jennifer L Stotka
Keyword(s):  
Cytochrome P450 ◽  
Drug Interactions ◽  
Ethinyl Estradiol ◽  
Enzyme System ◽  
Cytochrome P450 Enzyme ◽  
Cytochrome P450 Enzymes ◽  
Kidney Transplant Recipients ◽  
P450 Enzyme ◽  
Cytochrome P450 Enzyme System ◽  
Clinically Significant

Objective To describe the drug interactions of dirithromycin, a new macrolide, and to compare them with those of other macrolides. Data Sources A literature search was performed using MEDLINE to identify articles published between January 1980 and July 1995 concerning the drug interactions of macrolides. Published abstracts were also examined. All studies using dirithromycin were performed under the sponsorship of Eli Lilly and Company. Data Synthesis Erythromycin, the first macrolide discovered, is metabolized by the cytochrome P450 enzyme system. By decreasing their metabolism, erythromycin can interact with other drugs metabolized by the cytochrome P450 enzymes. The lack of such interactions would be a desirable feature in a newer macrolide. We describe studies performed to detect any interactions of dirithromycin with cyclosporine, theophylline, terfenadine, warfarin, and ethinyl estradiol. The studies showed that dirithromycin, like azithromycin, is much less likely to cause the interactions detected with clarithromycin and erythromycin. A review of the literature showed differences among macrolides in their abilities to inhibit cytochrome P450 enzymes and, thus, to cause drug–drug interactions. Erythromycin and clarithromycin inhibit cytochrome P450 enzymes, and have been implicated in clinically significant interactions. Azithromycin and dirithromycin neither inhibit cytochrome P450 enzymes nor are implicated in clinically significant drug–drug interactions. Conclusions Dirithromycin, a new macrolide, does not inhibit the cytochrome P450 enzyme system. The concomitant use of dirithromycin with cyclosporine, theophylline, terfenadine, warfarin, or ethinyl estradiol was studied in pharmacokinetic and pharmacodynamic studies. In vitro, dirithromycin did not bind cytochrome P450. In healthy subjects, erythromycin increases the clearance of cyclosporine by 51%, whereas dirithromycin causes no significant changes in the pharmacokinetics of cyclosporine. In kidney transplant recipients, administration of dirithromycin was associated with a significant (p < 0.003) decrease of 17.4% in the clearance of cyclosporine. In patients taking low-dose estradiol, the administration of dirithromycin caused a significant (p < 0.03) increase of 9.9% in the clearance of ethinyl estradiol; escape ovulation did not occur. Unlike erythromycin and clarithromycin, dirithromycin had no significant effects on the pharmacokinetics of theophylline, terfenadine, or warfarin. The alterations typical of drug interactions that are based on inhibition of the cytochrome P450 system occurring with erythromycin and clarithromycin were not observed with dirithromycin.

scholarly journals Characterization of Medicago truncatula (barrel medic) hydroperoxide lyase (CYP74C3), a water-soluble detergent-free cytochrome P450 monomer whose biological activity is defined by monomer–micelle association

2006 ◽  
Vol 395 (3) ◽  
pp. 641-652 ◽  
Author(s):  
Richard K. Hughes ◽  
Eric J. Belfield ◽  
Mylrajan Muthusamay ◽  
Anuja Khan ◽  
Arthur Rowe ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Cytochrome P450 ◽  
Medicago Truncatula ◽  
Water Soluble ◽  
Hydroperoxide Lyase ◽  
Cytochrome P450 Enzyme ◽  
Cytochrome P450 Enzymes ◽  
P450 Enzyme ◽  
Detergent Micelles

We describe the detailed biochemical characterization of CYP74C3 (cytochrome P450 subfamily 74C3), a recombinant plant cytochrome P450 enzyme with HPL (hydroperoxide lyase) activity from Medicago truncatula (barrel medic). Steady-state kinetic parameters, substrate and product specificities, RZ (Reinheitszahl or purity index), molar absorption coefficient, haem content, and new ligands for an HPL are reported. We show on the basis of gel filtration, sedimentation velocity (sedimentation coefficient distribution) and sedimentation equilibrium (molecular mass) analyses that CYP74C3 has low enzyme activity as a detergent-free, water-soluble, monomer. The enzyme activity can be completely restored by re-activation with detergent micelles, but not detergent monomers. Corresponding changes in the spin state equilibrium, and probably co-ordination of the haem iron, are novel for cytochrome P450 enzymes and suggest that detergent micelles have a subtle effect on protein conformation, rather than substrate presentation, which is sufficient to improve substrate binding and catalytic-centre activity by an order of magnitude. The kcat/Km of up to 1.6×108 M−1·s−1 is among the highest recorded, which is remarkable for an enzyme whose reaction mechanism involves the scission of a C–C bond. We carried out both kinetic and biophysical studies to demonstrate that this effect is a result of the formation of a complex between a protein monomer and a single detergent micelle. Association with a detergent micelle rather than oligomeric state represents a new mechanism of activation for membrane-associated cytochrome P450 enzymes. Highly concentrated and monodispersed samples of detergent-free CYP74C3 protein may be well suited for the purposes of crystallization and structural resolution of the first plant cytochrome P450 enzyme.

scholarly journals Conversion of viridicatic acid to crustosic acid by cytochrome P450 enzyme-catalysed hydroxylation and spontaneous cyclisation

2021 ◽  
Author(s):  
Jenny Zhou ◽  
Shu-Ming Li
Keyword(s):  
Cytochrome P450 ◽  
Genetic Manipulation ◽  
Selection Marker ◽  
Cytochrome P450 Monooxygenases ◽  
Cytochrome P450 Enzyme ◽  
Oxidation Reactions ◽  
Functional Identification ◽  
Marker Recycling ◽  
P450 Monooxygenases ◽  
P450 Enzyme

Abstract Cytochrome P450 monooxygenases (P450s) are considered nature’s most versatile catalysts and play a crucial role in regio- and stereoselective oxidation reactions on a broad range of organic molecules. The oxyfunctionalisation of unactivated carbon-hydrogen (C-H) bonds, in particular, represents a key step in the biosynthesis of many natural products as it provides substrates with increased reactivity for tailoring reactions. In this study, we investigated the function of the P450 enzyme TraB in the terrestric acid biosynthetic pathway. We firstly deleted the gene coding for the DNA repair subunit protein Ku70 by using split marker-based deletion plasmids for convenient recycling of the selection marker to improve gene targeting in Penicillium crustosum. Hereby, we reduced ectopic DNA integration and facilitated genetic manipulation in P. crustosum. Afterward, gene deletion in the Δku70 mutant of the native producer P. crustosum and heterologous expression in Aspergillus nidulans with precursor feeding proved the involvement of TraB in the formation of crustosic acid by catalysing the essential hydroxylation reaction of viridicatic acid. Key points •Deletion of Ku70 by using split marker approach for selection marker recycling. •Functional identification of the cytochrome P450 enzyme TraB. •Fulfilling the reaction steps in the terrestric acid biosynthesis.

Inhibitory Effects of Garcinia cambogia Extract on CYP2B6 Enzyme Activity

Planta Medica ◽  
2017 ◽  
Vol 83 (11) ◽  
pp. 895-900 ◽  
Author(s):  
Jun Yu ◽  
Min Choi ◽  
Jong Park ◽  
Shaheed Rehman ◽  
Katsunori Nakamura ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Enzyme Activities ◽  
Liver Microsomes ◽  
Cytochrome P450 Enzyme ◽  
Dependent Manner ◽  
Cytochrome P450 Enzymes ◽  
Inhibitory Effects ◽  
Concentration Dependent Manner ◽  
Garcinia Cambogia ◽  
P450 Enzyme

AbstractThis study assessed the inhibitory effects of Garcinia cambogia extract on the cytochrome P450 enzymes in vitro. G. cambogia extract was incubated with cytochrome P450 isozyme-specific substrates in human liver microsomes and recombinant CYP2B6 isozyme, and the formation of the marker metabolites was measured to investigate the inhibitory potential on cytochrome P450 enzyme activities. The results showed that G. cambogia extract has significant inhibitory effects on CYP2B6 activity in a concentration-dependent manner. Furthermore, the inhibition was potentiated following preincubation with NADPH, indicating that G. cambogia extract is a time-dependent inhibitor of CYP2B6. Meanwhile, hydroxycitric acid, the major bioactive ingredient of G. cambogia extract, did not exhibit significant inhibition effects on cytochrome P450 enzyme activities. G. cambogia extract could modulate the pharmacokinetics of CYP2B6 substrate drugs and lead to interactions with those drugs. Therefore, caution may be required with respect to concomitant intake of dietary supplements containing G. cambogia extract with CYP2B6 substrates.

Mechanism of Oxidation Reactions Catalyzed by Cytochrome P450 Enzyme

ChemInform ◽  
2004 ◽  
Vol 35 (46) ◽  
Author(s):  
Bernard Meunier ◽  
Samuel P. de Visser ◽  
Sason Shaik
Keyword(s):  
Cytochrome P450 ◽  
Cytochrome P450 Enzyme ◽  
Oxidation Reactions ◽  
P450 Enzyme ◽  
Mechanism Of Oxidation

scholarly journals The crystal structure of the cytochrome P450 enzyme TxtE

2014 ◽  
Vol 70 (a1) ◽  
pp. C1683-C1683
Author(s):  
Feng Yu ◽  
Minjun Li ◽  
Chunyan Xu ◽  
Zhijun Wang ◽  
Huan Zhou ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Cytochrome P450 ◽  
Substrate Recognition ◽  
Industrial Applications ◽  
Cytochrome P450 Enzyme ◽  
Cytochrome P450 Enzymes ◽  
Dominant Form ◽  
Thaxtomin A ◽  
Access Channel ◽  
P450 Enzyme

Thaxtomins, a family of phytotoxins produced by Streptomyces spp., can causes plant cell necrosis at nanomolar concentrations. Thaxtomin A is the dominant form from Streptomyces scabies and has demonstrated herbicidal action. TxtE, a cytochrome P450 enzyme from S. scabies 87.22, catalyzes direct nitration of the indolyl moiety of L-tryptophan to L-4-nitrotryptophan using nitric oxide, dioxygen and NADPH, which is the key step of Thaxtomin A biosynthesis. NO-related nitration is a common chemical process in organisms, particularly for tyrosine nitration. However, TxtE is the first reported enzyme that catalyzes a direct nitration reaction specifically in a biosynthetic pathway and thus it can potentially be developed for industrial applications. The crystal structure of TxtE was determined at 2.1 angstrom. A clearly defined substrate access channel is observed and can be classified as channel 2a, which is common in bacteria cytochrome P450 enzymes. A continuous hydrogen bond chain from the active site to the external solvent is observed. Compared with other cytochrome P450 enzymes, TxtE shows a unique proton transfer pathway which crosses the helix I distortion. Polar contacts of Arg59, Tyr89, Asn293, Thr296, and Glu394 with L-tryptophan are seen using molecular docking analysis, which are potentially important for substrate recognition and binding. After mutating Arg59, Asn293, Thr296 or Glu394 to leucine, the substrate binding ability of TxtE was lost or decreased significantly. According to docking and mutagenesis experiments, we propose a possible substrate recognition and binding mechanism, a possible mechanism for substrate recognition and binding is proposed.

scholarly journals Engineering cytochrome P450 enzyme systems for biomedical and biotechnological applications

2019 ◽  
Vol 295 (3) ◽  
pp. 833-849 ◽  
Author(s):  
Zhong Li ◽  
Yuanyuan Jiang ◽  
F. Peter Guengerich ◽  
Li Ma ◽  
Shengying Li ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Cytochrome P450 Enzyme ◽  
Cytochrome P450 Enzymes ◽  
Bulk Chemicals ◽  
Redox Partner ◽  
Substrate Engineering ◽  
P450 Enzyme ◽  
Living Organisms ◽  
Complex Organic ◽  
Made In

Cytochrome P450 enzymes (P450s) are broadly distributed among living organisms and play crucial roles in natural product biosynthesis, degradation of xenobiotics, steroid biosynthesis, and drug metabolism. P450s are considered as the most versatile biocatalysts in nature because of the vast variety of substrate structures and the types of reactions they catalyze. In particular, P450s can catalyze regio- and stereoselective oxidations of nonactivated C–H bonds in complex organic molecules under mild conditions, making P450s useful biocatalysts in the production of commodity pharmaceuticals, fine or bulk chemicals, bioremediation agents, flavors, and fragrances. Major efforts have been made in engineering improved P450 systems that overcome the inherent limitations of the native enzymes. In this review, we focus on recent progress of different strategies, including protein engineering, redox-partner engineering, substrate engineering, electron source engineering, and P450-mediated metabolic engineering, in efforts to more efficiently produce pharmaceuticals and other chemicals. We also discuss future opportunities for engineering and applications of the P450 systems.

Effects of phenol on metabolic activities and transcription profiles of cytochrome P450 enzymes inChironomus kiinensislarvae

2015 ◽  
Vol 106 (1) ◽  
pp. 73-80 ◽  
Author(s):  
C.W. Cao ◽  
L.L. Sun ◽  
F. Niu ◽  
P. Liu ◽  
D. Chu ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Exposure Period ◽  
Open Reading Frames ◽  
Cytochrome P450 Enzyme ◽  
Cytochrome P450 Enzymes ◽  
Transcription Profiles ◽  
P450 Enzyme ◽  
Metabolic Activities ◽  
P450 Activity ◽  
Phenol Stress

AbstractPhenol, also known as carbolic acid or phenic acid, is a priority pollutant in aquatic ecosystems. The present study has investigated metabolic activities and transcription profiles of cytochrome P450 enzymes inChironomus kiinensisunder phenol stress. Exposure ofC. kiinensislarvae to three sublethal doses of phenol (1, 10 and 100 µM) inhibited cytochrome P450 enzyme activity during the 96 h exposure period. The P450 activity measured after the 24 h exposure to phenol stress could be used to assess the level (low or high) of phenol contamination in the environment. To investigate the potential of cytochrome P450 genes as molecular biomarkers to monitor phenol contamination, the cDNA of ten CYP6 genes from the transcriptome ofC. kiinensiswere identified and sequenced. The open reading frames of the CYP6 genes ranged from 1266 to 1587 bp, encoding deduced polypeptides composed of between 421 and 528 amino acids, with predicted molecular masses from 49.01 to 61.94 kDa and isoelectric points (PI) from 6.01 to 8.89. Among the CYP6 genes, the mRNA expression levels of theCYP6EW3, CYP6EV9, CYP6FV1andCYP6FV2genes significantly altered in response to phenol exposure; therefore, these genes could potentially serve as biomarkers in the environment. This study shows that P450 activity combined with one or multipleCYP6genes could be used to monitor phenol pollution.

Sign in / Sign up

Export Citation Format

Share Document