tRNA modification in the mitochondrion (Homo sapiens)

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11, 15, 19, 2512, 23, 2661, 5, 7, 8, 16...10, 14, 21, 2712, 232, 173, 4, 9, 18, 20...mitochondrial matrixmitochondrioncytosolMTO1TRMUtRNA(Lys,Leu)containing5-taurinomethylU-34tRNA(Lys) containing 1-methylA-58 tRNA(Leu) containing 5-taurinomethyluridine-34 tRNA(Ser)(UCN) containing A-58 GTPBP3tRNA(Lys) containing U-34 KIAA0391 AdoMettRNA(Leu,Lys)containing U-34tRNA(Lys,Leu)containing5-taurinomethyl-2-thioU-34PPitRNA(Leu)(UUR) containing A-58 tRNA(Leu,Lys,Ser)containing A-58tRNA(Lys) containing 5-taurinomethyl-2-thiouridine-34 TRMT61B tetramertRNA(Lys) containing A-58 tRNA(Lys) containing 5-taurinomethyluridine-34 AdoHcyTRMT10C tRNA(Ser) containingA-37TRMT61B tRNA(Ser) containingisopentenylA-37tRNA(Leu,Lys,Ser)containing1-methylA-58tRNA(Leu)(UUR) containing 1-methylA-58 HSD17B10 PUS1-1AdoMettRNA containing G-9dimethylallyl-PPTRIT1tRNA(Ser)(UCN) containing 1-methylA-58 AdoHcytRNA(Lys,Ser)containingpseudoU-27,28tRNA(Ser)(UGA) containing pseudoU-27,28 tRNA containing1-methylG-9tRNA(Lys)(UUU) containing U-27,28 tRNA(Lys,Ser)containing U-27,U28tRNA(Leu) containing U-34 tRNA(Ser)(UGA) containing U-27,U28 mtRNase PL-CystRNA(Leu) containing 5-taurinomethyl-2-thiouridine-34 tRNA containing A-9tRNA(Lys)(UUU) containing pseudoU-27,28 tRNA containing1-methylA-91861328


Description

The 22 tRNAs encoded by the mitochondrial genome are modified in the mitochondrial matrix by enzymes encoded in the nucleus and imported into mitochondria (reviewed in Suzuki et al. 2011, Salinas-Giege et al. 2015). Some enzymes such as PUS1 and TRIT1 are located in more than one compartment and modify both mitochondrial tRNAs and cytosolic tRNAs. Other enzymes such as MTO1, TRMU, and TRMT61B are exclusively mitochondrial.
Modifications near the anticodon and near the 3' end of tRNAs tend to affect interaction of the tRNA with mRNA within ribosomes and with tRNA synthetases, respectively. Modifications in other regions, typically in the "core" of the tRNA tend to affect folding and stability of the tRNA (reviewed in Hou et al. 2015). The unusual modification 5-taurinomethyl-2-thiouridine-34 in the anticodon of at least 3 tRNAs is found only in mammalian mitochondria and mutations that affect the responsible biosynthetic enzymes (GTPBP3, MTO1, TRMU) cause mitochondrial dysfunction and disease (reviewed in Torres et al. 2014). View original pathway at:Reactome.

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Reactome-Converter 
Pathway is converted from Reactome ID: 6787450
Reactome-version 
Reactome version: 65
Reactome Author 
Reactome Author: May, Bruce

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Bibliography

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  1. Fernandez-Vizarra E, Berardinelli A, Valente L, Tiranti V, Zeviani M.; ''Nonsense mutation in pseudouridylate synthase 1 (PUS1) in two brothers affected by myopathy, lactic acidosis and sideroblastic anaemia (MLASA).''; PubMed Europe PMC Scholia
  2. Vilardo E, Rossmanith W.; ''Molecular insights into HSD10 disease: impact of SDR5C1 mutations on the human mitochondrial RNase P complex.''; PubMed Europe PMC Scholia
  3. Holzmann J, Frank P, Löffler E, Bennett KL, Gerner C, Rossmanith W.; ''RNase P without RNA: identification and functional reconstitution of the human mitochondrial tRNA processing enzyme.''; PubMed Europe PMC Scholia
  4. Salinas-Giegé T, Giegé R, Giegé P.; ''tRNA biology in mitochondria.''; PubMed Europe PMC Scholia
  5. Chujo T, Suzuki T.; ''Trmt61B is a methyltransferase responsible for 1-methyladenosine at position 58 of human mitochondrial tRNAs.''; PubMed Europe PMC Scholia
  6. Zeharia A, Shaag A, Pappo O, Mager-Heckel AM, Saada A, Beinat M, Karicheva O, Mandel H, Ofek N, Segel R, Marom D, Rötig A, Tarassov I, Elpeleg O.; ''Acute infantile liver failure due to mutations in the TRMU gene.''; PubMed Europe PMC Scholia
  7. Sasarman F, Antonicka H, Horvath R, Shoubridge EA.; ''The 2-thiouridylase function of the human MTU1 (TRMU) enzyme is dispensable for mitochondrial translation.''; PubMed Europe PMC Scholia
  8. Ghezzi D, Baruffini E, Haack TB, Invernizzi F, Melchionda L, Dallabona C, Strom TM, Parini R, Burlina AB, Meitinger T, Prokisch H, Ferrero I, Zeviani M.; ''Mutations of the mitochondrial-tRNA modifier MTO1 cause hypertrophic cardiomyopathy and lactic acidosis.''; PubMed Europe PMC Scholia
  9. Baruffini E, Dallabona C, Invernizzi F, Yarham JW, Melchionda L, Blakely EL, Lamantea E, Donnini C, Santra S, Vijayaraghavan S, Roper HP, Burlina A, Kopajtich R, Walther A, Strom TM, Haack TB, Prokisch H, Taylor RW, Ferrero I, Zeviani M, Ghezzi D.; ''MTO1 mutations are associated with hypertrophic cardiomyopathy and lactic acidosis and cause respiratory chain deficiency in humans and yeast.''; PubMed Europe PMC Scholia
  10. Patton JR, Bykhovskaya Y, Mengesha E, Bertolotto C, Fischel-Ghodsian N.; ''Mitochondrial myopathy and sideroblastic anemia (MLASA): missense mutation in the pseudouridine synthase 1 (PUS1) gene is associated with the loss of tRNA pseudouridylation.''; PubMed Europe PMC Scholia
  11. Sibert BS, Patton JR.; ''Pseudouridine synthase 1: a site-specific synthase without strict sequence recognition requirements.''; PubMed Europe PMC Scholia
  12. Vilardo E, Nachbagauer C, Buzet A, Taschner A, Holzmann J, Rossmanith W.; ''A subcomplex of human mitochondrial RNase P is a bifunctional methyltransferase--extensive moonlighting in mitochondrial tRNA biogenesis.''; PubMed Europe PMC Scholia
  13. Guan MX, Yan Q, Li X, Bykhovskaya Y, Gallo-Teran J, Hajek P, Umeda N, Zhao H, Garrido G, Mengesha E, Suzuki T, del Castillo I, Peters JL, Li R, Qian Y, Wang X, Ballana E, Shohat M, Lu J, Estivill X, Watanabe K, Fischel-Ghodsian N.; ''Mutation in TRMU related to transfer RNA modification modulates the phenotypic expression of the deafness-associated mitochondrial 12S ribosomal RNA mutations.''; PubMed Europe PMC Scholia
  14. Gaignard P, Gonzales E, Ackermann O, Labrune P, Correia I, Therond P, Jacquemin E, Slama A.; ''Mitochondrial Infantile Liver Disease due to TRMU Gene Mutations: Three New Cases.''; PubMed Europe PMC Scholia
  15. Boczonadi V, Smith PM, Pyle A, Gomez-Duran A, Schara U, Tulinius M, Chinnery PF, Horvath R.; ''Altered 2-thiouridylation impairs mitochondrial translation in reversible infantile respiratory chain deficiency.''; PubMed Europe PMC Scholia
  16. Suzuki T, Nagao A, Suzuki T.; ''Human mitochondrial tRNAs: biogenesis, function, structural aspects, and diseases.''; PubMed Europe PMC Scholia
  17. Bykhovskaya Y, Casas K, Mengesha E, Inbal A, Fischel-Ghodsian N.; ''Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA).''; PubMed Europe PMC Scholia
  18. Lamichhane TN, Mattijssen S, Maraia RJ.; ''Human cells have a limited set of tRNA anticodon loop substrates of the tRNA isopentenyltransferase TRIT1 tumor suppressor.''; PubMed Europe PMC Scholia
  19. Charette M, Gray MW.; ''Pseudouridine in RNA: what, where, how, and why.''; PubMed Europe PMC Scholia
  20. Yarham JW, Lamichhane TN, Pyle A, Mattijssen S, Baruffini E, Bruni F, Donnini C, Vassilev A, He L, Blakely EL, Griffin H, Santibanez-Koref M, Bindoff LA, Ferrero I, Chinnery PF, McFarland R, Maraia RJ, Taylor RW.; ''Defective i6A37 modification of mitochondrial and cytosolic tRNAs results from pathogenic mutations in TRIT1 and its substrate tRNA.''; PubMed Europe PMC Scholia
  21. Tischner C, Hofer A, Wulff V, Stepek J, Dumitru I, Becker L, Haack T, Kremer L, Datta AN, Sperl W, Floss T, Wurst W, Chrzanowska-Lightowlers Z, De Angelis MH, Klopstock T, Prokisch H, Wenz T.; ''MTO1 mediates tissue specificity of OXPHOS defects via tRNA modification and translation optimization, which can be bypassed by dietary intervention.''; PubMed Europe PMC Scholia
  22. Umeda N, Suzuki T, Yukawa M, Ohya Y, Shindo H, Watanabe K, Suzuki T.; ''Mitochondria-specific RNA-modifying enzymes responsible for the biosynthesis of the wobble base in mitochondrial tRNAs. Implications for the molecular pathogenesis of human mitochondrial diseases.''; PubMed Europe PMC Scholia
  23. Ofman R, Ruiter JP, Feenstra M, Duran M, Poll-The BT, Zschocke J, Ensenauer R, Lehnert W, Sass JO, Sperl W, Wanders RJ.; ''2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency is caused by mutations in the HADH2 gene.''; PubMed Europe PMC Scholia
  24. Asano K, Suzuki T, Saito A, Wei FY, Ikeuchi Y, Numata T, Tanaka R, Yamane Y, Yamamoto T, Goto T, Kishita Y, Murayama K, Ohtake A, Okazaki Y, Tomizawa K, Sakaguchi Y, Suzuki T.; ''Metabolic and chemical regulation of tRNA modification associated with taurine deficiency and human disease.''; PubMed Europe PMC Scholia
  25. Torres AG, Batlle E, Ribas de Pouplana L.; ''Role of tRNA modifications in human diseases.''; PubMed Europe PMC Scholia
  26. Sibert BS, Fischel-Ghodsian N, Patton JR.; ''Partial activity is seen with many substitutions of highly conserved active site residues in human Pseudouridine synthase 1.''; PubMed Europe PMC Scholia
  27. Suzuki T, Suzuki T, Wada T, Saigo K, Watanabe K.; ''Taurine as a constituent of mitochondrial tRNAs: new insights into the functions of taurine and human mitochondrial diseases.''; PubMed Europe PMC Scholia
  28. Helm M, Brulé H, Degoul F, Cepanec C, Leroux JP, Giegé R, Florentz C.; ''The presence of modified nucleotides is required for cloverleaf folding of a human mitochondrial tRNA.''; PubMed Europe PMC Scholia
  29. Hou YM, Gamper H, Yang W.; ''Post-transcriptional modifications to tRNA--a response to the genetic code degeneracy.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114828view16:32, 25 January 2021ReactomeTeamReactome version 75
113274view11:34, 2 November 2020ReactomeTeamReactome version 74
112486view15:44, 9 October 2020ReactomeTeamReactome version 73
101398view11:28, 1 November 2018ReactomeTeamreactome version 66
100936view21:04, 31 October 2018ReactomeTeamreactome version 65
100473view19:38, 31 October 2018ReactomeTeamreactome version 64
100018view16:22, 31 October 2018ReactomeTeamreactome version 63
99571view14:54, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99194view12:43, 31 October 2018ReactomeTeamreactome version 62
93745view13:33, 16 August 2017ReactomeTeamreactome version 61
93739view13:25, 16 August 2017ReactomeTeamreactome version 61
93260view11:18, 9 August 2017ReactomeTeamreactome version 61
87826view11:43, 25 July 2016MirellaKalafatiOntology Term : 'regulatory pathway' added !
86340view09:15, 11 July 2016ReactomeTeamreactome version 56
86214view11:11, 7 July 2016ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
AdoHcyMetaboliteCHEBI:16680 (ChEBI)
AdoMetMetaboliteCHEBI:15414 (ChEBI)
GTPBP3ProteinQ969Y2 (Uniprot-TrEMBL)
HSD17B10 ProteinQ99714 (Uniprot-TrEMBL)
KIAA0391 ProteinO15091 (Uniprot-TrEMBL)
L-CysMetaboliteCHEBI:35235 (ChEBI)
MTO1ProteinQ9Y2Z2 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
PUS1-1ProteinQ9Y606-1 (Uniprot-TrEMBL)
TRIT1ProteinQ9H3H1 (Uniprot-TrEMBL)
TRMT10C ProteinQ7L0Y3 (Uniprot-TrEMBL)
TRMT61B ProteinQ9BVS5 (Uniprot-TrEMBL)
TRMT61B tetramerComplexR-HSA-6787508 (Reactome)
TRMUProteinO75648 (Uniprot-TrEMBL)
dimethylallyl-PPMetaboliteCHEBI:16057 (ChEBI)
mtRNase PComplexR-HSA-6785726 (Reactome)
tRNA containing 1-methylA-9R-HSA-6787584 (Reactome)
tRNA containing 1-methylG-9R-HSA-6787587 (Reactome)
tRNA containing A-9R-HSA-6787556 (Reactome)
tRNA containing G-9R-HSA-6787559 (Reactome)
tRNA(Leu) containing 5-taurinomethyl-2-thiouridine-34 R-HSA-6787459 (Reactome)
tRNA(Leu) containing 5-taurinomethyluridine-34 R-HSA-6787375 (Reactome)
tRNA(Leu) containing U-34 R-HSA-6787474 (Reactome)
tRNA(Leu)(UUR) containing 1-methylA-58 R-HSA-6787522 (Reactome)
tRNA(Leu)(UUR) containing A-58 R-HSA-6787514 (Reactome)
tRNA(Leu,Lys) containing U-34ComplexR-HSA-6787446 (Reactome)
tRNA(Leu,Lys,Ser)

containing

1-methylA-58		ComplexR-HSA-6787517 (Reactome)
tRNA(Leu,Lys,Ser) containing A-58ComplexR-HSA-6787519 (Reactome)
tRNA(Lys) containing 1-methylA-58 R-HSA-6787509 (Reactome)
tRNA(Lys) containing 5-taurinomethyl-2-thiouridine-34 R-HSA-6787463 (Reactome)
tRNA(Lys) containing 5-taurinomethyluridine-34 R-HSA-6787395 (Reactome)
tRNA(Lys) containing A-58 R-HSA-6787520 (Reactome)
tRNA(Lys) containing U-34 R-HSA-6787392 (Reactome)
tRNA(Lys)(UUU) containing U-27,28 R-HSA-6787590 (Reactome)
tRNA(Lys)(UUU) containing pseudoU-27,28 R-HSA-6787593 (Reactome)
tRNA(Lys,Leu)

containing

5-taurinomethyl-2-thioU-34		ComplexR-HSA-6787387 (Reactome)
tRNA(Lys,Leu)

containing

5-taurinomethylU-34		ComplexR-HSA-6787473 (Reactome)
tRNA(Lys,Ser)

containing

pseudoU-27,28		ComplexR-HSA-6787558 (Reactome)
tRNA(Lys,Ser) containing U-27,U28ComplexR-HSA-6787562 (Reactome)
tRNA(Ser) containing A-37R-HSA-6787583 (Reactome)
tRNA(Ser) containing isopentenylA-37R-HSA-6787597 (Reactome)
tRNA(Ser)(UCN) containing 1-methylA-58 R-HSA-6787518 (Reactome)
tRNA(Ser)(UCN) containing A-58 R-HSA-6787511 (Reactome)
tRNA(Ser)(UGA) containing U-27,U28 R-HSA-6787586 (Reactome)
tRNA(Ser)(UGA) containing pseudoU-27,28 R-HSA-6787557 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
AdoHcyArrowR-HSA-6787525 (Reactome)
AdoHcyArrowR-HSA-6787591 (Reactome)
AdoHcyArrowR-HSA-6787594 (Reactome)
AdoMetR-HSA-6787525 (Reactome)
AdoMetR-HSA-6787591 (Reactome)
AdoMetR-HSA-6787594 (Reactome)
GTPBP3mim-catalysisR-HSA-6787403 (Reactome)
L-CysR-HSA-6787447 (Reactome)
MTO1mim-catalysisR-HSA-6787403 (Reactome)
PPiArrowR-HSA-6787567 (Reactome)
PUS1-1mim-catalysisR-HSA-6787566 (Reactome)
R-HSA-6787403 (Reactome) A conserved pathway consisting of at least GTPBP3 (MSS1 in Saccharomyces cerevisiae, MnmE in Escherichia coli) and MTO1 (MTO1 in S. cerevisiae, MnmG in E. coli) modifies the wobble nucleotide uridine-34 in mitochondrial tRNA. In humans a methyl group and a taurine group (2-aminoethylsulfonic acid) are conjugated to the 5 position of the uracil ring (Suzuki et al. 2002). In yeast and E. coli a methyl group and a glycine group are conjugated, yielding 5-carboxymethylaminomethyluridine. The details of the reaction mechanism are unknown. Modification of the wobble nucleotide is required for efficient and accurate translation. Mutations in constituents of the pathway cause disease symptoms characteristic of mitochondrial dysfunction: lactic acidosis, hypertrophic cardiomyopathy, respiratory chain defect, and, in association with the A1555G mutation in 12S rRNA, deafness (Ghezzi et al. 2012, Baruffini et al. 2013, Tischner et al. 2015).
R-HSA-6787447 (Reactome) TRMU (MTU1) transfers a sulfur atom from L-cysteine to the 2 position of 5-taurinomethyluridine-34 in tRNAs (Umeda et al. 2005, Sasarman et al. 2011). In Escherichia coli the sulfur is transferred along a relay system of proteins from L-cysteine to uridine. It is unknown if such a relay system also exists in humans. In yeast, mutations in MTU1, the homolog of TRMU act synergistically with mutations in the homologs of GTPBP3 and MTO1 to impair mitochondrial function (Umeda et al. 2005). In humans mutations in TRMU cause mitochondrial infantile liver disease (Zeharia et al. 2009, Gaignard et al. 2013), infantile respiratory chain disease (Boczonadi et al. 2013), and modify the severity of deafness associated with mutations in mitochondrial 12S rRNA (Guan et al. 2006), however abrogation of the thiouridylase function of TRMU may not be responsible for the phenotypes (Sasarman et al. 2011).
R-HSA-6787525 (Reactome) A TRMT61B oligomer, probably a tetramer, transfers a methyl group from S-adenosylmethionine to the (N)1 position of adenosine-58 in 3 mitochondrial tRNAs (tRNA(Leu)(UUR), tRNA(Lys), tRNA(Ser(UCN)) (Chujo and Suzuki 2012).
R-HSA-6787566 (Reactome) PUS1-1, the longer isoform of PUS1 located in the mitochondrion (Fernandez-Vizarra et al. 2007), converts uridine-27 and uridine-28 to pseudouridine residues in the anticodon stems of mitochondrial tRNA(Lys)(UUU) and tRNA(Ser)(UGA) (Patton et al. 2005, Fernandez-Vizarra et al. 2007, Sibert et al. 2008, Sibert and Patton 2012). Isomerization of uracil to pseudouridine creates an extra hydrogen bond donor and increases base stacking, acting to rigidify the RNA structure (reviewed in Charette and Gray 2000). As inferred from yeast Pus1p, PUS1 may also convert uridine to pseudouridine in other tRNAs and pre-tRNAs. Mutations in PUS1 cause mitochondrial myopathy and sideroblastic anemia (MLSA) (Bykhovskaya et al. 2004, Patton et al. 2005, Fernandez-Vizarra et al. 2007)
R-HSA-6787567 (Reactome) TRIT1 transfers a dimethylallyl group (isopentenyl group) from dimethylallyl diphosphate to the N6 position of adenosine-37 in mitochondrial tRNA(Ser,UCN), yielding N6-dimethylallyladenosine-37 (N6-isopentenyladenosine-37) (Lamichhane et al. 2013, Yarham et al. 2014). TRIT1 modifies both cytosolic and mitochondrial tRNAs and a mutation in TRIT1 causes defects in mitochondrial protein synthesis and respiration (Yarham et al. 2014).
R-HSA-6787591 (Reactome) TRMT10C in TRMT10C:HSD17B10 (TRMT10C:SDR5C1), a subcomplex of the mitochondrial RNase P complex, methylates the 1 position of guanosine-9 in mitochondrial tRNAs (Vilardo et al. 2012). 5 of 22 mitochondrial tRNAs have a G9 residue. Methylation of G9 appears to be important for correct folding of tRNA. Mutations in the SDR5C1 dehydrogenase subunit of RNase P impair dehydrogenation, tRNA methylation, and tRNA processing, causing HSD10 disease, which is characterized by progressive neurodegeneration and cardiomyopathy (Vilardo and Rossmanith 2015).
R-HSA-6787594 (Reactome) TRMT10C of TRMT10C:HSD17B10 (TRMT10C:SDR5C1), a subcomplex of the mitochondrial RNase P complex, methylates the 1 position of adenosine-9 in mitochondrial tRNAs (Vilardo et al. 2012). 14 of 22 mitochondrial tRNAs have an A9 residue. Methylation of A9 appears to be important for correct folding of tRNA (Helm et al. 1998). Mutations in the HSD17B10 (SDR5C1) dehydrogenase subunit of RNase P impair dehydrogenation, tRNA methylation, and tRNA processing, causing HSD10 disease, which is characterized by progressive neurodegeneration and cardiomyopathy (Vilardo and Rossmanith 2015).
TRIT1mim-catalysisR-HSA-6787567 (Reactome)
TRMT61B tetramermim-catalysisR-HSA-6787525 (Reactome)
TRMUmim-catalysisR-HSA-6787447 (Reactome)
dimethylallyl-PPR-HSA-6787567 (Reactome)
mtRNase Pmim-catalysisR-HSA-6787591 (Reactome)
mtRNase Pmim-catalysisR-HSA-6787594 (Reactome)
tRNA containing 1-methylA-9ArrowR-HSA-6787594 (Reactome)
tRNA containing 1-methylG-9ArrowR-HSA-6787591 (Reactome)
tRNA containing A-9R-HSA-6787594 (Reactome)
tRNA containing G-9R-HSA-6787591 (Reactome)
tRNA(Leu,Lys) containing U-34R-HSA-6787403 (Reactome)
tRNA(Leu,Lys,Ser)

containing

1-methylA-58		ArrowR-HSA-6787525 (Reactome)
tRNA(Leu,Lys,Ser) containing A-58R-HSA-6787525 (Reactome)
tRNA(Lys,Leu)

containing

5-taurinomethyl-2-thioU-34		ArrowR-HSA-6787447 (Reactome)
tRNA(Lys,Leu)

containing

5-taurinomethylU-34		ArrowR-HSA-6787403 (Reactome)
tRNA(Lys,Leu)

containing

5-taurinomethylU-34		R-HSA-6787447 (Reactome)
tRNA(Lys,Ser)

containing

pseudoU-27,28		ArrowR-HSA-6787566 (Reactome)
tRNA(Lys,Ser) containing U-27,U28R-HSA-6787566 (Reactome)
tRNA(Ser) containing A-37R-HSA-6787567 (Reactome)
tRNA(Ser) containing isopentenylA-37ArrowR-HSA-6787567 (Reactome)
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