Construction of an octosyl acid backbone catalyzed by a radical S-adenosylmethionine enzyme and a phosphatase in the biosynthesis of high-carbon sugar nucleoside antibiotics

He, Nisha; Wu, Pan; Lei, Yongxing; Xu, Bingxiang; Zhu, Xiaojun; Xu, Guanghua; Gao, Yang; Jing, Qi; Deng, Zixin; Tang, Gong‐Li; Chen, Wenqing; Xiao, Youli

doi:10.1039/c6sc01826b

Cited by 23 publications

(19 citation statements)

References 34 publications

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“…23 Later, the polH gene was shown to be essential for polyoxin biosynthesis, and deletion of the polH gene resulted in accumulation of a shunt metabolite, 5′-enolpyruvyl uridine. 87 These combined results established that NikJ and PolH are responsible for C5′–C6′ bond formation during the biosynthesis of the octosyl structure in the PN biosynthetic pathways.…”

Section: Radical Sam Enzymes With N-terminal Cofactor Binding Domainsmentioning

confidence: 77%

C–C bond forming radical SAM enzymes involved in the construction of carbon skeletons of cofactors and natural products

Yokoyama

Lilla

2018

Nat. Prod. Rep.

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C–C bond formations are frequently the key steps in cofactor and natural product biosynthesis. Historically, C–C bond formations were thought to proceed by two electron mechanisms, represented by Claisen condensation in fatty acids and polyketide biosynthesis. These types of mechanisms require activated substrates to create a nucleophile and an electrophile. More recently, increasing number of C–C bond formations catalyzed by radical SAM enzymes are being identified. These free radical mediated reactions can proceed between almost any sp3 and sp2 carbon centers, allowing introduction of C–C bonds at unconventional positions in metabolites. Therefore, free radical mediated C–C bond formations are frequently found in the construction of structurally unique and complex metabolites. This review discusses our current understanding of the functions and mechanisms of C–C bond forming radical SAM enzymes and highlights their important roles in the biosynthesis of structurally complex, naturally occurring organic molecules. Mechanistic consideration of C–C bond formation by radical SAM enzymes identifies the significance of three key mechanistic factors: radical initiation, acceptor substrate activation and radical quenching. Understanding the functions and mechanisms of these characteristic enzymes will be important not only in promoting our understanding of radical SAM enzymes, but also for understanding natural product and cofactor biosynthesis.

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Section: Radical Sam Enzymes With N-terminal Cofactor Binding Domainsmentioning

confidence: 77%

C–C bond forming radical SAM enzymes involved in the construction of carbon skeletons of cofactors and natural products

Yokoyama

Lilla

2018

Nat. Prod. Rep.

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“…The in vitro results strongly suggest that the pathway to the C-nucleoside malayamycin is as shown in Figure 6, in which the key precursor is 5 0 -J-MP rather than 5 0 -UMP. The adenosylcobalamin-dependent radical SAM enzyme MalJ is proposed to catalyze C-C bond formation as previously demonstrated for nikkomycin/polyoxin biosynthesis (Lilla and Yokoyama, 2016;He et al, 2017) to form J-octosyl acid When the malO gene of malayamycin cluster from S. malaysiensis was used to complement the DnikO mutant (DnikO:malO_Sm). C-linked nikkomycin Z (J-nikkomycin Z) was almost exclusively produced.…”

Section: Resultsmentioning

confidence: 94%

“…asoensis and Streptomyces aureochromogenes (Chen et al, 2009) has now led to a fairly detailed understanding of the enzymology of the pathway that leads from 5 0 -uridine monophosphate (UMP) 7 via 3 0 -enoylpyruvyl-UMP (3 0 -EPUMP) 8 and the high-carbon (>6Cs) sugar nucleoside octosyl acid 9 to the 5 0 -amino-5 0 -carboxy-5 0 -deoxyhexuronic acid 10 (Figure 2), the most advanced common intermediate in formation of uracil-based polyoxins and nikkomycins. However, it is not known to what extent this pathway (Lilla and Yokoyama, 2016;He et al, 2017) is also used in the biosynthesis of uracil C-nucleosides such as malayamycin, nor at which point the J nucleobase is introduced.…”

Section: Introductionmentioning

confidence: 99%

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

Hong

Samborskyy

Zhou

et al. 2019

Cell Chemical Biology

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“…The biosynthesis of PNs has been studied for more than three decades, and the BGCs for nikkomycins 6 , 11 and polyoxins 7 were reported in the 1990’s and 2000’s, respectively. Still, our understanding in the biosynthesis of AHA is limited to the first two steps: (i) coupling of uracil 5’-monophosphate (UMP, 4 ) and phosphoenol pyruvate to form enolpyruvyl UMP (EP-UMP, 5 ) by NikO/PolA ( Figure 1a , Supplementary Table 1 ) 7 , 12 and (ii) a radical-mediated cyclization of EP-UMP into octosyl acid 5’-phosphate (5’-OAP, 6 ) 13 , 14 . Subsequent steps in AHA biosynthesis remain uncharacterized.…”

Section: Introductionmentioning

confidence: 99%

Cryptic phosphorylation in nucleoside natural product biosynthesis

et al. 2020

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Kinases are annotated in many nucleoside biosynthetic gene clusters (BGCs) but generally are considered responsible only for self-resistance. Here, we report an unexpected 2’-phosphorylation of nucleoside biosynthetic intermediates in the nikkomycin and polyoxin pathways. This phosphorylation is a unique cryptic modification as it is introduced in the third of seven steps during aminohexuronic acid (AHA) nucleoside biosynthesis, retained throughout the pathway’s duration, and is removed in the last step of the pathway. Bioinformatic analysis of reported nucleoside BGCs suggests the presence of cryptic phosphorylation in other pathways and the importance of functional characterization of kinases in nucleoside biosynthetic pathways in general. This study also functionally characterized all of the enzymes responsible for AHA biosynthesis and revealed that AHA is constructed via a unique oxidative C-C bond cleavage reaction. The results suggest a divergent biosynthetic mechanism for three classes of antifungal nucleoside natural products.

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Construction of an octosyl acid backbone catalyzed by a radical S-adenosylmethionine enzyme and a phosphatase in the biosynthesis of high-carbon sugar nucleoside antibiotics

Abstract: This work provides, for the first time, significant in vitro evidence for the biosynthetic origins of octosyl acid through free radical and dephosphorylation enzymatic reactions.

Cited by 23 publications

References 34 publications

C–C bond forming radical SAM enzymes involved in the construction of carbon skeletons of cofactors and natural products

C–C bond forming radical SAM enzymes involved in the construction of carbon skeletons of cofactors and natural products

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

Cryptic phosphorylation in nucleoside natural product biosynthesis

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