UNIPROT:Q8NEX9 - FACTA Search

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Query: UNIPROT:Q8NEX9 (reductase)
26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Microsomal cytochrome P450s participate in xenobiotic detoxification, procarcinogen activation, and steroid hormone synthesis. The first structure of a mammalian microsomal P450 suggests that the association of P450s with the endoplasmic reticulum involves a hydrophobic surface of the protein formed by noncontiguous portions of the polypeptide chain. This interaction places the entrance of the putative substrate access channel in or near the membrane and orients the face of the protein proximal to the heme cofactor perpendicular to the plane of the membrane for interaction with the P450 reductase. This structure offers a template for modeling other mammalian P450s and should aid drug discovery and the prediction of drug-drug interactions.
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PMID:Mammalian microsomal cytochrome P450 monooxygenase: structural adaptations for membrane binding and functional diversity. 1067 74

Stachydrine (proline betaine) can be used by Sinorhizobium meliloti as a source of carbon and nitrogen. Catabolism depends on an initial N-demethylation, after which the resultant N-methyl proline enters general metabolism. Deletion and insertion mutagenesis demonstrated that the information necessary for catabolism is carried on the symbiotic plasmid (pSym) distal to nodD2 and the nod-nif cluster. Sequencing of an 8.5kb fragment spanning this region revealed four open reading frames with functional homology to known proteins, including a putative monooxygenase and a putative NADPH-FMN-reductase, which were shown by insertional and frame-shift mutagenesis to be necessary for stachydrine catabolism. Other open reading frames, encoding a putative flavoprotein and a repressor, were judged not to be required for stachydrine catabolism, since they were not included in a fragment capable of complementing a deletion of the entire stc region. Sequence and mutagenesis data suggest that stachydrine is demethylated by an iron-sulfur monooxygenase of the Rieske type with a requirement for a specific reductase. The stc catabolic cluster, therefore, resembles xenobiotic degradation in other bacteria and recalls rhizopine catabolism in S. meliloti. Stachydrine appears to have multiple roles in osmoprotection, nutrition and nodulation. Genes involved in stachydrine catabolism are also necessary for carnitine degradation; thus, they could be important in the catabolism of a variety of root exudates and mediate other relationships.
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PMID:The stachydrine catabolism region in Sinorhizobium meliloti encodes a multi-enzyme complex similar to the xenobiotic degrading systems in other bacteria. 1068 97

Procarcinogenic polycyclic aromatic hydrocarbons (PAHs) induce their own metabolism and activation by binding to the cytosolic aryl hydrocarbon receptor (AhR), which then translocates to the nucleus and activates CYP1A1 gene transcription via xenobiotic response elements (XREs). Although the AhR demonstrates a strict specificity for planar aromatics, nonplanar (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene also induced CYP1A1 expression in HepG2 cells over a delayed timecourse (approximately 6-12 h), suggesting a requirement for (+/-)trans-7,8-dihydrobenzo(a)pyrene metabolism. Aldo-keto reductase (AKR) inhibitors blocked this effect, suggesting that benzo(a)pyrene-7,8-dione (BPQ), a planar PAH o-quinone generated by AKRs, was the downstream inducer. BPQ was found to be a potent and rapid inducer of CYP1A1, with an EC50 value in HepG2 cells identical to that of the parent benzo(a)pyrene. BPQ was a more potent inducer of CYP1A1 when compared with the 1,6-, 3,6-, and 6,12-benzo(a)pyrene-diones. Multiple PAH o-quinones caused induction of CYP1A1, demonstrating that this was a general property of AKR-generated PAH o-quinones. HepG2-101L cells stably transfected with a XRE-luciferase construct showed that BPQ activated CYP1A1 transcription via a XRE-dependent mechanism. BPQ failed to induce CYP1A1 in AhR-deficient and AhR nuclear translocator-deficient murine hepatoma cell lines and confirmed that induction of CYP1A1 was AhR and AhR nuclear translocator-dependent. Electrophoretic mobility shift assays demonstrated the specific appearance of BPQ-activated AhR in the nucleus, and immunofluorescence studies confirmed that BPQ mediated nuclear translocation of the AhR. Classical bifunctional inducers elevate CYP1A1 expression via a XRE and are subsequently converted by CYP1A1 to electrophiles that induce phase II enzymes via an electrophilic response element/antioxidant response element PAH o-quinones represent a novel class of bifunctional inducer because they are electrophiles produced by phase II enzymes that simultaneously induce phase I enzymes via a XRE and phase II enzymes via a electrophilic response element/antioxidant response element (see also M. E. Burczynski et al., Cancer Res., 59: 607-614, 1999). This study shows that the AhR provides the only known mechanism by which genotoxic PAH o-quinones generated in the cytosol can be targeted to the nucleus with specificity.
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PMID:Genotoxic polycyclic aromatic hydrocarbon ortho-quinones generated by aldo-keto reductases induce CYP1A1 via nuclear translocation of the aryl hydrocarbon receptor. 1070 4

Cyclooxygenases catalyze the oxygenation of arachidonic acid to prostaglandin endoperoxides. Cyclooxygenase-2- and the xenobiotic-metabolizing cytochrome P450s 1A and 3A are all aberrantly expressed during colorectal carcinogenesis. To probe for a role of P450s in prostaglandin endoperoxide metabolism, we studied the 12-hydroxyheptadecatrienoate (HHT)/malondialdehyde (MDA) synthase activity of human liver microsomes and purified P450s. We found that human liver microsomes have HHT/MDA synthase activity that is concentration-dependent and inhibited by the P450 inhibitors, ketoconazole and clotrimazole with IC(50) values of 1 and 0.4 microM, respectively. This activity does not require P450 reductase. HHT/MDA synthase activity was present in purified P450s but not in heme alone or other heme proteins. The catalytic activities of various purified P450s were determined by measuring rates of MDA production from prostaglandin endoperoxide. At 50 microM substrate, the catalytic activities of purified human P450s varied from 10 +/- 1 to 0.62 +/- 0.02 min(-1), 3A4 >> 2E1 > 1A2. Oxabicycloheptane analogs of prostaglandin endoperoxide, U-44069 and U-46619, induced spectral changes in human P450 3A4 with K(s) values of 240 +/- 20 and 130 +/- 10 microM, respectively. These results suggest that co-expression of cyclooxygenase-2 and P450s in developing cancers may contribute to genomic instability due to production of the endogenous mutagen, MDA.
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PMID:Xenobiotic-metabolizing cytochromes P450 convert prostaglandin endoperoxide to hydroxyheptadecatrienoic acid and the mutagen, malondialdehyde. 1076 2

High levels of cytochrome P450 are present in the olfactory mucosa (OM) in mammalian animals and contribute to the known tissue-selective toxicity of numerous chemical compounds. Olfactory toxicity in the perinatal period may have a greater impact on behavior, growth, and development than in adults. To establish a molecular basis for determining the risk of developmental toxicity in OM, the expression of several cytochrome P450 enzymes, as well as NADPH-cytochrome P450 reductase and microsomal epoxide hydrolase, was examined in hepatic and nasal microsomes prepared from human fetal tissues at gestational day 91-125. The relative microsomal concentrations of these biotransformation enzymes were determined on immunoblots. Expression of CYP2A, CYP2J2, the reductase, and epoxide hydrolase was detected in both OM and liver. The microsomal levels of these enzymes were generally lower in OM than in liver of the same fetuses, except for the CYP2A-related proteins, which were expressed in OM at much higher levels. OM expression of CYP2A6, CYP2A13, CYP2B6, and CYP2J2 mRNAs was detected using RNA-PCR. These results document, for the first time, prenatal expression of xenobiotic-bioactivating cytochrome P450 enzymes in human OM and suggest that the human fetal OM may be a preferred target tissue for the toxicity of maternally derived chemical compounds that are activated by the CYP2A enzymes.
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PMID:Expression of biotransformation enzymes in human fetal olfactory mucosa: potential roles in developmental toxicity. 1082 11

Monocotyledonous crop plants are usually more resistant to herbicides than grass weeds and most dicots. Their resistance to herbicides is mediated in many cases by P450 oxygenases. Monocots thus constitute an appealing source of P450 enzymes for manipulating herbicide resistance and recombinant forms of the major xenobiotic metabolizing mooxygenases are potential tools for the optimization of new active molecules. We report here the isolation and functional characterization of the first P450 and P450 reductase coding sequences from wheat. The first attempts at expressing these cDNAs in yeast and tobacco led to levels of protein, which were extremely low, often not even detectable. The wheat P450 cDNAs were efficiently transcribed, but no protein or activity was found. Wheat coding sequences, like those of other monocots, are characterized by a high GC content and by a related strong bias of codon usage, different from that observed in yeast or dicots. Complete recoding of genes being costly, the reengineering their 5'-end using a single PCR megaprimer designed to comply with codon usage of the host was attempted. It was sufficient to relieve translation inhibition and to obtain good levels of protein expression. The same strategy also resulted in a dramatic increase in protein expression in tobacco. A basis for the success of such a partial recoding strategy, much easier and cheaper than complete recoding of the cDNA, is proposed.
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PMID:Increasing expression of P450 and P450-reductase proteins from monocots in heterologous systems. 1086 54

The microsomal fraction from tulip bulbs (Tulipa fosteriana, L.) contains cytochrome P450 (CYP3, EC 1.14.14.1) and peroxidase (EC 1.11.1.7.) enzymes catalyzing the NADPH--and hydrogen peroxide--dependent oxidation of the xenobiotic substrates, N-nitrosodimethylamine (NDMA), N-nitrosomethylaniline (NMA), aminopyrine and 1-phenylazo 2-hydroxynaphthalene (Sudan I), respectively. Oxidation of these model xenobiotics has also been assessed in a reconstituted electron-transport chain with a partially purified CYP fraction, phospholipid and isolated tulip NADPH:CYP reductase (EC 1.6.2.4.). Peroxidase isolated from tulip bulbs (isoenzyme C) oxidizes these xenobiotics, too. Values of kinetic parameters (Km, Vmax), requirements for cofactors (NADPH, hydrogen peroxide), the effect of inhibitors and identification of products formed from the xenobiotics by the microsomal fraction, partially purified CYP and peroxidase C were determined. These data were used to estimate the participation of the CYP preparation and peroxidase C in oxidation of two out of the four studied xenobiotics (NMA, Sudan I) in tulip microsomes. Using such detailed study, we found that the CYP-dependent enzyme system is responsible for the oxidation of these xenobiotics in the microsomal fraction of tulip bulbs. The results demonstrate the progress in resolving the role of plant CYP and peroxidase enzymes in oxidation of xenobiotics.
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PMID:Oxidation of xenobiotics by plant microsomes, a reconstituted cytochrome P450 system and peroxidase: a comparative study. 1089 75

Effect of vanadium on hepatic xenobiotic biotransformation in rats exposed to diethylnitrosamine (DENA, 200 mg/kg body weight, intraperitoneally) was investigated to elucidate a possible mechanism of vanadium mediated prevention of chemical carcinogenesis. Vanadium supplementation (0.5 ppm ad libitum with drinking water), at different phases before and after DENA treatment, significantly modulated the decrease in contents of total cytochrome P-450, cytochrome b5, activity of nicotinamide adenine dinucleotide phosphate (NADPH), (reduced form) cytochrome reductase, and uridine diphospho-glucuronyl transferase (UDPGT) in microsomal fractions of whole liver, hyperplastic nodules (HNs) and non nodular surrounding parenchyma (NNSP) as induced by DENA, 20 weeks following its administration. Supplementary vanadium had also substantial influence on the activities of cytosolic enzymes, like, uridine diphospho (UDP)-glucose dehydrogenase and NAD(P)H: quinone oxidoreductase (DT-diaphorase) in the concerned tissue which were observed to be remarkably decreased as a result of DENA treatment in comparison to that of the control counterparts. However, vanadium was found to have little or no effect on the lowering ofaryl hydrocarbon hydroxylase (AHH) activity by DENA administration. On the basis of significant modulation of DENA induced alterations in cytosolic and microsomal enzyme activity it can be presumed that the chemoprotective effect of vanadium might be mediated through elevation of phase II conjugating enzymes which in turn, lead to a move and shift of metabolic profile that reduces the intracellular concentration of carcinogen derived reactive intermediates.
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PMID:Differential modulation of xenobiotic metabolizing enzymes by vanadium during diethylnitrosamine-induced hepatocarcinogenesis in Sprague-Dawley rats. 1098 72

The two-component anthranilate 1,2-dioxygenase of the bacterium Acinetobacter sp. strain ADP1 was expressed in Escherichia coli and purified to homogeneity. This enzyme converts anthranilate (2-aminobenzoate) to catechol with insertion of both atoms of O(2) and consumption of one NADH. The terminal oxygenase component formed an alpha(3)beta(3) hexamer of 54- and 19-kDa subunits. Biochemical analyses demonstrated one Rieske-type [2Fe-2S] center and one mononuclear nonheme iron center in each large oxygenase subunit. The reductase component, which transfers electrons from NADH to the oxygenase component, was found to contain approximately one flavin adenine dinucleotide and one ferredoxin-type [2Fe-2S] center per 39-kDa monomer. Activities of the combined components were measured as rates and quantities of NADH oxidation, substrate disappearance, product appearance, and O(2) consumption. Anthranilate conversion to catechol was stoichiometrically coupled to NADH oxidation and O(2) consumption. The substrate analog benzoate was converted to a nonaromatic benzoate 1,2-diol with similarly tight coupling. This latter activity is identical to that of the related benzoate 1, 2-dioxygenase. A variant anthranilate 1,2-dioxygenase, previously found to convey temperature sensitivity in vivo because of a methionine-to-lysine change in the large oxygenase subunit, was purified and characterized. The purified M43K variant, however, did not hydroxylate anthranilate or benzoate at either the permissive (23 degrees C) or nonpermissive (39 degrees C) growth temperatures. The wild-type anthranilate 1,2-dioxygenase did not efficiently hydroxylate methylated or halogenated benzoates, despite its sequence similarity to broad-substrate specific dioxygenases that do. Phylogenetic trees of the alpha and beta subunits of these terminal dioxygenases that act on natural and xenobiotic substrates indicated that the subunits of each terminal oxygenase evolved from a common ancestral two-subunit component.
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PMID:Characterization and evolution of anthranilate 1,2-dioxygenase from Acinetobacter sp. strain ADP1. 1111 7

Carbonyl reductase (secondary-alcohol:NADP(+) oxidoreductase, EC 1.1. 1.184) belongs to the family of short chain dehydrogenases/reductases (SDR). Carbonyl reductases (CBRs) are NADPH-dependent, mostly monomeric, cytosolic enzymes with broad substrate specificity for many endogenous and xenobiotic carbonyl compounds. They catalyze the reduction of endogenous prostaglandins, steroids, and other aliphatic aldehydes and ketones. They also reduce a wide variety of xenobiotic quinones derived from polycyclic aromatic hydrocarbons. CBR reduces the anthracycline anticancer drugs, daunorubicin(dn) and doxorubicin (dox) to their C-13 hydroxy metabolites, changing the pharmacological properties of these drugs. Emerging data on CBRs over the last several years is generating new insights on the potential involvement of CBRs in a variety of cellular and molecular reactions associated with drug metabolism, detoxication, drug resistance, mutagenesis, and carcinogenesis.
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PMID:Carbonyl reductase. 1115 33

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