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Hung-wen Liu - One of the best experts on this subject based on the ideXlab platform.
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identification of the c glycoside synthases during biosynthesis of the pyrazole c nucleosides Formycin and pyrazofurin
Angewandte Chemie, 2019Co-Authors: Daan Ren, Shao-an Wang, Yujie Geng, Yasushi Ogasawara, Hung-wen LiuAbstract:C-Nucleosides are characterized by a C-C rather than a C-N linkage between the heterocyclic base and the ribofuranose ring. While the biosynthesis of pseudouridine-C-nucleosides has been studied, less is known about the pyrazole-C-nucleosides such as the Formycins and pyrazofurin. Herein, genome screening of Streptomyces candidus NRRL 3601 led to the discovery of the pyrazofurin biosynthetic gene cluster pyf. In vitro characterization of gene product PyfQ demonstrated that it is able to catalyze formation of the C-glycoside carboxyhydroxypyrazole ribonucleotide (CHPR) from 4-hydroxy-1H-pyrazole-3,5-dicarboxylic acid and phosphoribosyl pyrophosphate (PRPP). Similarly, ForT, the PyfQ homologue in the Formycin pathway, can catalyze the coupling of 4-amino-1H-pyrazole-3,5-dicarboxylic acid and PRPP to form carboxyaminopyrazole ribonucleotide. Finally, PyfP and PyfT are shown to catalyze amidation of CHPR to pyrazofurin 5′-phosphate thereby establishing the latter stages of both pyrazofurin and Formycin biosynthesis.
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Identification of the Formycin A Biosynthetic Gene Cluster from Streptomyces kaniharaensis Illustrates the Interplay between Biological Pyrazolopyrimidine Formation and de Novo Purine Biosynthesis.
Journal of the American Chemical Society, 2019Co-Authors: Shao-an Wang, Jia Zeng, Yujie Geng, Daan Ren, Yasushi Ogasawara, Seema Irani, Yan Zhang, Hung-wen LiuAbstract:Formycin A is a potent purine nucleoside antibiotic with a C-glycosidic linkage between the ribosyl moiety and the pyrazolopyrimidine base. Herein, a cosmid is identified from the Streptomyces kaniharaensis genome library that contains the for gene cluster responsible for the biosynthesis of Formycin. Subsequent gene deletion experiments and in vitro characterization of the forBCH gene products established their catalytic functions in Formycin biosynthesis. Results also demonstrated that PurH from de novo purine biosynthesis plays a key role in pyrazolopyrimidine formation during biosynthesis of Formycin A. The participation of PurH in both pathways represents a good example of how primary and secondary metabolism are interlinked.
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Identification of the Formycin A Biosynthetic Gene Cluster from Streptomyces kaniharaensis Illustrates the Interplay between Biological Pyrazolopyrimidine Formation and de Novo Purine Biosynthesis
2019Co-Authors: Shao-an Wang, Jia Zeng, Yujie Geng, Daan Ren, Yasushi Ogasawara, Seema Irani, Yan Zhang, Hung-wen LiuAbstract:Formycin A is a potent purine nucleoside antibiotic with a C-glycosidic linkage between the ribosyl moiety and the pyrazolopyrimidine base. Herein, a cosmid is identified from the Streptomyces kaniharaensis genome library that contains the for gene cluster responsible for the biosynthesis of Formycin. Subsequent gene deletion experiments and in vitro characterization of the forBCH gene products established their catalytic functions in Formycin biosynthesis. Results also demonstrated that PurH from de novo purine biosynthesis plays a key role in pyrazolopyrimidine formation during biosynthesis of Formycin A. The participation of PurH in both pathways represents a good example of how primary and secondary metabolism are interlinked
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Identification and Characterization of Enzymes Catalyzing Pyrazolopyrimidine Formation in the Biosynthesis of Formycin A.
Organic letters, 2017Co-Authors: Shao-an Wang, Yasushi Ogasawara, Mark W. Ruszczycky, Hung-wen LiuAbstract:Genome scanning of Streptomyces kaniharaensis, the producer of Formycin A, reveals two sets of purA, purB, purC, and purH genes. The Pur enzymes catalyze pyrimidine assembly of purine nucleobases. To test whether enzymes encoded by the second set of pur genes catalyze analogous transformations in Formycin biosynthesis, Formycin B 5′-phosphate was synthesized and shown to be converted by ForA and ForB to Formycin A 5′-phosphate. These results support that For enzymes are responsible for Formycin formation.
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Identification and Characterization of Enzymes Catalyzing Pyrazolopyrimidine Formation in the Biosynthesis of Formycin A
2017Co-Authors: Shao-an Wang, Yasushi Ogasawara, Mark W. Ruszczycky, Hung-wen LiuAbstract:Genome scanning of Streptomyces kaniharaensis, the producer of Formycin A, reveals two sets of purA, purB, purC, and purH genes. The Pur enzymes catalyze pyrimidine assembly of purine nucleobases. To test whether enzymes encoded by the second set of pur genes catalyze analogous transformations in Formycin biosynthesis, Formycin B 5′-phosphate was synthesized and shown to be converted by ForA and ForB to Formycin A 5′-phosphate. These results support that For enzymes are responsible for Formycin formation
Shao-an Wang - One of the best experts on this subject based on the ideXlab platform.
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identification of the c glycoside synthases during biosynthesis of the pyrazole c nucleosides Formycin and pyrazofurin
Angewandte Chemie, 2019Co-Authors: Daan Ren, Shao-an Wang, Yujie Geng, Yasushi Ogasawara, Hung-wen LiuAbstract:C-Nucleosides are characterized by a C-C rather than a C-N linkage between the heterocyclic base and the ribofuranose ring. While the biosynthesis of pseudouridine-C-nucleosides has been studied, less is known about the pyrazole-C-nucleosides such as the Formycins and pyrazofurin. Herein, genome screening of Streptomyces candidus NRRL 3601 led to the discovery of the pyrazofurin biosynthetic gene cluster pyf. In vitro characterization of gene product PyfQ demonstrated that it is able to catalyze formation of the C-glycoside carboxyhydroxypyrazole ribonucleotide (CHPR) from 4-hydroxy-1H-pyrazole-3,5-dicarboxylic acid and phosphoribosyl pyrophosphate (PRPP). Similarly, ForT, the PyfQ homologue in the Formycin pathway, can catalyze the coupling of 4-amino-1H-pyrazole-3,5-dicarboxylic acid and PRPP to form carboxyaminopyrazole ribonucleotide. Finally, PyfP and PyfT are shown to catalyze amidation of CHPR to pyrazofurin 5′-phosphate thereby establishing the latter stages of both pyrazofurin and Formycin biosynthesis.
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Identification of the Formycin A Biosynthetic Gene Cluster from Streptomyces kaniharaensis Illustrates the Interplay between Biological Pyrazolopyrimidine Formation and de Novo Purine Biosynthesis.
Journal of the American Chemical Society, 2019Co-Authors: Shao-an Wang, Jia Zeng, Yujie Geng, Daan Ren, Yasushi Ogasawara, Seema Irani, Yan Zhang, Hung-wen LiuAbstract:Formycin A is a potent purine nucleoside antibiotic with a C-glycosidic linkage between the ribosyl moiety and the pyrazolopyrimidine base. Herein, a cosmid is identified from the Streptomyces kaniharaensis genome library that contains the for gene cluster responsible for the biosynthesis of Formycin. Subsequent gene deletion experiments and in vitro characterization of the forBCH gene products established their catalytic functions in Formycin biosynthesis. Results also demonstrated that PurH from de novo purine biosynthesis plays a key role in pyrazolopyrimidine formation during biosynthesis of Formycin A. The participation of PurH in both pathways represents a good example of how primary and secondary metabolism are interlinked.
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Identification of the Formycin A Biosynthetic Gene Cluster from Streptomyces kaniharaensis Illustrates the Interplay between Biological Pyrazolopyrimidine Formation and de Novo Purine Biosynthesis
2019Co-Authors: Shao-an Wang, Jia Zeng, Yujie Geng, Daan Ren, Yasushi Ogasawara, Seema Irani, Yan Zhang, Hung-wen LiuAbstract:Formycin A is a potent purine nucleoside antibiotic with a C-glycosidic linkage between the ribosyl moiety and the pyrazolopyrimidine base. Herein, a cosmid is identified from the Streptomyces kaniharaensis genome library that contains the for gene cluster responsible for the biosynthesis of Formycin. Subsequent gene deletion experiments and in vitro characterization of the forBCH gene products established their catalytic functions in Formycin biosynthesis. Results also demonstrated that PurH from de novo purine biosynthesis plays a key role in pyrazolopyrimidine formation during biosynthesis of Formycin A. The participation of PurH in both pathways represents a good example of how primary and secondary metabolism are interlinked
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Identification and Characterization of Enzymes Catalyzing Pyrazolopyrimidine Formation in the Biosynthesis of Formycin A.
Organic letters, 2017Co-Authors: Shao-an Wang, Yasushi Ogasawara, Mark W. Ruszczycky, Hung-wen LiuAbstract:Genome scanning of Streptomyces kaniharaensis, the producer of Formycin A, reveals two sets of purA, purB, purC, and purH genes. The Pur enzymes catalyze pyrimidine assembly of purine nucleobases. To test whether enzymes encoded by the second set of pur genes catalyze analogous transformations in Formycin biosynthesis, Formycin B 5′-phosphate was synthesized and shown to be converted by ForA and ForB to Formycin A 5′-phosphate. These results support that For enzymes are responsible for Formycin formation.
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Identification and Characterization of Enzymes Catalyzing Pyrazolopyrimidine Formation in the Biosynthesis of Formycin A
2017Co-Authors: Shao-an Wang, Yasushi Ogasawara, Mark W. Ruszczycky, Hung-wen LiuAbstract:Genome scanning of Streptomyces kaniharaensis, the producer of Formycin A, reveals two sets of purA, purB, purC, and purH genes. The Pur enzymes catalyze pyrimidine assembly of purine nucleobases. To test whether enzymes encoded by the second set of pur genes catalyze analogous transformations in Formycin biosynthesis, Formycin B 5′-phosphate was synthesized and shown to be converted by ForA and ForB to Formycin A 5′-phosphate. These results support that For enzymes are responsible for Formycin formation
James H Naismith - One of the best experts on this subject based on the ideXlab platform.
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uncovering the chemistry of c c bond formation in c nucleoside biosynthesis crystal structure of a c glycoside synthase prpp complex
Chemical Communications, 2020Co-Authors: Sisi Gao, Valerie De Crecylagard, Wen Zhu, Nigel G J Richards, James H Naismith, Ashish Radadiya, Huanting LiuAbstract:The enzyme ForT catalyzes C–C bond formation between 5′-phosphoribosyl-1′-pyrophosphate (PRPP) and 4-amino-1H-pyrazole-3,5-dicarboxylate to make a key intermediate in the biosynthesis of Formycin A 5′-phosphate by Streptomyces kaniharaensis. We report the 2.5 A resolution structure of the ForT/PRPP complex and locate active site residues critical for PRPP recognition and catalysis.
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pmp diketopiperazine adducts form at the active site of a plp dependent enzyme involved in Formycin biosynthesis
Chemical Communications, 2019Co-Authors: Sisi Gao, H Liu, Valerie De Crecylagard, Wen Zhu, Nigel G J Richards, James H NaismithAbstract:ForI is a PLP-dependent enzyme from the biosynthetic pathway of the C-nucleoside antibiotic Formycin. Cycloserine is thought to inhibit PLP-dependent enzymes by irreversibly forming a PMP–isoxazole. We now report that ForI forms novel PMP–diketopiperazine derivatives following incubation with both D and L cycloserine. This unexpected result suggests chemical diversity in the chemistry of cycloserine inhibition.
F E Parkinson - One of the best experts on this subject based on the ideXlab platform.
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Effect of adenosine receptor agonists on release of the nucleoside analogue [3H]Formycin B from cultured smooth muscle DDT1 MF-2 cells.
European journal of pharmacology, 1998Co-Authors: S L Borgland, F E ParkinsonAbstract:Adenosine has receptor-mediated effects in a variety of cell types and is predominantly formed from ATP by a series of nucleotidase reactions. Adenosine formed intracellularly can be released by bidirectional nucleoside transport processes to activate cell surface receptors. We examined whether stimulation of adenosine receptors has a regulatory effect on transporter-mediated nucleoside release. DDT1 MF-2 smooth muscle cells, which possess nitrobenzylthioinosine-sensitive (ES) transporters as well as both adenosine A1 and A2 receptors, were loaded with the metabolically stable nucleoside analogue [3H]Formycin B. N6-cyclohexyladenosine (CHA), a selective adenosine A1 receptor agonist, produced a concentration-dependent inhibition of [3H]Formycin B release with an IC50 value of 2.7 microM. Further investigation revealed CHA interacts directly with nucleoside transporters with a Ki value of 3.3 microM. Neither 5'-N-ethylcarboxamidoadenosine (NECA), a mixed adenosine A1 and A2 receptor agonist, nor CGS 21680, a selective adenosine A2A receptor agonist, affected nucleoside release. We conclude that release of the nucleoside Formycin B from DDT1 MF-2 cells is not regulated by adenosine A1 or A2 receptor activation.
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uptake and release of 3h Formycin b via sodium dependent nucleoside transporters in mouse leukemic l1210 ma27 1 cells
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: S L Borgland, F E ParkinsonAbstract:At least seven functionally distinct nucleoside transport processes exist; however, mouse leukemic L1210/MA27.1 cells possess only one subtype, a Na+-dependent transporter termed N1/ cif . The capacity of this transporter subtype to release nucleosides from L1210/MA27.1 cells was investigated with the poorly metabolized inosine analog [3H]Formycin B. Uptake of [3H]Formycin B into these cells was inhibited by replacement of Na+ in the buffer with choline, or by blocking Na+/K+ ATPase with 2 mM ouabain, inhibiting glycolysis with 5 mM iodoacetic acid or inhibiting nucleoside transport with 1 mM phloridzin. Sodium stimulated uptake with an EC50 value of 12 mM. To measure release of [3H]Formycin B, cells were loaded with [3H]Formycin B (10 μM) then washed and resuspended in buffer. Replacement of Na+ in the buffer with choline enhanced [3H]Formycin B release by 20 to 47%, and significant stimulation of release was observed with Na+concentrations of 30 mM or less. Resuspending loaded cells into Na+ buffer containing 2 mM ouabain or 10 μM monensin, a Na+ ionophore, significantly enhanced [3H]Formycin B release during 20 min by 39% or 29%, respectively. Release of [3H]Formycin B into choline buffer was inhibited 26.5% by 10 mM phloridzin and 39.6% by 10 mM propentofylline, compounds known to inhibit various transporters including Na+-dependent nucleoside transporters. Release was also inhibited significantly by 100 μM concentrations of dilazep, dipyridamole and nitrobenzylthioinosine, inhibitors with selectivity for Na+-independent nucleoside transporters. In the absence of Na+, the permeants adenosine and uridine enhanced [3H]Formycin B release by up to 40.9% and 21.4%, respectively. These data indicate that in the absence of an inwardly directed Na+ gradient, Na+-dependent nucleoside transporters can function in the release of nucleosides.
Leroy B. Townsend - One of the best experts on this subject based on the ideXlab platform.
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The Synthesis of a New Pyrazolo[3,4-c]pyridine C-Nucleoside, StructurallyRelated to Formycin B
Synlett, 2002Co-Authors: Vassilios N. Kourafalos, Nicole Pouli, Panagiotis Marakos, Leroy B. TownsendAbstract:The first preparation of the 4-deaza analogue of Formycin B is described, via the reaction of 3-acetamido-2-methoxy-4-methylpyridine with a suitably protected ribonolactone and subsequent ring closure to result in the 3-substituted pyrazolo[3,4-c]pyridine riboside 12.