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)

Pyruvate, orthophosphate dikinase is a key enzyme in photosynthesis in some plants that exploit the C4 photosynthetic pathway for the fixation of CO2. The gene for this enzyme has been cloned and its primary structure has been analyzed. The sequence of the cloned genes spans about 12 kilobase pairs and consists of 19 exons. The site of initiation of transcription is located 211 nucleotides upstream from the first nucleotide of the initiation codon (position -211). Typical TATA and inverted CCAAT elements are present in the anticipated regions, as well as a sequence that is homologous to the binding site of Sp-1 protein (-51 to -42). Three long, direct-repeated sequences are present contiguously in the 5'-flanking region (-286 to -172), and two of the repeated sequences include sequences homologous to the core sequence of SV40 enhancer in the 3'-end portions. Southern blot analysis, coupled with mapping by analysis of restriction fragment length polymorphism, indicates that the gene for the enzyme involved in C4 photosynthesis is encoded by a single-copy gene and is located on chromosome 6. To test the promoter activity of the isolated gene, a chimeric gene composed of the 5'-flanking region of the gene and a structural gene for bacterial beta-glucuronidase was constructed and introduced into tobacco protoplasts by electroporation or used to transform tobacco plants by Agrobacterium-mediated transfer of the gene. In both cases, expression of the beta-glucuronidase gene was observed, indicating that the 5'-flanking region of the gene can act as a promoter in tobacco cells.
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PMID:Structure, genetic mapping, and expression of the gene for pyruvate, orthophosphate dikinase from maize. 217 Mar 54

In the dog, the major excretory metabolite of the antidepressant sertraline was characterized as sertraline carbamoyl-O-glucuronide. The intact conjugate was isolated from bile by HPLC. The metabolite was labile to beta-glucuronidase and produced sertraline as the single hydrolytic product, based on HPLC and GC-MS analyses. By fast atom bombardment MS analysis, [M+H]+ and [M+Na]+ ions at m/z 526 and 548 were observed, as were the proton and sodium adducts of the aglycone (m/z 350 and 372) due to cleavage of the glycosidic bond and elimination of the glucuronic acid moiety (176 amu). The observed mass of the aglycone was 44 amu greater than sertraline, indicating that a carbamic acid of this secondary amine was conjugated with glucuronic acid. These data suggest that sertraline in solution reversibly associates with CO2 before formation of sertraline carbamoyl-O-glucuronide. This novel amine glucuronide was also identified in human plasma after the oral administration of sertraline to each of seven subjects. The glucuronide was stable in plasma at both acidic and basic pH.
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PMID:Characterization of a carbamic acid ester glucuronide of the secondary amine sertraline. 256 71

Studies on the activity of the glucuronic acid pathway in alloxan diabetic rabbits were carried out. Amount of D-glucaric acid, L-ascorbic acid, and D-glucuronic acid in urine increased in the case of the alloxan diabetic rabbits. The transformation from D-glucuronolactone to D-glucaric acid was higher than normal in the diabetic animals. The expired 14-CO2 decreased and urinary excretion of labeled L-gulonic acid increased after administration of 6-14-C-glucuronolactone in the diabetic rabbits. L-Gulonic acid dehydrogenase, lactonase II, and beta-glucuronidase activities were reduced, and UDPGA-pyrophosphatase, D-glucuronic acid-1-phosphatase, and UDPGA-transferase activities increased in the diabetic rabbit liver. From these results, it may be concluded that an increase of endogenous D-glucuronic acid in the diabetic states could be attributed to a metabolid defect in the step of L-gulonic acid dehydrogenation and to the enhancement of UDPGA-pyrophosphatase and D-glucuronic acid-1-phosphate phosphatase activities.
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PMID:Glucuronic acid pathway in alloxan diabetic rabbits. (I). Urinary excretion of metabolites related to the glucuronic acid pathway. 446 73

Glycine decarboxylase is a mitochondrial enzyme complex, which is the site of photorespiratory CO2 and NH3 release. Although the proteins that constitute the complex are located within the mitochondria, because of their intimate association with photosynthesis their expression is controlled by light. Comparisons of the kinetics of mRNA accumulation between the small subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase and the H-protein of glycine decarboxylase during the greening of etiolated Arabidopsis thaliana suggest that their expression is controlled in parallel. A genomic clone for the H-protein (gdcH) was isolated from Arabidopsis and sequenced. The upstream region from -856 to +62 was fused to the beta-glucuronidase (GUS) reporter gene, and this construct was transformed into tobacco. This 5' upstream regulatory region appears to control GUS expression in a manner very similar to that of the endogenous H-protein gene. Constructs with deletions in the 5' upstream region were transformed into tobacco. These deletions revealed that light-dependent and tissue-specific expression was largely controlled by a 259-bp region between -376 and -117 bp. This region contains several putative GT boxes with the GGTTAA consensus core sequence. Once these strong light-dependent elements were removed, a second level of control was revealed. In constructs in which the gdcH 5' regulatory region was shortened to -117 bp or less, there was more GUS activity in the roots than in the leaves, and in dark-grown plants than in light-grown plants. This suggests that more proximal control elements may be responsible for the constitutive low levels of gene expression noted in all nonphotosynthetic tissues.
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PMID:Light-dependent and tissue-specific expression of the H-protein of the glycine decarboxylase complex. 748 Mar 20

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

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

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


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