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
Systematic 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
Other names
  • 7-{(3S)-4-methoxy-3-[(methoxycarbonyl)amino]-4-oxobutyl}-4,6-dimethyl-3-(β-D-ribofuranosyl)-3,4-dihydro-9H-imidazo[1,2-a]purin-9-one (CHEBI)
  • methyl 4-{3-[3,4-dihydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-yl]-4-methyl-6-methyl-8-oxo-1,3,4,5,7a-pentaaza-4,8-dihydro-3H-s-indacen-7-yl}-2-[methyl(oxycarbonylamino)]butanoate (ChemDoodle)
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

Biosynthesis

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 is produced from guanosine in several steps. All steps directly act on the number 37 site of tRNAPhe. [4]

  1. tRNA (guanine37-N1)-methyltransferase (yeast TRM5, human TRMT5) converts G37 to m1G37.
  2. S-adenosyl-L-methionine-dependent tRNA 4-demethylwyosine synthase (TYW1), using pyruvate as a C-3 source, forms the tricyclic core of wybutosine with flavin mononucleotide (FMN) as a cofactor. The result is called 4-demethylwyosine (abbreviation symbol imG-14, standing for "imidazomethylguanosine minus 14", or yW-187, for "wybutosine minus 187"). The "minus" indicates that the molecular mass is this many units lower than the derived compound being named.
  3. tRNA(Phe) (4-demethylwyosine(37)-C(7)) aminocarboxypropyltransferase (yeast TYW2, human TRMT12) 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 imG/yW-187 to form yW-86.
  4. tRNAPhe 7-[(3-amino-3-carboxypropyl)-4-demethylwyosine37-N4]-methyltransferase (TYW3) acts as a catalyst for N-4 methylation of yW-86 to produce yW-72.
  5. TYW4 methylates the α-carboxy group of yW-72 to give yW-57. [5]
  6. TYW4 performs methoxycarbonylation of the α-amino group of the yW-58 side chain to give wybutosine. [5]

Variation

Most eukaryotes have the entire pathway from TRM5 to TYW4. Variants occur by adding or removing steps:

Eukaryotes likely descended from the fusion of an archaeon host cell and a proto-mitochondrion bacterial symbioant. [9] Most archaeons have homologs of Trm5, Tyw1, and Tyw3, called aTrm5, Taw1, and Taw3 respectively. Some have a homolog of Tyw2 called Taw. [10] Based on the distribution of these enzymes among archaeal taxa, it is likely the ancestral archaeon already had these enzymes. [11] As a result, they also exhibit hypermodification of the G37 position of tRNA(Phe), although the lack of TRM4 prevents them from making wybutosine, so they use a different but similar base. [10]

Verification by chemical synthesis

Wybutosine and hydroxywybutosine has been chemically synthesized, allowing researchers to compare them with what is presumed to be these substances derived from natural sources. [12] [13]

yW-86 and yW-72 are yet to be chemically synthesized. Their presence in tRNA is inferred from mass spectroscopy and their structure from that of the final yW. [10]

Function

Structural effect

When magnesium ions are present, wyobutosine causes a shift in the position in the anticodon loop. The hydrophobic nature of yW causes a preference of UUC over UUU, as Watson–Crick pairing with U is prevented. [14]

Avoidance of frameshifting

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. [15] Through its large aromatic groups, stacking interactions with adjacent bases A36 and A38 are enhanced, which help to restrict the flexibility of the anticodon. [16] 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. A wyosine-type 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. [17] This has led to the assumption that tRNAPhe modification at position 37 correlates with the amount of polyuridine slippery sequences found in genomes. [18]

Alternatives

Besides the wyosine derivatives detailed above, these bases are also found in tRNAPhe across different types of life:

  • Isopentenyladenosine i6A, some eukaryotes (cytoplasmic) [6]
    • io6A, ms2i6A, ms2io6A (ms indicated methylthiolation, o indicates hydroxylation [oxygen]), derivatives in some bacteria and some eukaryotic organelles
  • Simple m1G (some bacteria, some archaea, some eukaryotes) [6]

Selective allowance of frameshifting?

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: the simplistic m1G also works to an extent. In Drosophila there is only m1G 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. [19] It has been suggested that frameshifting may be used in a programmed manner, possibly to increase coding diversity.[ citation needed ]

Downstream effects

The human gene SMARCAD1 contains many UUU codons. When human embryonic stem cells has the TYW1 gene knocked out, it can only make m1G, causing lower translational efficiency of SMARCAD1. This leads to disinhibition of HERVK, preventing the cell from properly differentiating into a neuron. [20]

References

  1. ↑ Noma A, Kirino Y, Ikeuchi Y, Suzuki T (2006). "Biosynthesis of wybutosine, a hyper-modified nucleoside in eukaryotic phenylalanine tRNA". The EMBO Journal. 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. 1 2 Suzuki, Yoko; Noma, Akiko; Suzuki, Tsutomu; Ishitani, Ryuichiro; Nureki, Osamu (May 2009). "Structural basis of tRNA modification with CO2 fixation and methylation by wybutosine synthesizing enzyme TYW4†". Nucleic Acids Research. 37 (9): 2910–2925. doi:10.1093/nar/gkp158. PMC   2685095 . PMID   19287006.
  6. 1 2 3 4 5 6 7 Urbonavičius, Jaunius; Droogmans, Louis; Armengaud, Jean; Grosjean, Henri (2013). "Deciphering the Complex Enzymatic Pathway for Biosynthesis of Wyosine Derivatives in Anticodon of tRNAPhe". Madame Curie Bioscience Database. Landes Bioscience.
  7. ↑ Noma, A; Ishitani, R; Kato, M; Nagao, A; Nureki, O; Suzuki, T (5 November 2010). "Expanding role of the jumonji C domain as an RNA hydroxylase". The Journal of Biological Chemistry. 285 (45): 34503–7. doi: 10.1074/jbc.M110.156398 . PMC   2966065 . PMID   20739293.
  8. ↑ Sample, PJ; Kořený, L; Paris, Z; Gaston, KW; Rubio, MA; Fleming, IM; Hinger, S; Horáková, E; Limbach, PA; Lukeš, J; Alfonzo, JD (30 April 2015). "A common tRNA modification at an unusual location: the discovery of wyosine biosynthesis in mitochondria". Nucleic Acids Research. 43 (8): 4262–73. doi:10.1093/nar/gkv286. PMC   4417183 . PMID   25845597.
  9. ↑ Williams, Tom A.; Cox, Cymon J.; Foster, Peter G.; Szöllősi, Gergely J.; Embley, T. Martin (2019-12-09). "Phylogenomics provides robust support for a two-domains tree of life". Nature Ecology & Evolution. 4 (1): 138–147. Bibcode:2019NatEE...4..138W. doi:10.1038/s41559-019-1040-x. PMC   6942926 . PMID   31819234.
  10. 1 2 3 4 5 6 Urbonavičius, J; Tauraitė, D (2 December 2020). "Biochemical Pathways Leading to the Formation of Wyosine Derivatives in tRNA of Archaea". Biomolecules. 10 (12): 1627. doi: 10.3390/biom10121627 . PMC   7761594 . PMID   33276555.
  11. ↑ de Crécy-Lagard, V; Brochier-Armanet, C; Urbonavicius, J; Fernandez, B; Phillips, G; Lyons, B; Noma, A; Alvarez, S; Droogmans, L; Armengaud, J; Grosjean, H (September 2010). "Biosynthesis of wyosine derivatives in tRNA: an ancient and highly diverse pathway in Archaea". Molecular Biology and Evolution. 27 (9): 2062–77. doi:10.1093/molbev/msq096. PMC   4481705 . PMID   20382657.
  12. ↑ Itaya T, Kanai T, Iida T (2002). "Practical synthesis of wybutosine, the hypermodified nucleoside of yeast phenylalanine transfer ribonucleic acid". Chemical and Pharmaceutical Bulletin. 50 (4): 530–3. doi: 10.1248/cpb.50.530 . PMID   11964003.
  13. ↑ 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: A European Journal. 19 (13): 4244–8. doi:10.1002/chem.201204209. PMID   23417961.
  14. ↑ Fandilolu, Prayagraj M.; Kamble, Asmita S.; Dound, Ambika S.; Sonawane, Kailas D. (17 December 2019). "Role of Wybutosine and Mg2+ Ions in Modulating the Structure and Function of tRNAPhe: A Molecular Dynamics Study". ACS Omega. 4 (25): 21327–21339. doi: 10.1021/acsomega.9b02238 . PMID   31867527.
  15. ↑ Helm, M; Alfonzo, JD (2014). "Posttranscriptional RNA Modifications: playing metabolic games in a cell's chemical Legoland". ACS Chemical Biology. 21 (2): 174–85. doi:10.1016/j.chembiol.2013.10.015. PMC   3944000 . PMID   24315934.
  16. ↑ Stuart, JW; Koshlap, KM; Guenther, R; Agris, PF (2003). "Naturally-occurring modification restricts the anticodon domain conformational space of tRNA(Phe)". Journal of Molecular Biology. 334 (5): 901–18. doi:10.1016/j.jmb.2003.09.058. PMID   14643656.
  17. ↑ Christian, T; Lahoud, G; Liu, C; Hou, YM (2010). "Control of catalytic cycle by a pair of analogous tRNA modification enzymes". Journal of Molecular Biology. 400 (2): 204–17. doi:10.1016/j.jmb.2010.05.003. PMC   2892103 . PMID   20452364.
  18. ↑ Jackman, JE; Alfonzo, JD (2013). "Transfer RNA modifications: nature's combinatorial chemistry playground". Wiley Interdisciplinary Reviews: RNA. 4 (1): 35–48. doi:10.1002/wrna.1144. PMC   3680101 . PMID   23139145.
  19. ↑ 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.
  20. ↑ Sun, Chuanbo; Guo, Ruirui; Ye, Xiangyan; Tang, Shiyi; Chen, Manqi; Zhou, Pei; Yang, Miaomiao; Liao, Caihua; Li, Hong; Lin, Bing; Zang, Congwen; Qi, Yifei; Han, Dingding; Sun, Yi; Li, Na; Zhu, Dengna; Xu, Kaishou; Hu, Hao (May 2024). "Wybutosine hypomodification of tRNAphe activates HERVK and impairs neuronal differentiation". iScience. 27 (5): 109748. Bibcode:2024iSci...27j9748S. doi:10.1016/j.isci.2024.109748. PMC   11066470 . PMID   38706838.
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