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100  structures 9297  species 11  interactions 122015  sequences 636  architectures

Family: Radical_SAM (PF04055)

Summary: Radical SAM superfamily

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This is the Wikipedia entry entitled "Radical SAM". More...

Radical SAM Edit Wikipedia article

SCOPe102114 / SUPFAM

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.[1][2] These enzymes utilize this potent radical intermediate to perform an array of unusual (from the perspective of organic chemistry) transformations, often to functionalize unactivated C-H bonds. More than 110,000 enzymes use adomet.[3] 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,[4][5] and have a cysteine-rich motif that matches or resembles CxxxCxxC.

Some radical SAMs release methyl radicals.[6]


An estimated 100,000 enzymes are classified as radical SAMs as of 2018.[2]


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 [7]
  • 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 - methylornithine synthase, 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) [8]
  • 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) [9]
  • Dph2 (PF01866) - diphthamide biosynthesis enzyme Dph2 (protein modification - diphthamide in translation elongation factor 2) (note different radical production, a 3-amino-3-carboxypropyl radical) [10]
  • PhnJ (PF06007) - phosphonate metabolism protein PhnJ (C-P phosphonate bond cleavage) [11]


  1. ^ 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 4002137. PMID 24476342.
  2. ^ a b Holliday GL, Akiva E, Meng EC, Brown SD, Calhoun S, Pieper U, et al. (2018). "Atlas of the Radical SAM Superfamily: Divergent Evolution of Function Using a "Plug and Play" Domain". Methods in Enzymology. 606: 1–71. doi:10.1016/bs.mie.2018.06.004. ISBN 978-0-12-812794-0. PMC 6445391. PMID 30097089.
  3. ^ Bridwell-Rabb J, Grell TA, Drennan CL (June 2018). "A Rich Man, Poor Man Story of S-Adenosylmethionine and Cobalamin Revisited". Annual Review of Biochemistry. 87: 555–584. doi:10.1146/annurev-biochem-062917-012500. PMID 29925255.
  4. ^ 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 29726. PMID 11222759.
  5. ^ 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.
  6. ^ 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 3999185. PMID 24328215.
  7. ^ 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 3079562. PMID 21240261.
  8. ^ 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 4829460. PMID 27007615.
  9. ^ Chatterjee A, Li Y, Zhang Y, Grove TL, Lee M, Krebs C, et al. (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 2587053. PMID 18953358.
  10. ^ Zhang Y, Zhu X, Torelli AT, Lee M, Dzikovski B, Koralewski RM, et al. (June 2010). "Diphthamide biosynthesis requires an organic radical generated by an iron-sulphur enzyme". Nature. 465 (7300): 891–6. doi:10.1038/nature09138. PMC 3006227. PMID 20559380.
  11. ^ 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 3245791. PMID 22089136.

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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

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.

Literature references

  1. 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

  2. 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

  3. Berteau O, Guillot A, Benjdia A, Rabot S; , J Biol Chem. 2006;281:22464-22470.: A new type of bacterial sulfatase reveals a novel maturation pathway in prokaryotes. PUBMED:16766528 EPMC:16766528

Internal database links

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].

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Seed source: Bateman A
Previous IDs: none
Type: Domain
Sequence Ontology: SO:0000417
Author: 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 %

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HMM build commands:
build method: hmmbuild -o /dev/null --hand HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 29.5 29.5
Trusted cut-off 29.5 29.5
Noise cut-off 29.4 29.4
Model length: 167
Family (HMM) version: 21
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There are 11 interactions for this family. More...

Radical_SAM LAM_C LAM_C Fer4_12 BATS Wyosine_form Fer4_12 SPASM Fer4_14 Mob_synth_C UPF0004


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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