Biology:Radical SAM

From HandWiki
Radical_SAM
Identifiers
SymbolRadical_SAM
PfamPF04055
InterProIPR007197
SCOP2102114 / SCOPe / SUPFAM

Radical SAM enzymes is 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 (5'-dAdo), as a critical intermediate.[1][2] These enzymes utilize this radical intermediate[3] to perform diverse 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,[4][5] and have a cysteine-rich motif that matches or resembles CxxxCxxC. Radical SAM enzymes comprise the largest superfamily of metal-containing enzymes.[6]

History and mechanism

As of 2001, 645 unique radical SAM enzymes have been identified from 126 species in all three domains of life.[4] According to the EFI and SFLD databases, more than 220,000 radical SAM enzymes are predicted to be involved in 85 types of biochemical transformations.[7]

The mechanism for these reactions entail transfer of a methyl or adenosyl group from sulfur to iron. The resulting organoiron complex subsequently releases the organic radical. The latter step is reminiscent of the behavior of adenosyl and methyl cobalamins.[8]

Nomenclature

All enzymes including radical SAM superfamily follow an easy guideline for systematic naming. Systematic naming of enzymes allows a uniform naming process that is recognized by all scientists to understand corresponding function. The first word of the enzyme name often shows the substrate of the enzyme. The position of the reaction on the substrate will also be in the beginning portion of the name. Lastly, the class of the enzyme will be described in the other half of the name which will end in suffix -ase. The class of an enzyme will describe what the enzyme is doing or changing on the substrate. For example, a ligase combines two molecules to form a new bond.[9]

Superimposition of three radical SAM core domains. Side views of radical SAM enzymes BioB (PDB: 1R30), MoaA (PDB: 1TV8) and phTYW1 (PDB: 2YX0) are shown front and back. This core fold consists of six β/α motifs arranged in a manner that is similar to TIM barrel and is responsible for radical generation.[10] β-sheets are colored yellow and α-helices are shown in cyan.

Reaction classification

Representative enzymes will be mentioned for each class. Radical SAM enzymes and their mechanisms known before 2008 are summarized by Frey et al.[5] Since 2015, additional review articles on radical SAM enzymes are available, including:

  1. Recent Advances in Radical SAM Enzymology: New Structures and Mechanisms:[11]
  2. Radical S-Adenosylmethionine Enzymes:[1]
  3. Radical S-Adenosylmethionine (SAM) Enzymes in Cofactor Biosynthesis: A Treasure Trove of Complex Organic Radical Rearrangement Reactions:[12]
  4. Molecular architectures and functions of radical enzymes and their (re)activating proteins:[13]
  5. Radical SAM enzymes in RiPP biosynthesis.[14]

Carbon methylation

Radical SAM methylases/methyltransferases are one of the largest yet diverse subgroups and are capable of methylating a broad range of unreactive carbon and phosphorus centers. These enzymes are divided into three classes (Class A, B and C) with representative methylation mechanisms. The shared characteristic is the usage of SAM, split into two distinct roles: one as a source of a methyl group donor, and the second as a source of 5'-dAdo radical.[15][16] Another class has been proposed (class D) but proved recently to be wrongly assigned.[17]

Class A sub-family

  • Class A enzymes methylates specific adenosine residues on rRNA and/or tRNA.[18][19] In other words, they are RNA base-modifying radical SAM enzymes.
  • The most mechanistically well-characterized are enzymes RlmN and Cfr. Both enzymes methylates substrate by adding a methylene fragment originating from SAM molecule.[16][20] Therefore, RlmN and Cfr are considered methyl synthases instead of methyltransferases.

Class B sub-family

  • Class B enzymes are the largest and most versatile which can methylate a wide range of carbon and phosphorus centers.[19]
  • These enzymes require a cobalamin (vitamin B12) cofactor as an intermediate methyl group carrier to transfer a methyl group from SAM to substrate.[18]
  • One well-investigated representative enzyme is TsrM which involves in tryptophan methylation in thiostrepton biosynthesis.[21]

Class C sub-family

  • Class C enzymes are reported to play roles in biosynthesis of complex natural products and secondary metabolites. These enzymes methylate heteroaromatic substrates [18][19] and are cobalamin-independent.[22]
  • These enzymes contain both the radical SAM motif and exhibit striking sequence similarity to coproporhyrinogen III oxidase (HemN), a radical SAM enzyme involved in heme biosynthesis [16][19]
  • Recently, detailed mechanistic investigation on two important class C radical SAM methylases have been reported:
    1. TbtI is involved in the biosynthesis of potent thiopeptide antibiotic thiomuracin.[23]
    2. Jaw5 is suggested to be responsible for cyclopropane modifications.[24]

Methylthiolation of tRNAs

Methythiotransferases belong to a subset of radical SAM enzymes that contain two [4Fe-4S]+ clusters and one radical SAM domain. Methylthiotransferases play a major role in catalyzing methylthiolation on tRNA nucleotides or anticodons through a redox mechanism. Thiolation modification is believed to maintain translational efficiency and fidelity.[11][25][26][27]

MiaB and RimO are both well-characterized and bacterial prototypes for tRNA-modifying methylthiotransferases

  • MiaB introduces a methylthio group to the isopentenylated A37 derivatives in the tRNA of S. Typhimurium and E. coli by utilizing one SAM molecule to generate 5'-dAdo radical to activate the substrate and a second SAM to donate a sulfur atom to the substrate.[28][29]
  • RimO is responsible for post-translational modification of Asp88 of the ribosomal protein S12 in E. coli.[30][31] A recently determined crystal structure sheds light on the mechanistic action of RimO. The enzyme catalyzes pentasulfide bridge formation linking two Fe-S clusters to allow for sulfur insertion to the substrate.[32]

eMtaB is the designated methylthiotransferase in eukaryotic and archaeal cells. eMtaB catalyzes the methylthiolation of tRNA at position 37 on N6-threonylcarbamoyladenosine.[33] A bacterial homologue of eMtaB, YqeV has been reported and suggested to function similarly to MiaB and RimO.[33]

Sulfur insertion into unreactive C-H bonds

Sulfurtransferases are a small subset of radical SAM enzymes. Two well-known examples are BioB and LipA which are independently responsible for biotin synthesis and lipoic acid metabolism, respectively.[1]

  • BioB or biotin synthase is a radical SAM enzyme that employs one [4Fe-4S] center to thiolate dethiobitin, thus converting it to biotin or also known as vitamin B7. Vitamin B7 is a cofactor used in carboxylation, decarboxylation, and transcarboxylation reactions in many organisms.[1]
  • LipA or lipoyl synthase is radical SAM sulfurtransferase utilizing two [4Fe-4S] clusters to catalyze the final step in lipoic acid biosynthesis.[1]

Carbon insertion

Nitrogenase is a metallozyme with essential function in the biological nitrogen fixation reaction. The M-cluster ([MoFe7S9C-homocitrate]) and P-cluster ([Fe8S7]) are highly unique metalloclusters present in nitrogenase. The best-studied nitrogenase up-to-date is Mo nitrogenase with M-cluster and P-cluster bearing important roles in substrate reduction.[34] The active site of Mo nitrogenase is the M-cluster, a metal-sulfur cluster containing a carbide at its core. Within the biosynthesis of M-cluster, radical SAM enzyme NifB has been recognized to catalyze a carbon insertion reaction, leading to formation of a Mo/homocitrate-free precursor of M-cluster.[35]

Anaerobic oxidative decarboxylation

  • One well-studied example is HemN. HemN or anaerobic coproporphyrinogen III oxidase is a radical SAM enzyme that catalyzes the oxidative decarboxylation of coproporphyrinogen III to protoporhyrinogen IX, an important intermediate in heme biosynthesis. A recently published study shows evidence supporting HemN utilizes two SAM molecules to mediate radical-mediated hydrogen transfer for the sequential decarboxylation of the two propionate groups of coproporphyrinogen III.[36]
  • Hyperthermophilic sulfate-reducing archaen Archaeoglobus fulgidus has been recently reported to enable anaerobic oxidation of long chain n-alkanes.[37] PflD is reported to be responsible for the capacity of A. fulgidus to grow on a wide range of unsaturated carbons and fatty acids. A detailed biochemical and mechanistic characterization of PflD is still undergoing but preliminary data suggest PflD may be a radical SAM enzyme.

Protein post-translational modification

  • Formyl-glycine dependent sulfatases[38] require the critical post-translational modification of an active site cysteine[39] or serine residue[40][41] into a Cα-formylglycine.[42] A radical SAM enzyme called anSME[43][41] catalyze this post-translational modification in an oxygen-independent manner.[40]

Protein radical formation

Glycyl radical enzyme activating enzymes (GRE-AEs) are radical SAM subset that can house a stable and catalytically essential glycyl radical in their active state. The underlying chemistry is considered to be the simplest in the radical SAM superfamily with H-atom abstraction by the 5'-dAdo radical being the product of the reaction.[1] A few examples include:

  • Pyruvate formate-lyase activating enzyme (PFL-AE) catalyzes the activation of PFL, a central enzyme in anaerobic glucose metabolism in microbes.[1]
  • Benzylsuccinate synthase (BSS) is a central enzyme in anaerobic toluene catabolism.[1]

Peptide modifications

Radical SAM enzymes that can catalyze sulfur-to-alpha carbon thioether cross-linked peptides (sactipeptides) are important to generate an essential class of peptide with significant antibacterial properties.[44][45] These peptides belong to the emerging class of ribosomally synthesized and post-translationally modified peptides (RiPPs).[7]

Another important subset of peptide-modifying radical SAM enzymes is SPASM/Twitch domain-carrying enzymes. SPASM/Twitch enzymes carry a functionalized C-terminal extension for the binding of two [4Fe-4S] clusters, especially important in post-translational modifications of peptides.[46][47][48][7]

The following examples are representative enzymes that can catalyze peptide modifications to generate specific natural products or cofactors.

  1. TsrM in thiostrepton biosynthesis[49][50]
  2. PoyD[51] and PoyC[52] in polytheonamide biosynthesis
  3. TbtI in thiomuracin biosynthesis[22]
  4. NosN in nosiheptide biosynthesis[53]
  5. YydG in biosynthesis[54][55]
  6. MoaA in molybdopterin biosynthesis[53][12]
  7. PqqE in pyrroloquinoline quinone biosynthesis[53]
  8. TunB in tunicamycin biosynthesis[53]
  9. OxsB in oxetanocin biosynthesis[53]
  10. BchE in anaerobic bacteriochlorophyll biosynthesis[53]
  11. F0 synthases in F420 cofactor biosynthesis[56][57]
  12. MqnE and MqnC in menaquinone biosynthesis[53][12]
  13. QhpD in post-translational processing of quinohemoprotein amine dehydrogenase[58]
  14. RumMC2 in ruminococcin C biosynthesis[44][59]

Epimerization

Radical SAM epimerases are responsible for the regioselective introduction of D-amino acids into RiPPs.[55] Two well-known enzymes have been thoroughly described in RiPP biosynthetic pathways.[7]

Two well-known enzymes have been thoroughly described in RiPP biosynthetic pathways.[7]

  • PoyD installs numerous D-stereocenters in enzyme PoyA to ultimately help facilitate polytheonamide biosynthesis.[51] Polytheoamide is a natural potent cytoxic agent by forming pores in membranes.[60] This peptide cytotoxin is naturally produced by uncultivated bacteria that exist as symbionts in a marine sponge.[61]
  • YydG epimerase modifies two amino acid positions on YydF in Gram-positive Bacillus subtilis.[7][55] A recent study has reported the extrinsically added YydF mediates subsequent dissipation of membrane potential via membrane permeabilization, resulting in death of the organism.[54]

Complex carbon skeleton rearrangements

Another subset of radical SAM superfamily has been shown to catalyze carbon skeleton rearrangements especially in the areas of DNA repair and cofactor biosynthesis.

Other reactions

  • A recent study has reported a novel radical SAM enzyme with intrinsic lyase activity that is able to catalyze lysine transfer reaction, generating archaea-specific archaosine-containing tRNAs.[67]
  • Viperin is an interferon-stimulated radical SAM enzyme which converts CTP to ddhCTP (3ʹ-deoxy-3′,4ʹdidehydro-CTP), which is a chain terminator for viral RdRps and therefore a natural antiviral compound.[68]

Clinical considerations

  • Deficiency in human tRNA methylthiotransferase eMtaB has been shown to be responsible for abnormal insulin synthesis and predisposition to type 2 diabetes.[69]
  • Mutations in human GTP cyclase MoaA has been reported to lead to molybdenum cofactor deficiency, a usually fatal disease accompanied by severe neurological symptoms.[70]
  • Mutations in human wybutosine-tRNA modifying enzyme Tyw1 promotes retrovirus infection.[71]
  • Alterations in human tRNA-modifying enzyme Elp3 results in progression into amyotrophic lateral sclerosis (ALS).[71]
  • Mutations in human antiviral RSAD1 has been shown to be associated with congenital heart disease.[71]
  • Mutations in human sulfurtransferase LipA has been implicated in glycine encephalopathy, pyruvate dehydrogenase and lipoic acid synthetase deficiency.[71]
  • Mutations in human methylthiotransferase MiaB are related to impaired cardiac and respiratory functions.[71]

Therapeutic applications

Microbes have been extensively used for the discovery of new antibiotics. However, a growing public concern of multi-drug resistant pathogens has been emerging in the last few decades. Thus, newly developed or novel antibiotics are in utmost demand. Ribosomally synthesized and post-translationally modified peptides (RiPPs) are getting more attention as a newer and major group of antibiotics thanks to having a very narrow of activity spectrum, which can benefit patients, as their side effects will be lesser than the broad-spectrum antibiotics.[72][73] Below are a few examples of radical SAM enzymes have been shown to be promising targets for antibiotic and antiviral development.

  • Inhibition of radical SAM enzyme MnqE in menaoquinone biosynthesis is reported to be an effective antibacterial strategy against H. pylori.[74]
  • Radical SAM enzyme BlsE has recently been discovered to be a central enzyme in blasticidin S biosynthetic pathway. Blasticidin S produced by Streptomyces griseochromogenes exhibits strong inhibitory activity against rice blast caused by Pyricularia oryzae Cavara. This compound specifically inhibits protein synthesis in both prokaryotes and eukaryotes through inhibition of peptide bond formation in the ribosome machinery.[75]
  • A new fungal radical SAM enzyme has also been recently reported to facilitate the biocatalytic routes for synthesis of 3'-deoxy nucleotides/nucleosides. 3'deoxynucleotides are an important class of drugs since they interfere with the metabolism of nucleotides, and their incorporation into DNA or RNA terminates cell division and replication. This activity explains why this compound is an essential group of antiviral, antibacterial or anticancer drug.[76]

Examples

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)
  • BzaF - 5-hydroxybenzimidazole (5-HBI) synthesis (cobalt binding ligand of cobalamin)
  • 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
  • DarE - darobactin maturase
  • 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 - molybdopterin)
  • 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 [77]
  • 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) [78]
  • SkfB - sporulation killing factor maturase
  • SplB - spore photoproduct lyase (DNA repair)
  • ThiC - 4-amino-5-hydroxymethyl-2-methylpyrimidine phosphate (HMP-P) biosynthesis (cofactor biosynthesis - thiamine)
  • ThiH - thiazole phosphate biosynthesis (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)


Non-canonical

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) [79]
  • Dph2 (PF01866) - diphthamide biosynthesis enzyme Dph2 (protein modification - diphthamide in translation elongation factor 2) (note different radical production, a 3-amino-3-carboxypropyl radical) [80]
  • PhnJ (PF06007) - phosphonate metabolism protein PhnJ (C-P phosphonate bond cleavage) [81]


References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 "Radical S-adenosylmethionine enzymes". Chemical Reviews 114 (8): 4229–317. April 2014. doi:10.1021/cr4004709. PMID 24476342. 
  2. ↑ Holliday, Gemma L.; Akiva, Eyal; Meng, Elaine C.; Brown, Shoshana D.; Calhoun, Sara; Pieper, Ursula; Sali, Andrej; Booker, Squire J. et al. (2018). "Atlas of the Radical SAM Superfamily: Divergent Evolution of Function Using a "Plug and Play" Domain". Radical SAM Enzymes. Methods in Enzymology. 606. pp. 1–71. doi:10.1016/bs.mie.2018.06.004. ISBN 978-0-12-812794-0. 
  3. ↑ Hoffman, Brian M.; Broderick, William E.; Broderick, Joan B. (2023-06-20). "Mechanism of Radical Initiation in the Radical SAM Enzyme Superfamily" (in en). Annual Review of Biochemistry 92 (1): 333–349. doi:10.1146/annurev-biochem-052621-090638. ISSN 0066-4154. PMID 37018846. https://www.annualreviews.org/doi/10.1146/annurev-biochem-052621-090638. 
  4. ↑ 4.0 4.1 "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. March 2001. doi:10.1093/nar/29.5.1097. PMID 11222759. 
  5. ↑ 5.0 5.1 "The Radical SAM Superfamily". Critical Reviews in Biochemistry and Molecular Biology 43 (1): 63–88. 2008. doi:10.1080/10409230701829169. PMID 18307109. 
  6. ↑ Martin, Lydie; Vernède, Xavier; Nicolet, Yvain (2021). "Methods to Screen for Radical SAM Enzyme Crystallization Conditions". Fe-S Proteins. Methods in Molecular Biology. 2353. pp. 333–348. doi:10.1007/978-1-0716-1605-5_17. ISBN 978-1-0716-1604-8. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 "Radical SAM Enzymes in the Biosynthesis of Ribosomally Synthesized and Post-translationally Modified Peptides (RiPPs)". Frontiers in Chemistry 5: 87. 2017. doi:10.3389/fchem.2017.00087. PMID 29167789. 
  8. ↑ "Mechanism of Radical Initiation in the Radical S-Adenosyl-l-methionine Superfamily". Accounts of Chemical Research 51 (11): 2611–2619. November 2018. doi:10.1021/acs.accounts.8b00356. PMID 30346729. 
  9. ↑ "Enzyme Classification". https://www.qmul.ac.uk/sbcs/iubmb/enzyme/rules.html. 
  10. ↑ "Structural insights into radical generation by the radical SAM superfamily". Chemical Reviews 111 (4): 2487–506. April 2011. doi:10.1021/cr9002616. PMID 21370834. 
  11. ↑ 11.0 11.1 11.2 11.3 11.4 "Recent advances in radical SAM enzymology: new structures and mechanisms". ACS Chemical Biology 9 (9): 1929–38. September 2014. doi:10.1021/cb5004674. PMID 25009947. 
  12. ↑ 12.0 12.1 12.2 "Radical S-adenosylmethionine (SAM) enzymes in cofactor biosynthesis: a treasure trove of complex organic radical rearrangement reactions". The Journal of Biological Chemistry 290 (7): 3980–6. February 2015. doi:10.1074/jbc.R114.623793. PMID 25477515. 
  13. ↑ Shibata, Naoki; Toraya, Tetsuo (2015). "Molecular architectures and functions of radical enzymes and their (Re)activating proteins". Journal of Biochemistry 158 (4): 271–292. doi:10.1093/jb/mvv078. PMID 26261050. 
  14. ↑ Benjdia, Alhosna; Balty, Clémence; Berteau, Olivier (2017). "Radical SAM Enzymes in the Biosynthesis of Ribosomally Synthesized and Post-translationally Modified Peptides (RiPPs)". Frontiers in Chemistry 5: 87. doi:10.3389/fchem.2017.00087. ISSN 2296-2646. PMID 29167789. 
  15. ↑ Fyfe, Cameron D.; Bernardo-García, Noelia; Fradale, Laura; Grimaldi, Stéphane; Guillot, Alain; Brewee, Clémence; Chavas, Leonard M. G.; Legrand, Pierre et al. (February 2022). "Crystallographic snapshots of a B12-dependent radical SAM methyltransferase" (in en). Nature 602 (7896): 336–342. doi:10.1038/s41586-021-04355-9. ISSN 1476-4687. PMID 35110733. Bibcode: 2022Natur.602..336F. 
  16. ↑ 16.0 16.1 16.2 "Radical SAM-mediated methylation reactions". Current Opinion in Chemical Biology 17 (4): 597–604. August 2013. doi:10.1016/j.cbpa.2013.05.032. PMID 23835516. 
  17. ↑ Lloyd, Cody T.; Iwig, David F.; Wang, Bo; Cossu, Matteo; Metcalf, William W.; Boal, Amie K.; Booker, Squire J. (September 2022). "Discovery, structure and mechanism of a tetraether lipid synthase" (in en). Nature 609 (7925): 197–203. doi:10.1038/s41586-022-05120-2. ISSN 1476-4687. PMID 35882349. Bibcode: 2022Natur.609..197L. 
  18. ↑ 18.0 18.1 18.2 Fyfe, Cameron D.; Bernardo-García, Noelia; Fradale, Laura; Grimaldi, Stéphane; Guillot, Alain; Brewee, Clémence; Chavas, Leonard M. G.; Legrand, Pierre et al. (2022). "Crystallographic snapshots of a B12-dependent radical SAM methyltransferase". Nature 602 (7896): 336–342. doi:10.1038/s41586-021-04355-9. PMID 35110733. Bibcode: 2022Natur.602..336F. 
  19. ↑ 19.0 19.1 19.2 19.3 "Mechanistic diversity of radical S-adenosylmethionine (SAM)-dependent methylation". The Journal of Biological Chemistry 290 (7): 3995–4002. February 2015. doi:10.1074/jbc.r114.607044. PMID 25477520. 
  20. ↑ "RNA methylation by radical SAM enzymes RlmN and Cfr proceeds via methylene transfer and hydride shift". Proceedings of the National Academy of Sciences of the United States of America 108 (10): 3930–4. March 2011. doi:10.1073/pnas.1017781108. PMID 21368151. Bibcode: 2011PNAS..108.3930Y. 
  21. ↑ Pierre, Stéphane; Guillot, Alain; Benjdia, Alhosna; Sandström, Corine; Langella, Philippe; Berteau, Olivier (2012). "Thiostrepton tryptophan methyltransferase expands the chemistry of radical SAM enzymes". Nature Chemical Biology 8 (12): 957–959. doi:10.1038/nchembio.1091. PMID 23064318. 
  22. ↑ 22.0 22.1 "Radical S-Adenosylmethionine Enzymes Involved in RiPP Biosynthesis". Biochemistry 56 (40): 5229–5244. October 2017. doi:10.1021/acs.biochem.7b00771. PMID 28895719. 
  23. ↑ "Mechanism of a Class C Radical S-Adenosyl-l-methionine Thiazole Methyl Transferase". Journal of the American Chemical Society 139 (51): 18623–18631. December 2017. doi:10.1021/jacs.7b10203. PMID 29190095. 
  24. ↑ "A radical S-adenosyl-L-methionine enzyme and a methyltransferase catalyze cyclopropane formation in natural product biosynthesis". Nature Communications 9 (1): 2771. July 2018. doi:10.1038/s41467-018-05217-1. PMID 30018376. Bibcode: 2018NatCo...9.2771J. 
  25. ↑ Agris, Paul F. (1996). The Importance of Being Modified: Roles of Modified Nucleosides and Mg2+ in RNA Structure and Function. Progress in Nucleic Acid Research and Molecular Biology. 53. pp. 79–129. doi:10.1016/s0079-6603(08)60143-9. ISBN 978-0-12-540053-4. 
  26. ↑ "Improvement of reading frame maintenance is a common function for several tRNA modifications". The EMBO Journal 20 (17): 4863–73. September 2001. doi:10.1093/emboj/20.17.4863. PMID 11532950. 
  27. ↑ "Formation of thiolated nucleosides present in tRNA from Salmonella enterica serovar Typhimurium occurs in two principally distinct pathways". Journal of Bacteriology 186 (3): 758–66. February 2004. doi:10.1128/jb.186.3.758-766.2004. PMID 14729702. 
  28. ↑ "MiaB protein is a bifunctional radical-S-adenosylmethionine enzyme involved in thiolation and methylation of tRNA". The Journal of Biological Chemistry 279 (46): 47555–63. November 2004. doi:10.1074/jbc.m408562200. PMID 15339930. 
  29. ↑ "Identification of the miaB gene, involved in methylthiolation of isopentenylated A37 derivatives in the tRNA of Salmonella typhimurium and Escherichia coli". Journal of Bacteriology 181 (23): 7256–65. December 1999. doi:10.1128/jb.181.23.7256-7265.1999. PMID 10572129. 
  30. ↑ "Beta-methylthio-aspartic acid: identification of a novel posttranslational modification in ribosomal protein S12 from Escherichia coli". Protein Science 5 (8): 1625–32. August 1996. doi:10.1002/pro.5560050816. PMID 8844851. 
  31. ↑ "RimO, a MiaB-like enzyme, methylthiolates the universally conserved Asp88 residue of ribosomal protein S12 in Escherichia coli". Proceedings of the National Academy of Sciences of the United States of America 105 (6): 1826–31. February 2008. doi:10.1073/pnas.0708608105. PMID 18252828. Bibcode: 2008PNAS..105.1826A. 
  32. ↑ "Two Fe-S clusters catalyze sulfur insertion by radical-SAM methylthiotransferases". Nature Chemical Biology 9 (5): 333–8. May 2013. doi:10.1038/nchembio.1229. PMID 23542644. 
  33. ↑ 33.0 33.1 "Identification of eukaryotic and prokaryotic methylthiotransferase for biosynthesis of 2-methylthio-N6-threonylcarbamoyladenosine in tRNA". The Journal of Biological Chemistry 285 (37): 28425–33. September 2010. doi:10.1074/jbc.m110.106831. PMID 20584901. 
  34. ↑ "Biosynthesis of nitrogenase metalloclusters". Chemical Reviews 114 (8): 4063–80. April 2014. doi:10.1021/cr400463x. PMID 24328215. 
  35. ↑ "Radical SAM-dependent carbon insertion into the nitrogenase M-cluster". Science 337 (6102): 1672–5. September 2012. doi:10.1126/science.1224603. PMID 23019652. Bibcode: 2012Sci...337.1672W. 
  36. ↑ "Revisiting the Mechanism of the Anaerobic Coproporphyrinogen III Oxidase HemN". Angewandte Chemie 58 (19): 6235–6238. May 2019. doi:10.1002/anie.201814708. PMID 30884058. 
  37. ↑ "Anaerobic oxidation of long-chain n-alkanes by the hyperthermophilic sulfate-reducing archaeon, Archaeoglobus fulgidus". The ISME Journal 8 (11): 2153–66. November 2014. doi:10.1038/ismej.2014.58. PMID 24763368. 
  38. ↑ "Sulfatases and radical SAM enzymes: emerging themes in glycosaminoglycan metabolism and the human microbiota". Biochemical Society Transactions 44 (1): 109–15. February 2016. doi:10.1042/BST20150191. PMID 26862195. 
  39. ↑ "A new type of bacterial sulfatase reveals a novel maturation pathway in prokaryotes". The Journal of Biological Chemistry 281 (32): 22464–70. August 2006. doi:10.1074/jbc.M602504200. PMID 16766528. 
  40. ↑ 40.0 40.1 "First evidences for a third sulfatase maturation system in prokaryotes from E. coli aslB and ydeM deletion mutants". FEBS Letters 581 (5): 1009–14. March 2007. doi:10.1016/j.febslet.2007.01.076. PMID 17303125. 
  41. ↑ 41.0 41.1 "Anaerobic sulfatase-maturating enzymes, first dual substrate radical S-adenosylmethionine enzymes". The Journal of Biological Chemistry 283 (26): 17815–26. June 2008. doi:10.1074/jbc.M710074200. PMID 18408004. 
  42. ↑ "Multiple sulfatase deficiency is caused by mutations in the gene encoding the human C(alpha)-formylglycine generating enzyme". Cell 113 (4): 435–44. May 2003. doi:10.1016/S0092-8674(03)00347-7. PMID 12757705. 
  43. ↑ "Anaerobic sulfatase-maturating enzymes: radical SAM enzymes able to catalyze in vitro sulfatase post-translational modification". Journal of the American Chemical Society 129 (12): 3462–3. March 2007. doi:10.1021/ja067175e. PMID 17335281. 
  44. ↑ 44.0 44.1 "Ruminococcin C, an anti-clostridial sactipeptide produced by a prominent member of the human microbiota Ruminococcus gnavus". The Journal of Biological Chemistry 294 (40): 14512–14525. October 2019. doi:10.1074/jbc.RA119.009416. PMID 31337708. 
  45. ↑ "Radical S-adenosylmethionine enzyme catalyzed thioether bond formation in sactipeptide biosynthesis". Current Opinion in Chemical Biology 17 (4): 605–12. August 2013. doi:10.1016/j.cbpa.2013.06.031. PMID 23891473. 
  46. ↑ "Bioinformatic evidence for a widely distributed, ribosomally produced electron carrier precursor, its maturation proteins, and its nicotinoprotein redox partners". BMC Genomics 12 (1): 21. January 2011. doi:10.1186/1471-2164-12-21. PMID 21223593. 
  47. ↑ "Biological systems discovery in silico: radical S-adenosylmethionine protein families and their target peptides for posttranslational modification". Journal of Bacteriology 193 (11): 2745–55. June 2011. doi:10.1128/jb.00040-11. PMID 21478363. 
  48. ↑ "SPASM and twitch domains in S-adenosylmethionine (SAM) radical enzymes". The Journal of Biological Chemistry 290 (7): 3964–71. February 2015. doi:10.1074/jbc.R114.581249. PMID 25477505. 
  49. ↑ "Thiostrepton tryptophan methyltransferase expands the chemistry of radical SAM enzymes". Nature Chemical Biology 8 (12): 957–9. December 2012. doi:10.1038/nchembio.1091. PMID 23064318. 
  50. ↑ "The thiostrepton A tryptophan methyltransferase TsrM catalyses a cob(II)alamin-dependent methyl transfer reaction". Nature Communications 6 (1): 8377. October 2015. doi:10.1038/ncomms9377. PMID 26456915. Bibcode: 2015NatCo...6.8377B. 
  51. ↑ 51.0 51.1 "Mechanistic Investigations of PoyD, a Radical S-Adenosyl-l-methionine Enzyme Catalyzing Iterative and Directional Epimerizations in Polytheonamide A Biosynthesis". Journal of the American Chemical Society 140 (7): 2469–2477. February 2018. doi:10.1021/jacs.7b08402. PMID 29253341. 
  52. ↑ "The B12-Radical SAM Enzyme PoyC Catalyzes Valine Cβ-Methylation during Polytheonamide Biosynthesis". Journal of the American Chemical Society 138 (48): 15515–15518. December 2016. doi:10.1021/jacs.6b06697. PMID 27934015. 
  53. ↑ 53.0 53.1 53.2 53.3 53.4 53.5 53.6 "C-C bond forming radical SAM enzymes involved in the construction of carbon skeletons of cofactors and natural products". Natural Product Reports 35 (7): 660–694. July 2018. doi:10.1039/c8np00006a. PMID 29633774. 
  54. ↑ 54.0 54.1 "The Epipeptide YydF Intrinsically Triggers the Cell Envelope Stress Response of Bacillus subtilis and Causes Severe Membrane Perturbations". Frontiers in Microbiology 11: 151. February 2020. doi:10.3389/fmicb.2020.00151. PMID 32117169. 
  55. ↑ 55.0 55.1 55.2 "Post-translational modification of ribosomally synthesized peptides by a radical SAM epimerase in Bacillus subtilis". Nature Chemistry 9 (7): 698–707. July 2017. doi:10.1038/nchem.2714. PMID 28644475. Bibcode: 2017NatCh...9..698B. 
  56. ↑ "Biosynthetic versatility and coordinated action of 5'-deoxyadenosyl radicals in deazaflavin biosynthesis". Journal of the American Chemical Society 137 (16): 5406–13. April 2015. doi:10.1021/ja513287k. PMID 25781338. 
  57. ↑ "Biosynthesis of F0, precursor of the F420 cofactor, requires a unique two radical-SAM domain enzyme and tyrosine as substrate". Journal of the American Chemical Society 134 (44): 18173–6. November 2012. doi:10.1021/ja307762b. PMID 23072415. 
  58. ↑ "The Radical S-Adenosyl-L-methionine Enzyme QhpD Catalyzes Sequential Formation of Intra-protein Sulfur-to-Methylene Carbon Thioether Bonds". The Journal of Biological Chemistry 290 (17): 11144–66. April 2015. doi:10.1074/jbc.M115.638320. PMID 25778402. 
  59. ↑ "Biosynthesis of the sactipeptide Ruminococcin C by the human microbiome: Mechanistic insights into thioether bond formation by radical SAM enzymes". The Journal of Biological Chemistry 295 (49): 16665–16677. December 2020. doi:10.1074/jbc.RA120.015371. PMID 32972973. 
  60. ↑ "Structural permutation of potent cytotoxin, polytheonamide B: discovery of cytotoxic Peptide with altered activity". ACS Medicinal Chemistry Letters 4 (1): 52–6. January 2013. doi:10.1021/ml300264c. PMID 24900563. 
  61. ↑ "Seven enzymes create extraordinary molecular complexity in an uncultivated bacterium". Nature Chemistry 9 (4): 387–395. April 2017. doi:10.1038/nchem.2666. PMID 28338684. Bibcode: 2017NatCh...9..387F. 
  62. ↑ "Structural insights into recognition and repair of UV-DNA damage by Spore Photoproduct Lyase, a radical SAM enzyme". Nucleic Acids Research 40 (18): 9308–18. October 2012. doi:10.1093/nar/gks603. PMID 22761404. 
  63. ↑ "Dinucleotide spore photoproduct, a minimal substrate of the DNA repair spore photoproduct lyase enzyme from Bacillus subtilis". The Journal of Biological Chemistry 281 (37): 26922–31. September 2006. doi:10.1074/jbc.M602297200. PMID 16829676. 
  64. ↑ "Spore photoproduct lyase: the known, the controversial, and the unknown". The Journal of Biological Chemistry 290 (7): 4003–9. February 2015. doi:10.1074/jbc.R114.573675. PMID 25477522. 
  65. ↑ "DNA repair and free radicals, new insights into the mechanism of spore photoproduct lyase revealed by single amino acid substitution". The Journal of Biological Chemistry 283 (52): 36361–8. December 2008. doi:10.1074/jbc.M806503200. PMID 18957420. 
  66. ↑ "DNA photolyases and SP lyase: structure and mechanism of light-dependent and independent DNA lyases". Current Opinion in Structural Biology 22 (6): 711–20. December 2012. doi:10.1016/j.sbi.2012.10.002. PMID 23164663. 
  67. ↑ "Identification of a radical SAM enzyme involved in the synthesis of archaeosine". Nature Chemical Biology 15 (12): 1148–1155. December 2019. doi:10.1038/s41589-019-0390-7. PMID 31740832. 
  68. ↑ "A unifying view of the broad-spectrum antiviral activity of RSAD2 (viperin) based on its radical-SAM chemistry". Metallomics 10 (4): 539–552. April 2018. doi:10.1039/C7MT00341B. PMID 29568838. 
  69. ↑ "Deficit of tRNA(Lys) modification by Cdkal1 causes the development of type 2 diabetes in mice". The Journal of Clinical Investigation 121 (9): 3598–608. September 2011. doi:10.1172/JCI58056. PMID 21841312. 
  70. ↑ "Crystal structure of the S-adenosylmethionine-dependent enzyme MoaA and its implications for molybdenum cofactor deficiency in humans". Proceedings of the National Academy of Sciences of the United States of America 101 (35): 12870–5. August 2004. doi:10.1073/pnas.0404624101. PMID 15317939. Bibcode: 2004PNAS..10112870H. 
  71. ↑ 71.0 71.1 71.2 71.3 71.4 "Radical S-Adenosylmethionine Enzymes in Human Health and Disease". Annual Review of Biochemistry 85 (1): 485–514. June 2016. doi:10.1146/annurev-biochem-060713-035504. PMID 27145839. 
  72. ↑ "Genome mining for ribosomally synthesized and post-translationally modified peptides (RiPPs) in anaerobic bacteria". BMC Genomics 15 (1): 983. November 2014. doi:10.1186/1471-2164-15-983. PMID 25407095. 
  73. ↑ "Ribosomally synthesized peptides with antimicrobial properties: biosynthesis, structure, function, and applications". Biotechnology Advances 21 (6): 465–99. September 2003. doi:10.1016/s0734-9750(03)00077-6. PMID 14499150. 
  74. ↑ "Antibacterial Strategy against H. pylori: Inhibition of the Radical SAM Enzyme MqnE in Menaquinone Biosynthesis". ACS Medicinal Chemistry Letters 10 (3): 363–366. March 2019. doi:10.1021/acsmedchemlett.8b00649. PMID 30891141. 
  75. ↑ "Discovery and characterization of BlsE, a radical S-adenosyl-L-methionine decarboxylase involved in the blasticidin S biosynthetic pathway". PLOS ONE 8 (7): e68545. 2013-07-18. doi:10.1371/journal.pone.0068545. PMID 23874663. Bibcode: 2013PLoSO...868545F. 
  76. ↑ "Mechanism of Diol Dehydration by a Promiscuous Radical-SAM Enzyme Homologue of the Antiviral Enzyme Viperin (RSAD2)". ChemBioChem 21 (11): 1605–1612. June 2020. doi:10.1002/cbic.201900776. PMID 31951306. https://ora.ox.ac.uk/objects/uuid:06047fd8-cbe5-497d-83ca-7bb146fdbc95. 
  77. ↑ "Radical-mediated enzymatic carbon chain fragmentation-recombination". Nature Chemical Biology 7 (3): 154–60. March 2011. doi:10.1038/nchembio.512. PMID 21240261. 
  78. ↑ "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. April 2016. doi:10.1021/acs.biochem.6b00145. PMID 27007615. 
  79. ↑ "Reconstitution of ThiC in thiamine pyrimidine biosynthesis expands the radical SAM superfamily". Nature Chemical Biology 4 (12): 758–65. December 2008. doi:10.1038/nchembio.121. PMID 18953358. 
  80. ↑ "Diphthamide biosynthesis requires an organic radical generated by an iron-sulphur enzyme". Nature 465 (7300): 891–6. June 2010. doi:10.1038/nature09138. PMID 20559380. Bibcode: 2010Natur.465..891Z. 
  81. ↑ "Intermediates in the transformation of phosphonates to phosphate by bacteria". Nature 480 (7378): 570–3. November 2011. doi:10.1038/nature10622. PMID 22089136. Bibcode: 2011Natur.480..570K. 

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