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Tomas Hudlicky - One of the best experts on this subject based on the ideXlab platform.
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microbial oxidation of aromatics in enantiocontrolled synthesis 2 rational design of aza sugars endo nitrogenous total synthesis of Kifunensine mannojirimycin and other glycosidase inhibitors
Journal of the American Chemical Society, 1994Co-Authors: Tomas Hudlicky, Jacques Rouden, Hector Luna, Scott E. AllenAbstract:A general method of synthesis for lactones and lactams related to carbohydrates has been developed that relies on the biocatalyticgeneration of 1-chloro-2,3-dihydroxycyclohexa-4,6-diene (l), obtained in excellent yield by fermentation of chlorobenzene with Pseudomonasputida 39D, followed by further functionalization to nitrogen-substituted cyclitols. These amino or azido cyclitols of type 15 are then subjected to controlled ozonolysis, which yields either lactones such as 27 or lactams containing five-membered (28) or six-membered (20 and 23) rings. Such compounds are useful intermediates for the preparation of aza sugars. Mannojirimycin (84 has been synthesized in seven steps from chlorobenzene. Kifunensine (7) has been prepared in 11 steps from chlorobenzene following an intersection with Hashimoto's procedure. Full experimental and spectral details are provided for all compounds. The potential of this general method and implications of the disclosed design features in the field of amino sugar and aza sugar synthesis are indicated.
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Enantioselective synthesis of alkaloids and carbohydrates via chemoenzymatic methods
Pure and Applied Chemistry, 1994Co-Authors: Tomas HudlickyAbstract:Homochiral diene diols of type 1, derived biocatalytically by microbial dioxygenation of halogenated aromatic compounds, have served as precursors to a number of oxygenated natural products. Specifically, D-chiro-inositol (9), D- erythuronolactone (lo), (+)-lycoricidine (14), (+)-Kifunensine (19), and L-threo- sphingosine (25) have all been synthesized from 1.
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Microbial oxidation of aromatics in enantiocontrolled synthesis. 2. Rational design of aza sugars (endo-nitrogenous). Total synthesis of +-Kifunensine, mannojirimycin, and other glycosidase inhibitors.
Journal of the American Chemical Society, 1994Co-Authors: Tomas Hudlicky, Jacques Rouden, Hector Luna, Scott E. AllenAbstract:A general method of synthesis for lactones and lactams related to carbohydrates has been developed that relies on the biocatalyticgeneration of 1-chloro-2,3-dihydroxycyclohexa-4,6-diene (l), obtained in excellent yield by fermentation of chlorobenzene with Pseudomonasputida 39D, followed by further functionalization to nitrogen-substituted cyclitols. These amino or azido cyclitols of type 15 are then subjected to controlled ozonolysis, which yields either lactones such as 27 or lactams containing five-membered (28) or six-membered (20 and 23) rings. Such compounds are useful intermediates for the preparation of aza sugars. Mannojirimycin (84 has been synthesized in seven steps from chlorobenzene. Kifunensine (7) has been prepared in 11 steps from chlorobenzene following an intersection with Hashimoto's procedure. Full experimental and spectral details are provided for all compounds. The potential of this general method and implications of the disclosed design features in the field of amino sugar and aza sugar synthesis are indicated.
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Total synthesis of (+)-Kifunensine, a potent glycosidase inhibitor
Journal of the Chemical Society Perkin Transactions 1, 1993Co-Authors: Jacques Rouden, Tomas HudlickyAbstract:(+)-Kifunensine, a potent inhibitor of mannosidase I, has been synthesized in 13 steps from chlorobenzene by microbial oxygenation with Pseudomonas putida 39D and stereocontrolled peripheral functionalization of cis-3-chlorocyclohexa-3,5-dienediol 3.
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total synthesis of Kifunensine a potent glycosidase inhibitor
Journal of The Chemical Society-perkin Transactions 1, 1993Co-Authors: Jacques Rouden, Tomas HudlickyAbstract:(+)-Kifunensine, a potent inhibitor of mannosidase I, has been synthesized in 13 steps from chlorobenzene by microbial oxygenation with Pseudomonas putida 39D and stereocontrolled peripheral functionalization of cis-3-chlorocyclohexa-3,5-dienediol 3.
Nektarios Barabutis - One of the best experts on this subject based on the ideXlab platform.
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Involvement of the unfolded protein response in the protective effects of growth hormone releasing hormone antagonists in the lungs
Journal of Cell Communication and Signaling, 2020Co-Authors: Mohammad S. Akhter, Khadeja-tul Kubra, Mohammad A. Uddin, Andrew V. Schally, Nektarios BarabutisAbstract:Growth hormone releasing hormone (GHRH) antagonists enhance endothelial barrier function and counteract the LPS-induced lung endothelial hyperpermeability, the cardinal feature of the acute respiratory distress syndrome (ARDS). The unfolded protein response (UPR) is a multifaceted molecular mechanism, strongly involved in tissue defense against injury. The current study introduces the induction of UPR by GHRH antagonists, since those peptides induced several UPR activation markers, including the inositol-requiring enzyme-1α (IRE1α), the protein kinase RNA-like ER kinase (PERK), and the activating transcription factor 6 (ATF6). On the other hand, the GHRH agonist MR-409 exerted the opposite effects. Furthermore, GHRH antagonists counteracted the Kifunensine (UPR suppressor)-induced lung endothelial barrier dysfunction. Our observations suggest that UPR mediates, at least in part, the protective effects of GHRH antagonists in the lung microvasculature. To the best of our knowledge; this is the first study to provide experimental evidence in support of the hypothesis that UPR induction is a novel mechanism by which GHRH antagonists oppose severe human disease, including ARDS.
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Luminespib counteracts the Kifunensine-induced lung endothelial barrier dysfunction
Current research in toxicology, 2020Co-Authors: Khadeja-tul Kubra, Mohammad A. Uddin, Mohammad S. Akhter, Nektarios BarabutisAbstract:Abstract Unfolded protein response (UPR) suppression by Kifunensine has been associated with lung hyperpermeability, the hallmark of Acute Respiratory Distress Syndrome. The present study investigates the effects of the heat shock protein 90 inhibitor Luminespib (AUY-922) towards the Kifunensine-triggered lung endothelial dysfunction. Our results indicate that the UPR inducer Luminespib counteracts the effects of Kifunensine in both human and bovine lung endothelial cells. Hence, we suggest that mild UPR induction may serve as a promising therapeutic strategy against potentially lethal respiratory disorders, including the ARDS related to COVID-19.
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Unfolded protein response regulates P53 expression in the pulmonary endothelium.
Journal of biochemical and molecular toxicology, 2019Co-Authors: Mohammad S. Akhter, Mohammad A. Uddin, Nektarios BarabutisAbstract:Lung endothelial barrier dysfunction leads to severe pathologies, including the lethal Acute Respiratory Distress Syndrome. P53 has been associated with anti-inflammatory activities. The current study employs a variety of unfolded protein response (UPR) activators and inhibitors to investigate the regulation of P53 by UPR in lung cells. The bovine cells that were exposed to the UPR inductors brefeldin A, dithiothreitol, and thapsigargin; demonstrated elevated expression levels of P53 compared to the vehicle-treated cells. On the contrary, the UPR inhibitors N-acetyl cysteine, Kifunensine, and ATP-competitive IRE1α kinase-inhibiting RNase attenuator; produced the opposite effects. The outcomes of the present study reveal a positive regulation between UPR and P53. Since it has been shown that a mild induction of the unfolded protein response opposes inflammation, we suggest that P53 is involved in those protective activities in the lung.
Karen A. Mcdonald - One of the best experts on this subject based on the ideXlab platform.
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Effects of Kifunensine on Production and N-Glycosylation Modification of Butyrylcholinesterase in a Transgenic Rice Cell Culture Bioreactor.
International journal of molecular sciences, 2020Co-Authors: Kantharakorn Macharoen, Somen Nandi, Carlito B Lebrilla, Veronica A. Márquez-escobar, Jasmine M. Corbin, Karen A. McdonaldAbstract:The production and N-glycosylation of recombinant human butyrylcholinesterase (BChE), a model highly glycosylated therapeutic protein, in a transgenic rice cell suspension culture treated with Kifunensine, a strong α-mannosidase I inhibitor, was studied in a 5 L bioreactor. A media exchange was performed at day 7 of cultivation by removing spent sugar-rich medium (NB+S) and adding fresh sugar-free (NB-S) medium to induce the rice α-amylase 3D (RAmy3D) promoter to produce rice recombinant human BChE (rrBChE). Using a 1.25X-concentrated sugar-free medium together with an 80% reduced working volume during the media exchange led to a total active rrBChE production level of 79 ± 2 µg (g FW)−1 or 7.5 ± 0.4 mg L−1 in the presence of Kifunensine, which was 1.5-times higher than our previous bioreactor runs using normal sugar-free (NB-S) media with no Kifunensine treatment. Importantly, the amount of secreted active rrBChE in culture medium was enhanced in the presence of Kifunensine, comprising 44% of the total active rrBChE at day 5 following induction. Coomassie-stained SDS-PAGE gel and Western blot analyses revealed different electrophoretic migration of purified rrBChE bands with and without Kifunensine treatment, which was attributed to different N-glycoforms. N-Glycosylation analysis showed substantially increased oligomannose glycans (Man5/6/7/8) in rrBChE treated with Kifunensine compared to controls. However, the mass-transfer limitation of Kifunensine was likely the major reason for incomplete inhibition of α-mannosidase I in this bioreactor study.
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Effects of Kifunensine on Production and N-glycosylation Modification of Butyrylcholinesterase in a Transgenic Rice Cell Culture Bioreactor
2020Co-Authors: Kantharakorn Macharoen, Somen Nandi, Carlito B Lebrilla, Veronica A. Márquez-escobar, Jasmine M. Corbin, Karen A. McdonaldAbstract:The production and N-glycosylation of recombinant human butyrylcholinesterase (BChE), a model highly glycosylated therapeutic protein, in a transgenic rice cell suspension culture treated with Kifunensine, a strong α-mannosidase I inhibitor, was studied in a 5 L bioreactor. A media exchange was performed at day 7 of cultivation by removing spent sugar rich media (NB+S) and adding fresh sugar free (NB-S) media to induce the rice α-amylase 3D (RAmy3D) promoter to produce rice recombinant human BChE (rrBChE). Using a 1.25X concentrated sugar-free medium together with an 80% reduced working volume during the media exchange lead to a total active rrBChE production level of 79 ± 2 µg (g FW)-1 or 7.5 ± 0.4 mg L-1 in the presence of Kifunensine, which is 1.5-times higher than our previous bioreactor runs using normal sugar free medium with no Kifunensine treatment. Importantly, the amount of secreted active rrBChE in culture medium was enhanced in the presence of Kifunensine, comprising 44% of the total active rrBChE at day 5 post-induction. Coomassie stained SDS-PAGE gel and Western blot analyses reveal different electrophoretic migration of purified rrBChE bands with and without Kifunensine treatment, which is attributed to different N-glycoforms. N-Glycosylation analysis shows substantial increase of oligomannose glycans (Man5/6/7/8) in rrBChE treated with Kifunensine compared to controls. However, mass transfer limitation of Kifunensine is likely the major reason for incomplete inhibition of α-mannosidase I in this bioreactor study.
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In Vivo Glycan Engineering via the Mannosidase I Inhibitor (Kifunensine) Improves Efficacy of Rituximab Manufactured in Nicotiana benthamiana Plants.
International journal of molecular sciences, 2019Co-Authors: Vally Kommineni, Somen Nandi, Karen A. Mcdonald, Matthew J. Markert, Zhongjie Ren, Sreenath R. Palle, Berenice Carrillo, Jasmine Deng, Armando Tejeda, Sylvain MarcelAbstract:N-glycosylation has been shown to affect the pharmacokinetic properties of several classes of biologics, including monoclonal antibodies, blood factors, and lysosomal enzymes. In the last two decades, N-glycan engineering has been employed to achieve a N-glycosylation profile that is either more consistent or aligned with a specific improved activity (i.e., effector function or serum half-life). In particular, attention has focused on engineering processes in vivo or in vitro to alter the structure of the N-glycosylation of the Fc region of anti-cancer monoclonal antibodies in order to increase antibody-dependent cell-mediated cytotoxicity (ADCC). Here, we applied the mannosidase I inhibitor Kifunensine to the Nicotiana benthamiana transient expression platform to produce an afucosylated anti-CD20 antibody (rituximab). We determined the optimal concentration of Kifunensine used in the infiltration solution, 0.375 µM, which was sufficient to produce exclusively oligomannose glycoforms, at a concentration 14 times lower than previously published levels. The resulting afucosylated rituximab revealed a 14-fold increase in ADCC activity targeting the lymphoma cell line Wil2-S when compared with rituximab produced in the absence of Kifunensine. When applied to the cost-effective and scalable N. benthamiana transient expression platform, the use of Kifunensine allows simple in-process glycan engineering without the need for transgenic hosts.
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glycoform modification of secreted recombinant glycoproteins through Kifunensine addition during transient vacuum agroinfiltration
International Journal of Molecular Sciences, 2018Co-Authors: Yongao Xiong, Muchena J Kailemia, Somen Nandi, Qiongyu Li, Carlito B Lebrilla, Karen A. McdonaldAbstract:Kifunensine, a potent and selective inhibitor of class I α-mannosidases, prevents α-mannosidases I from trimming mannose residues on glycoproteins, thus resulting in oligomannose-type glycans. We report for the first time that through one-time vacuum infiltration of Kifunensine in plant tissue, N-linked glycosylation of a recombinant protein transiently produced in whole-plants shifted completely from complex-type to oligomannose-type. Fc-fused capillary morphogenesis protein 2 (CMG2-Fc) containing one N-glycosylation site on the Fc domain, produced in Nicotiana benthamiana whole plants, served as a model protein. The CMG2-Fc fusion protein was produced transiently through vacuum agroinfiltration, with and without Kifunensine at a concentration of 5.4 µM in the agroinfiltration suspension. The CMG2-Fc N-glycan profile was determined using LC-MS/MS with a targeted dynamic multiple reaction monitoring (MRM) method. The CMG2-Fc expression level in the infiltrated plant tissue and the percentage of oligomannose-type N-glycans for Kifunensine treated plants was 874 mg/kg leaf fresh weight (FW) and 98.2%, respectively, compared to 717 mg/kg leaf FW and 2.3% for untreated plants. Oligomannose glycans are amenable to in vitro enzymatic modification to produce more human-like N-glycan structures that are preferred for the production of HIV-1 viral vaccine and certain monoclonal antibodies. This method allows glycan modifications using a bioprocessing approach without compromising protein yield or modification of the primary sequence, and could be expanded to other small molecule inhibitors of glycan-processing enzymes. For recombinant protein targeted for secretion, Kifunensine treatment allows collection of glycoform-modified target protein from apoplast wash fluid (AWF) with minimal plant-specific complex N-glycan at higher starting purity and concentration than in whole-leaf extract, thus simplifying the downstream processing.
Carlito B Lebrilla - One of the best experts on this subject based on the ideXlab platform.
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High Mannose N-Glycans Promote Migration of Bone-Marrow-Derived Mesenchymal Stromal Cells
International journal of molecular sciences, 2020Co-Authors: Vivian Alonso-garcia, Cutter Chaboya, Timothy J. Congleton, Jose C. Florez, Victoria Tran, Gang-yu Liu, Wei Yao, Carlito B LebrillaAbstract:For hundreds of indications, mesenchymal stromal cells (MSCs) have not achieved the expected therapeutic efficacy due to an inability of the cells to reach target tissues. We show that inducing high mannose N-glycans either chemically, using the mannosidase I inhibitor Kifunensine, or genetically, using an shRNA to silence the expression of mannosidase I A1 (MAN1A1), strongly increases the motility of MSCs. We show that treatment of MSCs with Kifunensine increases cell migration toward bone fracture sites after percutaneous injection, and toward lungs after intravenous injection. Mechanistically, high mannose N-glycans reduce the contact area of cells with its substrate. Silencing MAN1A1 also makes cells softer, suggesting that an increase of high mannose N-glycoforms may change the physical properties of the cell membrane. To determine if treatment with Kifunensine is feasible for future clinical studies, we used mass spectrometry to analyze the N-glycan profile of MSCs over time and demonstrate that the effect of Kifunensine is both transitory and at the expense of specific N-glycoforms, including fucosylations. Finally, we also investigated the effect of Kifunensine on cell proliferation, differentiation, and the secretion profile of MSCs. Our results support the notion of inducing high mannose N-glycans in MSCs in order to enhance their migration potential.
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Effects of Kifunensine on Production and N-Glycosylation Modification of Butyrylcholinesterase in a Transgenic Rice Cell Culture Bioreactor.
International journal of molecular sciences, 2020Co-Authors: Kantharakorn Macharoen, Somen Nandi, Carlito B Lebrilla, Veronica A. Márquez-escobar, Jasmine M. Corbin, Karen A. McdonaldAbstract:The production and N-glycosylation of recombinant human butyrylcholinesterase (BChE), a model highly glycosylated therapeutic protein, in a transgenic rice cell suspension culture treated with Kifunensine, a strong α-mannosidase I inhibitor, was studied in a 5 L bioreactor. A media exchange was performed at day 7 of cultivation by removing spent sugar-rich medium (NB+S) and adding fresh sugar-free (NB-S) medium to induce the rice α-amylase 3D (RAmy3D) promoter to produce rice recombinant human BChE (rrBChE). Using a 1.25X-concentrated sugar-free medium together with an 80% reduced working volume during the media exchange led to a total active rrBChE production level of 79 ± 2 µg (g FW)−1 or 7.5 ± 0.4 mg L−1 in the presence of Kifunensine, which was 1.5-times higher than our previous bioreactor runs using normal sugar-free (NB-S) media with no Kifunensine treatment. Importantly, the amount of secreted active rrBChE in culture medium was enhanced in the presence of Kifunensine, comprising 44% of the total active rrBChE at day 5 following induction. Coomassie-stained SDS-PAGE gel and Western blot analyses revealed different electrophoretic migration of purified rrBChE bands with and without Kifunensine treatment, which was attributed to different N-glycoforms. N-Glycosylation analysis showed substantially increased oligomannose glycans (Man5/6/7/8) in rrBChE treated with Kifunensine compared to controls. However, the mass-transfer limitation of Kifunensine was likely the major reason for incomplete inhibition of α-mannosidase I in this bioreactor study.
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Effects of Kifunensine on Production and N-glycosylation Modification of Butyrylcholinesterase in a Transgenic Rice Cell Culture Bioreactor
2020Co-Authors: Kantharakorn Macharoen, Somen Nandi, Carlito B Lebrilla, Veronica A. Márquez-escobar, Jasmine M. Corbin, Karen A. McdonaldAbstract:The production and N-glycosylation of recombinant human butyrylcholinesterase (BChE), a model highly glycosylated therapeutic protein, in a transgenic rice cell suspension culture treated with Kifunensine, a strong α-mannosidase I inhibitor, was studied in a 5 L bioreactor. A media exchange was performed at day 7 of cultivation by removing spent sugar rich media (NB+S) and adding fresh sugar free (NB-S) media to induce the rice α-amylase 3D (RAmy3D) promoter to produce rice recombinant human BChE (rrBChE). Using a 1.25X concentrated sugar-free medium together with an 80% reduced working volume during the media exchange lead to a total active rrBChE production level of 79 ± 2 µg (g FW)-1 or 7.5 ± 0.4 mg L-1 in the presence of Kifunensine, which is 1.5-times higher than our previous bioreactor runs using normal sugar free medium with no Kifunensine treatment. Importantly, the amount of secreted active rrBChE in culture medium was enhanced in the presence of Kifunensine, comprising 44% of the total active rrBChE at day 5 post-induction. Coomassie stained SDS-PAGE gel and Western blot analyses reveal different electrophoretic migration of purified rrBChE bands with and without Kifunensine treatment, which is attributed to different N-glycoforms. N-Glycosylation analysis shows substantial increase of oligomannose glycans (Man5/6/7/8) in rrBChE treated with Kifunensine compared to controls. However, mass transfer limitation of Kifunensine is likely the major reason for incomplete inhibition of α-mannosidase I in this bioreactor study.
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glycoform modification of secreted recombinant glycoproteins through Kifunensine addition during transient vacuum agroinfiltration
International Journal of Molecular Sciences, 2018Co-Authors: Yongao Xiong, Muchena J Kailemia, Somen Nandi, Qiongyu Li, Carlito B Lebrilla, Karen A. McdonaldAbstract:Kifunensine, a potent and selective inhibitor of class I α-mannosidases, prevents α-mannosidases I from trimming mannose residues on glycoproteins, thus resulting in oligomannose-type glycans. We report for the first time that through one-time vacuum infiltration of Kifunensine in plant tissue, N-linked glycosylation of a recombinant protein transiently produced in whole-plants shifted completely from complex-type to oligomannose-type. Fc-fused capillary morphogenesis protein 2 (CMG2-Fc) containing one N-glycosylation site on the Fc domain, produced in Nicotiana benthamiana whole plants, served as a model protein. The CMG2-Fc fusion protein was produced transiently through vacuum agroinfiltration, with and without Kifunensine at a concentration of 5.4 µM in the agroinfiltration suspension. The CMG2-Fc N-glycan profile was determined using LC-MS/MS with a targeted dynamic multiple reaction monitoring (MRM) method. The CMG2-Fc expression level in the infiltrated plant tissue and the percentage of oligomannose-type N-glycans for Kifunensine treated plants was 874 mg/kg leaf fresh weight (FW) and 98.2%, respectively, compared to 717 mg/kg leaf FW and 2.3% for untreated plants. Oligomannose glycans are amenable to in vitro enzymatic modification to produce more human-like N-glycan structures that are preferred for the production of HIV-1 viral vaccine and certain monoclonal antibodies. This method allows glycan modifications using a bioprocessing approach without compromising protein yield or modification of the primary sequence, and could be expanded to other small molecule inhibitors of glycan-processing enzymes. For recombinant protein targeted for secretion, Kifunensine treatment allows collection of glycoform-modified target protein from apoplast wash fluid (AWF) with minimal plant-specific complex N-glycan at higher starting purity and concentration than in whole-leaf extract, thus simplifying the downstream processing.
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Salmonella Typhimurium Enzymatically Landscapes the Host Intestinal Epithelial Cell (IEC) Surface Glycome to Increase Invasion.
Molecular & cellular proteomics : MCP, 2016Co-Authors: Dayoung Park, Narine Arabyan, Cynthia C. Williams, Ting Song, Anupam Mitra, Bart C. Weimer, Emanual Michael Maverakis, Carlito B LebrillaAbstract:Although gut host-pathogen interactions are glycan-mediated processes, few details are known about the participating structures. Here we employ high-resolution mass spectrometric profiling to comprehensively identify and quantitatively measure the exact modifications of native intestinal epithelial cell surface N-glycans induced by S. typhimurium infection. Sixty minutes postinfection, select sialylated structures showed decreases in terms of total number and abundances. To assess the effect of cell surface mannosylation, we selectively rerouted glycan expression on the host using the alpha-mannosidase inhibitor, Kifunensine, toward overexpression of high mannose. Under these conditions, internalization of S. typhimurium significantly increased, demonstrating that bacteria show preference for particular structures. Finally, we developed a novel assay to measure membrane glycoprotein turnover rates, which revealed that glycan modifications occur by bacterial enzyme activity rather than by host-derived restructuring strategies. This study is the first to provide precise structural information on how host N-glycans are altered to support S. typhimurium invasion.
Scott E. Allen - One of the best experts on this subject based on the ideXlab platform.
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microbial oxidation of aromatics in enantiocontrolled synthesis 2 rational design of aza sugars endo nitrogenous total synthesis of Kifunensine mannojirimycin and other glycosidase inhibitors
Journal of the American Chemical Society, 1994Co-Authors: Tomas Hudlicky, Jacques Rouden, Hector Luna, Scott E. AllenAbstract:A general method of synthesis for lactones and lactams related to carbohydrates has been developed that relies on the biocatalyticgeneration of 1-chloro-2,3-dihydroxycyclohexa-4,6-diene (l), obtained in excellent yield by fermentation of chlorobenzene with Pseudomonasputida 39D, followed by further functionalization to nitrogen-substituted cyclitols. These amino or azido cyclitols of type 15 are then subjected to controlled ozonolysis, which yields either lactones such as 27 or lactams containing five-membered (28) or six-membered (20 and 23) rings. Such compounds are useful intermediates for the preparation of aza sugars. Mannojirimycin (84 has been synthesized in seven steps from chlorobenzene. Kifunensine (7) has been prepared in 11 steps from chlorobenzene following an intersection with Hashimoto's procedure. Full experimental and spectral details are provided for all compounds. The potential of this general method and implications of the disclosed design features in the field of amino sugar and aza sugar synthesis are indicated.
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Microbial oxidation of aromatics in enantiocontrolled synthesis. 2. Rational design of aza sugars (endo-nitrogenous). Total synthesis of +-Kifunensine, mannojirimycin, and other glycosidase inhibitors.
Journal of the American Chemical Society, 1994Co-Authors: Tomas Hudlicky, Jacques Rouden, Hector Luna, Scott E. AllenAbstract:A general method of synthesis for lactones and lactams related to carbohydrates has been developed that relies on the biocatalyticgeneration of 1-chloro-2,3-dihydroxycyclohexa-4,6-diene (l), obtained in excellent yield by fermentation of chlorobenzene with Pseudomonasputida 39D, followed by further functionalization to nitrogen-substituted cyclitols. These amino or azido cyclitols of type 15 are then subjected to controlled ozonolysis, which yields either lactones such as 27 or lactams containing five-membered (28) or six-membered (20 and 23) rings. Such compounds are useful intermediates for the preparation of aza sugars. Mannojirimycin (84 has been synthesized in seven steps from chlorobenzene. Kifunensine (7) has been prepared in 11 steps from chlorobenzene following an intersection with Hashimoto's procedure. Full experimental and spectral details are provided for all compounds. The potential of this general method and implications of the disclosed design features in the field of amino sugar and aza sugar synthesis are indicated.
