Summary: Radical SAM superfamily
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Radical SAM Edit Wikipedia article
Radical SAM is a designation for a superfamily of enzymes that use a [4Fe-4S]+ cluster to reductively cleave S-adenosyl-L-methionine (SAM) to generate a radical, usually a 5′-deoxyadenosyl radical, as a critical intermediate. These enzymes utilize this potent radical intermediate to perform an array of unusual and chemically difficult transformations, often to functionalize unactivated C-H bonds. Radical SAM enzymes are involved in cofactor biosynthesis, enzyme activation, peptide modification, post-transcriptional and post-translational modifications, metalloprotein cluster formation, tRNA modification, lipid metabolism, biosynthesis of antibiotics and natural products etc. The vast majority of known radical SAM enzymes belong to the radical SAM superfamily, and have a cysteine-rich motif that matches or resembles CxxxCxxC.
Examples of radical SAM enzymes found within the radical SAM superfamily include:
- AblA - lysine 2,3-aminomutase (osmolyte biosynthesis - N-epsilon-acetyl-beta-lysine)
- AlbA - subtilosin maturase (peptide modification)
- AtsB - anaerobic sulfatase activase (enzyme activation)
- BchE - anaerobic magnesium protoporphyrin-IX oxidative cyclase (cofactor biosynthesis - chlorophyll)
- BioB - biotin synthase (cofactor biosynthesis - biotin)
- BlsE - cytosylglucuronic acid decarboxylase - blasticidin S biosynthesis
- BtrN - butirosin biosynthesis pathway oxidoreductase (aminoglycoside antibiotic biosynthesis)
- Cfr - 23S rRNA (adenine(2503)-C(8))-methyltransferase - rRNA modification for antibiotic resistance
- CofG - FO synthase, CofG subunit (cofactor biosynthesis - F420)
- CofH - FO synthase, CofH subunit (cofactor biosynthesis - F420)
- CutD - trimethylamine lyase-activating enzyme
- DesII - D-desosamine biosynthesis deaminase (sugar modification for macrolide antibiotic biosynthesis)
- EpmB - elongation factor P beta-lysylation protein (protein modification)
- HemN - oxygen-independent coproporphyrinogen III oxidase (cofactor biosynthesis - heme)
- HmdB - 5,10-methenyltetrahydromethanopterin hydrogenase cofactor biosynthesis protein HmdB (note unusual CX5CX2C motif)
- HpnR - hopanoid C-3 methylase (lipid biosynthesis - 3-methylhopanoid production)
- HydE - [FeFe] hydrogenase H-cluster radical SAM maturase (metallocluster assembly)
- HydG - [FeFe] hydrogenase H-cluster radical SAM maturase (metallocluster assembly)
- LipA - lipoyl synthase (cofactor biosynthesis - lipoyl)
- MftC - mycofactocin system maturase (peptide modification/cofactor biosynthesis - predicted)
- MiaB - tRNA methylthiotransferase (tRNA modification)
- MoaA - GTP 3',8-cyclase (cofactor biosynthesis - molybdenum cofactor)
- MqnC - dehypoxanthine futalosine cyclase (cofactor biosynthesis - menaquinone via futalosine)
- MqnE - aminofutalosine synthase (cofactor biosynthesis - menaquinone via futalosine)
- NifB - cofactor biosynthesis protein NifB (cofactor biosynthesis - FeMo cofactor)
- NirJ - heme d1 biosynthesis radical SAM protein NirJ (cofactor biosynthesis - heme d1)
- NosL - complex rearrangement of tryptophan to 3-methyl-2-indolic acid - nosiheptide biosynthesis 
- NrdG - anaerobic ribonucleoside-triphosphate reductase activase (enzyme activation)
- PflA - pyruvate formate-lyase activating enzyme (enzyme activation)
- PhpK - radical SAM P-methyltransferase - antibiotic biosynthesis
- PqqE - PQQ biosynthesis enzyme (peptide modification / cofactor biosynthesis - PQQ)
- PylB - pyrrolysine biosynthesis protein PylB (amino acid biosynthesis - pyrrolysine)
- QhpD (PeaB) - quinohemoprotein amine dehydrogenase maturation protein (enzyme activation)
- QueE - 7-carboxy-7-deazaguanine (CDG) synthase
- RimO - ribosomal protein S12 methylthiotransferase
- RlmN - 23S rRNA (adenine(2503)-C(2))-methyltransferase (rRNA modification)
- ScfB - SCIFF maturase (peptide modification by thioether cross-link formation) 
- SkfB - sporulation killing factor maturase
- SplB - spore photoproduct lyase (DNA repair)
- ThiH - thiazole biosynthesis protein ThiH (cofactor biosynthesis - thiamine)
- TrnC - thuricin biosynthesis
- TrnD - thuricin biosynthesis
- TsrT - tryptophan 2-C-methyltransferase (amino acid modification - antibiotic biosynthesis)
- TYW1 - 4-demethylwyosine synthase (tRNA modification)
- YqeV - tRNA methylthiotransferase (tRNA modification)
In addition, several non-canonical radical SAM enzymes have been described. These cannot be recognized by the Pfam hidden Markov model PF04055, but still use three Cys residues as ligands to a 4Fe4S cluster and produce a radical from S-adenosylmethionine. These include
- ThiC (PF01964) - thiamine biosynthesis protein ThiC (cofactor biosynthesis - thiamine) (Cys residues near extreme C-terminus) 
- Dph2 (PF01866) - diphthamide biosynthesis enzyme Dph2 (protein modification - diphthamide in translation elongation factor 2) (note different radical production, a 3-amino-3-carboxypropyl radical) 
- PhnJ (PF06007) - phosphonate metabolism protein PhnJ (C-P phosphonate bond cleavage) 
- Broderick JB, Duffus BR, Duschene KS, Shepard EM (April 2014). "Radical S-adenosylmethionine enzymes". Chemical Reviews. 114 (8): 4229–317. doi:10.1021/cr4004709. PMC . PMID 24476342.
- Booker SJ, Grove TL (July 2010). "Mechanistic and functional versatility of radical SAM enzymes". F1000 Biology Reports. 2: 52. doi:10.3410/B2-52. PMC . PMID 21152342.
- Sofia HJ, Chen G, Hetzler BG, Reyes-Spindola JF, Miller NE (March 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 Research. 29 (5): 1097–106. doi:10.1093/nar/29.5.1097. PMC . PMID 11222759.
- Frey PA, Hegeman AD, Ruzicka FJ (2008). "The Radical SAM Superfamily". Critical Reviews in Biochemistry and Molecular Biology. 43 (1): 63–88. doi:10.1080/10409230701829169. PMID 18307109.
- Ribbe MW, Hu Y, Hodgson KO, Hedman B (April 2014). "Biosynthesis of nitrogenase metalloclusters". Chemical Reviews. 114 (8): 4063–80. doi:10.1021/cr400463x. PMC . PMID 24328215.
- Zhang Q, Li Y, Chen D, Yu Y, Duan L, Shen B, Liu W (March 2011). "Radical-mediated enzymatic carbon chain fragmentation-recombination". Nature Chemical Biology. 7 (3): 154–60. doi:10.1038/nchembio.512. PMC . PMID 21240261.
- Bruender NA, Wilcoxen J, Britt RD, Bandarian V (April 2016). "Biochemical and Spectroscopic Characterization of a Radical S-Adenosyl-L-methionine Enzyme Involved in the Formation of a Peptide Thioether Cross-Link". Biochemistry. 55 (14): 2122–34. doi:10.1021/acs.biochem.6b00145. PMC . PMID 27007615.
- Chatterjee A, Li Y, Zhang Y, Grove TL, Lee M, Krebs C, Booker SJ, Begley TP, Ealick SE (December 2008). "Reconstitution of ThiC in thiamine pyrimidine biosynthesis expands the radical SAM superfamily". Nature Chemical Biology. 4 (12): 758–65. doi:10.1038/nchembio.121. PMC . PMID 18953358.
- Zhang Y, Zhu X, Torelli AT, Lee M, Dzikovski B, Koralewski RM, Wang E, Freed J, Krebs C, Ealick SE, Lin H (June 2010). "Diphthamide biosynthesis requires an organic radical generated by an iron-sulphur enzyme". Nature. 465 (7300): 891–6. doi:10.1038/nature09138. PMC . PMID 20559380.
- Kamat SS, Williams HJ, Raushel FM (November 2011). "Intermediates in the transformation of phosphonates to phosphate by bacteria". Nature. 480 (7378): 570–3. doi:10.1038/nature10622. PMC . PMID 22089136.
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Radical SAM superfamily Provide feedback
Radical SAM proteins catalyse diverse reactions, including unusual methylations, isomerisation, sulphur insertion, ring formation, anaerobic oxidation and protein radical formation.
Sofia HJ, Chen G, Hetzler BG, Reyes-Spindola JF, Miller NE; , Nucleic Acids Res 2001;29:1097-1106.: 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. PUBMED:11222759 EPMC:11222759
Benjdia A, Leprince J, Guillot A, Vaudry H, Rabot S, Berteau O; , J Am Chem Soc. 2007;129:3462-3463.: Anaerobic sulfatase-maturating enzymes: radical SAM enzymes able to catalyze in vitro sulfatase post-translational modification. PUBMED:17335281 EPMC:17335281
Internal database links
|SCOOP:||AP_endonuc_2 DUF1848 DUF4917 DUF5131 Fer4 Fer4_10 Fer4_12 Fer4_14 Fer4_16 Fer4_18 Fer4_2 Fer4_21 Fer4_4 Fer4_6 Fer4_7 Fer4_8 Fer4_9 His_biosynth HMGL-like LIAS_N TP_methylase|
|Similarity to PfamA using HHSearch:||Fer4_12 Fer4_14|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR007197
Radical SAM proteins catalyze diverse reactions, including unusual methylations, isomerization, sulphur insertion, ring formation, anaerobic oxidation and protein radical formation. Evidence exists that these proteins generate a radical species by reductive cleavage of S:-adenosylmethionine (SAM) through an unusual Fe-S centre [PUBMED:11222759, PUBMED:15317939].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||catalytic activity (GO:0003824)|
|iron-sulfur cluster binding (GO:0051536)|
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This large superfamily of TIM barrel enzymes all contain a common phosphate binding site. The phosphate is found in a variety of cofactors and ligands such as FMN [1,2].
The clan contains the following 59 members:4HFCP_synth Ala_racemase_N ALAD Aldolase AP_endonuc_2 BtpA CdhD ComA CutC DAHP_synth_1 DAHP_synth_2 DeoC DHDPS DHO_dh DHquinase_I DUF2090 DUF561 DUF692 DUF993 Dus F_bP_aldolase FMN_dh G3P_antiterm Glu_syn_central Glu_synthase His_biosynth HMGL-like IGPS IMPDH KDGP_aldolase Lys-AminoMut_A MtrH NanE NAPRTase NeuB NMO OAM_alpha OMPdecase Orn_Arg_deC_N Oxidored_FMN PcrB PdxJ PRAI PRMT5_TIM Pterin_bind QRPTase_C Radical_SAM RhaA Ribul_P_3_epim SOR_SNZ Tagatose_6_P_K TAL_FSA ThiC_Rad_SAM ThiG TIM TMP-TENI Trp_syntA UvdE UxuA
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|Seed source:||Bateman A|
|Number in seed:||518|
|Number in full:||122015|
|Average length of the domain:||169.10 aa|
|Average identity of full alignment:||14 %|
|Average coverage of the sequence by the domain:||42.15 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null --hand HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||21|
|Download:||download the raw HMM for this family|
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There are 11 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Radical_SAM domain has been found. There are 100 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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