C-Nucleoside Formation in the Biosynthesis of the Antifungal Malayamycin A

Hong, Hui; Samborskyy, Markiyan; Zhou, Yongjun; Leadlay, Peter F.

doi:10.1016/j.chembiol.2018.12.004

Cited by 22 publications

(44 citation statements)

References 39 publications

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“…Accordingly, it is possible that indigoidine biosynthesis from an increasing number of potential pathways may be associated with related unknown C- nucleoside molecules, because analogs of the MinA-MinB pair are in several cases concomitantly present in the specific gene clusters (Figure S5). L-glutamate is the common precursor for the aglycon of the C- nucleoside antibiotics, including MIN, formycin, pyrazofurin, and showdomycin (Suhadolnik and Reichenbach, 1981), which until recently have been unexplored at the molecular level (Hong et al., 2019, Palmu et al., 2017, Sosio et al., 2018, Wang et al., 2019). Hence, we propose that further insight into the molecular logics underlying the biosynthesis of C- nucleoside antibiotics will identify diverse and unique enzymes for potential synthetic biology purposes.…”

Section: Resultsmentioning

confidence: 99%

“…The C -nucleoside antibiotics (Figure 1) constitute an important sub-group of microbial natural products with unusual structural features and diverse biological activities (Isono, 1988, Maffioli et al., 2017). Their biosynthesis generally follows a succinct logic, with sequential modifications of simple precursors originating from primary metabolism (Hong et al., 2019, Isono, 1988, Palmu et al., 2017, Sosio et al., 2018, Wang et al., 2019). Less typically, minimycin (MIN, also called oxazinomycin) is produced by diverse bacterial strains, either Streptomyces sp.…”

Section: Introductionmentioning

confidence: 99%

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Divergent Biosynthesis of C-Nucleoside Minimycin and Indigoidine in Bacteria

Kong

Liu

et al. 2019

iScience

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SummaryMinimycin (MIN) is a C-nucleoside antibiotic structurally related to pseudouridine, and indigoidine is a naturally occurring blue pigment produced by diverse bacteria. Although MIN and indigoidine have been known for decades, the logic underlying the divergent biosynthesis of these interesting molecules has been obscure. Here, we report the identification of a minimal 5-gene cluster (min) essential for MIN biosynthesis. We demonstrated that a non-ribosomal peptide synthetase (MinA) governs “the switch” for the divergent biosynthesis of MIN and the cryptic indigoidine. We also demonstrated that MinCN (the N-terminal phosphatase domain of MinC), MinD (uracil phosphoribosyltransferase), and MinT (transporter) function together as the safeguard enzymes, which collaboratively constitute an unusual self-resistance system. Finally, we provided evidence that MinD, utilizing an unprecedented substrate-competition strategy for self-resistance of the producer cell, maintains competition advantage over the active molecule MIN-5′-monophosphate by increasing the UMP pool in vivo. These findings greatly expand our knowledge regarding natural product biosynthesis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Divergent Biosynthesis of C-Nucleoside Minimycin and Indigoidine in Bacteria

Kong

Liu

et al. 2019

iScience

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“…Indeed, nature has developed several diverse strategies for C-glycosidic bond construction during the biosynthesis of this group of antibiotics. Showdomycin biosynthesis uses a YeiN-like C-glycosyltransferase to build the C-C bond (3), while the biosynthesis of pseudouridimycin and malayamycin exploits a tRNA pseudouridylate synthase (TruD-like) for C-glycosidic bond construction (4,26). In the present study, FOR-A and PRF-A are shown to harness a totally different ␤-RFA-P synthase-like enzyme (ForT/PrfT) to catalyze the formation of C-glycosides (Fig.…”

Section: Discussionmentioning

confidence: 97%

Comparative Investigation into Formycin A and Pyrazofurin A Biosynthesis Reveals Branch Pathways for the Construction of C -Nucleoside Scaffolds

Zhang

et al. 2020

Appl Environ Microbiol

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Formycin A (FOR-A) and pyrazofurin A (PRF-A) are purine-related C-nucleoside antibiotics in which ribose and a pyrazole-derived base are linked by a C-glycosidic bond. However, the logic underlying the biosynthesis of these molecules has remained largely unexplored. Here, we report the discovery of the pathways for FOR-A and PRF-A biosynthesis from diverse actinobacteria and propose that their biosynthesis is likely initiated by a lysine N6-monooxygenase. Moreover, we show that forT and prfT (involved in FOR-A and PRF-A biosynthesis, respectively) mutants are correspondingly capable of accumulating the unexpected pyrazole-related intermediates 4-amino-3,5-dicarboxypyrazole and 3,5-dicarboxy-4-oxo-4,5-dihydropyrazole. We also decipher the enzymatic mechanism of ForT/PrfT for C-glycosidic bond formation in FOR-A/PRF-A biosynthesis. To our knowledge, ForT/PrfT represents an example of β-RFA-P (β-ribofuranosyl-aminobenzene 5ʹ-phosphate) synthase-like enzymes governing C-nucleoside scaffold construction in natural product biosynthesis. These data establish a foundation for combinatorial biosynthesis of related purine nucleoside antibiotics and also open the way for target-directed genome mining of PRF-A/FOR-A-related antibiotics. IMPORTANCE FOR-A and PRF-A are C-nucleoside antibiotics known for their unusual chemical structures and remarkable biological activities. Deciphering the enzymatic mechanism for the construction of a C-nucleoside scaffold during FOR-A/PRF-A biosynthesis will not only expand the biochemical repertoire for novel enzymatic reactions but also permit target-oriented genome mining of FOR-A/PRF-A-related C-nucleoside antibiotics. Moreover, the availability of FOR-A/PRF-A biosynthetic gene clusters will pave the way for the rational generation of designer FOR-A/PRF-A derivatives with enhanced/selective bioactivity via synthetic biology strategies.

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“…Actually, nature has developed diverse strategies for C -glycosidic bond construction during the biosynthesis of this group of antibiotics. Showdomycin biosynthesis uses a YeiN-like C -glycosyltransferase to build the C-C bond (5), while pseudouridimycin and malayamycin are deduced to exploit a tRNA (TruD-like) pseudouridylate synthase for C -glycosidic bond construction (6, 28). In the present study, FOR-A and PRF-A harness a totally different β-RFA-P synthase-like enzyme (ForT/PrfE) to catalyze the formation of C -glycosides.…”

Section: Discussionmentioning

confidence: 99%

Comparative investigation into formycin A and pyrazofurin A biosynthesis reveals branch pathways for the construction ofC-nucleoside scaffolds

Zhang

et al. 2019

Preprint

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24Formycin A (FOR-A) and pyrazofurin A (PRF-A) are purine-related C-nucleoside 25 antibiotics, in which ribose and a pyrazole-derived base are linked by a C-glycosidic 26 bond, however, the logic underlying the biosynthesis of these molecules has 27 remained largely unexplored. Here, we report the discovery of the pathways for 28 FOR-A and PRF-A biosynthesis from diverse actinobacteria, and demonstrate that 29 their biosynthesis is initiated by a lysine N 6 -monooxygenase. Moreover, we show 30 that the forT and prfE (individually related to FOR-A and PRF-A biosynthesis) 31 mutants are correspondingly capable of accumulating the unexpected 32 pyrazole-related intermediates, compound 11 and 9a. We also decipher the 33 enzymatic basis of ForT/PrfE for the C-glycosidic bond formation in FOR-A/PRF-A 34 biosynthesis. To our knowledge, ForT/PrfE represents the first example of β-RFA-P 35 (β-ribofuranosyl-aminobenzene 5'-phosphate) synthase-like enzymes governing 36 C-nucleoside scaffold construction in natural product biosynthesis. These data 37 establish a foundation for combinatorial biosynthesis of related purine nucleoside 38 antibiotics, and also open the way for target-directed genome mining of 39

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C-Nucleoside Formation in the Biosynthesis of the Antifungal Malayamycin A

Cited by 22 publications

References 39 publications

Divergent Biosynthesis of C-Nucleoside Minimycin and Indigoidine in Bacteria

Divergent Biosynthesis of C-Nucleoside Minimycin and Indigoidine in Bacteria

Comparative Investigation into Formycin A and Pyrazofurin A Biosynthesis Reveals Branch Pathways for the Construction of C -Nucleoside Scaffolds

Comparative investigation into formycin A and pyrazofurin A biosynthesis reveals branch pathways for the construction ofC-nucleoside scaffolds

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