In BR biosynthesis, Fujioka and Sakurai (1997b) have demonstrated that there are at least two branched biochemical pathways to the end product BL (Figure 1; Fujioka and Sakurai, 1997a, 1997b; Sakurai and Fujioka, 1997). Depending on the oxidation state of C-6, they are referred to as the early or late C-6 oxidation pathways. In the early pathway, the C-6 is oxidized to a ketone at campestanol (CN), whereas in the late pathway it is oxidized at 6-deoxocastasterone (6-deoxoCS). Otherwise, the two pathways share equivalent reactions. Our results from the experiments with the available BR intermediates clearly demonstrate that dwf4 is defective in the 22α-hydroxylation steps in each of the pathways. Application of all 22α-hydroxylated intermediates in these pathways, such as CT and 6-deoxoCT, cause dramatic elongation of dwf4 plants, but compounds not hydroxylated at C-22 had no effect. This result also suggests that DWF4 recognizes at least two substrates: CN and 6-oxoCN. It seems reasonable to ...
Hydroxylation is a chemical process that introduces a hydroxyl group (-OH) into an organic compound. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. Hydroxylation is the first step in the oxidative degradation of organic compounds in air. It is extremely important in detoxification since hydroxylation converts lipophilic compounds into water-soluble (hydrophilic) products that are more readily removed by the kidneys or liver and excreted. Some drugs (for example, steroids) are activated or deactivated by hydroxylation. The hydroxylation process involves conversion of a CH group into a COH group. Hydroxylation is an oxidative process. The oxygen that is inserted into the C-H bond is usually derived from atmospheric oxygen (O2). Since O2 itself is a slow hydroxylating agent, catalysts are required to accelerate the pace of the process.[citation needed] The principal hydroxylation agent in nature is cytochrome P-450, hundreds of variations of which are ...
CYP2B6 is emerging as a more significant component of the P450 enzyme system than previously recognized. The availability of selective probes of CYP2B6 catalytic activity would facilitate further examination of the role of this enzyme in xenobiotic metabolism. The in vitro studies described herein demonstrate that CYP2B6 is the predominant catalyst of BUP hydroxylation in human liver and expand on a preliminary report in which CYP2B6 demonstrated the highest rate of BUP hydroxylation among a panel of cDNA-expressed P450 isozymes (Wurm et al., 1996). The evidence, showing that CYP2B6 is the principal contributor to BUP hydroxylation in HLMs and supporting the use of BUP as a selective in vitro marker of CYP2B6 catalytic activity, consists of the following: 1) similarity in the apparentKm for BUP hydroxylation between HLMs and cDNA-expressed CYP2B6; 2) the rate of BUP hydroxylation was highest with CYP2B6 among a panel of cDNA-expressed P450 isozymes; 3) correlation of BUP hydroxylation with ...
Cytochrome P450 monooxygenases can catalyse the stereoselective C−H activation of a very broad range of substrates. Prediction and control of enantioselectivity of this enzyme class is of great interest for the synthesis of high-value chiral molecules. Here we have used a combination of molecular dynamics simulations and experimental screening to study the enantioselectivity of a library of active-site mutants of chimeric P450cam-RhFRed towards the benzylic hydroxylation of structurally related regioisomers of ethylmethylbenzene. Small variations either in substrate structure or in enzyme active site architecture were shown to lead to dramatic changes in enantioselectivity; this was broadly in agreement with computational predictions. In addition to validating computational approaches, these studies have provided us with a deeper understanding of effects that might control stereoselectivity in these biooxidation reactions ...
Citation: Boyd, D.R. et al. (1989) Sterospecific benzylic hydroxylation of bicyclic alkenes by Pseudomonas putida: isolation of (+) R 1 hydroxy 1,2 dihydronaphthalene, an arene hydrate of naphthalene from metabolism of 1,2 dihydronaphthalene. Journal of the Chemical Society: Chemical Communications, 6, pp. 339-340 ...
RF-Phos, Dukka KC, Random Forest, RF, computational biology, machine learning, hydroxylation site, protein classification, general phosphosite, phosphorylation site prediction, post-translational modification, Protein Structure Prediction, Protein Side Chain Packing, symmetry in protein, multi-domain protein structure prediction, North Carolina A&T State University, RFNR, Feature Extraction, Protein
Directed evolution of a monooxygenase to achieve very high enantioselectivity for hydroxylation at non-activated carbon atoms is demonstrated for the first time, where a triple mutant of P450pyr hydroxylase is obtained via determination of enzyme structure, iterative saturation mutagenesis, and high-throughput screening with a MS-based ee assay to increase the product ee from 53% to 98% for the hydroxylation of N-benzyl pyrrolidine to (S)-N-benzyl 3-hydroxypyrrolidine. This journal is © The Royal Society of Chemistry 2012 ...
To better understand the extrarenal production of active vitamin D metabolites by cells of the monocyte/macrophage lineage, we investigated the 25-hydroxyvitamin D (25OHD)-1-hydroxylation reaction in the v-myc-transformed chick myelomonocytic cell line HD-11; the 1-hydroxylation reaction in this cell line has a high affinity for 25-hydroxylated vitamin D substrates, is localized to mitochondria, and is associated with cytochrome P450 activity. In this study we demonstrated that the HD-11 cell 1-hydroxylation reaction in vitro is not affected by the majority of extracellular regulatory factors that modulate expression of the renal 25OHD-1-hydroxylase in vivo. A 50% increase in extracellular calcium and phosphate concentrations, physiological inhibitory events for renal 1,25-dihydroxyvitamin D [1,25-(OH)2D] synthesis, did not decrease basal expression of the HD-11 cell 1-hydroxylation reaction, nor did a 50% decrease in extracellular calcium and phosphate concentrations, stimulatory signals for ...
The conversion of cholesterol to pregnenolone is a physiologically essential process which initiates with two sequential hydroxylation processes catalyzed by cytochrome P450 side-chain cleavage enzyme (P450SCC). Extensive efforts have been exerted; however, the mechanistic details remain obscure. In this work, we employed the dispersion-corrected density functional theoretical (DFT-D) calculations to investigate the mechanistic details of such hydroxylation processes. Calculated results reveal that the active intermediate Compound I (CpdI) of P450SCC hydroxylates cholesterol efficiently, which coincides with previous spectrometric observations. The hydrogen bond effect of water molecule within the active site lowers the energy barrier significantly. Intriguingly, the adjacent hydrogen bond (H-bond) between the hydroxyl group of the substrate and the oxo group of CpdI in the second hydroxylation affects the H-abstraction significantly. Such H-bond was weakened during the C-H bond activation ...
... - reflects the multidimensional character of chemical biology, focusing in particular on the fundamental science of biological structures and systems, the use of chemical and biological techniques to elucidate
Meta I 3 C is a unique, highly stabilized formula designed to promote healthy estrogen metabolism and activity with indole-3-carbinol (I3C), which provides a full spectrum of beneficial metabolites-including diindolylmethane (DIM).Helps promote the health of estrogen-sensitive tissues-such as those of the breast and cervix.Promotes the formation of good, protective 2-OH via its influence on hydroxylation pathways.Supports the detoxification of estrogens, and may also support healthy metabolism of other steroid hormones and xenoestrogens.Provides rosemary extract to reduce oxidation and help ensure potency.Shelf-life evaluations guarantee stability.These statements have not been evaluated by the Food and Drug Administration (FDA). These products are not meant to diagnose, treat or cure any disease or medical condition. Please consult your doctor before starting any exercise or nutritional supplement program or before using these or any product during pregnancy or if you have a serious medical condition
Although EETs are weak activators of PPARα, the ω-hydroxylated derivatives of 11,12- and 14,15-EET are potent activators (22). These EETs derivatives are produced by CYP ω-oxidases, another class of CYP monooxygenases that utilize fatty acids as substrates. These enzymes insert a hydroxyl group at or near the methyl-terminal end of the fatty acid chain in a NADPH-dependent reaction (10).. 8,9-, 11,12-, and 14,15-EET are good substrates for CYP4A1 and CYP4A2 and are converted to 20-OH-EETs by these enzymes (22). The conversion of 14,15-EET to 20-OH-14,15-EET by a CYP ω-oxidase is illustrated in Fig. 2B. In a parinaric acid displacement assay used to measure the relative affinities of various compounds for the ligand-binding domain of PPARα, the Ki values for the EETs were between 22 and 46 nM. In contrast, the Ki value for 20-OH-14,15-EET was only 3 nM (22). Furthermore, in RK13 cells that overexpress either the human or mouse PPARα gene, 20-OH-14,15-EET increased PPARα-mediated gene ...
Treatment of MCF7 human mammary carcinoma cells with the nonsteroidal antioestrogens, tamoxifen and clomiphene, leads to a concentration-dependent decrease in cellular proliferation rate which can be resolved into oestrogen-reversible and oestrogen-irreversible components. This became more clearly apparent when cells were treated with the 4-hydroxylated derivatives of these compounds where, because of enhanced affinity for the oestrogen receptor (ER), the dose-response curves for the two components could be separated. Thus treatment with 4-hydroxyclomiphene resulted in a distinct biphasic effect on cell growth. In the concentration range 10(-10)-10(-8) M, cell proliferation was inhibited in a concentration-dependent manner to a maximum of 60-70%, there was no further effect between 10(-8) and 10(-6) M, but at concentrations greater than 10(-6) M there was another concentration-dependent decrease in cell growth. Studies with a series of vinyl-substituted hydroxytriphenylethylenes revealed that in the
1IZO: Substrate Recognition and Molecular Mechanism of Fatty Acid Hydroxylation by Cytochrome P450 from Bacillus subtilis. CRYSTALLOGRAPHIC, SPECTROSCOPIC, AND MUTATIONAL STUDIES.
Sigma-Aldrich offers abstracts and full-text articles by [W J Driscoll, S König, H M Fales, L K Pannell, B A Eipper, G P Mueller].
adrenal cortex also contained a CO-binding pigment similar to that reported by Klingenberg to be present in the liver. The function of this unique cytochrome (called P450) was initially revealed in 1963 in studies by Estabrook, Cooper, and Rosenthal7using microsomes from the adrenal cortex for the catalysis of the hydroxylation of 17-hydroxyprogesterone to deoxycorticosterone. Relying on earlier studies by Ryan and Engel8 that had shown that the adrenal C-21 hydroxylation reaction was inhibited by CO and the inhibition could be reversed by white light, Estabrook, Cooper and Rosenthal performed classic photoactivation experiments and proved that this cytochrome was the oxygen combining component in the C-21 hydroxylation of steroids.. In the 35 years since the identification of cytochrome P450 as the terminal component of oxygenation reactions the field has grown from an area of narrow interest to drug metabolism scientists to a major field of interest to molecular biologists, pharmacologists, ...
adrenal cortex also contained a CO-binding pigment similar to that reported by Klingenberg to be present in the liver. The function of this unique cytochrome (called P450) was initially revealed in 1963 in studies by Estabrook, Cooper, and Rosenthal7using microsomes from the adrenal cortex for the catalysis of the hydroxylation of 17-hydroxyprogesterone to deoxycorticosterone. Relying on earlier studies by Ryan and Engel8 that had shown that the adrenal C-21 hydroxylation reaction was inhibited by CO and the inhibition could be reversed by white light, Estabrook, Cooper and Rosenthal performed classic photoactivation experiments and proved that this cytochrome was the oxygen combining component in the C-21 hydroxylation of steroids.. In the 35 years since the identification of cytochrome P450 as the terminal component of oxygenation reactions the field has grown from an area of narrow interest to drug metabolism scientists to a major field of interest to molecular biologists, pharmacologists, ...
Two potential mechanisms by which S100 pretreatment might promote VHL binding are by performing a posttranslational modification of HIF-1α (531) that promotes VHL binding, or by providing a factor that serves to bridge HIF-1α (531) and VHL. To distinguish between these two, the following far Western analysis was performed. GST-HIF-1α (531) was first preincubated in the absence or presence of S100, subjected to SDS/PAGE, and then transferred to a membrane. Then, proteins bound to the membrane were renatured, incubated with 35S-labeled in vitro-translated VHL, washed, and then subjected to autoradiography. As shown in Fig. 1B, GST-HIF-1α (531) in the absence of S100 pretreatment fails to bind VHL (lane 2), whereas that which is pretreated binds to VHL (lane 3). Thus, S100 can induce a posttranslational modification of HIF-1α (531) that promotes its binding to VHL.. Binding of this HIF-1α fragment to VHL is weakened by cobalt and hypoxia (11). Therefore, we prepared S100 from cobalt-treated ...
3198 Precision-cut tissue slices in dynamic organ culture retain their cellular architecture and metabolic activity for several hours, suggesting that organ slices are a suitable in vitro model for studying tissue metabolism of xenobiotics. N-Nitrosonornicotine (NNN) is reported to induce tumors of the lung in A/J mice, and esophagus and nasal mucosa in the F344 rat. The major routes of NNN metabolism are α-hydroxylation to yield either 2-hydroxyNNN or 5-hydroxyNNN, pyridine-N-oxidation, and concerted denitrosation and oxidation to norcotinine. Minor pathways of metabolism include β-hydroxylation to yield either 3-hydroxyNNN or 4-hydroxyNNN. Of all the potential routes of NNN metabolism, 2-hydroxylation is thought to be the major activation pathway yielding target tissue DNA adducts, and the ratio of 2-hydroxylation to 5-hydroxylation is often considered to indicate the extent of NNN activation. 2-Hydroxylation of 0.004 to 1.2 μM [5-3H]NNN (27 Ci/mmol) in precision-cut A/J mouse lung ...
Van der Velden, UbelePage 115 - 124In humans, ascorbic acid, better known as vitamin C, is a true vitamin because humans lack the ability to synthesise it. Vitamin C exhibits a number of enzymatic and non-enzymatic effects but all are accounted for by the ability of vitamin C to donate electrons and therefore acts as a reducing agent. It has a wide range of functions. For example, it acts as co-factor for a number of enzymes including those involved in collagen hydroxylation, prevents oxidative damage to DNA and intracellular proteins, and in plasma it increases endothelium-dependent vasodilatation, and reduces extracellul ...
The major findings of this study are that BMK1 is a novel regulator of HIF1α and angiogenesis by increasing HIF1α ubiquitination and degradation in EC. BMK1 was recently shown to play a critical role in EC function because the conditional BMK1 knockout mouse rapidly dies because of disruption of vascular integrity.16 We recently showed an essential role for BMK1 in preventing EC apoptosis induced by serum deprivation and tumor necrosis factor-α.17 The present study further supports the key role of BMK1 in EC function. In particular, our data show a specific role for BMK1 in regulating HIF1α protein expression and subsequently VEGF expression during hypoxia. An interesting finding is that the effect of BMK1 to promote HIF1α degradation was independent of hydroxylation on Pro 402 and Pro 564, because the HIF1α mutant (P402A/P564G) lacking the consensus prolines was still ubiquitinated and degraded after BMK1 activation.. The mechanisms that regulate HIF1α function have been extensively ...
人はなぜ「冷たい」を「痛い」と感じるのか ―活性酸素と痛みセンサーTRPA1がカギを握る―. 京都大学プレスリリース. 2016-09-16.
Some EGF (epidermal growth factor)-type domains in extracellular proteins have conserved ASP/ASN residues that are substrates of an endoplasmic reticulum membrane-bound enzyme aspartyl/asparaginyl beta-hydroxylase (EC 1.14.11.16). The ASX residues are hydroxylated by the enzyme, forming the beta hydroxylated residue. Many blood coagulation factors, the LDL receptor, BMP-1, Thrombomodulin, and EGF have the modification. Drosophila proteins involved in development include crumbs, delta, notch, serrate, slit and tolloid. May be restricted to metazoans. The Prosite entry PS00010 lists many modified proteins ...
Sigma-Aldrich offers abstracts and full-text articles by [Remigiusz Żurawiński, Marian Mikołajczyk, Marcin Cieślak, Karolina Królewska, Julia Kaźmierczak-Barańska].
Oxysterols are hydroxylated cholesterols, which influence a wide variety of cellular pathways including endolysosomal trafficking, cholesterol biosynthesis and cell surface and nuclear receptor signaling among others. These intracellular effects manifest as major regulatory steps in lipid homeostasis, inflammatory signaling, neuromodulation and cell migration. We are interested in understanding how oxysterols influence neuroinflammation, synaptic dysfunction and neurodegeneration in Alzheimers disease.. Last updated October 2017.. ...
VH-298 is a potent VHL inhibitor that stabilizes HIF-α and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-α protein-protein interaction downstream of HIF-α hydroxylation by PHD enzymes. VH298 represents a high-quality chemical probe of the HIF signalling cascade and an attractive starting point to the development of potential new therapeutics targeting hypoxia signalling.
4-HYDROXYNORNANTENINE. A 4-HYDROXYLATED NORAPORPHINE. . Biblioteca virtual para leer y descargar libros, documentos, trabajos y tesis universitarias en PDF. Material universiario, documentación y tareas realizadas por universitarios en nuestra biblioteca. Para descargar gratis y para leer online.
BACKGROUND: Endogenous sex hormones are well-established risk factors for breast cancer; the contribution of specific oestrogen metabolites (EMs) and/or ratios of specific EMs is less clear. We have previously identified a CYP3A7*1C allele that is associated with lower urinary oestrone (E1) levels in premenopausal women. The purpose of this analysis was to determine whether this allele was associated with specific pathway EMs. METHODS: We measured successfully 12 EMs in mid-follicular phase urine samples from 30 CYP3A7*1C carriers and 30 non-carriers using HPLC-MS/MS. RESULTS: In addition to having lower urinary E1 levels, CYP3A7*1C carriers had significantly lower levels of four of the 2-hydroxylation pathway EMs that we measured (2-hydroxyestrone, P=1.1 × 10-12; 2-hydroxyestradiol, P=2.7 × 10-7; 2-methoxyestrone, P=1.9 × 10-12; and 2-methoxyestradiol, P=0.0009). By contrast, 16α-hydroxylation pathway EMs were slightly higher in carriers and significantly so for 17-epiestriol (P=0.002). ...
The oral anticoagulant acenocoumarol is given as a racemic mixture. The (S)-enantiomer is rapidly cleared and is the reason why only (R)-acenocoumarol contributes to the pharmacological effect. The objective of the study was to establish the cytochrome P450 (CYP) enzymes catalyzing the hydroxylations of the acenocoumarol enantiomers. Of various cDNA-expressed human CYPs, only CYP2C9 hydroxylated (S)-acenocoumarol. Hydroxylation occurred at the 6-, 7-, and 8-position with equal Km values and a ratio of 0.9:1:0.1 for Vmax. CYP2C9 also mediated the 6-, 7-, and 8-hydroxylations of (R)-acenocoumarol with Km values three to four times and Vmax values one-sixth times those of (S)-acenocoumarol. (R)Acenocoumarol was also metabolized by CYP1A2 (6-hydroxylation) and CYP2C19 (6-, 7-, and 8-hydroxylation). In human liver microsomes one enzyme only catalyzed (S)-acenocoumarol hydroxylations with Km values | 1 mM. In most of the samples tested the 7-hydroxylation of (R)-acenocoumarol was also catalyzed by one enzyme
The catalytic activity of highvalent iron-oxo active species of heme enzymes is known to be dependent on the nature of the axial ligand trans to the iron-oxo group. In a similar fashion, experimental studies on iron-oxo porphyrin biomimetic systems have shown a significant axial ligand effect on ethylbenzene hydroxylation, with an axial acetonitrile ligand leading to phenyl hydroxylation products and an axial chloride anion giving predominantly benzyl hydroxylation products. To elucidate the fundamental factors that distinguish this regioselectivity reversal in iron-oxo porphyrin catalysis, we have performed a series of density functional theory calculations on the hydroxylation of ethylbenzene by [FeIV=O(Por+)L] (Por = porphyrin; L = NCCH3 or Cl-), which affords 1-phenylethanol and p-ethylphenol products. The calculations confirm the experimentally determined product distributions. Furthermore, a detailed analysis of the electronic differences between the two oxidants shows that their reversed ...
Nimetazepam is distributed more rapidly in the brain than its desmethyl derivative (nitrazepam). The brain concentration of the active metabolites of the former is about twice that of Nitrazepam at 1-hour after oral administration. At least four kinds of reactions is involved in the biotransformation of nimetazepam and its desmethyl derivative (nitrazepam) (demethylation at N-1,hydroxylation at C-3, reduction of the nitro group at C-7 to the amino group and subsequent acetylation of the amino group. The 1-N-demethylation of nimetazepam is slow compared with the other three reactions. Nimetazepam is rapidly hydroxylated at C-3, while the 3-hydroxylation of its desmethyl derivative (nitrazepam) is very slow. The reduction of the nitro group at C-7 and subsequent acetylation are important routes for the excretion of these drugs ...
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1b) solavetivol + NADPH + H+ + O2 = solavetivone + NADP+ + 2 H2O. For diagram of reaction click here.. Glossary: ( )-premnaspirodiene = ( )-vetispiradiene. Other name(s): HPO; Hyoscymus muticus premnaspirodiene oxygenase. Systematic name: ( )-vetispiradiene,NADPH:oxygen 2α-oxidoreductase. Comments: A heme-thiolate protein (P-450). The enzyme from the plant Hyoscymus muticus also hydroxylates valencene at C-2 to give the α-hydroxy compound, nootkatol, and this is converted into nootkatone. 5-Epiaristolochene and epieremophilene are hydroxylated at C-2 to give a 2β-hydroxy derivative which is not further oxidized.. Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number: References:. 1. Takahashi, S., Yeo, Y.S., Zhao, Y., OMaille, P.E., Greenhagen, B.T., Noel, J.P., Coates, R.M. and Chappell, J. Functional characterization of premnaspirodiene oxygenase, a cytochrome P450 catalyzing regio- and stereo-specific hydroxylations of diverse sesquiterpene substrates. J. Biol. ...
This study compares the biliary and urinary metabolic profiles of 1,2-diethyl-3-hydroxypyridin-4-one (CP94), an orally active iron chelator, in the normal rat. Surprisingly, CP94 was found to form two phase II metabolites, the 3-O- and 4-O-glucuronides. These glucuronides accounted for 38 and 28% of the administered CP94 dose, in bile and urine, respectively. Unchanged CP94 accounted for 5% of the CP94 dose in both bile and urine. The 2-(1′-hydroxy) metabolite of CP94 was found to be the dominant metabolite in urine. In addition, an unstable metabolite was detected in the bile although its structure remains unknown at the present stage. The excretion of iron in bile, after administration of CP94, was found to parallel the biliary elimination of CP94 together with its hydroxylated derivatives, indicating the importance of metabolites in iron excretion.. ...
Background The fabrication of recombinant collagen and its prescribed variants has enormous potential in tissue regeneration, cell-matrix interaction investigations, and fundamental biochemical and biophysical studies of the extracellular matrix. from around 0% to 40%. The hydroxylation ideals attained by LC-MS are as accurate so when specific as those attained with the traditional approach to amino acid evaluation. Conclusions A facile, derivatization-free LC-MS method was developed that accurately determines the percentage of proline hydroxylation in different yeast expression systems. Using this assay, we decided that systems with a higher collagen-to-hydroxylase gene copy ratio yielded a lower percentage of hydroxylation, suggesting that a specifically balanced gene ratio is required to obtain higher hydroxylation levels. reported systems [5,6]. In comparison, fibrillar human being collagens from native tissues show 42C54% hydroxylation [7,8]. Given the large possible range of values, we ...
The effects of hydroxylated derivatives of vitamin D3 and aqueous extracts of Solanum malacoxylon on the intestinal absorption of calcium, phosphate, sodium, potassium and water have been studied in unstressed vitamin D-replete pigs each of which was surgically prepared beforehand with a Thirty-Vella loop of jejunum. The addition, for six 1 h periods of perfusion, of 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) or 1α-hydroxycholecalciferol at similar concentrations (3·6-3·75 pmol/ml) to the solution used to perfuse the intestinal loop caused a rapid increase in the absorption of calcium but increased the absorption of phosphate only after a delay of at least 12 h. The absorption of both calcium and phosphate reached a maximum on the day following the addition of the vitamin D derivative to the perfusate. The addition of 25-hydroxycholecalciferol (25-(OH)D3) at a concentration of 3·75 pmol/ml was without effect on absorption except for a small increase in the absorption of phosphate on the ...
The modified nucleoside 2-methylthio-N-6-isopentenyl adenosine (ms2i6A) is present at position 37 (3 of the anticodon) of tRNAs that read codons beginning with U except tRNA(I,V Ser) in Escherichia coli. Salmonella typhimurium 2-methylthio-cis-ribozeatin (ms2io6A) is found in tRNA, probably in the corresponding species that have ms2i6A in E. coli. The gene (miaE) for the tRNA(ms2io6A)hydroxylase of S. typhimurium was isolated by complementation in E. coli. The miaE gene was localized close to the argI gene at min 99 of the S. typhimurium chromosomal map. Its DNA sequence and transcription pattern together with complementation studies revealed that the miaE gene is the second gene of a dicistronic operon. Southern blot analysis showed that the miaE gene is absent in E. coli, a finding consistent with the absence of the hydroxylated derivative of ms2i6A in this species. Mutants of S. typhimurium which have MudJ inserted in the miaE gene and which, consequently, are blocked in the ms2i6A ...
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Renal Impairment: A single 20 mg oral dose of pravastatin was administered to 24 patients with varying degrees of renal impairment (as determined by creatinine clearance). No effect was observed on the pharmacokinetics of pravastatin or its 3α-hydroxy isomeric metabolite (SQ 31,906). Compared to healthy subjects with normal renal function, patients with severe renal impairment had 69% and 37% higher mean AUC and Cmax values, respectively, and a 0.61 hour shorter t½ for the inactive enzymatic ring hydroxylation metabolite (SQ 31,945). Hepatic Impairment: In a study comparing the kinetics of pravastatin in patients with biopsy confirmed cirrhosis (N=7) and normal subjects (N=7), the mean AUC varied 18-fold in cirrhotic patients and 5-fold in healthy subjects. Similarly, the peak pravastatin values varied 47-fold for cirrhotic patients compared to 6-fold for healthy subjects. Geriatric: In a single oral dose study using pravastatin 20 mg, the mean AUC for pravastatin was approximately 27% greater ...
In addition to mediating cellular responses to hypoxia, the HIF system has major functions in oxygenated cells ( 12) and can be activated by a range of nonhypoxic stimuli ( 1, 13- 15). To better understand these processes, we analyzed induction of HIF in a cell line model of monocyte/macrophage differentiation. PMA treatment of monocytic cell lines causes them to adhere, cease proliferation, and acquire characteristics of cells of the macrophage lineage ( 6, 33, 34). We show clear induction of HIF-1α in these cells, despite apparently normoxic culture conditions, and show that this is associated with lack of hydroxylation of at least one of the prolyl residues that normally target normoxic HIF-α for destruction.. PMA did not act by reducing expression of the PHD enzymes that catalyze HIF prolyl hydroxylation. Indeed, PHD2 is thought to be the predominant enzyme regulating HIF-1α levels in normoxia ( 24), especially when relatively more abundant than the other PHD enzymes ( 35), and PHD2 ...
coumarin 7-hydroxylase: CYP2A5 hyrdoxylates DHEA in at least three positions (7alpha, 7beta, and 2alpha); some enzyme preparations hydroxylate at position 3 & position 7; if cytochrome P-450coh is mutated at position 209, its substrate specificity is changed from coumarin hydroxylation (coh) to steroid hydroxylation
Squalamine, a 7,24 dihydroxylated 24-sulfated cholestane steroid conjugated to a spermidine at position C-3. This steroidal compound was initially found in tiss
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Biotinylated peptides derived from the HIF-1α oxygen-dependent degradation domain Biotin-Ahx-DLDLEALAPYIPADDDFQL or a hydroxylated control peptide Biotin-Ahx-DLDLEALAP[OH]YIPADDDFQL are immobilized on streptavidin-coated microplate. Tissue samples are homogenized in our tissue extraction buffer. Supernatants of the tissue homogenates are mixed with proprietary reaction buffer and incubated in the microplate. Peptide hydroxylation is recognized by a rabbit antibody specific for HIF-1α [Hydroxy Pro564] peptide, and detected with a donkey anti-rabbit HRP-conjugated secondary antibody. Upon the addition of the TMB substrate, the intensity of color is proportional to the activity of PHD2 in the samples. Positive and negative controls allow for assay quality assurance ...
Although bafilomycin induced HIF-1α levels under normoxic conditions, it has little effect on the expressions of HIF-1 targeted genes. This effect of bafilomycin on HIF-1α could be suspected of the factor-inhibiting HIF (FIH). In the absence of a hypoxic signal, HIF-1α can be inactivated by FIH. FIH hydroxylates an asparagine residue (Asn803) within the transactivation domain of HIF-1α, which blocks its recruitment of p300 coactivator (Lando et al., 2002). Moreover, under hypoxic conditions, asparagine hydroxylation is inhibited due to limited oxygen, and HIF-1α remains unmodified and activated. This seems to be one of the reasons why HIF-1α induced by bafilomycin has little transcriptional activity; similarly, HIF-1α induced by heat shock was found to have no transcriptional activity (Katschinski et al., 2002). However, HIF-1α induced by bafilomycin induced p21 transcription. Recently, Koshiji et al. (2004) demonstrated the mechanism of p21 induction by HIF-1α (i.e., c-Myc represses ...
Effects of NR1I2 TGT and CYP2B6*6 on induction of bupropion hydroxylation by SF.Individual profiles showing AUC_hyd/AUC_bup ratios for the basal and SF-induced
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Voltaren SR 75 mg and Voltaren Retard 100 mg: Judged by urinary recovery of unchanged diclofenac and its hydroxylated metabolites, the same amount of diclofenac ...
Das DECHEMA-Forschungsinstitut betreibt interdisziplinäre Forschung für nachhaltige Technologien auf den Themen Werkstoff- und Korrosionsforschung, chemische Technik, Elektrochemie und Biotechnologie
TY - JOUR. T1 - Simultaneous determination of phencyclidine and monohydroxylated metabolites in urine of man by gas chromatography-mass fragmentography with methane chemical ionization. AU - Cone, Edward J.. AU - Buchwald, William. AU - Yousefnejad, David. PY - 1981/5/8. Y1 - 1981/5/8. N2 - Phencyclidine and monohydroxy metabolites were measured in human urine using gas chromatography-mass fragmentography with methane chemical ionization. Samples were extracted either untreated or following acid hydrolysis, derivatized with heptafluorobutyric anhydride, separated on a 3% SE-30 column and analyzed by mass fragmentography. The assay was sensitive to ca. 0.01 μg/ml for phencyclidine and ca. 0.05 μg/ml for the metabolites. Urine samples from five human subjects enrolled in a methadone maintenance program who had ingested phencyclidine were analyzed. The phencyclidine concentration ranged from 0.3 to 23.7 μg/ml. The concentrations of metabolites ranged from 0 to 1.8 μg/ml. A new monohydroxy ...