Radical S-Adenosylmethionine Enzymes in Human Health and Disease

Annual Review of Biochemistry

Volumn 85, Issue , 2016, Pages 485-514

  Landgraf, Bradley J ^a   McCarthy, Erin L ^a   Booker, Squire J ^a  

^a PENNSYLVANIA STATE UNIVERSITY   (United States)

Author keywords

Elongator; Iron sulfur cluster; Lipoic acid; Molybdenum cofactor; Radicals; S adenosylmethionine; TRNA modifications; Viperin

Indexed keywords

2 METHYLTHIO N 6 ISOPENTENYLADENOSINE; 5 METHOXYCARBONYLMETHYL URIDINE; 6 N (3,3 DIMETHYLALLYL)ADENOSINE; ADENOSINE DERIVATIVE; ALDEHYDE OXIDASE; COPROPORPHYRINOGEN OXIDASE; CYCLIC PYRANOPTERIN PHOSPHATE; CYCLIN DEPENDENT KINASE 5; ENZYME; GUANOSINE PHOSPHATE; IRON SULFUR PROTEIN; METHYLTHIO N 6 THREONYLCARBAMOYLADENOSINE; MITOCHONDRIAL DNA; MITOCHONDRIAL PROTEIN; MOLYBDENUM; MOLYBDENUM COFACTOR; MOLYBDOPTERIN; PROTEIN A; RADICAL; RADICAL S ADENOSYLMETHIONINE ENZYME; S ADENOSYLMETHIONINE; SMALL INTERFERING RNA; SULFITE OXIDASE; THIOCTIC ACID; TRANSFER RNA; TRIOSEPHOSPHATE ISOMERASE; UNCLASSIFIED DRUG; URIDINE DERIVATIVE; VIPERIN; WYBUTOSINE; XANTHINE DEHYDROGENASE; CDK5RAP1 PROTEIN, HUMAN; CDKAL1 PROTEIN, HUMAN; ELP3 PROTEIN, HUMAN; HISTONE ACETYLTRANSFERASE; MOCS1 PROTEIN, HUMAN; NERVE PROTEIN; NUCLEAR PROTEIN; OXIDOREDUCTASE; PROTEIN; RSAD2 PROTEIN, HUMAN; SIGNAL PEPTIDE; TRANSFER RNA METHYLTRANSFERASE;

ANTIVIRAL ACTIVITY; ARTICLE; AUTOSOMAL RECESSIVE DISORDER; BIOSYNTHESIS; BRAIN DISEASE; CARBOXY TERMINAL SEQUENCE; CONGENITAL HEART DISEASE; DEGENERATIVE DISEASE; ENZYME ACTIVITY; ENZYME DEFICIENCY; GENE MUTATION; GENETIC DISORDER; HUMAN; INSULIN RELEASE; LEUKOENCEPHALOPATHY; LIPOGENESIS; LIPOYLATION; MITOCHONDRIAL RESPIRATION; MOLYBDENUM COFACTOR DEFICIENCY; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN MODIFICATION; PULMONARY HYPERTENSION; CONGENITAL HEART MALFORMATION; DISORDERS OF METAL METABOLISM; ENZYMOLOGY; GENE EXPRESSION; GENETICS; METABOLISM; MUTATION; PATHOLOGY;

DIABETES MELLITUS, TYPE 2; GENE EXPRESSION; HEART DEFECTS, CONGENITAL; HISTONE ACETYLTRANSFERASES; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; IRON-SULFUR PROTEINS; METAL METABOLISM, INBORN ERRORS; MUTATION; NERVE TISSUE PROTEINS; NEURODEGENERATIVE DISEASES; NUCLEAR PROTEINS; OXIDOREDUCTASES; PROTEINS; S-ADENOSYLMETHIONINE; THIOCTIC ACID; TRNA METHYLTRANSFERASES;

EID: 84974736098     PISSN: 00664154     EISSN: 15454509     Source Type: Book Series    
DOI: 10.1146/annurev-biochem-060713-035504     Document Type: Article

References (165)

1. Lu SC, Mato JM. 2012. S-Adenosylmethionine in liver health, injury, and cancer. Physiol. Rev. 92:1515-42
2. Roje S. 2006. S-Adenosyl-L-methionine: beyond the universalmethyl donor. Phytochemistry 67:1686-98
3. Sufrin JR, Finckbeiner S, Oliver CM. 2009. Marine-derived metabolites of S-adenosylmethionine as templates for new anti-infectives. Mar. Drugs 7:401-34
4. Fuqua C, Greenberg EP. 1998. Self perception in bacteria: quorum sensing with acylated homoserine lactones. Curr. Opin. Microbiol. 1:183-89
5. Eustáquio AS, Pojer F, Noel JP, Moore BS. 2008. Discovery and characterization of a marine bacterial SAM-dependent chlorinase. Nat. Chem. Biol. 4:69-74
6. Landgraf BJ, Booker SJ. 2013. Biochemistry: The ylide has landed. Nature 498:45-47
7. FontecaveM, Atta M, Mulliez E. 2004. S-Adenosylmethionine: nothing goes to waste. Trends Biochem. Sci. 29:243-9
8. Broderick JB, Duffus BR, Duschene KS, Shepard EM. 2014. Radical S-adenosylmethionine enzymes. Chem. Rev. 114:4229-317
9. Challand MR, Driesener RC, Roach PL. 2011. Radical S-adenosylmethionine enzymes: mechanism, control and function. Nat. Prod. Rep. 28:1696-721
10. Wang SC, Frey PA. 2007. S-adenosylmethionine as an oxidant: The radical SAM superfamily. Trends Biochem. Sci. 32:101-10
11. Wang SC, Frey PA. 2007. Binding energy in the one-electron reductive cleavage of Sadenosylmethionine in lysine 2, 3-aminomutase, a radical SAM enzyme. Biochemistry 46:12889-95
12. Hiscox MJ, Driesener RC, Roach PL. 2012. Enzyme catalyzed formation of radicals from S-adenosylmethionine and inhibition of enzyme activity by the cleavage products. Biochim. Biophys. Acta 1824:1165-77
13. Sofia HJ, Chen G, Hetzler BG, Reyes-Spindola JF, Miller NE. 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
14. Walsby CJ, Ortillo D, Yang J, Nnyepi MR, Broderick WE, et al. 2005. Spectroscopic approaches to elucidating novel iron-sulfur chemistry in the "radical-SAM" protein superfamily. Inorg. Chem. 44:727-41
15. Dowling DP, Vey JL, Croft AK, Drennan CL. 2012. Structural diversity in the AdoMet radical enzyme superfamily. Biochim. Biophys. Acta 1824:1178-95
16. Dey A, Peng Y, Broderick WE, Hedman B, Hodgson KO, 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
17. Cosper NJ, Booker SJ, Ruzicka F, FreyPA, ScottRA. 2000. Direct FeS cluster involvement in generation of a radical in lysine 2, 3-aminomutase. Biochemistry 39:15668-73
18. Nicolet Y, Amara P, Mouesca J-M, Fontecilla-Camps JC. 2009. Unexpected electron transfer mechanism upon AdoMet cleavage in radical SAM proteins. PNAS 106:14867-71
19. Grell TA, Goldman PJ, Drennan CL. 2015. SPASM and twitch domains in S-adenosylmethionine (SAM) radical enzymes. J. Biol. Chem. 290:3964-71
20. Deleted in proof
21. Akiva E, Brown S, Almonacid DE, Barber AE 2nd, Custer AF, et al. 2014. The structure-function linkage database. Nucleic Acids Res. 42:D521-30
22. Duschene KS, Veneziano SE, Silver SC, Broderick JB. 2009. Control of radical chemistry in the AdoMet radical enzymes. Curr. Opin. Chem. Biol. 13:74-83
23. Schwarz G, Mendel RR, Ribbe MW. 2009. Molybdenum cofactors, enzymes and pathways. Nature 460:839-47
24. McMaster J, Garner CD, Stiefel EI. 2007. Molybdenum enzymes. In Biological Inorganic Chemistry: Structure and Reactivity, ed. I Bertini, HB Gray, EI Stiefel, JS Valentine, pp. 518-30. Sausalito, CA: University Science Books
25. Schwarz G, Mendel RR. 2006. Molybdenum cofactor biosynthesis and molybdenum enzymes. Annu. Rev. Plant Biol. 57:623-47
26. Rieder C, Eisenreich W, O'Brien J, Richter G, Gotze E, 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
27. Wuebbens MM, Rajagopalan KV. 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
28. Hänzelmann P, Schwartz G, Mendel RR. 2002. Functionality of alternative splice forms of the first enzymes involved in human molybdenum cofactor biosynthesis. J. Biol. Chem. 277:18303-12
29. Hänzelmann P, Schindelin H. 2004. Crystal structure of the S-adenosylmethionine-dependent enzyme MoaA and its implications for molybdenum cofactor deficiency in humans. PNAS 101:12870-75
30. Hänzelmann P, Schindelin H. 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
31. Lees NS, Hänzelmann P, Hernandez HL, Subramanian S, Schindelin H, 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
32. Hover BM, Loksztejn A, Ribeiro AA, Yokoyama K. 2013. Identification of a cyclic nucleotide as a cryptic intermediate in molybdenum cofactor biosynthesis. J. Am. Chem. Soc. 135:7019-32
33. Hover BM, Tonthat NK, Schumacher MA, Yokoyama K. 2015. Mechanism of pyranopterin ring formation in molybdenum cofactor biosynthesis. PNAS 112:6347-52
34. Mehta AP, Hanes JW, Abdelwahed SH, Hilmey DG, Hänzelmann P, Begley TP. 2013. Catalysis of a new ribose carbon-insertion reaction by the molybdenum cofactor biosynthetic enzyme MoaA. Biochemistry 52:1134-36
35. Mehta AP, Abdelwahed SH, Begley TP. 2013. Molybdopterin biosynthesis: Trapping an unusual purine ribose adduct in the MoaA-catalyzed reaction. J. Am. Chem. Soc. 135:10883-85
36. Mehta AP, Abdelwahed SH, XuH, Begley TP. 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
37. Schwarz G, Santamaria-Araujo JA, Wolf S, Lee H-J, Adham IM, et al. 2004. Rescue of lethal molybdenum cofactor deficiency by a biosynthetic precursor from Escherichia coli. Hum. Mol. Genet. 13:1249-55
38. Reiss J, Johnson JL. 2003. Mutations in the molybdenum cofactor biosynthetic genes MOCS1, MOCS2, and GEPH. Hum. Mutat. 21:569-76
39. Johnson JL. 2003. Prenatal diagnosis of molybdenum cofactor deficiency and isolated sulfite oxidase deficiency. Prenat. Diagn. 23:6-8
40. Lee H-J, Adham IM, Schwarz G, Kneussel M, Sass JO, et al. 2002. Molybdenum cofactor-deficient mice resemble the phenotype of human patients. Hum. Mol. Genet. 11:3309-17
41. Duran M, Beemer FA, van de Heiden C, Korteland J, de Bree PK, 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
42. Reiss J, Christensen E, KurlemannG, Zabot M-T, Dorche C. 1998. Genomic structure andmutational spectrum of the bicistronic MOCS1 gene defective in molybdenum cofactor deficiency type A. Hum. Genet. 103:639-44
43. Leimkuhler S, Charcosset M, Latour P, Dorche C, Kleppe S, 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
44. Hänzelmann P, Schindelin H. 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
45. Deleted in proof
46. Veldman A, Santamaria-Araujo JA, Sollazzo S, Pitt J, Gianello R, et al. 2010. Successful treatment of molybdenum cofactor deficiency type A with cPMP. Pediatrics 125:e1249-54
47. Reed L. 1974. Multienzyme complexes. Acc. Chem. Res. 7:40-46
48. Packer L, Kraemer K, Rimbach G. 2001. Molecular aspects of lipoic acid in the prevention of diabetes complications. Nutrition 17:888-95
49. Yi X, Xu L, Hiller S, Kim HS, Nickeleit V, et al. 2012. Reduced expression of lipoic acid synthase accelerates diabetic nephropathy. J. Am. Soc. Nephrol. 23:103-11
50. Padmalayam I, Hasham S, Saxena U, Pillarisetti S. 2009. Lipoic acid synthase (LASY): A novel role in inflammation, mitochondrial function, and insulin resistance. Diabetes 58:600-608
51. Cronan JE, Zhao X, Jiang Y. 2005. Function, attachment and synthesis of lipoic acid in Escherichia coli. Adv. Microb. Physiol. 50:103-46
52. Wada H, Shintani D, Ohlrogge J. 1997. Why do mitochondria synthesize fatty acids? Evidence for involvement in lipoic acid production. PNAS 94:1591-96
53. Fujiwara K, Takeuchi S, Okamura-Ikeda K, Motokawa Y. 2001. Purification, characterization, and cDNA cloning of lipoate-activating enzyme from bovine liver. J. Biol. Chem. 276:28819-23
54. Fujiwara K, Okamura-Ikeda K, Motokawa Y. 1994. Purification and characterization of lipoyl-AMP:N epsilon-lysine lipoyltransferase from bovine liver mitochondria. J. Biol. Chem. 269:16605-9
55. Fujiwara K, Okamura-Ikeda K, Motokawa Y. 1996. Lipoylation of acyltransferase components of ketoacid dehydrogenase complexes. J. Biol. Chem. 271:12932-36
56. Billgren ES, Cicchillo RM, Nesbitt NM, Booker SJ. 2010. Lipoic acid biosynthesis and enzymology. In Comprehensive Natural Products II Chemistry and Biology, ed. LMander, H-W Liu, pp. 181-212. Oxford: Elsevier
57. Lanz ND, Booker SJ. 2014. The role of iron-sulfur clusters in the biosynthesis of the lipoyl cofactor. In Iron-Sulfur Clusters in Chemistry and Biology, ed. TA Rouault, pp. 211-31. Berlin:Walter de Gruyter
58. Cicchillo RM, Lee K-H, Baleanu-Gogonea C, Nesbitt NM, Krebs C, Booker SJ. 2004. Escherichia coli lipoyl synthase binds two distinct [4Fe-4S] clusters per polypeptide. Biochemistry 43:11770-81
59. Harmer JE, Hiscox MJ, Dinis PC, Fox SJ, Lliopoulos A, et al. 2014. Structures of lipoyl synthase reveal a compact active site for controlling sequential sulfur insertion reactions. Biochem. J. 464:123-33
60. Cicchillo RM, Booker SJ. 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
61. Lanz ND, Pandelia ME, Kakar ES, Lee K-H, Krebs C, Booker SJ. 2014. Evidence for a catalytically and kinetically competent enzyme-substrate cross-linked intermediate in catalysis by lipoyl synthase. Biochemistry 53:4557-72
62. Douglas P, Kriek M, Bryant P, Roach PL. 2006. Lipoyl synthase inserts sulfur atoms into an octanoyl substrate in a stepwise manner. Angew. Chem. 118:5321-23
63. Parry RJ, Trainor DA. 1978. Biosynthesis of lipoic acid. 2. Stereochemistry of sulfur introduction at C-6 of octanoic acid. J. Am. Chem. Soc. 100:5243-44
64. Booker SJ, Cicchillo RM, Grove TL. 2007. Self-sacrifice in radical S-adenosylmethionine proteins. Curr. Opin. Chem. Biol. 11:543-52
65. Cicchillo RM, Iwig DF, Jones AD, Nesbitt NM, Baleanu-Gogonea C, et al. 2004. Lipoyl synthase requires two equivalents of S-adenosyl-L-methionine to synthesize one equivalent of lipoic acid. Biochemistry 43:6378-86
66. Baker PR 2nd, Friederich MW, Swanson MA, Shaikh T, Bhattacharya K, et al. 2014. Variant nonketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5. Brain 137:366-79
67. Mayr JA, Feichtinger RG, Tort F, Ribes A, SperlW. 2014. Lipoic acid biosynthesis defects. J. Inherit. Metab. Dis. 37:553-63
68. Tsurusaki Y, Tanaka R, Shimada S, Shimojima K, ShiinaM, et al. 2015. Novel compound heterozygous LIAS mutations cause glycine encephalopathy. J. Hum. Genet. 60:631-35
69. Hoover-Fong JE, Shah S, Van Hove JL, Applegarth D, Toone J, Hamosh A. 2004. Natural history of nonketotic hyperglycinemia in 65 patients. Neurology 63:1847-53
70. Mayr JA, Zimmermann FA, Fauth C, Bergheim C, Meierhofer D, 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
71. Rouault TA, Tong WH. 2008. Iron-sulfur cluster biogenesis and human disease. Trends Genet. 24:398-407
72. StehlingO, WilbrechtC, Lill R. 2014. Mitochondrial iron-sulfur protein biogenesis and human disease. Biochimie 100:61-77
73. Cameron JM, Janer A, Levandovskiy V, Mackay N, Rouault TA, 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
74. Invernizzi F, Ardissone A, Lamantea E, Garavaglia B, Zeviani M, et al. 2014. Cavitating leukoencephalopathy with multiple mitochondrial dysfunction syndrome and NFU1 mutations. Front. Genet. 5:412
75. Navarro-Sastre A, Tort F, StehlingO, UzarskaMA, Arranz JA, et al. 2011. A fatal mitochondrial disease is associated with defectiveNFU1 function in the maturation of a subset of mitochondrial Fe-S proteins. Am. J. Hum. Genet. 89:656-67
76. Nizon M, Boutron A, Boddaert N, Slama A, Delpech H, et al. 2014. Leukoencephalopathy with cysts and hyperglycinemia may result from NFU1 deficiency. Mitochondrion 15:59-64
77. Seyda A, Newbold RF, Hudson TJ, Verner A, MacKay N, 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
78. El Yacoubi B, Bailly M, de Crécy-Lagard V. 2012. Biosynthesis and function of posttranscriptional modifications of transfer RNAs. Annu. Rev. Genet. 46:69-95
79. Torres AG, Batlle E, de Pouplana LR. 2014. Role of tRNA modifications in human diseases. Trends Mol. Med. 20:306-14
80. Atta M, Mulliez E, Arragain S, Forouhar F, Hunt JF, Fontecave M. 2010. S-adenosylmethioninedependent radical-based modification of biological macromolecules. Curr. Opin. Struct. Biol. 20:1-9
81. Anton BP, Russell SP, Vertrees J, Kasif S, Raleigh EA, et al. 2010. Functional characterization of the YmcB and YqeV tRNA methylthiotransferases of Bacillus subtilis. Nucleic Acids Res. 38:6195-205
82. Arragain S, Garcá-Serres R, Blondin G, Douki T, Clemancey M, 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 82a.
83. Landgraf BJ, Booker SJ. 2016. Stereochemical course of the reaction catalyzed by RimO, a radical SAM methylthiotransferase. J. Am. Chem. Soc. 138:2889-92
84. Anton BP, Saleh L, Benner JS, Raleigh EA, Kasif S, Roberts RJ. 2008. RimO, a MiaB-like enzyme, methylthiolates the universally conserved Asp88 residue of ribosomal protein S12 in Escherichia coli. PNAS 105:1826-31
85. Arragain S, Handelman SK, Forouhar F, Wei FY, Tomizawa K, et al. 2010. Identification of eukaryotic and prokaryotic methylthiotransferase for biosynthesis of 2-methylthio-N6-threonylcarbamoyladenosine in tRNA. J. Biol. Chem. 285:28425-33
86. Pierrel F, Björk GR, Fontecave M, Atta M. 2002. Enzymatic modification of tRNAs: MiaB is an iron-sulfur protein. J. Biol. Chem. 277:13367-70
87. Pierrel F, Douki T, Fontecave M, Atta M. 2004. MiaB protein is a bifunctional radical-Sadenosylmethionine enzyme involved in thiolation and methylation of tRNA. J. Biol. Chem. 279:47555-653
88. Mitchell A, Chang HY, Daugherty L, Fraser M, Hunter S, et al. 2015. The InterPro protein families database: The classification resource after 15 years. Nucleic Acids Res. 43:D213-21
89. Bartz JK, Kline LK, Soll D. 1970. N6-(2-isopentenyl)adenosine: biosynthesis in vitro in transfer RNA by an enzyme purified from Escherichia coli. Biochem. Biophys. Res. Commun. 40:1481-87
90. Rosenbaum N, Gefter ML. 1972. -2-Isopentenylpyrophosphate: Transfer ribonucleic acid -2-isopentenyltransferase from Escherichia coli. Purification and properties of the enzyme. J. Biol. Chem. 247:5675-80
91. Deutsch C, El Yacoubi B, de Crecy-Lagard V, Iwata-ReuylD. 2012. Biosynthesis of threonylcarbamoyl adenosine (t6A), a universal tRNA nucleoside. J. Biol. Chem. 287:13666-73
92. Connolly DM, Winkler ME. 1991. Structure of Escherichia coli K-12 miaA and characterization of the mutator phenotype caused by miaA insertion mutations. J. Bacteriol. 173:1711-21
93. Esberg B, Björk GR. 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
94. Urbonavicius J, Qian Q, Durand JMB, Hagervall TG, Björk GR. 2001. Improvement of reading frame maintenance is a common function for several tRNA modifications. EMBO J. 20:4863-73
95. Forouhar F, Arragain S, Atta M, Gambarelli S, Mouesca J-M, et al. 2013. Two Fe-S clusters catalyze sulfur insertion by radical-SAM methylthiotransferases. Nat. Chem. Biol. 9:333-38
96. Lee K-H, Saleh L, Anton BP, Madinger CL, Benner JS, et al. 2009. Characterization of RimO, a new member of themethylthiotransferase subclass of the radicalSAMsuperfamily. Biochemistry 48:10162-74
97. Pierrel F, Hernandez HL, Johnson MK, FontecaveM, Atta M. 2003. Characterization of an extremely thermophilic tRNA-methylthiotransferase. J. Biol. Chem. 278:29515-24
98. Landgraf BJ, Arcinas AJ, Lee K-H, Booker SJ. 2013. Identification of an intermediate methyl carrier in the radical S-adenosylmethionine methylthiotransferases RimO and MiaB. J. Am. Chem. Soc. 135:15404-16
99. Agris PF, Armstrong DJ, Schafer KP, SollD. 1975. Maturation of a hypermodified nucleoside in transfer RNA. Nucleic Acids Res. 2:691-98
100. Zou X, Ji C, Jin F, Liu J, WuM, 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
101. Ching Y-P, Pang ASH, Lam W-H, Qi RZ, Wang JH. 2002. Identification of a neuronal Cdk5 activatorbinding protein as Cdk5 inhibitor. J. Biol. Chem. 277:15237-40
102. Dhaven R, Tsai L-H. 2001. A decade of CDK5. Nat. Rev. Mol. Cell Biol. 2:749-59
103. Reiter V, Matschkal DMS, WagnerM, Globisch D, Kneuttinger AC, et al. 2012. The CDK5 repressor CDK5RAP1 is a methylthiotransferase acting on nuclear and mitochondrial RNA. Nucleic Acids Res. 40:6235-40
104. Wei FY, Zhou B, Suzuki T, Miyata K, Ujihara Y, 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
105. Sakurai M, Ohtsuki T, Suzuki T, Watanabe K. 2005. Unusual usage of wobble modifications in mitochondrial tRNAs of the nematode Ascaris suum. FEBS Lett. 579:2767-72
106. Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, et al. 2007. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1331-36
107. Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, et al. 2007. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316:1341-45
108. Steinthorsdottir V, Thorleifsson G, Reynisdottir I, Benediktsson R, Jonsdottir T, et al. 2007. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat. Genet. 39:770-75
109. Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, et al. 2007. Replication of genomewide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316:1336-41
110. Wei FY, Suzuki T, Watanabe S, Kimura S, Kaitsuka T, et al. 2011. Deficit of tRNALys modification by Cdkal1 causes the development of type 2 diabetes in mice. J. Clin. Invest. 121:3598-608
111. Stuart JW, Koshlap KM, Guenther R, Agris PF. 2003. Naturally-occurring modification restricts the anticodon domain conformational space of tRNAPhe. J. Mol. Biol. 334:901-18
112. Noma A, Kirino Y, Ikeuchi Y, Suzuki T. 2006. Biosynthesis of wybutosine, a hyper-modified nucleoside in eukaryotic phenylalanine tRNA. EMBO J. 25:2142-54
113. Goto-Ito S, Ishii R, Ito T, Shibata R, Fusatomi E, 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
114. Suzuki Y, Noma A, Suzuki T, Senda M, Senda T, et al. 2007. Crystal structure of the radical SAM enzyme catalyzing tricyclic modified base formation in tRNA. J. Mol. Biol. 372:1204-14
115. Young AP, Bandarian V. 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
116. Young AP, Bandarian V. 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
117. Perche-Letuvée P, Kathirvelu V, Berggren G, Clemancey M, Latour J-M, 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
118. Farabaugh PJ. 1996. Programmed translational frameshifting. Microbiol. Rev. 60:103-34
119. Jacks T, Madhani HD, Masiarz FR, Varmus HE. 1988. Signals for ribosomal frameshifting in the Rous sarcoma virus gag-pol region. Cell 55:447-58
120. Hatfield D, Feng Y-X, Lee BJ, Rein A, Levin JG, Oroszlan S. 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
121. Carlson BA, Kwon SY, Chamorro M, Oroszlan S, Hatfield DL, Lee BJ. 1999. Transfer RNA modification status influences retroviral ribosomal frameshifting. Virology 255:2-8
122. Carlson BA, Mushinski JF, Henderson DW, Kwon SY, Crain PF, 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
123. Mushinski JF, Marini M. 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
124. Kuchino Y, Borek E, Grunberger D, Mushinski JF, Nishimura S. 1982. Changes of post-transcriptional modification of wye base in tumor-specific tRNAPhe. Nucleic Acids Res. 10:6421-32
125. Winkler GS, Petrakis TG, Ethelberg S, Tokunaga M, Erdjument-Bromage H, et al. 2001. RNA polymerase II elongator holoenzyme is composed of two discrete subcomplexes. J. Biol. Chem. 276:32743-49
126. Winkler GS, Kristjuhan A, Erdjument-Bromage H, Tempst P, Svejstrup JQ. 2002. Elongator is a histone H3 and H4 acetyltransferase important for normal histone acetylation levels in vivo. PNAS 99:3517-22
127. Johansson MJO, Esberg A, Huang B, Björk GR, Byström AS. 2008. Eukaryotic wobble uridine modifications promote a functionally redundant decoding system. Mol. Cell. Biol. 28:3301-12
128. Glatt S, Muller CW. 2013. Structural insights into Elongator function. Curr. Opin. Struct. Biol. 23:235-42
129. Wittschieben BØ, Otero G, de Bizemont T, Fellows J, Erdjument-Bromage H, et al. 1999. A novel histone acetyltransferase is an integral subunit of elongating RNA polymerase II holoenzyme. Mol. Cell 4:123-28
130. Paraskevopoulou C, Fairhurst SA, Lowe DJ, Brick P, Onesti S. 2006. The Elongator subunit Elp3 contains a Fe4S4 cluster and binds S-adenosylmethionine. Mol. Microbiol. 59:795-806
131. Huang B, JohanssonMJ, Bystrom AS. 2005. An early step inwobble uridine tRNA modification requires the Elongator complex. RNA 11:424-36
132. Hawkes NA, Otero G, Winkler GS, Marshall N, Dahmus ME, et al. 2002. Purification and characterization of the human Elongator complex. J. Biol. Chem. 277:3047-52
133. Greenwood C, Selth LA, Dirac-Svejstrup AB, Svejstrup JQ. 2009. An iron-sulfur cluster domain in Elp3 important for the structural integrity of elongator. J. Biol. Chem. 284:141-49
134. Okada Y, Yamagata K, Hong K, Wakayama T, Zhang Y. 2010. A role for the elongator complex in zygotic paternal genome demethylation. Nature 463:554-58
135. Selvadurai K, Wang P, Seimetz J, Huang RH. 2014. Archaeal Elp3 catalyzes tRNA wobble uridine modification at C5 via a radical mechanism. Nat. Chem. Biol. 10:810-12
136. Rowland LP, Shneider NA. 2001. Amyotrophic lateral sclerosis. N. Engl. J. Med. 344:1688-700
137. Tandan R, Bradley WG. 1985. Amyotrophic lateral sclerosis: part 1. Clinical features, pathology, and ethical issues in management. Ann. Neurol. 18:271-80
138. Simpson CL, Lemmens R, Miskiewicz K, Broom WJ, Hansen VK, et al. 2009. Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration. Hum. Mol. Genet. 18:472-81
139. Wagh DA, Rasse TM, Asan E, Hofbauer A, Schwenkert I, 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
140. Mískiewicz K, Jose Liya E, Bento-Abreu A, Fislage M, Taes I, et al. 2011. ELP3 controls active zone morphology by acetylating the ELKS family member Bruchpilot. Neuron 72:776-88
141. Layer G, Verfurth K, Mahlitz E, Jahn D. 2002. Oxygen-independent coproporphyrinogen-III oxidase HemN from Escherichia coli. J. Biol. Chem. 277:34136-42
142. Parish T, Schaeffer M, Roberts G, Duncan K. 2005. HemZ is essential for heme biosynthesis in Mycobacterium tuberculosis. Tuberculosis 85:197-204
143. Deleted in proof
144. Homuth G, Rompf A, Schumann W, Jahn D. 1999. Transcriptional control of Bacillus subtilis hemN and hemZ. J. Bacteriol. 181:5922-29
145. Hunt RD. 2006. Radical S-adenosyl methionine domain containing-1 (rsad1): A novel gene essential for cell survival during vertebrate development. PhD Thesis, Univ. Tex. , Houston
146. Yu YE, MorishimaM, Pao A, Wang D-Y, Wen X-Y, et al. 2006. A deficiency in the region homologous to human 17q21. 33-q23. 2 causes heart defects in mice. Genetics 173:297-307
147. Kliegman RM, Stanton BF, Schor NF, St. Geme JW III, Behrman RE, eds. 2011. Nelson Textbook of Pediatrics. Philadelphia: Elsevier
148. Jiang D, Guo H, Xu C, Chang J, Gu B, et al. 2008. Identification of three interferon-inducible cellular enzymes that inhibit the replication of hepatitis C virus. J. Virol. 82:1665-78
149. Nasr N, Maddocks S, Turville SG, Harman AN, Woolger N, et al. 2012. HIV-1 infection of human macrophages directly induces viperin which inhibits viral production. Blood 120:778-88
150. Szretter KJ, Brien JD, Thackray LB, Virgin HW, Cresswell P, Diamond MS. 2011. The interferoninducible gene viperin restrictsWest Nile virus pathogenesis. J. Virol. 85:11557-66
151. Wang X, Hinson ER, Cresswell P. 2007. The interferon-inducible protein viperin inhibits influenza virus release by perturbing lipid rafts. Cell Host Microbe 2:96-105
152. Chin KC, Cresswell P. 2001. Viperin (cig5), an IFN-inducible antiviral protein directly induced by human cytomegalovirus. PNAS 98:15125-30
153. Hinson ER, CresswellP. 2009. The antiviral protein, viperin, localizes to lipid droplets via its N-terminal amphipathic helix. PNAS 106:20452-57
154. Hinson ER, Cresswell P. 2009. The N-terminal amphipathic helix of viperinmediates localization to the cytosolic face of the endoplasmic reticulum and inhibits protein secretion. J. Biol. Chem. 284:4705-12
155. Helbig KJ, EyreNS, Yip E, Narayana S, Li K, et al. 2011. The antiviral protein viperin inhibits hepatitis C virus replication via interaction with nonstructural protein 5A. Hepatology 54:1506-17
156. Gao L, Aizaki H, He JW, Lai MM. 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
157. Wang S, Wu X, Pan T, SongW, Wang Y, 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
158. Duschene KS, Broderick JB. 2010. The antiviral protein viperin is a radical SAM enzyme. FEBS Lett. 584:1263-67
159. Shaveta G, Shi J, Chow VT, Song J. 2010. Structural characterization reveals that viperin is a radical S-adenosyl-L-methionine (SAM) enzyme. Biochem. Biophys. Res. Commun. 391:1390-95
160. Upadhyay AS, Vonderstein K, Pichlmair A, Stehling O, Bennett KL, et al. 2014. Viperin is an ironsulfur protein that inhibits genome synthesis of tick-borne encephalitis virus via radical SAM domain activity. Cell Microbiol. 16:834-48
161. Carlton-Smith C, Elliott RM. 2012. Viperin, MTAP44, and protein kinase R contribute to the interferon-induced inhibition of Bunyamwera Orthobunyavirus replication. J. Virol. 86:11548-57
162. Zahoor MA, Xue G, Sato H, Murakami T, Takeshima SN, Aida Y. 2014. HIV-1Vpr induces interferonstimulated genes in human monocyte-derived macrophages. PLOS ONE 9:e106418
163. Seo JY, Yaneva R, Hinson ER, Cresswell P. 2011. Human cytomegalovirus directly induces the antiviral protein viperin to enhance infectivity. Science 332:1093-97
164. Chan YL, Chang TH, Liao CL, Lin YL. 2008. The cellular antiviral protein viperin is attenuated by proteasome-mediated protein degradation in Japanese encephalitis virus-infected cells. J. Virol. 82:10455-64
165. Shen G, Wang K, Wang S, Cai M, Li ML, Zheng C. 2014. Herpes simplex virus 1 counteracts viperin via its virion host shutoff protein UL41. J. Virol. 88:12163-66