Nucleic Acids Research, 2001, Vol. 29, No. 5 1097-1106
© 2001 Oxford University Press
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
1Applied Mathematics, Environmental Molecular Sciences Laboratory (EMSL), Pacific Northwest National Laboratory, Richland, WA 99352, USA, 2Biology Department, Whitman College, Walla Walla, WA 99362, USA and 3Statistics Resources, 4Synthesis, Analysis and Visualization of Information (SAVI) and 5Information Sciences and Engineering, Pacific Northwest National Laboratory, Richland, WA 99352, USA
A novel protein superfamily with over 600 members was discovered by iterative profile searches and analyzed with powerful bioinformatics and information visualization methods. Evidence exists that these proteins generate a radical species by reductive cleavage of S-adenosylmethionine (SAM) through an unusual Fe-S center. The superfamily (named here Radical SAM) provides evidence that radical-based catalysis is important in a number of previously well- studied but unresolved biochemical pathways and reflects an ancient conserved mechanistic approach to difficult chemistries. Radical SAM proteins catalyze diverse reactions, including unusual methylations, isomerization, sulfur insertion, ring formation, anaerobic oxidation and protein radical formation. They function in DNA precursor, vitamin, cofactor, antibiotic and herbicide biosynthesis and in biodegradation pathways. One eukaryotic member is interferon-inducible and is considered a candidate drug target for osteoporosis; another is observed to bind the neuronal Cdk5 activator protein. Five defining members not previously recognized as homologs are lysine 2,3-aminomutase, biotin synthase, lipoic acid synthase and the activating enzymes for pyruvate formate-lyase and anaerobic ribonucleotide reductase. Two functional predictions for unknown proteins are made based on integrating other data types such as motif, domain, operon and biochemical pathway into an organized view of similarity relationships.
* To whom correspondence should be addressed at: Environmental Molecular Sciences Laboratory (EMSL), Pacific Northwest National Laboratory, PO Box 999, K1-83, 906 Battelle Boulevard, Richland, WA 99352, USA. Tel: +1 509 372 4216; Fax: +1 509 375 6631; Email: heidi.sofia{at}pnl.gov
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Y. Nicolet, J. K. Rubach, M. C. Posewitz, P. Amara, C. Mathevon, M. Atta, M. Fontecave, and J. C. Fontecilla-Camps X-ray Structure of the [FeFe]-Hydrogenase Maturase HydE from Thermotoga maritima J. Biol. Chem., July 4, 2008; 283(27): 18861 - 18872. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. W. Lee, D. A. Mitchell, A. L. Markley, M. E. Hensler, D. Gonzalez, A. Wohlrab, P. C. Dorrestein, V. Nizet, and J. E. Dixon From the Cover: Discovery of a widely distributed toxin biosynthetic gene cluster PNAS, April 15, 2008; 105(15): 5879 - 5884. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Hemschemeier, J. Jacobs, and T. Happe Biochemical and Physiological Characterization of the Pyruvate Formate-Lyase Pfl1 of Chlamydomonas reinhardtii, a Typically Bacterial Enzyme in a Eukaryotic Alga Eukaryot. Cell, March 1, 2008; 7(3): 518 - 526. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Jiang, H. Guo, C. Xu, J. Chang, B. Gu, L. Wang, T. M. Block, and J.-T. Guo Identification of Three Interferon-Inducible Cellular Enzymes That Inhibit the Replication of Hepatitis C Virus J. Virol., February 15, 2008; 82(4): 1665 - 1678. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. P. Anton, L. Saleh, J. S. Benner, E. A. Raleigh, S. Kasif, and R. J. Roberts RimO, a MiaB-like enzyme, methylthiolates the universally conserved Asp88 residue of ribosomal protein S12 in Escherichia coli PNAS, February 12, 2008; 105(6): 1826 - 1831. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-M. Toh, L. Xiong, T. Bae, and A. S. Mankin The methyltransferase YfgB/RlmN is responsible for modification of adenosine 2503 in 23S rRNA RNA, January 1, 2008; 14(1): 98 - 106. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ibrahim, A. Guillot, F. Wessner, F. Algaron, C. Besset, P. Courtin, R. Gardan, and V. Monnet Control of the Transcription of a Short Gene Encoding a Cyclic Peptide in Streptococcus thermophilus: a New Quorum-Sensing System? J. Bacteriol., December 15, 2007; 189(24): 8844 - 8854. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Raschke, L. Burkle, N. Muller, A. Nunes-Nesi, A. R. Fernie, D. Arigoni, N. Amrhein, and T. B. Fitzpatrick Vitamin B1 biosynthesis in plants requires the essential iron sulfur cluster protein, THIC PNAS, December 4, 2007; 104(49): 19637 - 19642. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. G. Butcher, Y.-P. Lin, and J. D. Helmann The yydFGHIJ Operon of Bacillus subtilis Encodes a Peptide That Induces the LiaRS Two-Component System J. Bacteriol., December 1, 2007; 189(23): 8616 - 8625. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. G. M. Chew, N.-U. Frigaard, and D. A. Bryant Bacteriochlorophyllide c C-82 and C-121 Methyltransferases Are Essential for Adaptation to Low Light in Chlorobaculum tepidum J. Bacteriol., September 1, 2007; 189(17): 6176 - 6184. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kriek, F. Martins, R. Leonardi, S. A. Fairhurst, D. J. Lowe, and P. L. Roach Thiazole Synthase from Escherichia coli: AN INVESTIGATION OF THE SUBSTRATES AND PURIFIED PROTEINS REQUIRED FOR ACTIVITY IN VITRO J. Biol. Chem., June 15, 2007; 282(24): 17413 - 17423. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. G. Longstaff, R. C. Larue, J. E. Faust, A. Mahapatra, L. Zhang, K. B. Green-Church, and J. A. Krzycki A natural genetic code expansion cassette enables transmissible biosynthesis and genetic encoding of pyrrolysine PNAS, January 16, 2007; 104(3): 1021 - 1026. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Song, F. W Bazer, and T. E Spencer Pregnancy and interferon tau regulate RSAD2 and IFIH1 expression in the ovine uterus Reproduction, January 1, 2007; 133(1): 285 - 295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Chandor, O. Berteau, T. Douki, D. Gasparutto, Y. Sanakis, S. Ollagnier-de-Choudens, M. Atta, and M. Fontecave Dinucleotide Spore Photoproduct, a Minimal Substrate of the DNA Repair Spore Photoproduct Lyase Enzyme from Bacillus subtilis J. Biol. Chem., September 15, 2006; 281(37): 26922 - 26931. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Buis, J. Cheek, E. Kalliri, and J. B. Broderick Characterization of an Active Spore Photoproduct Lyase, a DNA Repair Enzyme in the Radical S-Adenosylmethionine Superfamily J. Biol. Chem., September 8, 2006; 281(36): 25994 - 26003. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Berteau, A. Guillot, A. Benjdia, and S. Rabot A New Type of Bacterial Sulfatase Reveals a Novel Maturation Pathway in Prokaryotes J. Biol. Chem., August 11, 2006; 281(32): 22464 - 22470. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Dougherty and D. M. Downs A connection between iron-sulfur cluster metabolism and the biosynthesis of 4-amino-5-hydroxymethyl-2-methylpyrimidine pyrophosphate in Salmonella enterica. Microbiology, August 1, 2006; 152(Pt 8): 2345 - 2353. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. S. Long, J. Poehlsgaard, C. Kehrenberg, S. Schwarz, and B. Vester The Cfr rRNA Methyltransferase Confers Resistance to Phenicols, Lincosamides, Oxazolidinones, Pleuromutilins, and Streptogramin A Antibiotics. Antimicrob. Agents Chemother., July 1, 2006; 50(7): 2500 - 2505. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Layer, A. J. Pierik, M. Trost, S. E. Rigby, H. K. Leech, K. Grage, D. Breckau, I. Astner, L. Jansch, P. Heathcote, et al. The Substrate Radical of Escherichia coli Oxygen-independent Coproporphyrinogen III Oxidase HemN J. Biol. Chem., June 9, 2006; 281(23): 15727 - 15734. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Boll, C. Hofmann, B. Heitmann, G. Hauser, S. Glaser, T. Koslowski, T. Friedrich, and A. Bechthold The Active Conformation of Avilamycin A Is Conferred by AviX12, a Radical AdoMet Enzyme J. Biol. Chem., May 26, 2006; 281(21): 14756 - 14763. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ono, T. Okajima, M. Tani, S. Kuroda, D. Sun, V. L. Davidson, and K. Tanizawa Involvement of a Putative [Fe-S]-cluster-binding Protein in the Biogenesis of Quinohemoprotein Amine Dehydrogenase J. Biol. Chem., May 12, 2006; 281(19): 13672 - 13684. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Atteia, R. van Lis, G. Gelius-Dietrich, A. Adrait, J. Garin, J. Joyard, N. Rolland, and W. Martin Pyruvate Formate-lyase and a Novel Route of Eukaryotic ATP Synthesis in Chlamydomonas Mitochondria J. Biol. Chem., April 14, 2006; 281(15): 9909 - 9918. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Curatti, P. W. Ludden, and L. M. Rubio From the Cover: NifB-dependent in vitro synthesis of the iron-molybdenum cofactor of nitrogenase PNAS, April 4, 2006; 103(14): 5297 - 5301. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Putz, P. Dolezal, G. Gelius-Dietrich, L. Bohacova, J. Tachezy, and K. Henze Fe-Hydrogenase Maturases in the Hydrogenosomes of Trichomonas vaginalis Eukaryot. Cell, March 1, 2006; 5(3): 579 - 586. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Corbett, Y. Hu, A. W. Fay, M. W. Ribbe, B. Hedman, and K. O. Hodgson Structural insights into a protein-bound iron-molybdenum cofactor precursor PNAS, January 31, 2006; 103(5): 1238 - 1243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Brazzolotto, J. K. Rubach, J. Gaillard, S. Gambarelli, M. Atta, and M. Fontecave The [Fe-Fe]-Hydrogenase Maturation Protein HydF from Thermotoga maritima Is a GTPase with an Iron-Sulfur Cluster J. Biol. Chem., January 13, 2006; 281(2): 769 - 774. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. W. Lepore, F. J. Ruzicka, P. A. Frey, and D. Ringe The x-ray crystal structure of lysine-2,3-aminomutase from Clostridium subterminale PNAS, September 27, 2005; 102(39): 13819 - 13824. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Layer, K. Grage, T. Teschner, V. Schunemann, D. Breckau, A. Masoumi, M. Jahn, P. Heathcote, A. X. Trautwein, and D. Jahn Radical S-Adenosylmethionine Enzyme Coproporphyrinogen III Oxidase HemN: FUNCTIONAL FEATURES OF THE [4Fe-4S] CLUSTER AND THE TWO BOUND S-ADENOSYL-L-METHIONINES J. Biol. Chem., August 12, 2005; 280(32): 29038 - 29046. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.S. Olofsson, K. Jatta, D. Wagsater, S. Gredmark, U. Hedin, G. Paulsson-Berne, C. Soderberg-Naucler, G.K. Hansson, and A. Sirsjo The Antiviral Cytomegalovirus Inducible Gene 5/Viperin Is Expressed in Atherosclerosis and Regulated by Proinflammatory Agents Arterioscler. Thromb. Vasc. Biol., July 1, 2005; 25(7): e113 - e116. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. D. Walker, K. Klettke, T. Akiyama, and R. Croteau Cloning, Heterologous Expression, and Characterization of a Phenylalanine Aminomutase Involved in Taxol Biosynthesis J. Biol. Chem., December 24, 2004; 279(52): 53947 - 53954. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Brede, T. Faye, O. Johnsborg, I. Odegard, I. F. Nes, and H. Holo Molecular and Genetic Characterization of Propionicin F, a Bacteriocin from Propionibacterium freudenreichii Appl. Envir. Microbiol., December 1, 2004; 70(12): 7303 - 7310. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Skovran, C. T. Lauhon, and D. M. Downs Lack of YggX Results in Chronic Oxidative Stress and Uncovers Subtle Defects in Fe-S Cluster Metabolism in Salmonella enterica J. Bacteriol., November 15, 2004; 186(22): 7626 - 7634. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Pierrel, T. Douki, M. Fontecave, and M. Atta MiaB Protein Is a Bifunctional Radical-S-Adenosylmethionine Enzyme Involved in Thiolation and Methylation of tRNA J. Biol. Chem., November 12, 2004; 279(46): 47555 - 47563. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. C. Martinez-Gomez, M. Robers, and D. M. Downs Mutational Analysis of ThiH, a Member of the Radical S-Adenosylmethionine (AdoMet) Protein Superfamily J. Biol. Chem., September 24, 2004; 279(39): 40505 - 40510. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Phillips, F. G. Whitby, C. A. Warby, P. Labbe, C. Yang, J. W. Pflugrath, J. D. Ferrara, H. Robinson, J. P. Kushner, and C. P. Hill Crystal Structure of the Oxygen-dependant Coproporphyrinogen Oxidase (Hem13p) of Saccharomyces cerevisiae J. Biol. Chem., September 10, 2004; 279(37): 38960 - 38968. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. R. Buan, S.-J. Suh, and J. C. Escalante-Semerena The eutT Gene of Salmonella enterica Encodes an Oxygen-Labile, Metal-Containing ATP:Corrinoid Adenosyltransferase Enzyme J. Bacteriol., September 1, 2004; 186(17): 5708 - 5714. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Hanzelmann and H. Schindelin Crystal structure of the S-adenosylmethionine-dependent enzyme MoaA and its implications for molybdenum cofactor deficiency in humans PNAS, August 31, 2004; 101(35): 12870 - 12875. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Hanzelmann, H. L. Hernandez, C. Menzel, R. Garcia-Serres, B. H. Huynh, M. K. Johnson, R. R. Mendel, and H. Schindelin Characterization of MOCS1A, an Oxygen-sensitive Iron-Sulfur Protein Involved in Human Molybdenum Cofactor Biosynthesis J. Biol. Chem., August 13, 2004; 279(33): 34721 - 34732. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Nicolet and C. L. Drennan AdoMet radical proteins--from structure to evolution--alignment of divergent protein sequences reveals strong secondary structure element conservation Nucleic Acids Res., August 2, 2004; 32(13): 4015 - 4025. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. E. Wyckoff, M. Schmitt, A. Wilks, and S. M. Payne HutZ Is Required for Efficient Heme Utilization in Vibrio cholerae J. Bacteriol., July 1, 2004; 186(13): 4142 - 4151. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Posewitz, P. W. King, S. L. Smolinski, L. Zhang, M. Seibert, and M. L. Ghirardi Discovery of Two Novel Radical S-Adenosylmethionine Proteins Required for the Assembly of an Active [Fe] Hydrogenase J. Biol. Chem., June 11, 2004; 279(24): 25711 - 25720. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Lehtio and A. Goldman The pyruvate formate lyase family: sequences, structures and activation Protein Eng. Des. Sel., June 1, 2004; 17(6): 545 - 552. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. T. Lauhon, E. Skovran, H. D. Urbina, D. M. Downs, and L. E. Vickery Substitutions in an Active Site Loop of Escherichia coli IscS Result in Specific Defects in Fe-S Cluster and Thionucleoside Biosynthesis in Vivo J. Biol. Chem., May 7, 2004; 279(19): 19551 - 19558. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Leonardi and P. L. Roach Thiamine Biosynthesis in Escherichia coli: IN VITRO RECONSTITUTION OF THE THIAZOLE SYNTHASE ACTIVITY J. Biol. Chem., April 23, 2004; 279(17): 17054 - 17062. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Fang, J. Peng, and T. Dierks Post-translational Formylglycine Modification of Bacterial Sulfatases by the Radical S-Adenosylmethionine Protein AtsB J. Biol. Chem., April 9, 2004; 279(15): 14570 - 14578. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Crack, J. Green, and A. J. Thomson Mechanism of Oxygen Sensing by the Bacterial Transcription Factor Fumarate-Nitrate Reduction (FNR) J. Biol. Chem., March 5, 2004; 279(10): 9278 - 9286. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Ye and A. Godzik Comparative Analysis of Protein Domain Organization Genome Res., March 1, 2004; 14(3): 343 - 353. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Jager, R. Leipuviene, M. G. Pollard, Q. Qian, and G. R. Bjork The Conserved Cys-X1-X2-Cys Motif Present in the TtcA Protein Is Required for the Thiolation of Cytidine in Position 32 of tRNA from Salmonella enterica serovar Typhimurium J. Bacteriol., February 1, 2004; 186(3): 750 - 757. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Leipuviene, Q. Qian, and G. R. Bjork Formation of Thiolated Nucleosides Present in tRNA from Salmonella enterica serovar Typhimurium Occurs in Two Principally Distinct Pathways J. Bacteriol., February 1, 2004; 186(3): 758 - 766. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Berkovitch, Y. Nicolet, J. T. Wan, J. T. Jarrett, and C. L. Drennan Crystal Structure of Biotin Synthase, an S-Adenosylmethionine-Dependent Radical Enzyme Science, January 2, 2004; 303(5654): 76 - 79. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Breckau, E. Mahlitz, A. Sauerwald, G. Layer, and D. Jahn Oxygen-dependent Coproporphyrinogen III Oxidase (HemF) from Escherichia coli Is Stimulated by Manganese J. Biol. Chem., November 21, 2003; 278(47): 46625 - 46631. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Pierrel, H. L. Hernandez, M. K. Johnson, M. Fontecave, and M. Atta MiaB Protein from Thermotoga maritima: CHARACTERIZATION OF AN EXTREMELY THERMOPHILIC tRNA-METHYLTHIOTRANSFERASE J. Biol. Chem., August 8, 2003; 278(32): 29515 - 29524. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. Cosper, N. J. Cosper, W. Hong, J. E. Shokes, W. E. Broderick, J. B. Broderick, M. K. Johnson, and R. A. Scott Structural studies of the interaction of S-adenosylmethionine with the [4Fe-4S] clusters in biotin synthase and pyruvate formate-lyase activating enzyme Protein Sci., July 1, 2003; 12(7): 1573 - 1577. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Picciocchi, R. Douce, and C. Alban The Plant Biotin Synthase Reaction: IDENTIFICATION AND CHARACTERIZATION OF ESSENTIAL MITOCHONDRIAL ACCESSORY PROTEIN COMPONENTS J. Biol. Chem., June 27, 2003; 278(27): 24966 - 24975. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Raynaud, P. Sarcabal, I. Meynial-Salles, C. Croux, and P. Soucaille Molecular characterization of the 1,3-propanediol (1,3-PD) operon of Clostridium butyricum PNAS, April 29, 2003; 100(9): 5010 - 5015. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Marquordt, Q. Fang, E. Will, J. Peng, K. von Figura, and T. Dierks Posttranslational Modification of Serine to Formylglycine in Bacterial Sulfatases. RECOGNITION OF THE MODIFICATION MOTIF BY THE IRON-SULFUR PROTEIN AtsB J. Biol. Chem., January 17, 2003; 278(4): 2212 - 2218. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Skovran and D. M. Downs Lack of the ApbC or ApbE Protein Results in a Defect in Fe-S Cluster Metabolism in Salmonella enterica Serovar Typhimurium J. Bacteriol., January 1, 2003; 185(1): 98 - 106. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. T. Lauhon Requirement for IscS in Biosynthesis of All Thionucleosides in Escherichia coli J. Bacteriol., December 15, 2002; 184(24): 6820 - 6829. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|