Wybutosine

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Wybutosine
Wybutosine.svg
Names
IUPAC name
Methyl (2S)-4-(3,4′′-dimethyl-3H-imidazo[1′′,2′′:1,2]inosin-5′′-yl)-2-[(methoxycarbonyl)amino]butanoate
Preferred IUPAC name
Methyl (2S)-4-{3-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-4,6-dimethyl-9-oxo-4,9-dihydro-3H-imidazo[1,2-a]purin-7-yl}-2-[(methoxycarbonyl)amino]butanoate
Identifiers
3D model (JSmol)
AbbreviationsyW
ChEBI
ChemSpider
PubChem CID
UNII
  • Key: QAOHCFGKCWTBGC-QHOAOGIMSA-N
  • InChI=1S/C21H28N6O9/c1-9-11(6-5-10(19(32)34-3)24-21(33)35-4)27-17(31)13-16(25(2)20(27)23-9)26(8-22-13)18-15(30)14(29)12(7-28)36-18/h8,10,12,14-15,18,28-30H,5-7H2,1-4H3,(H,24,33)/t10-,12+,14+,15+,18+/m0/s1
  • Cc1c(n2c(=O)c3c(n(c2n1)C)n(cn3)[C@H]4[C@@H]([C@@H]([C@H](O4)CO)O)O)CC[C@@H](C(=O)OC)NC(=O)OC
Properties
C21H28N6O9
Molar mass 508.488 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

In biochemistry, wybutosine (yW) is a heavily modified nucleoside of phenylalanine transfer RNA that stabilizes interactions between the codons and anti-codons during protein synthesis. [1] [2] Ensuring accurate synthesis of protein is essential in maintaining health as defects in tRNA modifications are able to cause disease. In eukaryotic organisms, it is found only in position 37, 3'-adjacent to the anticodon, of phenylalanine tRNA. Wybutosine enables correct translation through the stabilization of the codon-anticodon base pairing during the decoding process. [3]

Contents

Biosynthetic pathway

Using an S. cerevisiae model, the biosynthetic pathway of wybutosine was proposed. Proceeding through a multi-enzymatic process, the first step of the synthesis involves the enzyme N1-methyltransferase TRM5 which methylates the G37 site of phenylalanine tRNA and converts it to m1G37. Then m1G37 acts as a substrate for the enzyme TYW1 and, using pyruvate as a C-3 source, forms the tricyclic core of wybutosine with flavin mononucleotide (FMN) as a cofactor. The enzyme TYW2 then transfers the α-amino-α-carboxypropyl group from Ado-Met, a common substrate involved in methyl group transfers, to the lateral side chain at the C-7 position of yW-187 to form yW-86. TYW3 acts as a catalyst for N-4 methylation of yW-86 to produce yW-72. TYW4 and Ado-Met-dependent carboxymethyltransferase then methylates the α-carboxy group of yW-72 to give yW-57. Finally by a predicted second function of TYW4 or other unidentified factors, the methoxycarbonylation of the α-amino group of the yW-58 side chain gives wybutosine. [4]

Wybutosine and enzymes that aid in its biosynthesis. Each enzyme and group is highlighted using colors. Wybutosine.png
Wybutosine and enzymes that aid in its biosynthesis. Each enzyme and group is highlighted using colors.

Wybutosine has been chemically synthesized. [5] [6]

Hypermodification and roles in RNA stabilization

Wybutosine and other unnatural nucleosides have been proposed to lead to a single outcome of hypermodification. This hypermodification at position 37 of tRNAPhe may allow for base- stacking interactions which play a key role in maintenance of the reading frame. [7] Through its large aromatic groups, stacking interactions with adjacent bases A36 and A38 are enhanced, which help to restrict the flexibility of the anticodon. [8] It has been found that when tRNAPhe lacks wybutosine, increased frameshifting occurs. Generally, modifications at position 37 prevent base pairing with neighboring nucleotides by helping to maintain and open the loop conformation, as well as generating an anticodon loop for decoding. The wybutosine modification of tRNAPhe is found to be conserved in archaea and eukarya but is not found in bacteria. Studies from the 1960s and 1970s noted that many mutations could lead to problems in translational accuracy. Further study of the mechanisms involved in translational accuracy revealed the importance of modifications on positions 34 and 37 of tRNA. Regardless of species, these sites of tRNA are almost always modified. The fact that wybutosine and its various derivatives are only found at position 37 may be indicative of the nature of the phenylalanine codons, UUU and UUC, and their predilection for ribosome slippage. [9] This has led to the assumption that tRNAPhe modification at position 37 correlates with the amount of polyuridine slippery sequences found in genomes. [10]

Frameshifting potential

Wybutosine’s role in prevention of frameshifts has raised some questions into its importance, as there are other strategies beside modification with yW to prevent a shift. In Drosophila there is no modification at position 37 while in mammals yW is modified there. To explain this variability the idea of frameshifting potential has come about. This implies that cells use frameshifting as a mechanism to regulate themselves rather than trying to avoid frameshifting at all times. [11] It has been suggested that frameshifting may be used in a programmed manner, possibly to increase coding diversity.

Related Research Articles

Genetic code Rules by which information encoded within genetic material is translated into proteins

The genetic code is the set of rules used by living cells to translate information encoded within genetic material into proteins. Translation is accomplished by the ribosome, which links proteinogenic amino acids in an order specified by messenger RNA (mRNA), using transfer RNA (tRNA) molecules to carry amino acids and to read the mRNA three nucleotides at a time. The genetic code is highly similar among all organisms and can be expressed in a simple table with 64 entries.

Protein biosynthesis Assembly of proteins inside biological cells

Protein biosynthesis is a core biological process, occurring inside cells, balancing the loss of cellular proteins through the production of new proteins. Proteins perform a number of critical functions as enzymes, structural proteins or hormones. Protein synthesis is a very similar process for both prokaryotes and eukaryotes but there are some distinct differences.

RNA Family of large biological molecules

Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid (DNA) are nucleic acids. Along with lipids, proteins, and carbohydrates, nucleic acids constitute one of the four major macromolecules essential for all known forms of life. Like DNA, RNA is assembled as a chain of nucleotides, but unlike DNA, RNA is found in nature as a single strand folded onto itself, rather than a paired double strand. Cellular organisms use messenger RNA (mRNA) to convey genetic information that directs synthesis of specific proteins. Many viruses encode their genetic information using an RNA genome.

Pyrrolysine Chemical compound

Pyrrolysine is an α-amino acid that is used in the biosynthesis of proteins in some methanogenic archaea and bacteria; it is not present in humans. It contains an α-amino group, a carboxylic acid group. Its pyrroline side-chain is similar to that of lysine in being basic and positively charged at neutral pH.

Transfer RNA RNA that facilitates the addition of amino acids to a new protein

Transfer RNA is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length, that serves as the physical link between the mRNA and the amino acid sequence of proteins. Transfer RNA (tRNA) does this by carrying an amino acid to the protein synthesizing machinery of a cell called the ribosome. Complementation of a 3-nucleotide codon in a messenger RNA (mRNA) by a 3-nucleotide anticodon of the tRNA results in protein synthesis based on the mRNA code. As such, tRNAs are a necessary component of translation, the biological synthesis of new proteins in accordance with the genetic code.

Wobble base pair RNA base pair that does not follow Watson-Crick base pair rules

A wobble base pair is a pairing between two nucleotides in RNA molecules that does not follow Watson-Crick base pair rules. The four main wobble base pairs are guanine-uracil (G-U), hypoxanthine-uracil (I-U), hypoxanthine-adenine (I-A), and hypoxanthine-cytosine (I-C). In order to maintain consistency of nucleic acid nomenclature, "I" is used for hypoxanthine because hypoxanthine is the nucleobase of inosine; nomenclature otherwise follows the names of nucleobases and their corresponding nucleosides. The thermodynamic stability of a wobble base pair is comparable to that of a Watson-Crick base pair. Wobble base pairs are fundamental in RNA secondary structure and are critical for the proper translation of the genetic code.

A nucleoside triphosphate is a molecule containing a nitrogenous base bound to a 5-carbon sugar, with three phosphate groups bound to the sugar. It is an example of a nucleotide. They are the molecular precursors of both DNA and RNA, which are chains of nucleotides made through the processes of DNA replication and transcription. Nucleoside triphosphates also serve as a source of energy for cellular reactions and are involved in signalling pathways.

Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. This process often consists of metabolic pathways. Some of these biosynthetic pathways are located within a single cellular organelle, while others involve enzymes that are located within multiple cellular organelles. Examples of these biosynthetic pathways include the production of lipid membrane components and nucleotides. Biosynthesis is usually synonymous with anabolism.

RNA editing Molecular process

RNA editing is a molecular process through which some cells can make discrete changes to specific nucleotide sequences within an RNA molecule after it has been generated by RNA polymerase. It occurs in all living organisms and is one of the most evolutionarily conserved properties of RNAs. RNA editing may include the insertion, deletion, and base substitution of nucleotides within the RNA molecule. RNA editing is relatively rare, with common forms of RNA processing not usually considered as editing. It can affect the activity, localization as well as stability of RNAs, and has been linked with human diseases.

Pseudouridine Chemical compound

Pseudouridine is an isomer of the nucleoside uridine in which the uracil is attached via a carbon-carbon instead of a nitrogen-carbon glycosidic bond.

EF-Tu Prokaryotic elongation factor

EF-Tu is a prokaryotic elongation factor responsible for catalyzing the binding of an aminoacyl-tRNA (aa-tRNA) to the ribosome. It is a G-protein, and facilitates the selection and binding of an aa-tRNA to the A-site of the ribosome. As a reflection of its crucial role in translation, EF-Tu is one of the most abundant and highly conserved proteins in prokaryotes. It is found in eukaryotic mitochrondria as TUFM.

Queuine Chemical compound

Queuine (Q) is a hypermodified nucleobase found in the first position of the anticodon of tRNAs specific for Asn, Asp, His, and Tyr, in most eukaryotes and prokaryotes.

Phenylalanine—tRNA ligase

In enzymology, a phenylalanine—tRNA ligase is an enzyme that catalyzes the chemical reaction

Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during translation that results in the production of multiple, unique proteins from a single mRNA. The process can be programmed by the nucleotide sequence of the mRNA and is sometimes affected by the secondary, 3-dimensional mRNA structure. It has been described mainly in viruses, retrotransposons and bacterial insertion elements, and also in some cellular genes.

Queuosine Chemical compound

Queuosine is a modified nucleoside that is present in certain tRNAs in bacteria and eukaryotes. It contains the nucleobase queuine. Originally identified in E. coli, queuosine was found to occupy the first anticodon position of tRNAs for histidine, aspartic acid, asparagine and tyrosine. The first anticodon position pairs with the third "wobble" position in codons, and queuosine improves accuracy of translation compared to guanosine. Synthesis of queuosine begins with GTP. In bacteria, three structurally unrelated classes of riboswitch are known to regulate genes that are involved in the synthesis or transport of pre-queuosine1, a precursor to queuosine: PreQ1-I riboswitches, PreQ1-II riboswitches and PreQ1-III riboswitches.

Agmatidine Chemical compound

Agmatidine (2-agmatinylcytidine, symbol C+ or agm2C) is a modified cytidine present in the wobble position of the anticodon of several archaeal AUA decoding tRNAs. Agmatidine is essential for correct decoding of the AUA codon in many archaea and is required for aminoacylation of tRNAIle2 with isoleucine.

Radical SAM is a designation for a superfamily of enzymes that use a [4Fe-4S]+ cluster to reductively cleave S-adenosyl-L-methionine (SAM) to generate a radical, usually a 5′-deoxyadenosyl radical, as a critical intermediate. These enzymes utilize this radical intermediate to perform diverse transformations, often to functionalize unactivated C-H bonds. Radical SAM enzymes are involved in cofactor biosynthesis, enzyme activation, peptide modification, post-transcriptional and post-translational modifications, metalloprotein cluster formation, tRNA modification, lipid metabolism, biosynthesis of antibiotics and natural products etc. The vast majority of known radical SAM enzymes belong to the radical SAM superfamily, and have a cysteine-rich motif that matches or resembles CxxxCxxC. rSAMs comprise the largest superfamily of metal-containing enzymes.

TRNAIle-lysidine synthase (EC 6.3.4.19, TilS, mesJ (gene), yacA (gene), isoleucine-specific transfer ribonucleate lysidine synthetase, tRNAIle-lysidine synthetase) is an enzyme with systematic name L-lysine:(tRNAIle2)-cytidine34 ligase (AMP-forming). This enzyme catalyses the following chemical reaction

A nucleoside-modified messenger RNA (modRNA) is a synthetic messenger RNA (mRNA) in which some nucleosides are replaced by other naturally modified nucleosides or by synthetic nucleoside analogues. modRNA is used to induce the production of a desired protein in certain cells. An important application is the development of mRNA vaccines, of which the first authorized were COVID-19 vaccines.

N1-Methylpseudouridine Chemical compound

N1-Methylpseudouridine is a natural archaeal tRNA component as well as a synthetic pyrimidine nucleoside used in biochemistry and molecular biology for in vitro transcription and is found in the SARS-CoV-2 mRNA vaccines tozinameran (Pfizer–BioNTech) and elasomeran (Moderna).

References

  1. ↑ Noma A, Kirino Y, Ikeuchi Y, Suzuki T (2006). "Biosynthesis of wybutosine, a hyper-modified nucleoside in eukaryotic phenylalanine tRNA". EMBO J. 25 (10): 2142–54. doi:10.1038/sj.emboj.7601105. PMC   1462984 . PMID   16642040.
  2. ↑ Perche-Letuvée, Phanélie; Molle, Thibaut; Forouhar, Farhad; Mulliez, Etienne; Atta, Mohamed (2 December 2014). "Wybutosine biosynthesis: Structural and mechanistic overview". RNA Biology. 11 (12): 1508–1518. doi:10.4161/15476286.2014.992271. PMC   4615248 . PMID   25629788.
  3. ↑ Suzuki, Yoko; Noma, Akiko; Suzuki, Tsutomu; Senda, Miki; Senda, Toshiya; Ishitani, Ryuichiro; Nureki, Osamu (October 2007). "Crystal Structure of the Radical SAM Enzyme Catalyzing Tricyclic Modified Base Formation in tRNA". Journal of Molecular Biology. 372 (5): 1204–1214. doi:10.1016/j.jmb.2007.07.024. PMID   17727881.
  4. 1 2 Young, Anthony P.; Bandarian, Vahe (2018). "TYW1: A Radical SAM Enzyme Involved in the Biosynthesis of Wybutosine Bases". Radical SAM Enzymes. Methods in Enzymology. Vol. 606. pp. 119–153. doi:10.1016/bs.mie.2018.04.024. ISBN   978-0-12-812794-0. PMC   6448148 . PMID   30097090.
  5. ↑ Itaya T, Kanai T, Iida T (2002). "Practical synthesis of wybutosine, the hypermodified nucleoside of yeast phenylalanine transfer ribonucleic acid". Chem. Pharm. Bull. 50 (4): 530–3. doi: 10.1248/cpb.50.530 . PMID   11964003.
  6. ↑ Hienzsch A, Deiml C, Reiter V, Carell T (2013). "Total synthesis of the hypermodified RNA bases wybutosine and hydroxywybutosine and their quantification together with other modified RNA bases in plant materials". Chemistry. 19 (13): 4244–8. doi:10.1002/chem.201204209. PMID   23417961.
  7. ↑ Helm, M; Alfonzo, JD (2014). "Posttranscriptional RNA Modifications: playing metabolic games in a cell's chemical Legoland". Chem. Biol. 21 (2): 174–85. doi:10.1016/j.chembiol.2013.10.015. PMC   3944000 . PMID   24315934.
  8. ↑ Stuart, JW; Koshlap, KM; Guenther, R; Agris, PF (2003). "Naturally-occurring modification restricts the anticodon domain conformational space of tRNA(Phe)". J Mol Biol. 334 (5): 901–18. doi:10.1016/j.jmb.2003.09.058. PMID   14643656.
  9. ↑ Christian, T; Lahoud, G; Liu, C; Hou, YM (2010). "Control of catalytic cycle by a pair of analogous tRNA modification enzymes". J Mol Biol. 400 (2): 204–17. doi:10.1016/j.jmb.2010.05.003. PMC   2892103 . PMID   20452364.
  10. ↑ Jackman, JE; Alfonzo, JD (2013). "Transfer RNA modifications: nature's combinatorial chemistry playground". Wiley Interdiscip Rev RNA. 4 (1): 35–48. doi:10.1002/wrna.1144. PMC   3680101 . PMID   23139145.
  11. ↑ Waas, William F.; Druzina, Zhanna; Hanan, Melanie; Schimmel, Paul (September 2007). "Role of a tRNA Base Modification and Its Precursors in Frameshifting in Eukaryotes". Journal of Biological Chemistry. 282 (36): 26026–26034. doi: 10.1074/jbc.m703391200 . PMID   17623669.
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