- OleD Loki as a Catalyst for Tertiary Amine and Hydroxamate Glycosylation
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We describe the ability of an engineered glycosyltransferase (OleD Loki) to catalyze the N-glycosylation of tertiary-amine-containing drugs and trichostatin hydroxamate glycosyl ester formation. As such, this study highlights the first bacterial model catalyst for tertiary-amine N-glycosylation and further expands the substrate scope and synthetic potential of engineered OleDs. In addition, this work could open the door to the discovery of similar capabilities among other permissive bacterial glycosyltransferases.
- Hughes, Ryan R.,Shaaban, Khaled A.,Zhang, Jianjun,Cao, Hongnan,Phillips, George N.,Thorson, Jon S.
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- Glycyrrhetinic acid exhibits strong inhibitory effects towards UDP-glucuronosyltransferase (UGT) 1A3 and 2B7
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The aim of the present study is to evaluate the inhibitory effects of liver UDP-glucuronosyltransferases (UGTs) by glycyrrhizic acid and glycyrrhetinic acid, which are the bioactive ingredients isolated from licorice. The results showed that glycyrrhetini
- Huang, Yin-Peng,Cao, Yun-Feng,Fang, Zhong-Ze,Zhang, Yan-Yan,Hu, Cui-Min,Sun, Xiao-Yu,Yu, Zhen-Wen,Zhu, Xu,Hong, Mo,Yang, Lu,Sun, Hong-Zhi
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- The Novel UDP Glycosyltransferase 3A2: Cloning, catalytic properties, and tissue distribution
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The human UDP glycosyltransferase (UGT) 3A family is one of three families involved in the metabolism of small lipophilic compounds. Members of these families catalyze the addition of sugar residues to chemicals, which enhances their excretion from the body. The UGT1 and UGT2 family members primarily use UDP glucuronic acid to glucuronidate numerous compounds, such as steroids, bile acids, and therapeutic drugs. We showed recently that UGT3A1, the first member of the UGT3 family to be characterized, is unusual in using UDP N-acetylglucosamine as sugar donor, rather than UDP glucuronic acid or other UDP sugar nucleotides (J Biol Chem 283:36205-36210, 2008). Here, we report the cloning, expression, and characterization of UGT3A2, the second member of the UGT3 family. Like UGT3A1, UGT3A2 is inactive with UDP glucuronic acid as sugar donor. However, in contrast to UGT3A1, UGT3A2 uses both UDP glucose and UDP xylose but not UDP N-acetylglucosamine to glycosidate a broad range of substrates including 4-methylumbelliferone, 1-hydroxypyrene, bioflavones, and estrogens. It has low activity toward bile acids and androgens. UGT3A2 transcripts are found in the thymus, testis, and kidney but are barely detectable in the liver and gastrointestinal tract. The low expression of UGT3A2 in the latter, which are the main organs of drug metabolism, suggests that UGT3A2 has a more selective role in protecting the organs in which it is expressed against toxic insult rather than a more generalized role in drug metabolism. The broad substrate and novel UDP sugar specificity of UGT3A2 would be advantageous for such a function. Copyright
- MacKenzie, Peter I.,Rogers, Anne,Elliot, David J.,Chau, Nuy,Hulin, Julie-Ann,Miners, John O.,Meech, Robyn
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- Molecular cloning and biochemical characterization of a new coumarin glycosyltransferase CtUGT1 from Cistanche tubulosa
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UDP-glycosyltransferases (UGTs) are an important and functionally diverse family of enzymes involved in secondary metabolite biosynthesis. Coumarin is one of the most common skeletons of natural products with candidate pharmacological activities. However, to date, many reported GTs from plants mainly recognized flavonoids as sugar acceptors. Only limited GTs could catalyze the glycosylation of coumarins. In this study, a new UGT was cloned from Cistanche tubulosa, a valuable traditional tonic Chinese herb, which is abundant with diverse glycosides such as phenylethanoid glycosides, lignan glycosides, and iridoid glycosides. Sequence alignment and phylogenetic analysis showed that CtUGT1 is phylogenetically distant from most of the reported flavonoid UGTs and adjacent to phenylpropanoid UGTs. Extensive in vitro enzyme assays found that although CtUGT1 was not involved in the biosynthesis of bioactive glycosides in C. tubulosa, it could catalyze the glucosylation of coumarins umbelliferone 1, esculetine 2, and hymecromone 3 in considerable yield. The glycosylated products were identified by comparison with the reference standards or NMR spectroscopy, and the results indicated that CtUGT1 can regiospecifically catalyze the glucosylation of hydroxyl coumarins at the C7-OH position. The key residues that determined CtUGT1's activity were further discussed based on homology modeling and molecular docking analyses. Combined with site-directed mutagenesis results, it was found that H19 played an irreplaceable role as the crucial catalysis basis. CtUGT1 could be used in the enzymatic preparation of bioactive coumarin glycosides.
- Xu, Xiping,Yan, Yaru,Huang, Wenqian,Mo, Ting,Wang, Xiaohui,Wang, Juan,Li, Jun,Shi, Shepo,Liu, Xiao,Tu, Pengfei
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- Solvent-Dependent Mechanism and Stereochemistry of Mitsunobu Glycosylation with Unprotected Pyranoses
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An SN2 mechanism was proposed for highly stereoselective glycosylation of benzoic acid with unprotected α-d-glucose under Mitsunobu conditions in dioxane, while an SN1 mechanism was indicated for nonstereoselective glycosylation in DMF. The SN2-type stereoselective Mitsunobu glycosylation is generally applicable to various unprotected pyranoses as glycosyl donors in combination with a wide range of acidic glycosyl acceptors such as carboxylic acids, phenols, and imides, retaining its high stereoselectivity (33 examples). Glycosylation of a carboxylic acid with unprotected α-d-mannose proceeded also in an SN2 manner to directly afford a usually less accessible 1,2-cis-mannoside. One-or two-step total syntheses of five simple natural glycosides were performed using the glycosylation strategy presented here using unprotected α-d-glucose.
- Fujimori, Yusuke,Furuta, Takumi,Kawabata, Takeo,Nagaishi, Masaru,Sasamori, Takahiro,Shibayama, Hiromitsu,Takeuchi, Hironori,Tokitoh, Norihiro,Ueda, Yoshihiro,Yoshimura, Tomoyuki
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supporting information
(2020/06/29)
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- Based on 4 - methyl [...] synthesis method of a plurality of glycoside
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The invention discloses a method for synthesizing various glucosides on a basis of 4-methylumbelliferone. According to the invention, a glycosyl donor peracetyl saccharide and a glycosyl acceptor 4-methylumbelliferone are subjected to a glycosylation reaction under room temperature or under heating with dichloromethane or 1,2-dichloroethane as a solvent and with the combined effect of Lewis acid boron trifluoride ethyl ether and organic alkali triethylamine or pyridine; and protecting groups are removed, such that various glucosides based on 4-methylumbelliferone can be obtained. The glucosides include 4-methylumbelliferone-beta-D-glucopyranosiduronide, 4-methylumbelliferone-beta-D-glucopyranoside, 4-methylumbelliferone-beta-D-xylopyranoside, 4-methylumbelliferone-beta-D-ribofuranoside, 4-methylumbelliferone-alpha-D-galactopyranoside, and 4-methylumbelliferone-alpha-D-mannopyranoside. The method is simple, and can produce a beta or alpha single-configuration target. A glycosylation reaction yield can reach 17-93%.
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Paragraph 0080; 0081
(2018/10/11)
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- Glucosyltransferase Capable of Catalyzing the Last Step in Neoandrographolide Biosynthesis
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ApUGT, a diterpene glycosyltransferase from Andrographis paniculata, could transfer a glucose to the C-19 hydroxyl moiety of andrograpanin to form neoandrographolide. This glycosyltransferase has a broad substrate scope, and it can glycosylate 26 natural and unnatural compounds of different structural types. This study provides a basis for exploring the glycosylation mechanism of ent-labdane-type diterpenes and plays an important role in diversifying the structures used in drug discovery.
- Li, Yuan,Lin, Hui-Xin,Wang, Jian,Yang, Jian,Lai, Chang-Jiang-Sheng,Wang, Xing,Ma, Bao-Wei,Tang, Jin-Fu,Li, Yong,Li, Xin-Lin,Guo, Juan,Gao, Wei,Huang, Lu-Qi
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supporting information
p. 5999 - 6002
(2018/10/20)
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- Stereocontrolled Synthesis of Phenolic α-d-Glycopyranosides
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Adopting the ‘remote activation concept’ toward stereocontrolled glycoside synthesis with minimal use of protection groups, a general synthesis of phenolic 1,2-cis glycopyranosides is reported, as exemplified by aryl α-d-galacto-, α-d-gluco- and 2-azido α-d-glucopyranosides among others using glycosyl donors bearing an anomeric (3-bromo-2-pyridyloxy) group and catalyzed by methyl triflate.
- St-Pierre, Gabrielle,Dafik, Laila,Klegraf, Ellen,Hanessian, Stephen
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supporting information
p. 3575 - 3588
(2016/10/17)
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- An improved helferich method for the α/β-stereoselective synthesis of 4-methylumbelliferyl glycosides for the detection of microorganisms
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An improved Helferich method is presented. It involves the glycosylation of 4-methyl-umbelliferone with glycosyl acetates in the presence of boron trifluoride etherate combined with triethylamine, pyridine, or 4-dimethylaminopyridine under mild conditions, followed by deprotection to give fluorogenic 4-methylumbelliferyl glycoside substrates. Due to the use of base, the glycosylation reaction proceeds more easily, is uncommonly α- or β-stereoselective, and affords the corresponding products in moderate to excellent yields (51%-94%) under appropriate conditions.
- Wei, Xianhu,Ma, Yanxia,Wu, Qingping,Zhang, Jumei,Cai, Zhihe,Lu, Mianfei,Ferro, Vito
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p. 21681 - 21699
(2016/01/25)
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- Exploring the catalytic promiscuity of a new glycosyltransferase from Carthamus tinctorius
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The catalytic promiscuity of a new glycosyltransferase (UGT73AE1) from Carthamus tinctorius was explored. UGT73AE1 showed the capability to glucosylate a total of 19 structurally diverse types of acceptors and to generate O-, S-, and N-glycosides, making it the first reported trifunctional plant glycosyltransferase. The catalytic reversibility and regioselectivity were observed and modeled in a one-pot reaction transferring a glucose moiety from icariin to emodin. These findings demonstrate the potential versatility of UGT73AE1 in the glycosylation of bioactive natural products.
- Xie, Kebo,Ridao, Chen,Li, Jianhua,Wang, Ruishan,Chen, Dawei,Dou, Xiaoxiang,Dai, Jungui
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supporting information
p. 4874 - 4877
(2015/04/27)
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- CARBONIC ANHYDRASE INHIBITORS WITH ANTIMETASTATIC ACTIVITY
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Compositions for the treatment of cancer comprising coumarin and thiocoumarin derivatives of Formulas I- XII are disclosed. Said derivatives preferentially inhibit carbonic anhydrase IX and XII (which are associated with hypoxic and metastatic tumours) over inhibiting carbonic anhydrase I and II activity. The compositions therefore are suited for treatment of hypoxic or metastatic cancers due to this selective mechanism of action.
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Page/Page column 22-29
(2012/06/15)
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- Glycosyl coumarin carbonic anhydrase IX and XII inhibitors strongly attenuate the growth of primary breast tumors
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A series of 7-substituted coumarins incorporating various glycosyl moieties were synthesized and investigated for the inhibition of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). These coumarins were very weak or ineffective as inhibitors of the housekeeping, offtarget isoforms CA I and II, but some of them inhibited tumor-associated CA IX and XII in the low nanomolar range. They also significantly inhibited the growth of primary tumors by the highly aggressive 4T1 syngeneic mouse mammary tumor cells at 30 mg/kg, constituting interesting candidates for the development of conceptually novel anticancer drugs. Because CA IX is overexpressed in hypoxic tumors and exhibits very limited expression in normal tissues, such compounds may be useful for treating cancers not responsive to classic chemo- and radiotherapy.
- Touisni, Nadia,Maresca, Alfonso,McDonald, Paul C.,Lou, Yuanmei,Scozzafava, Andrea,Dedhar, Shoukat,Winum, Jean-Yves,Supuran, Claudiu T.
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p. 8271 - 8277
(2012/02/06)
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- Enzymatic synthesis of 4-methylumbelliferyl (1→3)-β-D-glucooligosaccharides - New substrates for β-1,3-1,4-D-glucanase
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The transglycosylation reactions catalyzed by β-1,3-D-glucanases (laminaranases) were used to synthesize a number of 4-methylumbelliferyl (MeUmb) (1→3)-β-D-gluco-oligosaccharides having the common structure [β-D-Glcp-(1→3)]n-β-D-Glcp-MeUmb, where n=1-5. The β-1,3-D-glucanases used were purified from the culture liquid of Oerskovia sp. and from a homogenate of the marine mollusc Spisula sachalinensis. Laminaran and curdlan were used as (1→3)-β-D-glucan donor substrates, while MeUmb-β-D-glucoside (MeUmbGlcp) was employed as a transglycosylation acceptor. Modification of [β-D-Glcp-(1→3)]2-β-D-Glcp-MeUmb (MeUmbG3) gives 4,6-O-benzylidene-D-glucopyranosyl or 4,6-O-ethylidene-D-glucopyranosyl groups at the non-reducing end of artificial oligosaccharides. The structures of all oligosaccharides obtained were solved by 1H and 13C NMR spectroscopy and electrospray tandem mass spectrometry. The synthetic oligosaccharides were shown to be substrates for a β-1,3-1,4-D-glucanase from Rhodothermus marinus, which releases MeUmb from β-di- and β-triglucosides and from acetal-protected β-triglucosides. When acting upon substrates with d.p.>3, the enzyme exhibits an endolytic activity, primarily cleaving off MeUmbGlcp and MeUmbG2.
- Borriss, Rainer,Krah, Martin,Brumer III, Harry,Kerzhner, Maxim A.,Ivanen, Dina R.,Eneyskaya, Elena V.,Elyakova, Lyudmila A.,Shishlyannikov, Sergei M.,Shabalin, Konstantin A.,Neustroev, Kirill N.
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p. 1455 - 1467
(2007/10/03)
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- Synthesis of 4-methylumbelliferyl-β-D-glucan oligosaccharides as specific chromophoric substrates of (1 -> 3),(1 -> 4)-β-D-glucan 4-glucanohydrolases
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Keywords: β-D-Glucan oligosaccharides; 4-Methylumbelliferyl glycosides; β-Glucanase substrates; NMR data
- Malet, Carles,Viladot, Josep Lluis,Ochoa, Ana,Gallego, Belen,Brosa, Carme,Planas, Antoni
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p. 285 - 302
(2007/10/02)
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