Radical -adenosylmethionine (SAM) enzymes catalyze an astonishing array of complex and chemically challenging reactions across all domains of life. Of approximately 114,000 of these enzymes, 8 are known to be present in humans: MOCS1, molybdenum cofactor biosynthesis; LIAS, lipoic acid biosynthesis; CDK5RAP1, 2-methylthio-6-isopentenyladenosine biosynthesis; CDKAL1, methylthio-6-threonylcarbamoyladenosine biosynthesis; TYW1, wybutosine biosynthesis; ELP3, 5-methoxycarbonylmethyl uridine; and RSAD1 and viperin, both of unknown function. Aberrations in the genes encoding these proteins result in a variety of diseases. In this review, we summarize the biochemical characterization of these 8 radical -adenosylmethionine enzymes and, in the context of human health, describe the deleterious effects that result from such genetic mutations.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Lu SC, Mato JM. 1.  2012. S-Adenosylmethionine in liver health, injury, and cancer. Physiol. Rev. 92:1515–42 [Google Scholar]
  2. Roje S. 2.  2006. S-Adenosyl-l-methionine: beyond the universal methyl donor. Phytochemistry 67:1686–98 [Google Scholar]
  3. Sufrin JR, Finckbeiner S, Oliver CM. 3.  2009. Marine-derived metabolites of S-adenosylmethionine as templates for new anti-infectives. Mar. Drugs 7:401–34 [Google Scholar]
  4. Fuqua C, Greenberg EP. 4.  1998. Self perception in bacteria: quorum sensing with acylated homoserine lactones. Curr. Opin. Microbiol. 1:183–89 [Google Scholar]
  5. Eustáquio AS, Pojer F, Noel JP, Moore BS. 5.  2008. Discovery and characterization of a marine bacterial SAM-dependent chlorinase. Nat. Chem. Biol. 4:69–74 [Google Scholar]
  6. Landgraf BJ, Booker SJ. 6.  2013. Biochemistry: The ylide has landed. Nature 498:45–47 [Google Scholar]
  7. Fontecave M, Atta M, Mulliez E. 7.  2004. S-Adenosylmethionine: nothing goes to waste. Trends Biochem. Sci. 29:243–9 [Google Scholar]
  8. Broderick JB, Duffus BR, Duschene KS, Shepard EM. 8.  2014. Radical S-adenosylmethionine enzymes. Chem. Rev. 114:4229–317 [Google Scholar]
  9. Challand MR, Driesener RC, Roach PL. 9.  2011. Radical S-adenosylmethionine enzymes: mechanism, control and function. Nat. Prod. Rep. 28:1696–721 [Google Scholar]
  10. Wang SC, Frey PA. 10.  2007. S-adenosylmethionine as an oxidant: the radical SAM superfamily. Trends Biochem. Sci. 32:101–10 [Google Scholar]
  11. Wang SC, Frey PA. 11.  2007. Binding energy in the one-electron reductive cleavage of S-adenosylmethionine in lysine 2,3-aminomutase, a radical SAM enzyme. Biochemistry 46:12889–95 [Google Scholar]
  12. Hiscox MJ, Driesener RC, Roach PL. 12.  2012. Enzyme catalyzed formation of radicals from S-adenosylmethionine and inhibition of enzyme activity by the cleavage products. Biochim. Biophys. Acta 1824:1165–77 [Google Scholar]
  13. Sofia HJ, Chen G, Hetzler BG, Reyes-Spindola JF, Miller NE. 13.  2001. Radical SAM, a novel protein superfamily linking unresolved steps in familiar biosynthetic pathways with radical mechanisms: functional characterization using new analysis and information visualization methods. Nucleic Acids Res. 29:1097–106 [Google Scholar]
  14. Walsby CJ, Ortillo D, Yang J, Nnyepi MR, Broderick WE. 14.  et al. 2005. Spectroscopic approaches to elucidating novel iron-sulfur chemistry in the “radical-SAM” protein superfamily. Inorg. Chem. 44:727–41 [Google Scholar]
  15. Dowling DP, Vey JL, Croft AK, Drennan CL. 15.  2012. Structural diversity in the AdoMet radical enzyme superfamily. Biochim. Biophys. Acta 1824:1178–95 [Google Scholar]
  16. Dey A, Peng Y, Broderick WE, Hedman B, Hodgson KO. 16.  et al. 2011. S K-edge XAS and DFT calculations on SAM-dependent pyruvate formate-lyase activating enzyme: Nature of interaction between the Fe4S4 cluster and SAM and its role in reactivity. J. Am. Chem. Soc. 133:18656–62 [Google Scholar]
  17. Cosper NJ, Booker SJ, Ruzicka F, Frey PA, Scott RA. 17.  2000. Direct FeS cluster involvement in generation of a radical in lysine 2,3-aminomutase. Biochemistry 39:15668–73 [Google Scholar]
  18. Nicolet Y, Amara P, Mouesca J-M, Fontecilla-Camps JC. 18.  2009. Unexpected electron transfer mechanism upon AdoMet cleavage in radical SAM proteins. PNAS 106:14867–71 [Google Scholar]
  19. Grell TA, Goldman PJ, Drennan CL. 19.  2015. SPASM and twitch domains in S-adenosylmethionine (SAM) radical enzymes. J. Biol. Chem. 290:3964–71 [Google Scholar]
  20. 20.  Deleted in proof
  21. Akiva E, Brown S, Almonacid DE, Barber AE. Custer AF. 21.  2nd, et al. 2014. The structure-function linkage database. Nucleic Acids Res. 42:D521–30 [Google Scholar]
  22. Duschene KS, Veneziano SE, Silver SC, Broderick JB. 22.  2009. Control of radical chemistry in the AdoMet radical enzymes. Curr. Opin. Chem. Biol. 13:74–83 [Google Scholar]
  23. Schwarz G, Mendel RR, Ribbe MW. 23.  2009. Molybdenum cofactors, enzymes and pathways. Nature 460:839–47 [Google Scholar]
  24. McMaster J, Garner CD, Stiefel EI. 24.  2007. Molybdenum enzymes. Biological Inorganic Chemistry: Structure and Reactivity I Bertini, HB Gray, EI Stiefel, JS Valentine 518–30 Sausalito, CA: University Science Books [Google Scholar]
  25. Schwarz G, Mendel RR. 25.  2006. Molybdenum cofactor biosynthesis and molybdenum enzymes. Annu. Rev. Plant Biol. 57:623–47 [Google Scholar]
  26. Rieder C, Eisenreich W, O'Brien J, Richter G, Gotze E. 26.  et al. 1998. Rearrangement reactions in the biosynthesis of molybdopterin: an NMR study with multiply 13C/15N labelled precursors. Eur. J. Biochem. 255:24–36 [Google Scholar]
  27. Wuebbens MM, Rajagopalan KV. 27.  1995. Investigation of the early steps of molybdopterin biosynthesis in Escherichia coli through the use of in vivo labeling studies. J. Biol. Chem. 270:1082–87 [Google Scholar]
  28. Hänzelmann P, Schwartz G, Mendel RR. 28.  2002. Functionality of alternative splice forms of the first enzymes involved in human molybdenum cofactor biosynthesis. J. Biol. Chem. 277:18303–12 [Google Scholar]
  29. Hänzelmann P, Schindelin H. 29.  2004. Crystal structure of the S-adenosylmethionine-dependent enzyme MoaA and its implications for molybdenum cofactor deficiency in humans. PNAS 101:12870–75 [Google Scholar]
  30. Hänzelmann P, Schindelin H. 30.  2006. Binding of 5′-GTP to the C-terminal FeS cluster of the radical S-adenosylmethionine enzyme MoaA provides insights into its mechanism. PNAS 103:6829–34 [Google Scholar]
  31. Lees NS, Hänzelmann P, Hernandez HL, Subramanian S, Schindelin H. 31.  et al. 2009. ENDOR spectroscopy shows that guanine N1 binds to [4Fe-4S] cluster II of the S-adenosylmethionine-dependent enzyme MoaA: mechanistic implications. J. Am. Chem. Soc. 131:9184–85 [Google Scholar]
  32. Hover BM, Loksztejn A, Ribeiro AA, Yokoyama K. 32.  2013. Identification of a cyclic nucleotide as a cryptic intermediate in molybdenum cofactor biosynthesis. J. Am. Chem. Soc. 135:7019–32 [Google Scholar]
  33. Hover BM, Tonthat NK, Schumacher MA, Yokoyama K. 33.  2015. Mechanism of pyranopterin ring formation in molybdenum cofactor biosynthesis. PNAS 112:6347–52 [Google Scholar]
  34. Mehta AP, Hanes JW, Abdelwahed SH, Hilmey DG, Hänzelmann P, Begley TP. 34.  2013. Catalysis of a new ribose carbon-insertion reaction by the molybdenum cofactor biosynthetic enzyme MoaA. Biochemistry 52:1134–36 [Google Scholar]
  35. Mehta AP, Abdelwahed SH, Begley TP. 35.  2013. Molybdopterin biosynthesis: trapping an unusual purine ribose adduct in the MoaA-catalyzed reaction. J. Am. Chem. Soc. 135:10883–85 [Google Scholar]
  36. Mehta AP, Abdelwahed SH, Xu H, Begley TP. 36.  2014. Molybdopterin biosynthesis: trapping of intermediates for the MoaA-catalyzed reaction using 2′-deoxyGTP and 2′-chloroGTP as substrate analogues. J. Am. Chem. Soc. 136:10609–14 [Google Scholar]
  37. Schwarz G, Santamaria-Araujo JA, Wolf S, Lee H-J, Adham IM. 37.  et al. 2004. Rescue of lethal molybdenum cofactor deficiency by a biosynthetic precursor from Escherichia coli. Hum. Mol. Genet. 13:1249–55 [Google Scholar]
  38. Reiss J, Johnson JL. 38.  2003. Mutations in the molybdenum cofactor biosynthetic genes MOCS1, MOCS2, and GEPH. Hum. Mutat. 21:569–76 [Google Scholar]
  39. Johnson JL. 39.  2003. Prenatal diagnosis of molybdenum cofactor deficiency and isolated sulfite oxidase deficiency. Prenat. Diagn. 23:6–8 [Google Scholar]
  40. Lee H-J, Adham IM, Schwarz G, Kneussel M, Sass JO. 40.  et al. 2002. Molybdenum cofactor-deficient mice resemble the phenotype of human patients. Hum. Mol. Genet. 11:3309–17 [Google Scholar]
  41. Duran M, Beemer FA, van de Heiden C, Korteland J, de Bree PK. 41.  et al. 1978. Combined deficiency of xanthine oxidase and sulphite oxidase: a defect of molybdenum metabolism or transport?. J. Inherit. Metab. Dis. 1:175–78 [Google Scholar]
  42. Reiss J, Christensen E, Kurlemann G, Zabot M-T, Dorche C. 42.  1998. Genomic structure and mutational spectrum of the bicistronic MOCS1 gene defective in molybdenum cofactor deficiency type A. Hum. Genet. 103:639–44 [Google Scholar]
  43. Leimkuhler S, Charcosset M, Latour P, Dorche C, Kleppe S. 43.  et al. 2005. Ten novel mutations in the molybdenum cofactor genes MOCS1 and MOCS2 and in vitro characterization of a MOCS2 mutation that abolishes the binding ability of molybdopterin synthase. Hum. Genet. 117:565–70 [Google Scholar]
  44. Hänzelmann P, Schindelin H. 44.  2006. Binding of 5′-GTP to the C-terminal FeS cluster of the radical S-adenosylmethionine enzyme MoaA provides insights into its mechanism. PNAS 103:6829–34 [Google Scholar]
  45. Deleted in proof
  46. Veldman A, Santamaria-Araujo JA, Sollazzo S, Pitt J, Gianello R. 46.  et al. 2010. Successful treatment of molybdenum cofactor deficiency type A with cPMP. Pediatrics 125:e1249–54 [Google Scholar]
  47. Reed L. 47.  1974. Multienzyme complexes. Acc. Chem. Res. 7:40–46 [Google Scholar]
  48. Packer L, Kraemer K, Rimbach G. 48.  2001. Molecular aspects of lipoic acid in the prevention of diabetes complications. Nutrition 17:888–95 [Google Scholar]
  49. Yi X, Xu L, Hiller S, Kim HS, Nickeleit V. 49.  et al. 2012. Reduced expression of lipoic acid synthase accelerates diabetic nephropathy. J. Am. Soc. Nephrol. 23:103–11 [Google Scholar]
  50. Padmalayam I, Hasham S, Saxena U, Pillarisetti S. 50.  2009. Lipoic acid synthase (LASY): a novel role in inflammation, mitochondrial function, and insulin resistance. Diabetes 58:600–608 [Google Scholar]
  51. Cronan JE, Zhao X, Jiang Y. 51.  2005. Function, attachment and synthesis of lipoic acid in Escherichia coli. Adv. Microb. Physiol. 50:103–46 [Google Scholar]
  52. Wada H, Shintani D, Ohlrogge J. 52.  1997. Why do mitochondria synthesize fatty acids? Evidence for involvement in lipoic acid production. PNAS 94:1591–96 [Google Scholar]
  53. Fujiwara K, Takeuchi S, Okamura-Ikeda K, Motokawa Y. 53.  2001. Purification, characterization, and cDNA cloning of lipoate-activating enzyme from bovine liver. J. Biol. Chem. 276:28819–23 [Google Scholar]
  54. Fujiwara K, Okamura-Ikeda K, Motokawa Y. 54.  1994. Purification and characterization of lipoyl-AMP:N epsilon-lysine lipoyltransferase from bovine liver mitochondria. J. Biol. Chem. 269:16605–9 [Google Scholar]
  55. Fujiwara K, Okamura-Ikeda K, Motokawa Y. 55.  1996. Lipoylation of acyltransferase components of α-ketoacid dehydrogenase complexes. J. Biol. Chem. 271:12932–36 [Google Scholar]
  56. Billgren ES, Cicchillo RM, Nesbitt NM, Booker SJ. 56.  2010. Comprehensive Natural Products II Chemistry and Biology L Mander, H-W Liu 181–212 Oxford: Elsevier [Google Scholar]
  57. Lanz ND, Booker SJ. 57.  2014. The role of iron-sulfur clusters in the biosynthesis of the lipoyl cofactor.. Iron-Sulfur Clusters in Chemistry and Biology TA Rouault 211–31 Berlin: Walter de Gruyter [Google Scholar]
  58. Cicchillo RM, Lee K-H, Baleanu-Gogonea C, Nesbitt NM, Krebs C, Booker SJ. 58.  2004. Escherichia coli lipoyl synthase binds two distinct [4Fe-4S] clusters per polypeptide. Biochemistry 43:11770–81 [Google Scholar]
  59. Harmer JE, Hiscox MJ, Dinis PC, Fox SJ, Lliopoulos A. 59.  et al. 2014. Structures of lipoyl synthase reveal a compact active site for controlling sequential sulfur insertion reactions. Biochem. J. 464:123–33 [Google Scholar]
  60. Cicchillo RM, Booker SJ. 60.  2005. Mechanistic investigations of lipoic acid biosynthesis in Escherichia coli: Both sulfur atoms in lipoic acid are contributed by the same lipoyl synthase polypeptide. J. Am. Chem. Soc. 127:2860–61 [Google Scholar]
  61. Lanz ND, Pandelia ME, Kakar ES, Lee K-H, Krebs C, Booker SJ. 61.  2014. Evidence for a catalytically and kinetically competent enzyme-substrate cross-linked intermediate in catalysis by lipoyl synthase. Biochemistry 53:4557–72 [Google Scholar]
  62. Douglas P, Kriek M, Bryant P, Roach PL. 62.  2006. Lipoyl synthase inserts sulfur atoms into an octanoyl substrate in a stepwise manner. Angew. Chem. 118:5321–23 [Google Scholar]
  63. Parry RJ, Trainor DA. 63.  1978. Biosynthesis of lipoic acid. 2. Stereochemistry of sulfur introduction at C-6 of octanoic acid. J. Am. Chem. Soc. 100:5243–44 [Google Scholar]
  64. Booker SJ, Cicchillo RM, Grove TL. 64.  2007. Self-sacrifice in radical S-adenosylmethionine proteins. Curr. Opin. Chem. Biol. 11:543–52 [Google Scholar]
  65. Cicchillo RM, Iwig DF, Jones AD, Nesbitt NM, Baleanu-Gogonea C. 65.  et al. 2004. Lipoyl synthase requires two equivalents of S-adenosyl-l-methionine to synthesize one equivalent of lipoic acid. Biochemistry 43:6378–86 [Google Scholar]
  66. Baker PR 2nd, Friederich MW, Swanson MA, Shaikh T, Bhattacharya K. 66.  et al. 2014. Variant non-ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5. Brain 137:366–79 [Google Scholar]
  67. Mayr JA, Feichtinger RG, Tort F, Ribes A, Sperl W. 67.  2014. Lipoic acid biosynthesis defects. J. Inherit. Metab. Dis. 37:553–63 [Google Scholar]
  68. Tsurusaki Y, Tanaka R, Shimada S, Shimojima K, Shiina M. 68.  et al. 2015. Novel compound heterozygous LIAS mutations cause glycine encephalopathy. J. Hum. Genet. 60:631–35 [Google Scholar]
  69. Hoover-Fong JE, Shah S, Van Hove JL, Applegarth D, Toone J, Hamosh A. 69.  2004. Natural history of nonketotic hyperglycinemia in 65 patients. Neurology 63:1847–53 [Google Scholar]
  70. Mayr JA, Zimmermann FA, Fauth C, Bergheim C, Meierhofer D. 70.  et al. 2011. Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation. Am. J. Hum. Genet. 89:792–97 [Google Scholar]
  71. Rouault TA, Tong WH. 71.  2008. Iron–sulfur cluster biogenesis and human disease. Trends Genet. 24:398–407 [Google Scholar]
  72. Stehling O, Wilbrecht C, Lill R. 72.  2014. Mitochondrial iron-sulfur protein biogenesis and human disease. Biochimie 100:61–77 [Google Scholar]
  73. Cameron JM, Janer A, Levandovskiy V, Mackay N, Rouault TA. 73.  et al. 2011. Mutations in iron-sulfur cluster scaffold genes NFU1 and BOLA3 cause a fatal deficiency of multiple respiratory chain and 2-oxoacid dehydrogenase enzymes. Am. J. Hum. Genet. 89:486–95 [Google Scholar]
  74. Invernizzi F, Ardissone A, Lamantea E, Garavaglia B, Zeviani M. 74.  et al. 2014. Cavitating leukoencephalopathy with multiple mitochondrial dysfunction syndrome and NFU1 mutations. Front. Genet. 5:412 [Google Scholar]
  75. Navarro-Sastre A, Tort F, Stehling O, Uzarska MA, Arranz JA. 75.  et al. 2011. A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins. Am. J. Hum. Genet. 89:656–67 [Google Scholar]
  76. Nizon M, Boutron A, Boddaert N, Slama A, Delpech H. 76.  et al. 2014. Leukoencephalopathy with cysts and hyperglycinemia may result from NFU1 deficiency. Mitochondrion 15:59–64 [Google Scholar]
  77. Seyda A, Newbold RF, Hudson TJ, Verner A, MacKay N. 77.  et al. 2001. A novel syndrome affecting multiple mitochondrial functions, located by microcell-mediated transfer to chromosome 2p14-2p13. Am. J. Hum. Genet. 68:386–96 [Google Scholar]
  78. El Yacoubi B, Bailly M, de Crécy-Lagard V. 78.  2012. Biosynthesis and function of posttranscriptional modifications of transfer RNAs. Annu. Rev. Genet. 46:69–95 [Google Scholar]
  79. Torres AG, Batlle E, de Pouplana LR. 79.  2014. Role of tRNA modifications in human diseases. Trends Mol. Med. 20:306–14 [Google Scholar]
  80. Atta M, Mulliez E, Arragain S, Forouhar F, Hunt JF, Fontecave M. 80.  2010. S-adenosylmethionine-dependent radical-based modification of biological macromolecules. Curr. Opin. Struct. Biol. 20:1–9 [Google Scholar]
  81. Anton BP, Russell SP, Vertrees J, Kasif S, Raleigh EA. 81.  et al. 2010. Functional characterization of the YmcB and YqeV tRNA methylthiotransferases of Bacillus subtilis. Nucleic Acids Res. 38:6195–205 [Google Scholar]
  82. Arragain S, García-Serres R, Blondin G, Douki T, Clemancey M. 82.  et al. 2010. Post-translational modification of ribosomal proteins: structural and functional characterization of RimO from Thermotoga maritima, a radical S-adenosylmethionine methylthiotransferase. J. Biol. Chem. 285:5792–801 [Google Scholar]
  83. Landgraf BJ, Booker SJ. 82a.  2016. Stereochemical course of the reaction catalyzed by RimO, a radical SAM methylthiotransferase. J. Am. Chem. Soc. 138:2889–92 [Google Scholar]
  84. Anton BP, Saleh L, Benner JS, Raleigh EA, Kasif S, Roberts RJ. 83.  2008. RimO, a MiaB-like enzyme, methylthiolates the universally conserved Asp88 residue of ribosomal protein S12 in Escherichia coli. PNAS 105:1826–31 [Google Scholar]
  85. Arragain S, Handelman SK, Forouhar F, Wei FY, Tomizawa K. 84.  et al. 2010. Identification of eukaryotic and prokaryotic methylthiotransferase for biosynthesis of 2-methylthio-N6-threonylcarbamoyladenosine in tRNA. J. Biol. Chem. 285:28425–33 [Google Scholar]
  86. Pierrel F, Björk GR, Fontecave M, Atta M. 85.  2002. Enzymatic modification of tRNAs: MiaB is an iron–sulfur protein. J. Biol. Chem. 277:13367–70 [Google Scholar]
  87. Pierrel F, Douki T, Fontecave M, Atta M. 86.  2004. MiaB protein is a bifunctional radical-S-adenosylmethionine enzyme involved in thiolation and methylation of tRNA. J. Biol. Chem. 279:47555–653 [Google Scholar]
  88. Mitchell A, Chang HY, Daugherty L, Fraser M, Hunter S. 87.  et al. 2015. The InterPro protein families database: the classification resource after 15 years. Nucleic Acids Res. 43:D213–21 [Google Scholar]
  89. Bartz JK, Kline LK, Soll D. 88.  1970. N6-(Δ2-isopentenyl)adenosine: biosynthesis in vitro in transfer RNA by an enzyme purified from Escherichia coli. Biochem. Biophys. Res. Commun. 40:1481–87 [Google Scholar]
  90. Rosenbaum N, Gefter ML. 89.  1972. Δ2-Isopentenylpyrophosphate: transfer ribonucleic acid Δ2-isopentenyltransferase from Escherichia coli. Purification and properties of the enzyme. J. Biol. Chem. 247:5675–80 [Google Scholar]
  91. Deutsch C, El Yacoubi B, de Crecy-Lagard V, Iwata-Reuyl D. 90.  2012. Biosynthesis of threonylcarbamoyl adenosine (t6A), a universal tRNA nucleoside. J. Biol. Chem. 287:13666–73 [Google Scholar]
  92. Connolly DM, Winkler ME. 91.  1991. Structure of Escherichia coli K-12 miaA and characterization of the mutator phenotype caused by miaA insertion mutations. J. Bacteriol. 173:1711–21 [Google Scholar]
  93. Esberg B, Björk GR. 92.  1995. The methylthio group (ms2) of N6-(4-hydroxyisopentenyl)-2-methylthioadenosine (ms2io6A) present next to the anticodon contributes to the decoding efficiency of the tRNA. J. Bacteriol. 177:1967–75 [Google Scholar]
  94. Urbonavicius J, Qian Q, Durand JMB, Hagervall TG, Björk GR. 93.  2001. Improvement of reading frame maintenance is a common function for several tRNA modifications. EMBO J. 20:4863–73 [Google Scholar]
  95. Forouhar F, Arragain S, Atta M, Gambarelli S, Mouesca J-M. 94.  et al. 2013. Two Fe-S clusters catalyze sulfur insertion by radical-SAM methylthiotransferases. Nat. Chem. Biol. 9:333–38 [Google Scholar]
  96. Lee K-H, Saleh L, Anton BP, Madinger CL, Benner JS. 95.  et al. 2009. Characterization of RimO, a new member of the methylthiotransferase subclass of the radical SAM superfamily. Biochemistry 48:10162–74 [Google Scholar]
  97. Pierrel F, Hernandez HL, Johnson MK, Fontecave M, Atta M. 96.  2003. Characterization of an extremely thermophilic tRNA-methylthiotransferase. J. Biol. Chem. 278:29515–24 [Google Scholar]
  98. Landgraf BJ, Arcinas AJ, Lee K-H, Booker SJ. 97.  2013. Identification of an intermediate methyl carrier in the radical S-adenosylmethionine methylthiotransferases RimO and MiaB. J. Am. Chem. Soc. 135:15404–16 [Google Scholar]
  99. Agris PF, Armstrong DJ, Schafer KP, Soll D. 98.  1975. Maturation of a hypermodified nucleoside in transfer RNA. Nucleic Acids Res. 2:691–98 [Google Scholar]
  100. Zou X, Ji C, Jin F, Liu J, Wu M. 99.  et al. 2004. Cloning, characterization and expression of CDK5RAP1_v3 and CDK5RAP1_v4, two novel splice variants of human CDK5RAP1. Genes Genet. Syst. 79:177–82 [Google Scholar]
  101. Ching Y-P, Pang ASH, Lam W-H, Qi RZ, Wang JH. 100.  2002. Identification of a neuronal Cdk5 activator-binding protein as Cdk5 inhibitor. J. Biol. Chem. 277:15237–40 [Google Scholar]
  102. Dhaven R, Tsai L-H. 101.  2001. A decade of CDK5. Nat. Rev. Mol. Cell Biol. 2:749–59 [Google Scholar]
  103. Reiter V, Matschkal DMS, Wagner M, Globisch D, Kneuttinger AC. 102.  et al. 2012. The CDK5 repressor CDK5RAP1 is a methylthiotransferase acting on nuclear and mitochondrial RNA. Nucleic Acids Res. 40:6235–40 [Google Scholar]
  104. Wei FY, Zhou B, Suzuki T, Miyata K, Ujihara Y. 103.  et al. 2015. Cdk5rap1-mediated 2-methylthio modification of mitochondrial tRNAs governs protein translation and contributes to myopathy in mice and humans. Cell Metab. 21:428–42 [Google Scholar]
  105. Sakurai M, Ohtsuki T, Suzuki T, Watanabe K. 104.  2005. Unusual usage of wobble modifications in mitochondrial tRNAs of the nematode Ascaris suum. FEBS Lett. 579:2767–72 [Google Scholar]
  106. Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI. 105.  et al. 2007. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1331–36 [Google Scholar]
  107. Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y. 106.  et al. 2007. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316:1341–45 [Google Scholar]
  108. Steinthorsdottir V, Thorleifsson G, Reynisdottir I, Benediktsson R, Jonsdottir T. 107.  et al. 2007. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat. Genet. 39:770–75 [Google Scholar]
  109. Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS. 108.  et al. 2007. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316:1336–41 [Google Scholar]
  110. Wei FY, Suzuki T, Watanabe S, Kimura S, Kaitsuka T. 109.  et al. 2011. Deficit of tRNALys modification by Cdkal1 causes the development of type 2 diabetes in mice. J. Clin. Invest. 121:3598–608 [Google Scholar]
  111. Stuart JW, Koshlap KM, Guenther R, Agris PF. 110.  2003. Naturally-occurring modification restricts the anticodon domain conformational space of tRNAPhe. J. Mol. Biol. 334:901–18 [Google Scholar]
  112. Noma A, Kirino Y, Ikeuchi Y, Suzuki T. 111.  2006. Biosynthesis of wybutosine, a hyper-modified nucleoside in eukaryotic phenylalanine tRNA. EMBO J. 25:2142–54 [Google Scholar]
  113. Goto-Ito S, Ishii R, Ito T, Shibata R, Fusatomi E. 112.  et al. 2007. Structure of an archaeal TYW1, the enzyme catalyzing the second step of wye-base biosynthesis. Acta Crystallogr. Sect. D 63:1059–68 [Google Scholar]
  114. Suzuki Y, Noma A, Suzuki T, Senda M, Senda T. 113.  et al. 2007. Crystal structure of the radical SAM enzyme catalyzing tricyclic modified base formation in tRNA. J. Mol. Biol. 372:1204–14 [Google Scholar]
  115. Young AP, Bandarian V. 114.  2011. Pyruvate is the source of the two carbons that are required for formation of the imidazoline ring of 4-demethylwyosine. Biochemistry 50:10573–75 [Google Scholar]
  116. Young AP, Bandarian V. 115.  2015. Mechanistic studies of the radical S-adenosyl-L-methionine enzyme 4-demethylwyosine synthase reveal the site of hydrogen atom abstraction. Biochemistry 54:3569–72 [Google Scholar]
  117. Perche-Letuvée P, Kathirvelu V, Berggren G, Clemancey M, Latour J-M. 116.  et al. 2012. 4-Demethylwyosine synthase from Pyrococcus abyssi is a radical-S-adenosyl-L-methionine enzyme with an additional [4Fe-4S]+2 cluster that interacts with the pyruvate co-substrate. J. Biol. Chem. 287:41174–85 [Google Scholar]
  118. Farabaugh PJ. 117.  1996. Programmed translational frameshifting. Microbiol. Rev. 60:103–34 [Google Scholar]
  119. Jacks T, Madhani HD, Masiarz FR, Varmus HE. 118.  1988. Signals for ribosomal frameshifting in the Rous sarcoma virus gag-pol region. Cell 55:447–58 [Google Scholar]
  120. Hatfield D, Feng Y-X, Lee BJ, Rein A, Levin JG, Oroszlan S. 119.  1989. Chromatographic analysis of the aminoacyl-tRNAs which are required for translation of codons at and around the ribosomal frameshift sites of HIV, HTLV-1, and BLV. Virology 173:736–42 [Google Scholar]
  121. Carlson BA, Kwon SY, Chamorro M, Oroszlan S, Hatfield DL, Lee BJ. 120.  1999. Transfer RNA modification status influences retroviral ribosomal frameshifting. Virology 255:2–8 [Google Scholar]
  122. Carlson BA, Mushinski JF, Henderson DW, Kwon SY, Crain PF. 121.  et al. 2001. 1-Methylguanosine in place of Y base at position 37 in phenylalanine tRNA is responsible for its shiftiness in retroviral ribosomal frameshifting. Virology 279:130–35 [Google Scholar]
  123. Mushinski JF, Marini M. 122.  1979. Tumor-associated phenylalanyl transfer RNA found in a wide spectrum of rat and mouse tumors but absent in normal adult, fetal, and regenerating tissues. Cancer Res. 39:1253–58 [Google Scholar]
  124. Kuchino Y, Borek E, Grunberger D, Mushinski JF, Nishimura S. 123.  1982. Changes of post-transcriptional modification of wye base in tumor-specific tRNAPhe. Nucleic Acids Res. 10:6421–32 [Google Scholar]
  125. Winkler GS, Petrakis TG, Ethelberg S, Tokunaga M, Erdjument-Bromage H. 124.  et al. 2001. RNA polymerase II elongator holoenzyme is composed of two discrete subcomplexes. J. Biol. Chem. 276:32743–49 [Google Scholar]
  126. Winkler GS, Kristjuhan A, Erdjument-Bromage H, Tempst P, Svejstrup JQ. 125.  2002. Elongator is a histone H3 and H4 acetyltransferase important for normal histone acetylation levels in vivo. PNAS 99:3517–22 [Google Scholar]
  127. Johansson MJO, Esberg A, Huang B, Björk GR, Byström AS. 126.  2008. Eukaryotic wobble uridine modifications promote a functionally redundant decoding system. Mol. Cell. Biol. 28:3301–12 [Google Scholar]
  128. Glatt S, Muller CW. 127.  2013. Structural insights into Elongator function. Curr. Opin. Struct. Biol. 23:235–42 [Google Scholar]
  129. Wittschieben , Otero G, de Bizemont T, Fellows J, Erdjument-Bromage H. 128.  et al. 1999. A novel histone acetyltransferase is an integral subunit of elongating RNA polymerase II holoenzyme. Mol. Cell 4:123–28 [Google Scholar]
  130. Paraskevopoulou C, Fairhurst SA, Lowe DJ, Brick P, Onesti S. 129.  2006. The Elongator subunit Elp3 contains a Fe4S4 cluster and binds S-adenosylmethionine. Mol. Microbiol. 59:795–806 [Google Scholar]
  131. Huang B, Johansson MJ, Bystrom AS. 130.  2005. An early step in wobble uridine tRNA modification requires the Elongator complex. RNA 11:424–36 [Google Scholar]
  132. Hawkes NA, Otero G, Winkler GS, Marshall N, Dahmus ME. 131.  et al. 2002. Purification and characterization of the human Elongator complex. J. Biol. Chem. 277:3047–52 [Google Scholar]
  133. Greenwood C, Selth LA, Dirac-Svejstrup AB, Svejstrup JQ. 132.  2009. An iron-sulfur cluster domain in Elp3 important for the structural integrity of elongator. J. Biol. Chem. 284:141–49 [Google Scholar]
  134. Okada Y, Yamagata K, Hong K, Wakayama T, Zhang Y. 133.  2010. A role for the elongator complex in zygotic paternal genome demethylation. Nature 463:554–58 [Google Scholar]
  135. Selvadurai K, Wang P, Seimetz J, Huang RH. 134.  2014. Archaeal Elp3 catalyzes tRNA wobble uridine modification at C5 via a radical mechanism. Nat. Chem. Biol. 10:810–12 [Google Scholar]
  136. Rowland LP, Shneider NA. 135.  2001. Amyotrophic lateral sclerosis. N. Engl. J. Med. 344:1688–700 [Google Scholar]
  137. Tandan R, Bradley WG. 136.  1985. Amyotrophic lateral sclerosis: part 1. Clinical features, pathology, and ethical issues in management. Ann. Neurol. 18:271–80 [Google Scholar]
  138. Simpson CL, Lemmens R, Miskiewicz K, Broom WJ, Hansen VK. 137.  et al. 2009. Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration. Hum. Mol. Genet. 18:472–81 [Google Scholar]
  139. Wagh DA, Rasse TM, Asan E, Hofbauer A, Schwenkert I. 138.  et al. 2006. Bruchpilot, a protein with homology to ELKS/CAST, is required for structural integrity and function of synaptic active zones in Drosophila. Neuron 49:833–44 [Google Scholar]
  140. Miśkiewicz K, Jose Liya E, Bento-Abreu A, Fislage M, Taes I. 139.  et al. 2011. ELP3 controls active zone morphology by acetylating the ELKS family member Bruchpilot. Neuron 72:776–88 [Google Scholar]
  141. Layer G, Verfurth K, Mahlitz E, Jahn D. 140.  2002. Oxygen-independent coproporphyrinogen-III oxidase HemN from Escherichia coli. J. Biol. Chem. 277:34136–42 [Google Scholar]
  142. Parish T, Schaeffer M, Roberts G, Duncan K. 141.  2005. HemZ is essential for heme biosynthesis in Mycobacterium tuberculosis. Tuberculosis 85:197–204 [Google Scholar]
  143. 142.  Deleted in proof
  144. Homuth G, Rompf A, Schumann W, Jahn D. 143.  1999. Transcriptional control of Bacillus subtilis hemN and hemZ. J. Bacteriol. 181:5922–29 [Google Scholar]
  145. Hunt RD. 144.  2006. Radical S-adenosyl methionine domain containing-1 (rsad1): A novel gene essential for cell survival during vertebrate development PhD Thesis, Univ. Tex., Houston [Google Scholar]
  146. Yu YE, Morishima M, Pao A, Wang D-Y, Wen X-Y. 145.  et al. 2006. A deficiency in the region homologous to human 17q21.33–q23.2 causes heart defects in mice. Genetics 173:297–307 [Google Scholar]
  147. Kliegman RM, Stanton BF, Schor NF, St. Geme JW III, Behrman RE. 146.  2011. Nelson Textbook of Pediatrics Philadelphia: Elsevier [Google Scholar]
  148. Jiang D, Guo H, Xu C, Chang J, Gu B. 147.  et al. 2008. Identification of three interferon-inducible cellular enzymes that inhibit the replication of hepatitis C virus. J. Virol. 82:1665–78 [Google Scholar]
  149. Nasr N, Maddocks S, Turville SG, Harman AN, Woolger N. 148.  et al. 2012. HIV-1 infection of human macrophages directly induces viperin which inhibits viral production. Blood 120:778–88 [Google Scholar]
  150. Szretter KJ, Brien JD, Thackray LB, Virgin HW, Cresswell P, Diamond MS. 149.  2011. The interferon-inducible gene viperin restricts West Nile virus pathogenesis. J. Virol. 85:11557–66 [Google Scholar]
  151. Wang X, Hinson ER, Cresswell P. 150.  2007. The interferon-inducible protein viperin inhibits influenza virus release by perturbing lipid rafts. Cell Host Microbe 2:96–105 [Google Scholar]
  152. Chin KC, Cresswell P. 151.  2001. Viperin (cig5), an IFN-inducible antiviral protein directly induced by human cytomegalovirus. PNAS 98:15125–30 [Google Scholar]
  153. Hinson ER, Cresswell P. 152.  2009. The antiviral protein, viperin, localizes to lipid droplets via its N-terminal amphipathic α-helix. PNAS 106:20452–57 [Google Scholar]
  154. Hinson ER, Cresswell P. 153.  2009. The N-terminal amphipathic α-helix of viperin mediates localization to the cytosolic face of the endoplasmic reticulum and inhibits protein secretion. J. Biol. Chem. 284:4705–12 [Google Scholar]
  155. Helbig KJ, Eyre NS, Yip E, Narayana S, Li K. 154.  et al. 2011. The antiviral protein viperin inhibits hepatitis C virus replication via interaction with nonstructural protein 5A. Hepatology 54:1506–17 [Google Scholar]
  156. Gao L, Aizaki H, He JW, Lai MM. 155.  2004. Interactions between viral nonstructural proteins and host protein hVAP-33 mediate the formation of hepatitis C virus RNA replication complex on lipid raft. J. Virol. 78:3480–88 [Google Scholar]
  157. Wang S, Wu X, Pan T, Song W, Wang Y. 156.  et al. 2012. Viperin inhibits hepatitis C virus replication by interfering with binding of NS5A to host protein hVAP-33. J. Gen. Virol. 93:83–92 [Google Scholar]
  158. Duschene KS, Broderick JB. 157.  2010. The antiviral protein viperin is a radical SAM enzyme. FEBS Lett. 584:1263–67 [Google Scholar]
  159. Shaveta G, Shi J, Chow VT, Song J. 158.  2010. Structural characterization reveals that viperin is a radical S-adenosyl-l-methionine (SAM) enzyme. Biochem. Biophys. Res. Commun. 391:1390–95 [Google Scholar]
  160. Upadhyay AS, Vonderstein K, Pichlmair A, Stehling O, Bennett KL. 159.  et al. 2014. Viperin is an iron-sulfur protein that inhibits genome synthesis of tick-borne encephalitis virus via radical SAM domain activity. Cell Microbiol. 16:834–48 [Google Scholar]
  161. Carlton-Smith C, Elliott RM. 160.  2012. Viperin, MTAP44, and protein kinase R contribute to the interferon-induced inhibition of Bunyamwera Orthobunyavirus replication. J. Virol. 86:11548–57 [Google Scholar]
  162. Zahoor MA, Xue G, Sato H, Murakami T, Takeshima SN, Aida Y. 161.  2014. HIV-1 Vpr induces interferon-stimulated genes in human monocyte-derived macrophages. PLOS ONE 9:e106418 [Google Scholar]
  163. Seo JY, Yaneva R, Hinson ER, Cresswell P. 162.  2011. Human cytomegalovirus directly induces the antiviral protein viperin to enhance infectivity. Science 332:1093–97 [Google Scholar]
  164. Chan YL, Chang TH, Liao CL, Lin YL. 163.  2008. The cellular antiviral protein viperin is attenuated by proteasome-mediated protein degradation in Japanese encephalitis virus-infected cells. J. Virol. 82:10455–64 [Google Scholar]
  165. Shen G, Wang K, Wang S, Cai M, Li ML, Zheng C. 164.  2014. Herpes simplex virus 1 counteracts viperin via its virion host shutoff protein UL41. J. Virol. 88:12163–66 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error