Pseudouridine, a Carbon-Carbon Linked Ribonucleoside in Ribonucleic Acids: Isolation, Structure, and Chemical Characteristics

Cohn, Waldo E.

doi:10.1016/s0021-9258(18)69432-3

“…Although showdomycin and 1'-epi-showdomycin were both detected as autoxidation products of 16,t his result cannot be referred to the stereochemistry of 16 or 15 without more direct evidence.T his is because C-nucleosides are known to be susceptible to epimerization at C1' under acidic conditions. [33][34][35][36]…”

Section: Discussionmentioning

confidence: 99%

Identification of a Pyrrole Intermediate Which Undergoes C‐Glycosidation and Autoxidation to Yield the Final Product in Showdomycin Biosynthesis

Ren

¹

,

Kim

²

,

Wang

³

et al. 2021

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Showdomycin is aC -nucleoside bearing an electrophilic maleimide base.H erein, the biosynthetic pathwayo f showdomycin is presented. The initial stages of the pathway involve non-ribosomal peptide synthetase (NRPS) mediated assembly of a2 -amino-1H-pyrrole-5-carboxylic acid intermediate.This intermediate is prone to air oxidation whereupon it undergoes oxidative decarboxylation to yield an imine of maleimide,which in turn yields the maleimide upon acidification. It is also shown that this pyrrole intermediate serves as the substrate for the C-glycosidase SdmA in the pathway.A fter coupling with ribose 5-phosphate,t he resulting C-nucleoside undergoes as imilar sequence of oxidation, decarboxylation and deamination to affordshowdomcyin after exposure to air. These results suggest that showdomycin could be an artifact due to aerobic isolation;h owever,t he autoxidation maya lso serve to convert an otherwise inert product of the biosynthetic pathway to an electrophilic C-nucleotide thereby endowing showdomycin with its observed bioactivities. Results and DiscussionTo address these unresolved questions,t he sdm gene cluster was analyzed, and acassette consisting of sdmC, D, E, Figure 1. C-Ribosylnucleoside antibiotics.

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“…Although showdomycin and 1'-epi-showdomycin were both detected as autoxidation products of 16,t his result cannot be referred to the stereochemistry of 16 or 15 without more direct evidence.T his is because C-nucleosides are known to be susceptible to epimerization at C1' under acidic conditions. [33][34][35][36] Thef inal tailoring steps that convert 16 to showdomycin are expected to include oxidation, decarboxylation and deamination reactions.H owever,t he observed instability of compound 16 indicates that the final steps of showdomycin formation can proceed via as eries of nonenzymatic transformations to afford 1,1 '-epi-1 and the pyranose isomers of showdomycin (33 and 34). Hence,t he C-nucleoside 16 may actually be the true product of the showdomycin biosynthetic pathway with showdomycin itself being an artifact due to isolation under aerobic and acidic conditions.S imilar examples of misidentified biosynthetic products due to oxidation, decomposition or further modifications upon isolation have also been reported in other natural product systems,m aking such ap ossibility not without precedent.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Pyrrole Intermediate Which Undergoes C‐Glycosidation and Autoxidation to Yield the Final Product in Showdomycin Biosynthesis

Ren

¹

,

Kim

²

,

Wang

³

et al. 2021

View full text Add to dashboard Cite

Showdomycin is aC -nucleoside bearing an electrophilic maleimide base.H erein, the biosynthetic pathwayo f showdomycin is presented. The initial stages of the pathway involve non-ribosomal peptide synthetase (NRPS) mediated assembly of a2 -amino-1H-pyrrole-5-carboxylic acid intermediate.This intermediate is prone to air oxidation whereupon it undergoes oxidative decarboxylation to yield an imine of maleimide,which in turn yields the maleimide upon acidification. It is also shown that this pyrrole intermediate serves as the substrate for the C-glycosidase SdmA in the pathway.A fter coupling with ribose 5-phosphate,t he resulting C-nucleoside undergoes as imilar sequence of oxidation, decarboxylation and deamination to affordshowdomcyin after exposure to air. These results suggest that showdomycin could be an artifact due to aerobic isolation;h owever,t he autoxidation maya lso serve to convert an otherwise inert product of the biosynthetic pathway to an electrophilic C-nucleotide thereby endowing showdomycin with its observed bioactivities. Results and DiscussionTo address these unresolved questions,t he sdm gene cluster was analyzed, and acassette consisting of sdmC, D, E, Figure 1. C-Ribosylnucleoside antibiotics.

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“…Pseudouridine (Ψ) was one of the first RNA modifications to be discovered (Cohn, 1960) and is thought to be one of the most abundant, found in all domains of life. Ψ is a seemingly simple modification derived from base‐specific isomerization of uridine (U) and occurs via a snoRNA‐guided mechanism requiring H/ACA RNPs containing the Cbf5/dyskerin enzyme in yeast and humans, respectively, or snoRNA‐independent mechanisms catalyzed by pseudouridine synthases, also called Pus enzymes in eukaryotes (Li et al., 2016a; Rintala‐Dempsey & Kothe, 2017; Spenkuch et al., 2014).…”

Section: Candidate Trypanosomatid Writer Enzymes For M6a M1a M5c ψ and Ac4cmentioning

confidence: 99%

Epitranscriptome machinery in Trypanosomatids: New players on the table?

Maran

¹

,

Pitta

²

,

Vasconcelos

³

et al. 2021

Molecular Microbiology

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Trypanosoma and Leishmania parasites cause devastating tropical diseases resulting in serious global health consequences. These organisms have complex life cycles with mammalian hosts and insect vectors. The parasites must, therefore, survive in different environments, demanding rapid physiological and metabolic changes. These responses depend upon regulation of gene expression, which primarily occurs posttranscriptionally. Altering the composition or conformation of RNA through nucleotide modifications is one posttranscriptional mechanism of regulating RNA fate and function, and modifications including N6‐methyladenosine (m6A), N1‐methyladenosine (m1A), N5‐methylcytidine (m5C), N4‐acetylcytidine (ac4C), and pseudouridine (Ψ), dynamically regulate RNA stability and translation in diverse organisms. Little is known about RNA modifications and their machinery in Trypanosomatids, but we hypothesize that they regulate parasite gene expression and are vital for survival. Here, we identified Trypanosomatid homologs for writers of m1A, m5C, ac4C, and Ψ and analyze their evolutionary relationships. We systematically review the evidence for their functions and assess their potential use as therapeutic targets. This work provides new insights into the roles of these proteins in Trypanosomatid parasite biology and treatment of the diseases they cause and illustrates that Trypanosomatids provide an excellent model system to study RNA modifications, their molecular, cellular, and biological consequences, and their regulation and interplay.

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Pseudouridine, a Carbon-Carbon Linked Ribonucleoside in Ribonucleic Acids: Isolation, Structure, and Chemical Characteristics

Cited by 354 publications

References 30 publications

Identification of a Pyrrole Intermediate Which Undergoes C‐Glycosidation and Autoxidation to Yield the Final Product in Showdomycin Biosynthesis

Identification of a Pyrrole Intermediate Which Undergoes C‐Glycosidation and Autoxidation to Yield the Final Product in Showdomycin Biosynthesis

Identification of a Pyrrole Intermediate Which Undergoes C‐Glycosidation and Autoxidation to Yield the Final Product in Showdomycin Biosynthesis

Epitranscriptome machinery in Trypanosomatids: New players on the table?

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