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: EC:3.2.1.31 (beta-glucuronidase)
7,680 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When bone is cultured in acidic medium produced by a reduced bicarbonate concentration ([HCO(3-)]), a model of metabolic acidosis, there is greater net calcium efflux than when the same decrement in pH is produced by an increased partial pressure of carbon dioxide (PCO2), a model of respiratory acidosis. To determine the effects of metabolic and respiratory acidosis on bone cell function we cultured neonatal mouse calvariae for 48 h under control conditions (pH approximately 7.40, PCO2 approximately 41 mmHg, [HCO(3-)] approximately 25 meq/l) or under isohydric acidic conditions simulating metabolic (pH approximately 7.09, [HCO(3-)] approximately 12) or respiratory (pH approximately 7.10, PCO2 approximately 86) acidosis and measured osteoblastic collagen synthesis and alkaline phosphatase activity and osteoclastic beta-glucuronidase activity. Collagen synthesis was inhibited by metabolic (23.2 +/- 1.3 vs. 30.3 +/- 1.0% in control) but was not altered by respiratory (32.3 +/- 0.6) acidosis. Alkaline phosphatase activity was inhibited by metabolic (402 +/- 16 vs. 471 +/- 15 nmol P.min-1.mg protein-1 in control) but not altered by respiratory (437 +/- 25) acidosis. beta-Glucuronidase activity was stimulated by metabolic (1.02 +/- 0.06 vs. 0.78 +/- 0.05 micrograms phenolphthalein released.bone-1.h-1 in control) but not altered by respiratory (0.73 +/- 0.06) acidosis. Net calcium efflux in control was increased by metabolic (783 +/- 57 vs. 20 +/- 57 nmol.bone-1.48 h-1 in control) and by respiratory (213 +/- 45) acidosis; however, calcium efflux with metabolic was greater than with respiratory acidosis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stimulated osteoclastic and suppressed osteoblastic activity in metabolic but not respiratory acidosis. 784 Jan 63

The four component proteins of the glycine decarboxylase multienzyme complex (the P-, H-, T-, and L-proteins) comprise over one-third of the soluble proteins in mitochondria isolated from the leaves of C3 plants. Together with serine hydroxymethyltransferase, glycine decarboxylase converts glycine to serine and is the site of photorespiratory CO2 and NH3 release. The component proteins of the complex are encoded on nuclear genes with N-terminal presequences that target them to the mitochondria. The isolated complex readily dissociates into its component proteins and reassociates into the intact complex in vitro. Because of the intimate association between photosynthesis and photorespiration, the proteins of the complex are present at higher levels in leaves in the light. The expression of these genes is controlled at the transcriptional level and the kinetics of expression are closely related to those of the small subunit of Rubisco. Deletion analysis of fusions between the promoter of the H-protein of the complex and the reporter gene beta-glucuronidase in transgenic tobacco has identified a region responsible for the tissue specificity and light dependence of gene expression. Gel shift experiments show that a nuclear protein in leaves binds to this region. Glycine decarboxylase has proven to be an excellent system for studying problems in plant biochemistry ranging from protein-protein interactions to control of gene expression.
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PMID:Glycine decarboxylase: protein chemistry and molecular biology of the major protein in leaf mitochondria. 859 76

The design and synthesis of the mustard pro-prodrugs which can be used in ADEPT is reported. Prodrugs 1 and 2 include a glucuronide group which is connected to the drug via an aromatic and/or aliphatic bis-carbamate spacer. The design of these new prodrugs takes advantage of a spontaneous 1,6-elimination and/or an intramolecular cyclization reaction after enzymatic cleavage. Thus, enzymatic-catalyzed hydrolysis of the glucuronyl moiety of 1 by Escherichia coli beta-glucuronidase results in the liberation of the parent mustard drug 20 with formation of CO2, 2-nitro-4-hydroxymethylphenol 19 and dimethylimidazolidinone 21. Surprisingly, prodrug 2 was not cleaved under the same conditions. According to in vitro experiments, prodrugs 1 and 2 were approximately 50- and 80-fold less cytotoxic than the parent drug and, when treated with beta-glucuronidase, the level of cytotoxic activity of 1 became comparable to that of the drug. Stability of 1 in phosphate buffer was satisfactory. These results demonstrate that 1 is a prodrug that can be specifically activated to release the cytotoxic agent.
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PMID:Synthesis of self-immolative glucuronide-based prodrugs of a phenol mustard. 1033 72

A bacterial ethylene-forming enzyme (EFE) catalyzes oxygenation of 2-oxoglutarate to produce ethylene and carbon dioxide in contrast to a plant enzyme which uses 1-aminocyclopropane-1-carboxylic acid as a substrate. We constructed several lines of transgenic tobacco plants which expressed an EFE from Pseudomonas syringae pv. phaseolicola PK2. The gene encoding a chimeric protein consisting of EFE and beta-glucuronidase (GUS) was introduced into the tobacco genome using a binary vector which directs expression of the EFE-GUS fusion protein under the control of constitutive promoter of cauliflower mosaic virus 35S RNA. Two lines of transgenic plants produced ethylene at consistently higher rates than the untransformed plant, and their GUS activities were expressed in different tissues. A significant dwarf morphology observed in the transgenic tobacco displaying the highest ethylene production resembled the phenotype of a wild-type plant exposed to excess ethylene. These results demonstrate a potential use of bacterial EFE to supply ethylene as a hormonal signal via an alternative route using an ubiquitous substrate 2-oxoglutarate in plant tissues.
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PMID:Ethylene formation and phenotypic analysis of transgenic tobacco plants expressing a bacterial ethylene-forming enzyme. 1080 96

Due to their unique structure and function, guard cells have attracted much attention at the physiological level. Very little, however, is known about the molecular events involved in the determination and maintenance of guard cell specificity. The KST1 gene encodes a K+ influx channel of guard cells in potato, and was therefore chosen as a model to study regulation of guard cell-specific gene expression. Transgenic potato plants carrying a fusion between the KST1 promoter and the E. coli uidA (beta-glucuronidase) reporter gene revealed promoter activity in guard cells and in flowers. A detailed dissection of the KST1 promoter led to the discovery of two independent small TATA box-proximal regulatory units, each of which was sufficient to direct guard cell-specific gene transcription. Both fragments contain the sequence motif, 5'-TAAAG-3', which is related to known target sites for a novel class of zinc finger transcription factors, called Dof proteins. Block mutagenesis of these Dof target sites in the context of different promoter constructs dramatically reduced guard cell promoter activity. A Dof gene, StDof1, was cloned and shown to be expressed in epidermal fragments highly enriched for guard cells. In gel retardation experiments, the StDof1 protein interacted in a sequence-specific manner with a KST1 promoter fragment containing the TAAAG motif. These results provide evidence that TAAAG elements are target sites for trans-acting Dof proteins controlling guard cell-specific gene expression. Our data will add to the design of tailor-made guard cell promoters as a further tool in molecular engineering of guard cell function and, hence, control of stomatal carbon dioxide (CO2) uptake and water loss in crop plants.
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PMID:Involvement of TAAAG elements suggests a role for Dof transcription factors in guard cell-specific gene expression. 1173 82

Talc ore may contain several other minerals including calcite, dolomite, magnesite, tremolite, anthophyllite, antigorite, quartz, pyrophyllite, micas, or chlorites. Talc products are sold in a multitude of grades which have physical or functional characteristics especially suited for particular applications, so occupational and consumer exposures to talc are complex. Epidemiology studies have suggested an association between non-fibrous talc and lung cancer risk. Talc was nominated by the National Institute of Occupational Safety and Health (NIOSH) for study by the NTP because of widespread human exposure and because of the lack of adequate information on its chronic toxicity and potential carcinogenicity. Toxicology and carcinogenicity studies of talc (non-asbestiform, cosmetic grade), a finely powdered hydrous magnesium silicate, were conducted by exposing groups of F344/N rats to aerosols for 6 hours per day, 5 days per week for up to 113 weeks (males) or 122 weeks (females). Groups of B6C3F1 mice were exposed similarly for up to 104 weeks. LIFETIME STUDY IN RATS: Groups of 49 or 50 male and 50 female rats were exposed to aerosols of 0, 6, or 18 mg/m(3) talc until mortality in any exposure group reached 80% (113 weeks for males and 122 weeks for females). These exposures were selected based on 4-week inhalation studies of the terminal lung talc burden in F344/N rats; concentrations greater than 18 mg/m(3) were expected to overwhelm lung clearance mechanisms and impair lung function. These exposure concentrations provided a dose equivalent of 0, 2.8, or 8.4 mg/kg per day for male rats and 0, 3.2, or 9.6 mg/kg per day for female rats. In a special study, additional groups of 22 male and 22 female rats were similarly exposed and examined for interim pathology evaluations or pulmonary function tests after 6, 11, 18, and 24 months and lung biochemistry and cytology studies after 24 months. The talc aerosols had a median mass aerodynamic diameter of 2.7 mm in the 6 mg/m(3) chamber and a median diameter of 3.2 mm in the 18 mg/m(3) chamber, with geometric standard deviations of 1.9 mm. However, there was a 7-week period beginning at study week 11 during which the chamber concentration for the 18 mg/m(3) rats varied from approximately 30 to 40 mg/m(3) because of difficulties with the aerosol concentration monitoring system. Further, there was a 12-week period beginning at approximately week 70 during which there were difficulties in generating the talc aerosol, and the chamber concentrations for rats and mice were substantially lower than the target concentrations. Survival, Body Weights, and Clinical Findings: The survival of male and female rats exposed to talc was similar to that of the controls. Mean body weights of rats exposed to 18 mg/m(3) were slightly lower than those of controls after week 65. No clinical findings were attributed to talc exposure. Pathology Findings: Absolute and relative lung weights of male rats exposed to 18 mg/m(3) were significantly greater than those of controls at the 6-, 11-, and 18-month interim evaluations and at the end of the lifetime study, while those of female rats exposed to 18 mg/m(3) were significantly greater at the 11-, 18-, and 24-month interim evaluations and at the end of the lifetime study. Inhalation exposure of rats to talc produced a spectrum of inflammatory, reparative, and proliferative processes in the lungs. Granulomatous inflammation occurred in nearly all exposed rats and the severity increased with exposure duration and concentration. Hyperplasia of the alveolar epithelium and interstitial fibrosis occurred in or near foci of inflammation in many exposed rats, while squamous metaplasia of the alveolar epithelium and squamous cysts were also occasionally seen. Accumulations of macrophages (histiocytes), most containing talc particles, were found in the peribronchial lymphoid tissue of the lung and in the bronchial and mediastinal Iymph nodes. In female rats, the incidences of alveolar/bronchiolar adenoma, carcinoma, and adenoma or carcinoma (combined) in the 18 mg/m(8 mg/m(3) group were significantly greater than those of controls. The incidences of pulmonary neoplasms in exposed male rats were similar to those in controls. Minor alterations attributed to talc exposure were also observed in the upper respiratory tract. Hyperplasia of the respiratory epithelium of the nasal mucosa in males and accumulation of cytoplasmic, eosinophilic droplets in the nasal mucosal epithelium in male and female rats occurred with a concentration-related increased incidence in the exposed groups. Adrenal medulla pheochromocytomas [benign, malignant, or complex (combined)] occurred with a significant positive trend in male and female rats, and the incidences in the 18 mg/m(3) groups were significantly greater than those of controls. Although adrenal medulla hyperplasia occurred with similar frequency among exposed and control females, the incidences of hyperplasia in exposed males were significantly lower than in controls. Lung Talc Burden: Lung talc burdens of male and female rats exposed to 6 mg/m(3) were similar and increased progressively from 6 to 24 months. Lung talc burdens of females exposed to 18 mg/m(3) also increased progressively from 6 to 24 months, while those of males exposed to 18 mg/m(3) remained about the same after 18 months. Lung burdens were generally proportional to exposure concentration at each interim evaluation. Pulmonary Function, Bronchoalveolar Lavage, and Lung Biochemistry: In exposed male and female rats there was a concentration-related impairment of respiratory function which increased in severity with increasing exposure duration. The impairment was characterized by reductions in lung volume (total lung capacity, vital capacity, and forced vital capacity), lung compliance, gas exchange efficiency (carbon monoxide diffusing capacity), and nonuniform intrapulmonary gas distribution. After 24 months, males exposed to 6 mg/m(3) talc had a significant increase in beta-glucuronidase and polymorphonuclear leukocytes; males exposed 18 mg/m(3) had significant increases in b -glucuronidase, lactate dehydrogenase, alkaline phosphatase, and total protein in bronchoalveolar lavage fluid. All exposed females had significantly increased a-glucuronidase, lactate dehydrogenase, alkaline phosphatase, total protein, and polymorphonuclear leukocytes; 18 mg/m(3) females also had significantly increased glutathione reductase. Viability and phagocytic activity of macrophages recovered from lavage fluid were not affected by talc exposure. Total lung collagen was significantly increased in rats at both exposure concentrations after 24 months, while collagenous peptides in lavage fluid and the percentages of newly synthesized protein from females, but not males, were also significantly increased at the 6 or 18 mg/m(3) levels. In addition, lung proteinase activity, primarily cathepsin D-like activity, was significantly greater in exposed males and females. Rats exposed to talc also had significant increases in collagenous peptides and acid proteinase in lung homogenates. 2-YEAR STUDY IN MICE: Groups of 47 to 49 male and 48 to 50 female mice were exposed to aerosols containing 0, 6, or 18 mg/m(3) talc for up to 104 weeks. These exposures were selected based on 4-week inhalation studies of the terminal lung talc burden in B6C3F1 mice; concentrations greater than 18 mg/m(3) were expected to overwhelm lung clearance mechanisms and impair lung function. These exposure concentrations provide a dose equivalent of 0, 2, or 6 mg/kg per day for male mice and 0, 1.3, or 3.9 mg/kg per day for female mice. In a special study, additional groups of 39 or 40 male and 39 or 40 female mice similarly exposed were examined for interim pathology evaluations, lung biochemistry, and cytology studies after 6, 12, and 18 months of exposure. The talc aerosols had a median mass aerodynamic diameter of 3.3 mm with a geometric standard deviation of 1.9 mm in the 6 mg/m(3) chamber, and a median diameter of 3.6 mm with a geometric standard deviation of 2.0 mm in the 18 mg/m(3) chamber. Further, there was a 12-week period beginning at approximately week 70 during which there were difficulties in generating the talc aerosol, and the chamber concentrations for rats and mice were substantially lower than the target concentrations. Survival, Body Weights, and Clinical Findings: Survival and final mean body weights of male and female mice exposed to talc were similar to those of the controls. There were no clinical findings attributed to talc exposure. Pathology Findings: Inhalation exposure of mice to talc was associated with chronic active inflammation and the accumulation of macrophages in the lung. In contrast to rats, hyperplasia of the alveolar epithelium, squamous metaplasia, or interstitial fibrosis were not associated with the inflammatory response in mice, and the incidences of pulmonary neoplasms in exposed and control groups of mice were similar. Accumulations of macrophages (histiocytes) containing talc particles were also present in the bronchial Iymph node. In the upper respiratory tract, cytoplasmic alteration, consisting of the accumulation of cytoplasmic eosinophilic droplets in the nasal mucosal epithelium, occurred with a concentration-related increased incidence in exposed male and female mice. Lung Talc Burden: Lung talc burdens of mice exposed to 6 mg/m(3) were similar between males and females and increased progressively from 6 to 24 months, except for males at 18 months. The lung talc burdens of mice exposed to 18 mg/m(3) were also similar between the sexes at each interim evaluation. Although the talc burdens of males and females increased substantially from 6 to 24 months, the values at 12 and 18 months were similar. Generally, lung burdens of mice exposed to 18 mg/m(3) were disproportionately greater than those of mice exposed to 6 mg/m(3), suggesting that clearance of talc from the lung was impaired, or impaired to a greater extent, in mice exposed to 18 mg/m(3) than in mice exposed to 6 mg/m(3). Bronchoalveolar Lavage and Lung Biochemistry: Increases in total protein, beta-glucuronidase, lactate dehydrogenase, glutathione reductase, total nucleated cells, and polymorphonuclear leukocytes in bronchoalveolar lavage fluid were observed primarily in mice exposed to 18 mg/m(3), although some parameters were also increased in mice exposed to 6 mg/m(3). The amount of collagenous peptides in lavage fluid and total lung collagen were increased in male and female mice exposed to 18 mg/m(3). Acid proteinase activity, principally cathepsin D-like activity, of lung homogenate supernatant fluid was also significantly increased in mice at the 18 mg/m(3) exposure concentration. CONCLUSIONS: Under the conditions of these inhalation studies, there was some evidence of carcinogenic activity of talc in male F344/N rats based on an increased incidence of benign or malignant pheochromocytomas of the adrenal gland. There was clear evidence of carcinogenic activity of talc in female F344/N rats based on increased incidences of alveolar/bronchiolar adenomas and carcinomas of the lung and benign or malignant pheochromocytomas of the adrenal gland. There was no evidence of carcinogenic activity of talc in male or female B6C3F1 mice exposed to 6 or 18 mg/m(3). The principal toxic lesions associated with inhalation exposure to the same concentrations of talc in rats included chronic granulomatous inflammation, alveolar epithelial hyperplasia, squamous metaplasia and squamous cysts, and interstitial fibrosis of the lung. These lesions were accompanied by impaired pulmonary function characterized primarily by reduced lung volumes, reduced dynamic and/or quasistatic lung compliance, reduced gas exchange efficiency, and nonuniform intrapulmonary gas distribution. In mice, inhalation exposure to talc produced chronic inflammation of the lung with the accumulation of alveolar macrophages. Synonyms: talcum; agalite; emtal 596; non-asbestiform talc; non-fibrous talc; steatite; hydrous magnesium silicate
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PMID:NTP Toxicology and Carcinogenesis Studies of Talc (CAS No. 14807-96-6)(Non-Asbestiform) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1261 90

ActS-ActR proteins belong to a highly conserved family of two-component signal transduction systems involved in global regulation in the alpha-proteobacteria; they were first identified in Sinorhizobium medicae (previously Sinorhizobium meliloti) as essential for acid-tolerance. This paper reports on the identification of genes regulated by ActS and/or ActR in S. medicae. To do this, random gusA fusions were created in S. medicae to follow gene transcription in an actS chromosomal knockout mutant containing plasmid-borne actS. Plasmid borne actS was cured from the mutants and beta-glucuronidase (GUS) activity compared between the different genetic backgrounds. We detected actS-dependent regulation of the genes gst1 (detoxification), hyuA (hydantoin utilization) and fixN2 (microaerobic respiration). We show that ActR is involved in regulating cbbS (CO2 fixation), narB (nitrate assimilation) and required for low pH and microaerobic induction of the nitrogen fixation regulators fixK and nifA. In particular, we demonstrate that the transcriptional activation of fixN2 is regulated by ActR through FixK.
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PMID:Sinorhizobium medicae genes whose regulation involves the ActS and/or ActR signal transduction proteins. 1521 86

The absorption, metabolism, and excretion of N-[3-fluoro-4-[2-(propylamino)ethoxy]phenyl]-4,5,6,7-tetrahydro-4-oxo-1H-indole-3-carboxamide monomethanesulfonate (1), a GABAA receptor partial agonist potentially useful in treating generalized anxiety disorder, have been evaluated in both Sprague-Dawley rats and cynomolgus monkeys using [14C]1. In both species, mass balance was achieved within 48 h postdose, with the majority of drug-related material excreted within the feces; the clearance of 1 in each species had both metabolic and renal components. In addition to the metabolites produced by aliphatic hydroxylation and/or N-dealkylation of 1, two unique metabolites were detected: a putative carbamic acid (M7) in rat plasma and monkey bile, and an N-carbamoyl glucuronide (M8) in both rat and monkey bile. Metabolite M8 was structurally deciphered by liquid chromatographytandem mass spectrometry and NMR, and was readily generated in vitro upon incubation of [14C]1 with rat liver microsomes fortified with uridine 5'-diphosphoglucuronic acid trisodium salt and alamethicin under a CO2 atmosphere. Treatment of M8 with beta-glucuronidase afforded 1 directly. The presence of M8 in bile and its notable absence from other matrices suggests the enterohepatic cycling of 1 via M8. Although the structure of M7 was not elucidated unequivocally due to its inability to be formed in vitro and its minimal absolute quantities in limited biological matrices, data herein clearly support its structural rationalization. Furthermore, since M7 is the precursor of M8, detection of M8 is indirect evidence of its existence. It is proposed that M7 arises from an equilibrium between 1 and dissolved CO2-equivalents both in vivo and in vitro, similar to carbamino bonds observed in hemoglobin and certain amino acids, respectively.
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PMID:Biotransformation of a GABAA receptor partial agonist in sprague-dawley rats and cynomolgus monkeys: identification of two unique N-carbamoyl metabolites. 1608 72

Mitochondrial serine hydroxymethyltransferase (SHMT), combined with glycine decarboxylase, catalyzes an essential sequence of the photorespiratory C2 cycle, namely, the conversion of two molecules of glycine into one molecule each of CO2, NH4+, and serine. The Arabidopsis (Arabidopsis thaliana) mutant shm (now designated shm1-1) is defective in mitochondrial SHMT activity and displays a lethal photorespiratory phenotype when grown at ambient CO2, but is virtually unaffected at elevated CO2. The Arabidopsis genome harbors seven putative SHM genes, two of which (SHM1 and SHM2) feature predicted mitochondrial targeting signals. We have mapped shm1-1 to the position of the SHM1 gene (At4g37930). The mutation is due to a G --> A transition at the 5' splice site of intron 6 of SHM1, causing aberrant splicing and a premature termination of translation. A T-DNA insertion allele of SHM1, shm1-2, and the F1 progeny of a genetic cross between shm1-1 and shm1-2 displayed the same conditional lethal phenotype as shm1-1. Expression of wild-type SHM1 under the control of either the cauliflower mosaic virus 35S or the SHM1 promoter in shm1-1 abrogated the photorespiratory phenotype of the shm mutant, whereas overexpression of SHM2 or expression of SHM1 under the control of the SHM2 promoter did not rescue the mutant phenotype. Promoter-beta-glucuronidase analyses revealed that SHM1 is predominantly expressed in leaves, whereas SHM2 is mainly transcribed in the shoot apical meristem and roots. Our findings establish SHM1 as the defective gene in the Arabidopsis shm1-1 mutant.
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PMID:The photorespiratory Arabidopsis shm1 mutant is deficient in SHM1. 1633 99

Land plants must balance CO2 assimilation with transpiration in order to minimize drought stress and maximize their reproductive success. The ratio of assimilation to transpiration is called transpiration efficiency (TE). TE is under genetic control, although only one specific gene, ERECTA, has been shown to regulate TE. We have found that the alpha-subunit of the heterotrimeric G protein in Arabidopsis (Arabidopsis thaliana), GPA1, is a regulator of TE. gpa1 mutants, despite having guard cells that are hyposensitive to abscisic acid-induced inhibition of stomatal opening, have increased TE under ample water and drought stress conditions and when treated with exogenous abscisic acid. Leaf-level gas-exchange analysis shows that gpa1 mutants have wild-type assimilation versus internal CO2 concentration responses but exhibit reduced stomatal conductance compared with ecotype Columbia at ambient and below-ambient internal CO2 concentrations. The increased TE and reduced whole leaf stomatal conductance of gpa1 can be primarily attributed to stomatal density, which is reduced in gpa1 mutants. GPA1 regulates stomatal density via the control of epidermal cell size and stomata formation. GPA1 promoter::beta-glucuronidase lines indicate that the GPA1 promoter is active in the stomatal cell lineage, further supporting a function for GPA1 in stomatal development in true leaves.
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PMID:The alpha-subunit of the Arabidopsis heterotrimeric G protein, GPA1, is a regulator of transpiration efficiency. 2020 73


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