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H. N. Kirkman - One of the best experts on this subject based on the ideXlab platform.
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Measurements of Uridine Diphosphate glucose and Uridine Diphosphate galactose--an appraisal.
European journal of pediatrics, 1995Co-Authors: H. N. KirkmanAbstract:The recent disproof of a major deficiency of Uridine Diphosphate galactose in galactosemia should not lead investigators to assume either that enzymatic methods are unreliable for Uridine sugar assays or that a defect in galactosylation in galactosemia has been excluded.
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Erythrocytic Uridine Diphosphate galactose in galactosaemia
Journal of Inherited Metabolic Disease, 1992Co-Authors: H. N. KirkmanAbstract:An earlier claim of a deficiency of Uridine Diphosphate galactose in erythrocytes of galactosaemia patients was not confirmed. Enzymic techniques similar to those of the earlier investigators were used to determine not only the concentration of Uridine Diphosphate galactose but also the ratio of this concentration to the sum of the Uridine sugar Diphosphates (Uridine Diphosphate galactose and Uridine Diphosphate glucose). The values in erythrocytes of galactosaemic subjects were similar to those of non-galactosaemic children on a galactose-restricted diet and to those of normal adults. These results cast doubt on the claim of a major deficiency of Uridine Diphosphate galactose in galactosaemia and on the need for treating galactosaemic children with Uridine.
Philip M. Rosoff - One of the best experts on this subject based on the ideXlab platform.
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myelodysplasia and deficiency of Uridine Diphosphate galactose 4 epimerase
The Journal of Pediatrics, 1995Co-Authors: Philip M. RosoffAbstract:A 4-year-old girl known to have peripheral Uridine Diphosphate-galactose 4-epimerase deficiency was examined for bruising and thrombocytopenia. She had dysplastic peripheral blood and bone marrow changes, with a global platelet function defect. Uridine Diphosphate-galactose-4-epimerase participates in a metabolic pathway that provides substrates for posttranslational glycosylation of secreted and membrane glycoproteins, including hematopoietic growth factors and their receptors; there may be a causal relationship between the two disorders.
Zhengtao Wang - One of the best experts on this subject based on the ideXlab platform.
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Biosynthesis of rare 20(R)-protopanaxadiol/protopanaxatriol type ginsenosides through Escherichia coli engineered with Uridine Diphosphate glycosyltransferase genes
Elsevier, 2019Co-Authors: Yuan Chen, Li Yang, Jie Shi, Rufeng Wang, Yingbo Yang, Shujuan Zhao, Zhengtao WangAbstract:Background: Ginsenosides are known as the principal pharmacological active constituents in Panax medicinal plants such as Asian ginseng, American ginseng, and Notoginseng. Some ginsenosides, especially the 20(R) isomers, are found in trace amounts in natural sources and are difficult to chemically synthesize. The present study provides an approach to produce such trace ginsenosides applying biotransformation through Escherichia coli modified with relevant genes. Methods: Seven Uridine Diphosphate glycosyltransferase (UGT) genes originating from Panax notoginseng, Medicago sativa, and Bacillus subtilis were synthesized or cloned and constructed into pETM6, an ePathBrick vector, which were then introduced into E. coli BL21star (DE3) separately. 20(R)-Protopanaxadiol (PPD), 20(R)-protopanaxatriol (PPT), and 20(R)-type ginsenosides were used as substrates for biotransformation with recombinant E. coli modified with those UGT genes. Results: E. coli engineered with GT95syn selectively transfers a glucose moiety to the C20 hydroxyl of 20(R)-PPD and 20(R)-PPT to produce 20(R)-CK and 20(R)-F1, respectively. GTK1- and GTC1-modified E. coli glycosylated the C3OH of 20(R)-PPD to form 20(R)-Rh2. Moreover, E. coli containing p2GT95synK1, a recreated two-step glycosylation pathway via the ePathBrich, implemented the successive glycosylation at C20OH and C3OH of 20(R)-PPD and yielded 20(R)-F2 in the biotransformation broth. Conclusion: This study demonstrates that rare 20(R)-ginsenosides can be produced through E. coli engineered with UTG genes. Keywords: biosynthesis, 20(R)-ginsenosides, ginsenoside, UDP-glycosyltransferas
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biosynthesis of rare 20 r protopanaxadiol protopanaxatriol type ginsenosides through escherichia coli engineered with Uridine Diphosphate glycosyltransferase genes
Journal of Ginseng Research, 2017Co-Authors: Li Yang, Zhengtao Wang, Yuan Chen, Rufeng Wang, Yingbo Yang, Shujuan Zhao, Lu YuAbstract:Abstract Background Ginsenosides are known as the principal pharmacological active constituents in Panax medicinal plants such as Asian ginseng, American ginseng, and Notoginseng. Some ginsenosides, especially the 20( R ) isomers, are found in trace amounts in natural sources and are difficult to chemically synthesize. The present study provides an approach to produce such trace ginsenosides applying biotransformation through Escherichia coli modified with relevant genes. Methods Seven Uridine Diphosphate glycosyltransferase (UGT) genes originating from Panax notoginseng , Medicago sativa , and Bacillus subtilis were synthesized or cloned and constructed into pETM6, an ePathBrick vector, which were then introduced into E. coli BL21star (DE3) separately. 20( R )-Protopanaxadiol (PPD), 20( R )-protopanaxatriol (PPT), and 20( R )-type ginsenosides were used as substrates for biotransformation with recombinant E. coli modified with those UGT genes. Results E. coli engineered with GT95 syn selectively transfers a glucose moiety to the C20 hydroxyl of 20( R )-PPD and 20( R )-PPT to produce 20( R )-CK and 20( R )-F1, respectively. GTK1- and GTC1 -modified E. coli glycosylated the C3OH of 20( R )-PPD to form 20( R )-Rh2. Moreover, E. coli containing p2GT95 syn K1, a recreated two-step glycosylation pathway via the ePathBrich, implemented the successive glycosylation at C20OH and C3OH of 20( R )-PPD and yielded 20( R )-F2 in the biotransformation broth. Conclusion This study demonstrates that rare 20( R )-ginsenosides can be produced through E. coli engineered with UTG genes.
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characterization of nuciferine metabolism by p450 enzymes and Uridine Diphosphate glucuronosyltransferases in liver microsomes from humans and animals
Acta Pharmacologica Sinica, 2010Co-Authors: Miao Wang, Li Zhang, Li Yang, Zhengtao WangAbstract:Characterization of nuciferine metabolism by P450 enzymes and Uridine Diphosphate glucuronosyltransferases in liver microsomes from humans and animals
Peter I. Mackenzie - One of the best experts on this subject based on the ideXlab platform.
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coexpression of human hepatic Uridine Diphosphate glucuronosyltransferase proteins implications for ontogenetic mechanisms and isoform coregulation
The Journal of Clinical Pharmacology, 2020Co-Authors: Yuejian Liu, Peter I. Mackenzie, Michael W H Coughtrie, Justine Badee, Ryan H Takahashi, Stephan Schmidt, Neil Parrott, Stephen Fowler, Abby C CollierAbstract:Uridine Diphosphate glucuronosyltransferases (UGTs) catalyze glucuronidation to facilitate systemic and local clearance of numerous chemicals and drugs. To investigate whether UGT expression is coregulated in human liver, we analyzed the protein expression of UGTs 1A1, 1A3, 1A4, 1A6, 1A9, 2B7, 3A1, and 3A2 using western blots from 164 healthy human liver samples, comparing expression with age and sex. UGT1A6 levels were significantly higher in children than adults, and UGT3A1 and 3A2 expression significantly increased with age from childhood to age >65 yearas. In children aged 18 years. UGT1A3 expression was always significantly correlated with other UGT1A isoforms in all adults aged >18 years. In individuals aged ≥12 years, expression of UGT1A1/1A4, UGT1A1/1A6, UGT1A1/1A9, and UGT1A4/1A6 significantly correlated, which was not observed in children aged <12 years. In contrast, UGT1A4/2B7 showed significant correlation in children aged <12 years, but not in individuals aged ≥12 years, and this was observed in female but not male individuals. Expression of UGT1A6/1A9 and UGT3A1/3A2 correlated in the entire sample population, but UGT3As did not correlate with other UGTs. These correlations were sex dependent, as UGT1A3/1A1, UGT1A4/2B7 and UGT3A1/3A2 correlated more highly in male than female individuals, while UGT1A4/1A6 protein correlated more significantly in female than male individuals. This is the first report on the ontogeny of UGT3A isoforms, showing maximal expression in the elderly, and is the first demonstration that UGT isoforms commonly coexpress in vivo, in both age-dependent and sex-dependent manners.
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identification of Uridine Diphosphate glucuronosyltransferases involved in the metabolism and clearance of mycophenolic acid
Therapeutic Drug Monitoring, 2000Co-Authors: Peter I. MackenzieAbstract:Mycophenolic acid, the active metabolite of the immunosuppressant and antiproliferative agent, mycophenolate mofetil, is primarily metabolized by glucuronidation to the inactive 7-O-glucuronide. Although the Uridine Diphosphate (UDP) 7-O-glucuronide is the principal excretion product of this drug, carboxyl-linked glucuronides have also been detected in vitro and in vivo. To identify human UDP glucuronosyltransferases that are active in the glucuronidation of mycophenolic acid, cDNAs encoding individual UDP glucuronosyltransferase forms have been expressed in cell culture, and the capacity of the expressed enzymes to use mycophenolic acid as a substrate has been assessed. Two UDP glucuronosyltransferase forms, UGT1A8 and UGT1A10, were active in the glucuronidation of mycophenolic acid. Both enzymes are predominantly expressed in the gastrointestinal tract and hence, may play a role in the metabolism of mycophenolic acid in the gastrointestinal tract and in the acquisition of resistance to the mito-inhibitory effects of this drug in cultured human colorectal carcinoma cell lines. The identities of the UDP glucuronosyltransferase forms that are mainly responsible for the glucuronidation of mycophenolic acid in the liver and kidney remain unknown; however, UGT1A9 may be important in this respect as the cDNA-expressed enzyme has some capacity to glucuronidate mycophenolic acid. Other UGT1A forms in the liver and kidney (UGT1A1, UGT1A3, UGT1A4, and UGT1A6) were inactive toward mycophenolic acid.
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structure and function of Uridine Diphosphate glucuronosyltransferases
Clinical and Experimental Pharmacology and Physiology, 1997Co-Authors: Robyn Meech, Peter I. MackenzieAbstract:1. The Uridine Diphosphate (UDP)-glucuronosyltransferases (UGT) are a family of enzymes that catalyse the covalent addition of glucuronic acid to a wide range of lipophilic chemicals. They play a major role in the detoxification of many exogenous and endogenous compounds by generating products that are more polar and, thus, more readily excreted in bile or urine. 2. Inherited deficiencies in UGT forms are deleterious, as exemplified by the debilitating effects of hyperbilirubinaemia and neurotoxicity in subjects with mutations in the enzyme that converts bilirubin to its more polar glucuronide. 3. The UGT protein can be conceptually divided into two domains with the amino-terminal half of the protein demonstrating greater sequence divergence between isoforms. This region apparently determines aglycone specificity. The aglycone binding site is presumed to be a 'loose' fit, as many structurally diverse substrates can be bound by the same UGT isoform. The carboxyl-terminal half, which is more conserved in sequence between different isoforms, is believed to contain a binding site for the cosubstrate UDP glucuronic acid (UDPGA). 4. Uridine Diphosphate glucuronosyltransferase is localized to the endoplasmic reticulum (ER) and spans the membrane with a type I topology. The putative transmembrane domain is located near the carboxyl terminus of the protein such that only a small portion of the protein resides in the cytosol. This cytosolic tail is believed to contain an ER-targeting signal. The major portion of the protein is located in the ER lumen, including the proposed substrate-binding domains and the catalytic site. 5. The microsomal membrane impedes the access of UDPGA to the active site, resulting in latency of UGT activity in intact ER-derived microsomes. Active transport of UDPGA is believed to occur in hepatocytes, but the transport system has not been fully characterized. Uridine Diphosphate glucuronosyltransferase activity is also highly lipid dependent and the enzyme may contain regions of membrane association in addition to the transmembrane domain.
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Complementary deoxyribonucleic acid cloning and expression of a human liver Uridine Diphosphate-glucuronosyltransferase glucuronidating carboxylic acid-containing drugs.
The Journal of pharmacology and experimental therapeutics, 1993Co-Authors: Chunjing Jin, John O Miners, K J Lillywhite, Peter I. MackenzieAbstract:A cDNA clone, designated UGT2B7 variant, encoding a 529-amino acid human liver microsomal Uridine Diphosphate-glucuronosyltransferase (UGT) was isolated from a lambda gt11 human liver cDNA library. UGT2B7 variant synthesized in COS-7 cells was screened for activity toward a range of clinically used drugs and other xenobiotics. The expressed enzyme glucuronidated several carboxylic acid-containing nonsteroidal antiinflammatory agents including, in order of relative substrate activity, naproxen, ketoprofen, ibuprofen, fenoprofen, tiaprofenic acid, benoxprofen, zomepirac, diflunisal and indomethacin. Additionally, the stereoselectivity of ketoprofen, naproxen (S/R ratio approximately unity) and ibuprofen (S/R ratio 1.62) glucuronidation by the UGT2B7 variant was shown to differ. Two other carboxylic acid-containing drugs (clofibric acid and valproic acid) and a limited range of drugs containing an alcohol or phenolic functional group were also glucoronidated by expressed UGT2B7 variant. The deduced amino sequence of UGT2B7 variant was shown to differ only in one amino acid (tyrosine for histidine at position 268) from a previously published Uridine Diphosphate-glucuronosyltransferase cDNA, UGT2B7. Like the previously reported enzyme, this variant efficiently glucuronidated hyodeoxycholic acid, estriol, 4-hydroxyestrone and 2-hydroxyestriol. It is, therefore, apparent that UGT2B7 variant has the capacity to glucuronidate with a degree of specificity both endogenous compounds and xenobiotics. Preferred substrates for UGT2B7 variant include xenobiotic carboxylic acids, polyhydroxylated estrogens and hyodeoxycholic acid.
Ying Liu - One of the best experts on this subject based on the ideXlab platform.
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a systematic review of the Uridine Diphosphate galactose glucose 4 epimerase uge in plants
Plant Growth Regulation, 2021Co-Authors: Jiaming Hou, Shaokai Tian, Lin Yang, Zhixin Zhang, Ying LiuAbstract:Uridine Diphosphate (UDP)-Galactose/Glucose-4-epimerase (UGE) is the third enzyme involved in the Leloir pathway. It catalyzes the conversion of UDP-Galactose to UDP-Glucose, which is a rate-limiting step for polysaccharides biosynthesis. As the main cell wall materials, polysaccharides play an irreplaceable role throughout the whole life history of plant. In this review, 1243 UGE mRNA sequences registered in NCBI were obtained and their evolutionary relationship was analyzed by constructing a neighbor-joining tree based on representative sequences. The physicochemical properties of 15 specific UGEs were analyzed, and four UGE sequences of Setaria italica, Zea mays, Ricinus Communis, and Oryza sativa were selected for further secondary structure, three-dimensional protein modeling, transmembrane structure, and signal peptide prediction analyses. The results demonstrate that UGEs are mostly conservative without signal peptides and exert activities in cytoplasm. Then, studies related to the catalytic reaction, characteristic structure, function, and regulation of UGE were summarized, which provide strong evidence that UGE plays a crucial role in cell growth, cell differentiation, cell-to-cell communication, primary metabolism, secondary metabolism, and defense responses. However, the molecular mechanisms whereby UGE regulates the plant stress resistance and useful secondary metabolites accumulation are far from clear. This paper will lay a foundation for further studies and applications of UGE.
