The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Gregory L. Challis - One of the best experts on this subject based on the ideXlab platform.
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Genomics-driven discovery of a novel glutarimide antibiotic from Burkholderia gladioli reveals an unusual polyketide synthase chain release mechanism.
Angewandte Chemie International Edition, 2020Co-Authors: Gregory L. Challis, Matthew Jenner, Joleen Masschelein, Isolda Romero-canelón, Yousef Dashti, Ioanna T. Nakou, Eshwar MahenthiralingamAbstract:A gene cluster encoding a cryptic trans -acyl transferase polyketide synthase (PKS) was identified in the genomes of Burkholderia gladioli BCC0238 and BCC1622, both isolated from the lungs of cystic fibrosis patients. Bioinfomatics analyses indicated the PKS assembles a novel member of the glutarimide class of antibiotics, hitherto only isolated from Streptomyces species. Screening of a range of growth parameters enabled gladiostatin, the Metabolic Product of the PKS, to be identified. NMR spectroscopic analysis revealed that gladiostatin, which has promising activity against several human cancer cell lines and inhibits tumor cell migration, contains an unusual 2-acyl-4-hydroxy-3-methylbutenolide in addition to the glutarimide pharmacophore. An AfsA-like domain at the C-terminus of the PKS was shown to catalyze condensation of 3-ketothioesters with dihydroxyacetone phosphate, indicating it plays a key role in polyketide chain release and butenolide formation.
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genomics driven discovery of a novel glutarimide antibiotic from burkholderia gladioli reveals an unusual polyketide synthase chain release mechanism
Angewandte Chemie, 2020Co-Authors: Ioanna T. Nakou, Matthew Jenner, Joleen Masschelein, Yousef Dashti, Eshwar Mahenthiralingam, Gregory L. Challis, Isolda RomerocanelonAbstract:A gene cluster encoding a cryptic trans-acyl transferase polyketide synthase (PKS) was identified in the genomes of Burkholderia gladioli BCC0238 and BCC1622, both isolated from the lungs of cystic fibrosis patients. Bioinfomatics analyses indicated the PKS assembles a novel member of the glutarimide class of antibiotics, hitherto only isolated from Streptomyces species. Screening of a range of growth parameters led to the identification of gladiostatin, the Metabolic Product of the PKS. NMR spectroscopic analysis revealed that gladiostatin, which has promising activity against several human cancer cell lines and inhibits tumor cell migration, contains an unusual 2-acyl-4-hydroxy-3-methylbutenolide in addition to the glutarimide pharmacophore. An AfsA-like domain at the C-terminus of the PKS was shown to catalyze condensation of 3-ketothioesters with dihydroxyacetone phosphate, thus indicating it plays a key role in polyketide chain release and butenolide formation.
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structure and biosynthesis of scabichelin a novel tris hydroxamate siderophore produced by the plant pathogen streptomyces scabies 87 22
Organic and Biomolecular Chemistry, 2013Co-Authors: Shinya Kodani, Lijiang Song, Joanna Bicz, Robert J Deeth, Mayumi Ohnishikameyama, Mitsuru Yoshida, Kozo Ochi, Gregory L. ChallisAbstract:Scabichelin and turgichelin, novel tris-hydroxamate siderophores, were isolated from Streptomyces antibioticus NBRC 13838/Streptomyces scabies JCM 7914 and Streptomyces turgidiscabies JCM 10429, respectively. The planar structures of scabichelin and turgichelin were elucidated by mass spectrometry, and 1- and 2-D NMR spectroscopic analyses of their gallium(III) complexes. The relative and absolute stereochemistry of the metabolites was determined by the modified Marfey's method in conjunction with computational modelling and NOESY NMR analysis of Ga-scabichelin and Ga-turgichelin. Genome sequence analysis of the plant pathogen Streptomyces scabies 87.22 identified a gene cluster containing a gene encoding a nonribosomal peptide synthetase (NRPS) that was predicted to direct the Production of a pentapeptide with structural similarities to scabichelin and turgichelin. Comparative LC-MS/MS analyses of iron-deficient culture supernatants from wild type S. scabies 87.22 and a mutant in which the NRPS gene had been disrupted, and scabichelin purified from S. antibioticus, showed that scabichelin is the Metabolic Product of the cryptic gene cluster, strongly suggesting that it functions as a siderophore.
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structure and biosynthesis of the unusual polyketide alkaloid coelimycin p1 a Metabolic Product of the cpk gene cluster of streptomyces coelicolor m145
Chemical Science, 2012Co-Authors: Juan Pablo Gomezescribano, Lijiang Song, David J Fox, Valerie Yeo, Mervyn J Bibb, Gregory L. ChallisAbstract:Cryptic natural Product biosynthetic pathways discovered by genome mining are a promising source of novel bioactive natural Products. Here we report the identification, isolation and structure elucidation of coelimycin P1, an unusual yellow-pigmented Metabolic Product of the cpk cryptic polyketide biosynthetic gene cluster of Streptomyces coelicolor M145, using a genetic engineering strategy designed to increase Metabolic flux through the biosynthetic pathway. This resulted in overProduction of the yellow pigment, which was identified by HPLC comparison of the metabolite profile of culture supernatants of the engineered strain and an equivalent strain from which the cpk gene cluster had been deleted. Isolation and structure elucidation of the pigment revealed that it is a novel alkaloid containing a unique functionalized 1,5-oxathiocane. Sequence analysis of the enzymes encoded by the cpk gene cluster led us to propose a pathway for coelimycin P1 biosynthesis that is fully consistent with the results of incorporation experiments utilizing isotope-labelled precursors.
Magnus Schou - One of the best experts on this subject based on the ideXlab platform.
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increased brain exposure of an alpha synuclein fibrillization modulator by utilization of an activated ester prodrug strategy
ACS Chemical Neuroscience, 2018Co-Authors: Andrew G Cairns, Ana Vazquezromero, Mohammad Mahdimoein, Jorgen Aden, Charles S Elmore, Akihiro Takano, Ryosuke Arakawa, Andrea Varrone, Fredrik Almqvist, Magnus SchouAbstract:Previous work in our laboratories has identified a series of peptidomimetic 2-pyridone molecules as modulators of alpha-synuclein (α-syn) fibrillization in vitro. As a first step toward developing molecules from this scaffold as positron emission tomography imaging agents, we were interested in evaluating their blood-brain barrier permeability in nonhuman primates (NHP) in vivo. For this purpose, 2-pyridone 12 was prepared and found to accelerate α-syn fibrillization in vitro. Acid 12, and its acetoxymethyl ester analogue 14, were then radiolabeled with 11C (t1/2 = 20.4 min) at high radiochemical purity (>99%) and high specific radioactivity (>37 GBq/μmol). Following intravenous injection of each compound in NHP, a 4-fold higher radioactivity in brain was observed for [11C]14 compared to [11C]12 (0.8 vs 0.2 SUV, respectively). [11C]14 was rapidly eliminated from plasma, with [11C]12 as the major Metabolic Product observed by radio-HPLC. The presented prodrug approach paves the way for future development o...
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Increased Brain Exposure of an Alpha-Synuclein Fibrillization Modulator by Utilization of an Activated Ester Prodrug Strategy
2018Co-Authors: Andrew G. Cairns, Charles S Elmore, Akihiro Takano, Ryosuke Arakawa, Andrea Varrone, Fredrik Almqvist, Ana Vazquez-romero, Mohammad Mahdi Moein, Jörgen Ådén, Magnus SchouAbstract:Previous work in our laboratories has identified a series of peptidomimetic 2-pyridone molecules as modulators of alpha-synuclein (α-syn) fibrillization in vitro. As a first step toward developing molecules from this scaffold as positron emission tomography imaging agents, we were interested in evaluating their blood-brain barrier permeability in nonhuman primates (NHP) in vivo. For this purpose, 2-pyridone 12 was prepared and found to accelerate α-syn fibrillization in vitro. Acid 12, and its acetoxymethyl ester analogue 14, were then radiolabeled with 11C (t1/2 = 20.4 min) at high radiochemical purity (>99%) and high specific radioactivity (>37 GBq/μmol). Following intravenous injection of each compound in NHP, a 4-fold higher radioactivity in brain was observed for [11C]14 compared to [11C]12 (0.8 vs 0.2 SUV, respectively). [11C]14 was rapidly eliminated from plasma, with [11C]12 as the major Metabolic Product observed by radio-HPLC. The presented prodrug approach paves the way for future development of 2-pyridones as imaging biomarkers for in vivo imaging of α-synuclein deposits in brain
Eshwar Mahenthiralingam - One of the best experts on this subject based on the ideXlab platform.
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Genomics-driven discovery of a novel glutarimide antibiotic from Burkholderia gladioli reveals an unusual polyketide synthase chain release mechanism.
Angewandte Chemie International Edition, 2020Co-Authors: Gregory L. Challis, Matthew Jenner, Joleen Masschelein, Isolda Romero-canelón, Yousef Dashti, Ioanna T. Nakou, Eshwar MahenthiralingamAbstract:A gene cluster encoding a cryptic trans -acyl transferase polyketide synthase (PKS) was identified in the genomes of Burkholderia gladioli BCC0238 and BCC1622, both isolated from the lungs of cystic fibrosis patients. Bioinfomatics analyses indicated the PKS assembles a novel member of the glutarimide class of antibiotics, hitherto only isolated from Streptomyces species. Screening of a range of growth parameters enabled gladiostatin, the Metabolic Product of the PKS, to be identified. NMR spectroscopic analysis revealed that gladiostatin, which has promising activity against several human cancer cell lines and inhibits tumor cell migration, contains an unusual 2-acyl-4-hydroxy-3-methylbutenolide in addition to the glutarimide pharmacophore. An AfsA-like domain at the C-terminus of the PKS was shown to catalyze condensation of 3-ketothioesters with dihydroxyacetone phosphate, indicating it plays a key role in polyketide chain release and butenolide formation.
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genomics driven discovery of a novel glutarimide antibiotic from burkholderia gladioli reveals an unusual polyketide synthase chain release mechanism
Angewandte Chemie, 2020Co-Authors: Ioanna T. Nakou, Matthew Jenner, Joleen Masschelein, Yousef Dashti, Eshwar Mahenthiralingam, Gregory L. Challis, Isolda RomerocanelonAbstract:A gene cluster encoding a cryptic trans-acyl transferase polyketide synthase (PKS) was identified in the genomes of Burkholderia gladioli BCC0238 and BCC1622, both isolated from the lungs of cystic fibrosis patients. Bioinfomatics analyses indicated the PKS assembles a novel member of the glutarimide class of antibiotics, hitherto only isolated from Streptomyces species. Screening of a range of growth parameters led to the identification of gladiostatin, the Metabolic Product of the PKS. NMR spectroscopic analysis revealed that gladiostatin, which has promising activity against several human cancer cell lines and inhibits tumor cell migration, contains an unusual 2-acyl-4-hydroxy-3-methylbutenolide in addition to the glutarimide pharmacophore. An AfsA-like domain at the C-terminus of the PKS was shown to catalyze condensation of 3-ketothioesters with dihydroxyacetone phosphate, thus indicating it plays a key role in polyketide chain release and butenolide formation.
Toshihide Kubo - One of the best experts on this subject based on the ideXlab platform.
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methionine adenosyltransferase i iii deficiency neurological manifestations and relevance of s adenosylmethionine
Molecular Genetics and Metabolism, 2012Co-Authors: Mahoko Furujo, Masako Kinoshita, Masayoshi Nagao, Toshihide KuboAbstract:Methionine adenosyltransferase I/III (MAT I/III) deficiency, caused by mutations in the MAT1A gene, is an inherited Metabolic disorder characterized by persistent hypermethioninemia, usually detected by newborn mass screening. There is a wide range of clinical manifestations, from completely asymptomatic to neurological problems associated with brain demyelination. Physiological role of S-adenosylmethionine (SAM), the Metabolic Product of methionine catalyzed by MAT, in the central nervous system has been investigated in vivo and in vitro, and case reports demonstrated an effectiveness of supplementary treatment of SAM in the improvement of neurological development and myelination. Methionine restriction can be an additional therapeutic strategy because hypermethioninemia alone may be neurotoxic; however, lowering methionine carries a risk to decrease the synthesis of SAM.
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s adenosylmethionine treatment in methionine adenosyltransferase deficiency a case report
Molecular Genetics and Metabolism, 2012Co-Authors: Mahoko Furujo, Masako Kinoshita, Masayoshi Nagao, Toshihide KuboAbstract:Reported is a female patient with methionine adenosyltransferase I/III (MAT I/III) deficiency, who was found to have pronounced hypermethioninemia on newborn mass spectroscopy screening, and had two compound heterozygous missense mutations in the gene encoding human MAT1A protein. Hypermethioninemia persisted and her mental development was deficient. At 4 years and 8 months, we started with the supplementary treatment of S-adenosylmethionine, the Metabolic Product of methionine catalyzed by MAT, which was effective in her neurological development.
Andrew G Cairns - One of the best experts on this subject based on the ideXlab platform.
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increased brain exposure of an alpha synuclein fibrillization modulator by utilization of an activated ester prodrug strategy
ACS Chemical Neuroscience, 2018Co-Authors: Andrew G Cairns, Ana Vazquezromero, Mohammad Mahdimoein, Jorgen Aden, Charles S Elmore, Akihiro Takano, Ryosuke Arakawa, Andrea Varrone, Fredrik Almqvist, Magnus SchouAbstract:Previous work in our laboratories has identified a series of peptidomimetic 2-pyridone molecules as modulators of alpha-synuclein (α-syn) fibrillization in vitro. As a first step toward developing molecules from this scaffold as positron emission tomography imaging agents, we were interested in evaluating their blood-brain barrier permeability in nonhuman primates (NHP) in vivo. For this purpose, 2-pyridone 12 was prepared and found to accelerate α-syn fibrillization in vitro. Acid 12, and its acetoxymethyl ester analogue 14, were then radiolabeled with 11C (t1/2 = 20.4 min) at high radiochemical purity (>99%) and high specific radioactivity (>37 GBq/μmol). Following intravenous injection of each compound in NHP, a 4-fold higher radioactivity in brain was observed for [11C]14 compared to [11C]12 (0.8 vs 0.2 SUV, respectively). [11C]14 was rapidly eliminated from plasma, with [11C]12 as the major Metabolic Product observed by radio-HPLC. The presented prodrug approach paves the way for future development o...