Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: KEGG:D02011 (FAD)
5,530 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The in vivo S-oxidation of albendazole was measured from the pharmacokinetic profile of albendazole sulphoxide and sulphone determined in young male sheep receiving oral albendazole (1.9 mg/kg). Studies were carried out before, and each month after, oral infestation by 150 metacercariae of Fasciola hepatica. 2. Parasitic pathology was ascertained by clinical observation of animals, and the increase in plasma antibodies directed against liver flukes. 3. Rate of conversion of sulphoxide to sulphone and rate of sulphone elimination, were respectively decreased by 47% and 87% at week 8 post-infection, whereas significant increases in the area under plasma sulphone concentrations versus time curve and mean residence time, occurred 4-12 weeks following the infestation. 4. A 58% decrease in albendazole sulphonation was demonstrated in liver microsomal preparations obtained from 8-week-infected sheep, while there was no change in the FAD-directed sulphoxidation of albendazole. 5. The transient impairment of albendazole sulphonation could be related to the decrease in liver microsomal cytochrome P450-dependent monooxygenases observed in sheep with a similar parasitic pathology.
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PMID:Decrease in albendazole sulphonation during experimental fascioliasis in sheep. 177 67

Treatment of rat liver microsomes with alkaline phosphatase results in a loss in the FMN but not the FAD flavin prosthetic group of NADPH-cytochrome P-450 reductase (Taniguchi, H. and Pyerin, W. (1987) Biochim. Biophys. Acta 912, 295-307). Experiments were carried out to evaluate the effect of preventing electron transfer from the FADH2 to FMN component of the reductase, and subsequent mixed function oxidase activity, on reduction of ferric chelates, production of H2O2, and the generation of .OH-like species by microsomes. Treatment with alkaline phosphatase was confirmed to decrease NADPH-cytochrome c, but not NADPH-ferricyanide, reductase activity by microsomes and by purified NADPH cytochrome P-450 reductase. The oxidation of hydroxyl radical scavenging agents by microsomes and reductase was decreased by the alkaline phosphatase treatment in accordance with the decline in cytochrome c reductase activity. This decrease in hydroxyl radical production occurred in the presence of various ferric chelate catalysts. Rates of microsomal reduction of the ferric chelates were also inhibited after alkaline phosphatase treatment. Production of H2O2 was decreased in accordance to the fall in cytochrome c reductase activity and .OH production. Rates of H2O2 production appeared to be rate-limiting for the overall generation of .OH as the addition of an external H2O2-generating system stimulated .OH production as well as prevented the decline in .OH production caused by the alkaline phosphatase treatment. These results suggest that both the FAD and FMN flavin prosthetic groups of the reductase contribute towards the reduction of various ferric chelates. However, loss of the FMN component and activities dependent on electron transfer from this prosthetic group result in a decrease in H2O2 production, which appears to be responsible for the decline in the generation of .OH-like species by microsomes after treatment with alkaline phosphatase.
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PMID:Inhibition of the oxidation of hydroxyl radical scavenging agents after alkaline phosphatase treatment of rat liver microsomes. 190 77

Comparison of the amino acid sequences of several microsomal cytochrome P-450 reductases to the flavoprotein domain (BMR) of cytochrome P-450BM-3 has revealed that this class of flavoproteins contains evolutionarily conserved regions that are important for their interaction with nucleotide substrates and cofactors. In order to understand the properties of BMR, the region encoding this protein, beginning at residue Lys-472 of cytochrome P-450BM-3, was subcloned and expressed in Escherichia coli. The recombinant protein (more than 50% of host-soluble proteins) was purified to homogeneity using conventional purification procedures. BMR (Mr 66,000) showed typical flavoenzyme absorbance spectra, contained FAD and FMN in a stoichiometry of 1:1, and catalyzed reduction of several artificial electron acceptors with rates comparable to those of the microsomal NADPH-cytochrome P-450 oxidoreductase. Limited trypsinolysis of BMR, under non-denaturing conditions, revealed that the protease removed the NH2-terminal 122 residues. This region was postulated to contain amino acids that are important for FMN binding (Porter, T. D. (1991) Trends Biochem. Sci. 16, 154-158). Consistent with this hypothesis, the major tryptic product of BMR (BMR-52, Mr 52,000) contained only FAD, in an equimolar ratio to the protein. Also, like the FMN-depleted microsomal NADPH-cytochrome P-450 oxidoreductase (Kurzban, G. P., Howarth, J., Palmer, G., and Strobel, H. W. (1990) J. Biol. Chem. 265, 12272-12279), BMR-52 was active for only catalyzing ferricyanide reduction. These data provide strong experimental evidence for a discrete multidomain structure of BMR, as proposed for the membrane-bound reductases, with an amino-terminal FMN binding region and carboxyl-terminal FAD- and NADPH binding regions. Thus, BMR strongly resembles the microsomal cytochrome P-450 reductase and offers an opportunity to better understand the structure-function relationships of this class of flavoproteins.
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PMID:Expression, purification, and properties of the flavoprotein domain of cytochrome P-450BM-3. Evidence for the importance of the amino-terminal region for FMN binding. 193 79

When I began this review my goal was to present a coherent overview of the biochemistry and regulation of the inducible P450 cytochromes of bacteria. Now, at the end, I wonder if a unified perspective is possible at this time. On the basis of admittedly limited data, bacterial P450 systems seem as different from each other as they are, as a group, from the mammalian P450 cytochromes. The most obvious physical difference between the bacterial monooxygenases and their mammalian counterparts is solubility; with several possible exceptions (69, 70, 76), bacterial P450s are soluble whereas the microsomal and mitochondrial P450s are membrane-associated proteins. In structure and organization, however, the few well-characterized prokaryotic P450-dependent systems vary widely. The three-component arrangement is probably most common but even here variation is apparent. The P450cam putidaredoxin reductase contains only FAD and is quite specific for NADH (35, 39); the P450meg megaredoxin reductase contains only FMN and is specific for NADPH (59, 60). Putitive two-component P450 systems in bacteria have not yet been adequately characterized but the P450oct and P450npd monooxygenases (69, 70, 93) could well be organized in this way. The catalytically self-sufficient P450BM-3 is currently the only single-component P450-dependent monooxygenase known but additional examples of this arrangement may well be found in other bacteria. Paradoxically, P450BM-3 is structurally much more analogous to liver microsomal P450 systems than to any other bacterial P450 monooxygenase characterized to date. Another generally recognized difference between prokaryotic and eukaryotic P450s pertains to function; most known bacterial P450-dependent systems initiate the oxidation of recalcitrant carbon compounds so that the hosts can utilize them as sole carbon sources for growth. Some lower eukaryotes [certain yeasts, for example (134)] also employ P450-dependent systems in this way but, among most fungi as well as in higher eukaryotes, P450 cytochromes are involved in specific pathways of sterol or other lipid syntheses or, as in the mammalian liver microsomal systems, in detoxification reactions.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:P450BM-3 and other inducible bacterial P450 cytochromes: biochemistry and regulation. 206 73

31P-nuclear-magnetic-resonance spectroscopy has been employed to probe the structure of the detergent-solubilized form of liver microsomal NADPH--cytochrome-P-450 reductase. In addition to the resonances due to the FMN and FAD coenzymes, additional phosphorus resonances are observed and are assigned to the tightly bound adenosine 2'-phosphate (2'-AMP) and to phospholipids. The phospholipid content was found to vary with the preparation; however, the 2'-AMP resonance was observed in all preparations tested. In agreement with published results [Otvos et al. (1986) Biochemistry 25, 7220-7228] for the protease-solubilized enzyme, the addition of Mn(II) to the oxidized enzyme did not result in any observable line-broadening of the FMN and FAD phosphorus resonances. The phospholipid resonances, however, were extensively broadened and the line width of the phosphorus resonance assigned to the bound 2'-AMP was broadened by approximately 70 Hz. The data show that only the phosphorus moieties of the phospholipids and the 2'-AMP, but not the flavin coenzymes are exposed to the bulk solvent. Removal of the FMN moiety from the enzyme substantially alters the 31P-NMR spectrum as compared with the native enzyme. The 2'-AMP is removed from the enzyme during the FMN-depletion procedure and the pyrophosphate resonances of the bound FAD are significantly altered. Reconstitution of the FMN-depleted protein with FMN results in the restoration of the coenzyme spectral properties. Reduction of FMN to its air-stable paramagnetic semiquinone form results in broadening of the FMN and 2'-AMP resonances in the detergent-solubilized enzyme. In agreement with previous results. FMN semiquinone formation had little or no effect on the line width of the FMN phosphorus resonance for the proteolytically solubilized enzyme. 31P-NMR experiments with Azotobacter flavodoxin semiquinone, both in its free form and in a complex with spinach ferredoxin-NADP+ reductase, mimic the differential paramagnetic effects of the flavin semiquinone on the line width of the FMN phosphorus resonance, observed by comparison of the detergent-solubilized and protease-solubilized forms of the reductase. The data demonstrate that assignment of the site of flavin semiquinone formation to a particular flavin coenzyme may not always be possible by 31P-NMR experiments in multi-flavin containing enzymes.
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PMID:A 31P-nuclear-magnetic-resonance study of NADPH-cytochrome-P-450 reductase and of the Azotobacter flavodoxin/ferredoxin-NADP+ reductase complex. 211 40

cDNA clones to rat liver NADPH-cytochrome P-450 oxidoreductase were used to isolate genomic clones from a Wistar-Furth inbred rat genomic DNA library. Fifteen exons containing the coding region and 3'-nontranslated segment of the P-450 reductase gene were identified, spanning 20 kilobases of DNA contained in 3 lambda-Charon 35 clones. The organization of this single copy gene reveals a general correspondence between exons and structural domains of the protein, with the segment responsible for anchoring the reductase to the microsomal membrane and several segments involved in FMN, FAD, and NADPH binding encoded by discrete exons.
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PMID:NADPH-cytochrome P-450 oxidoreductase gene organization correlates with structural domains of the protein. 212 83

Isolated hepatocytes and liver microsomes incubated with monomethyl-1,1 dimethyl- and 1,2 dimethyl-hydrazines produced free radical intermediates which were detected by ESR spectroscopy by using 4-pyridyl-1-oxide-t-butyl nitrone (4-POBN) as spin trapping agent. The spectral features of the spin adducts derived from all three hydrazine derivatives corresponded to the values reported for the methyl free radical adduct of 4-POBN. In the microsomal preparations inhibitors of the mixed function oxidase system and the destruction of cytochrome P450 by pretreating the rats with CoCl2 all decreased the free radical formation. Methimazole, an inhibitor of FAD-containing monoxygenase system, similarly decreased the activation of 1,1 dimethyl-hydrazine, but not that of monomethyl- and 1,2 dimethyl-hydrazines. The addition to liver microsomes of physiological concentrations of glutathione (GSH) lowered by approx. 80% the intensities of the ESR signals. Consistently, incubation of isolated hepatocytes with methyl-hydrazines decreased the intracellular GSH content, suggesting that GSH can effectively scavenge the methyl free radicals. The results obtained suggest that methyl free radicals could be the alkylating species responsible for the toxic and/or carcinogenic effect of methyl-hydrazines.
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PMID:Free radical activation of monomethyl and dimethyl hydrazines in isolated hepatocytes and liver microsomes. 253 41

The influence of Ebselen, an organoselenium anti-inflammatory agent, on the two electron transport chains present in rat liver microsomes has been studied. At low micromolar concentrations, Ebselen markedly inhibited the flow of reducing equivalents from NADPH-cytochrome P450 reductase to both its natural electron acceptor, cytochrome P450, and its artificial electron acceptor, cytochrome c. Similarly, the microsomal NADH-cytochrome c reductase system consisting of cytochrome b5 and its flavoprotein, NADH-cytochrome b5 reductase, was also significantly inhibited by Ebselen. The inhibition appears to be due to the inability of the reduced pyridine nucleotide to transfer electrons to the flavin (FAD and/or FMN) in the flavoprotein reductase. This was shown with the purified NADPH-cytochrome P450 reductase, which in the presence of Ebselen was not converted to the semiquinone form following the addition of NADPH. The addition of Ebselen to a suspension of hepatic microsomes from either untreated or phenobarbital-treated rats did not result in any spectral change characteristic of type I, type II, or reverse type I.
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PMID:Disruption of rat hepatic microsomal electron transport chains by the selenium-containing anti-inflammatory agent Ebselen. 291 42

Adrenodoxin reductase is an NADP dependent flavoenzyme which functions as the reductase of mitochondrial P 450 systems. We sequenced two adrenodoxin reductase cDNAs isolated from a bovine adrenal cortex cDNA library. The deduced amino acid sequence shows no similarity to the sequence of the microsomal P 450 systems or other known protein sequences. Nonetheless, by sequence analysis and c comparisons with known sequences of dinucleotide-binding folds of two NADP-binding flavoenzymes, two regions of adrenodoxin reductase sequence were identified as the FAD- and NADP-binding sites. These analyses revealed a consensus sequence for the NADP-binding dinucleotide fold (GXGXXAXXXAXXXXXXG, in one-letter amino acid code) that differs from FAD and NAD-binding dinucleotide-fold sequences. In the data base of protein sequences, the NADP-binding-site sequence appears solely in NADP-dependent enzymes, the binding sites of which were not known to date. Thus, this sequence may be used for identification of a certain type of NADP-binding site of enzymes that show no significant sequence similarity.
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PMID:cDNA sequence of adrenodoxin reductase. Identification of NADP-binding sites in oxidoreductases. 292 77

Titration of NADPH-cytochrome P-450 reductase with a fluorigenic maleimide suggests that approximately four cysteines are initially accessible and in close proximity to four tryptophans. Perturbation of the cysteines and/or tryptophans results in concomitant decreases in enzymic activity. These cysteines were correlated with functional components by binding studies and subsequent tryptic peptide mapping on the acid mobile phase-reverse phase HPLC. Adenine nucleotides and cytochrome c block labelling of the more hydrophilic peptides, while detergents facilitate labelling of the more hydrophobic peptides. The more hydrophobic peptides contain the microsomal binding site of cytochrome P-450. Removal of the prosthetic flavins exposes more cysteines in the more hydrophilic and hydrophobic regions of the peptide map, associating the former with FAD and the latter with FMN binding sites.
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PMID:Fluorescence probing of the function-specific cysteines of rat microsomal NADPH-cytochrome P-450 reductase. 300 41


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