Radical SAM

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. 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,[3][4] and have a cysteine-rich motif that matches or resembles CxxxCxxC.

Radical_SAM
Identifiers
SymbolRadical_SAM
PfamPF04055
InterProIPR007197
SCOPe102114 / SUPFAM

History and mechanism

As of 2001, 645 unique radical SAM enzymes have been identified from 126 species in all three domains of life.[5] 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.[6]

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.[7]

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.[8]

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.[9] β-sheets are colored yellow and α-helices are shown in cyan.

Reaction classification

Representative/Prototype enzymes will only be mentioned for each reaction scheme. The audience is highly encouraged to research more into current studies on radical SAM enzymes. Many of which are responsible for fascinating yet important reactions.

Radical SAM enzymes and their mechanisms known before 2008 are well-summarized by Frey et al, 2008 (). Since 2015, more review articles on radical SAM enzymes are open to the public. The following are only a few out of many informative resources on radical SAM enzymes.

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

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 four classes (Class A, B, C and D) with representative methylation mechanisms. The shared characteristic of the three major classes A, B and C 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.[10][11] The recently documented class D utilizes a different methylation mechanism.

Class A sub-family
  • Class A enzymes methylates specific adenosine residues on rRNA and/or tRNA.[12][13] 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.[10][14] 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.[13]
  • These enzymes require a cobalamin (vitamin B12) cofactor as an intermediate methyl group carrier to transfer a methyl group from SAM to substrate.[12]
  • One well-investigated representative enzyme is TsrM which involves in tryptophan methylation in thiostrepton biosynthesis.[10]

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 [12][13] and are cobalamin-independent.[15]
  • 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 [10][13]
  • 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.[16]
    2. Jaw5 is suggested to be responsible for cyclopropane modifications.[17]

Class D sub-family
  • Class D is the most recently discovered and has been shown to not use SAM for methylation which is different from the three classes described above.[11] Instead, these enzymes use methylenetetrahydrofolate as the methyl donor.
  • The prototype MJ0619 is proposed to play a role in the biosynthesis of cofactor methanopterin which is required in methanogesis, an essential methane-producing pathway dominantly found in the Archaean domain.[13][11]

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.[18][19][20][21]

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.[22][23]
  • RimO is responsible for post-translational modification of Asp88 of the ribosomal protein S12 in E. coli.[24][25] 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.[26]

eMtaB is the designated methylthiotransferase in eukaryotic and archaeal cells. eMtaB catalyzes the methylthiolation of tRNA at position 37 on N6-threonylcarbamoyladenosine.[27] A bacterial homologue of eMtaB, YqeV has been reported and suggested to function similarly to MiaB and RimO.[27]

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.[28]

  • 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.[28]
  • LipA or lipoyl synthase is radical SAM sulfurtransferase utilizing two [4Fe-4S] clusters to catalyze the final step in lipoic acid biosynthesis.[28]

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.[29] 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.[30]

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.[31]
  • Hyperthermophilic sulfate-reducing archaen Archaeoglobus fulgidus has been recently reported to enable anaerobic oxidation of long chain n-alkanes.[32] 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 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 or sulfur-to-beta thioether cross-linked peptides (sactipeptides and lanthipeptides, respectively) are important to generate an essential class of peptide with significant antibacterial, spermicidal and hemolytic properties.[33] Another common name for this peptide class is ribosomally synthesized and post-translationally modified peptides (RiPPs).[6][34]

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.[35][36][37]

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

  1. TsrM in thiostrepton biosynthesis[15]
  2. PoyD and PoyC in polytheonamide biosynthesis[15]
  3. TbtI in thiomuracin biosynthesis[15]
  4. NosN in nosiheptide biosynthesis[38]
  5. MoaA in molybdopterin biosynthesis[38][39]
  6. PqqE in pyrroloquinoline quinone biosynthesis[38]
  7. TunB in tunicamycin biosynthesis[38]
  8. OxsB in oxetanocin biosynthesis[38]
  9. BchE in anaerobic bacteriochlorophyll biosynthesis[38]
  10. F0 synthases in F420 cofactor biosynthesis[38]
  11. MqnE and MqnC in menaquinone biosynthesis[38][39]
  12. QhpD in post-translational processing of quinohemoprotein amine dehydrogenase[40]

Epimerization

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

  • PoyD installs numerous D-stereocenters in enzyme PoyA to ultimately help facilitate polytheonamide biosynthesis.[15] Polytheoamide is a natural potent cytoxic agent by forming pores in membranes.[41] This peptide cytotoxin is naturally produced by uncultivated bacteria that exist as symbionts in a marine sponge.[42]
  • YydG epimerase modifies two amino acid positions on YydF in Gram-positive Bacillus subtilis.[15] A recent study has reported the extrinsically added YydF mediates subsequent dissipation of membrane potential via membrane permeabilization, resulting in death of the organism.[43]

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.

  • DNA spore photoproduct lysase (SPL) is a radical SAM that can repair DNA thymine dimers (spore product, SP) caused by UV radiation. Despite of remaining unknowns and controversies involving SPL-catalyzed reaction, it is certain that SPL utilizes SAM as a cofactor to generate 5'-dAdo radical to revert SP to two thymine residues.[18][44]
  • HydG is a radical SAM responsible for generating CO and CN− ligands in the [Fe-Fe]-hydrogenase (HydA) in various anaerobic bacteria.[18]
  • Radical SAM MoaA and MoaC are involved in converting GTP into cyclic pyranopterin monophosphate (cPMP). Overall, both play important roles in molybdopterinbiosynthesis.[18]

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.[45]
  • 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.[46]

Clinical considerations
  • Deficiency in human tRNA methylthiotransferase eMtaB has been shown to be responsible for abnormal insulin synthesis and predisposition to type 2 diabetes.[47]
  • Mutations in human GTP cyclase MoaA has been reported to lead to molybdenum cofactor deficiency, a usually fatal disease accompanied by severe neurological symptoms.[48]
  • Mutations in human wybutosine-tRNA modifying enzyme Tyw1 promotes retrovirus infection.[49]
  • Alterations in human tRNA-modifying enzyme Elp3 results in progression into amyotrophic lateral sclerosis (ALS).[49]
  • Mutations in human antiviral RSAD1 has been shown to be associated with congenital heart disease.[49]
  • Mutations in human sulfurtransferase LipA has been implicated in glycine encephalopathy, pyruvate dehydrogenase and lipoic acid synthetase deficiency.[49]
  • Mutations in human methylthiotransferase MiaB are related to impaired cardiac and respiratory functions.[49]

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.[50][51] 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.[52]
  • 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.[53]
  • 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.[54]

Examples

Radical

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
  • 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 [55]
  • 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) [56]
  • 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)

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) [57]
  • Dph2 (PF01866) - diphthamide biosynthesis enzyme Dph2 (protein modification - diphthamide in translation elongation factor 2) (note different radical production, a 3-amino-3-carboxypropyl radical) [58]
  • PhnJ (PF06007) - phosphonate metabolism protein PhnJ (C-P phosphonate bond cleavage) [59]
gollark: Testbot, servers.
gollark: Or had?
gollark: Epicbot has this.
gollark: Testbot, take ☭.
gollark: Denied.

References
  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. 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. 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.
  4. 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. S2CID 86816844.
  5. 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.
  6. Benjdia A, Balty C, Berteau O (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. PMC 5682303. PMID 29167789.
  7. Broderick, William E.; Hoffman, Brian M.; Broderick, Joan B. (2018). "Mechanism of Radical Initiation in the Radical S-Adenosyl-l-methionine Superfamily". Accounts of Chemical Research. 51 (11): 2611–2619. doi:10.1021/acs.accounts.8b00356. PMC 6324848. PMID 30346729.
  8. "Enzyme Classification". www.qmul.ac.uk. Retrieved 2020-03-27.
  9. Vey JL, Drennan CL (April 2011). "Structural insights into radical generation by the radical SAM superfamily". Chemical Reviews. 111 (4): 2487–506. doi:10.1021/cr9002616. PMC 5930932. PMID 21370834.
  10. Fujimori DG (August 2013). "Radical SAM-mediated methylation reactions". Current Opinion in Chemical Biology. 17 (4): 597–604. doi:10.1016/j.cbpa.2013.05.032. PMC 3799849. PMID 23835516.
  11. Allen KD, Xu H, White RH (September 2014). "Identification of a unique radical S-adenosylmethionine methylase likely involved in methanopterin biosynthesis in Methanocaldococcus jannaschii". Journal of Bacteriology. 196 (18): 3315–23. doi:10.1128/jb.01903-14. PMC 4135684. PMID 25002541.
  12. Benítez-Páez A, Villarroya M, Armengod ME (October 2012). "The Escherichia coli RlmN methyltransferase is a dual-specificity enzyme that modifies both rRNA and tRNA and controls translational accuracy". RNA. 18 (10): 1783–95. doi:10.1261/rna.033266.112. PMC 3446703. PMID 22891362.
  13. Bauerle MR, Schwalm EL, Booker SJ (February 2015). "Mechanistic diversity of radical S-adenosylmethionine (SAM)-dependent methylation". The Journal of Biological Chemistry. 290 (7): 3995–4002. doi:10.1074/jbc.r114.607044. PMC 4326810. PMID 25477520.
  14. Yan F, Fujimori DG (March 2011). "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. Bibcode:2011PNAS..108.3930Y. doi:10.1073/pnas.1017781108. PMC 3054002. PMID 21368151.
  15. Mahanta N, Hudson GA, Mitchell DA (October 2017). "Radical S-Adenosylmethionine Enzymes Involved in RiPP Biosynthesis". Biochemistry. 56 (40): 5229–5244. doi:10.1021/acs.biochem.7b00771. PMC 5634935. PMID 28895719.
  16. Zhang Z, Mahanta N, Hudson GA, Mitchell DA, van der Donk WA (December 2017). "Mechanism of a Class C Radical S-Adenosyl-l-methionine Thiazole Methyl Transferase". Journal of the American Chemical Society. 139 (51): 18623–18631. doi:10.1021/jacs.7b10203. PMC 5748327. PMID 29190095.
  17. Jin WB, Wu S, Jian XH, Yuan H, Tang GL (July 2018). "A radical S-adenosyl-L-methionine enzyme and a methyltransferase catalyze cyclopropane formation in natural product biosynthesis". Nature Communications. 9 (1): 2771. Bibcode:2018NatCo...9.2771J. doi:10.1038/s41467-018-05217-1. PMC 6050322. PMID 30018376.
  18. Wang J, Woldring RP, Román-Meléndez GD, McClain AM, Alzua BR, Marsh EN (September 2014). "Recent advances in radical SAM enzymology: new structures and mechanisms". ACS Chemical Biology. 9 (9): 1929–38. doi:10.1021/cb5004674. PMC 4168785. PMID 25009947.
  19. Agris PF (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. Elsevier. 53: 79–129. doi:10.1016/s0079-6603(08)60143-9. ISBN 978-0-12-540053-4. PMID 8650309.
  20. Urbonavicius J, Qian Q, Durand JM, Hagervall TG, Björk GR (September 2001). "Improvement of reading frame maintenance is a common function for several tRNA modifications". The EMBO Journal. 20 (17): 4863–73. doi:10.1093/emboj/20.17.4863. PMC 125605. PMID 11532950.
  21. Leipuviene R, Qian Q, Björk GR (February 2004). "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. doi:10.1128/jb.186.3.758-766.2004. PMC 321476. PMID 14729702.
  22. Pierrel F, Douki T, Fontecave M, Atta M (November 2004). "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. doi:10.1074/jbc.m408562200. PMID 15339930.
  23. Esberg B, Leung HC, Tsui HC, Björk GR, Winkler ME (December 1999). "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. doi:10.1128/jb.181.23.7256-7265.1999. PMC 103688. PMID 10572129.
  24. Kowalak JA, Walsh KA (August 1996). "Beta-methylthio-aspartic acid: identification of a novel posttranslational modification in ribosomal protein S12 from Escherichia coli". Protein Science. 5 (8): 1625–32. doi:10.1002/pro.5560050816. PMC 2143476. PMID 8844851.
  25. Anton BP, Saleh L, Benner JS, Raleigh EA, Kasif S, Roberts RJ (February 2008). "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. Bibcode:2008PNAS..105.1826A. doi:10.1073/pnas.0708608105. PMC 2538847. PMID 18252828.
  26. Forouhar F, Arragain S, Atta M, Gambarelli S, Mouesca JM, Hussain M, et al. (May 2013). "Two Fe-S clusters catalyze sulfur insertion by radical-SAM methylthiotransferases". Nature Chemical Biology. 9 (5): 333–8. doi:10.1038/nchembio.1229. PMC 4118475. PMID 23542644.
  27. Arragain S, Handelman SK, Forouhar F, Wei FY, Tomizawa K, Hunt JF, et al. (September 2010). "Identification of eukaryotic and prokaryotic methylthiotransferase for biosynthesis of 2-methylthio-N6-threonylcarbamoyladenosine in tRNA". The Journal of Biological Chemistry. 285 (37): 28425–33. doi:10.1074/jbc.m110.106831. PMC 2937867. PMID 20584901.
  28. Broderick JB, Duffus BR, Duschene KS, Shepard EM (April 2014). "Radical S-adenosylmethionine enzymes". Chemical Reviews. 114 (8): 4229–317. doi:10.1021/cr4004709. PMID 24476342.
  29. 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.
  30. Wiig JA, Hu Y, Chung Lee C, Ribbe MW (September 2012). "Radical SAM-dependent carbon insertion into the nitrogenase M-cluster". Science. 337 (6102): 1672–5. Bibcode:2012Sci...337.1672W. doi:10.1126/science.1224603. PMC 3836454. PMID 23019652.
  31. Ji X, Mo T, Liu WQ, Ding W, Deng Z, Zhang Q (May 2019). "Revisiting the Mechanism of the Anaerobic Coproporphyrinogen III Oxidase HemN". Angewandte Chemie. 58 (19): 6235–6238. doi:10.1002/anie.201814708. PMID 30884058.
  32. Khelifi N, Amin Ali O, Roche P, Grossi V, Brochier-Armanet C, Valette O, et al. (November 2014). "Anaerobic oxidation of long-chain n-alkanes by the hyperthermophilic sulfate-reducing archaeon, Archaeoglobus fulgidus". The ISME Journal. 8 (11): 2153–66. doi:10.1038/ismej.2014.58. PMC 4992073. PMID 24763368.
  33. Flühe L, Marahiel MA (August 2013). "Radical S-adenosylmethionine enzyme catalyzed thioether bond formation in sactipeptide biosynthesis". Current Opinion in Chemical Biology. 17 (4): 605–12. doi:10.1016/j.cbpa.2013.06.031. PMID 23891473.
  34. Davis KM, Schramma KR, Hansen WA, Bacik JP, Khare SD, Seyedsayamdost MR, Ando N (September 2017). "Structures of the peptide-modifying radical SAM enzyme SuiB elucidate the basis of substrate recognition". Proceedings of the National Academy of Sciences of the United States of America. 114 (39): 10420–10425. doi:10.1073/pnas.1703663114. PMC 5625900. PMID 28893989.
  35. Haft DH (January 2011). "Bioinformatic evidence for a widely distributed, ribosomally produced electron carrier precursor, its maturation proteins, and its nicotinoprotein redox partners". BMC Genomics. 12 (1): 21. doi:10.1186/1471-2164-12-21. PMC 3023750. PMID 21223593.
  36. Haft DH, Basu MK (June 2011). "Biological systems discovery in silico: radical S-adenosylmethionine protein families and their target peptides for posttranslational modification". Journal of Bacteriology. 193 (11): 2745–55. doi:10.1128/jb.00040-11. PMC 3133131. PMID 21478363.
  37. Grell TA, Goldman PJ, Drennan CL (February 2015). "SPASM and twitch domains in S-adenosylmethionine (SAM) radical enzymes". The Journal of Biological Chemistry. 290 (7): 3964–71. doi:10.1074/jbc.R114.581249. PMC 4326806. PMID 25477505.
  38. Yokoyama K, Lilla EA (July 2018). "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. doi:10.1039/c8np00006a. PMC 6051890. PMID 29633774.
  39. Mehta AP, Abdelwahed SH, Mahanta N, Fedoseyenko D, Philmus B, Cooper LE, et al. (February 2015). "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. doi:10.1074/jbc.R114.623793. PMC 4326808. PMID 25477515.
  40. Nakai T, Ito H, Kobayashi K, Takahashi Y, Hori H, Tsubaki M, et al. (April 2015). "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. doi:10.1074/jbc.M115.638320. PMC 4409272. PMID 25778402.
  41. Itoh H, Inoue M (January 2013). "Structural permutation of potent cytotoxin, polytheonamide B: discovery of cytotoxic Peptide with altered activity". ACS Medicinal Chemistry Letters. 4 (1): 52–6. doi:10.1021/ml300264c. PMC 4027433. PMID 24900563.
  42. Freeman MF, Helf MJ, Bhushan A, Morinaka BI, Piel J (April 2017). "Seven enzymes create extraordinary molecular complexity in an uncultivated bacterium". Nature Chemistry. 9 (4): 387–395. Bibcode:2017NatCh...9..387F. doi:10.1038/nchem.2666. PMID 28338684.
  43. Popp PF, Benjdia A, Strahl H, Berteau O, Mascher T (2020). "Bacillus subtilis and Causes Severe Membrane Perturbations". Frontiers in Microbiology. 11: 151. doi:10.3389/fmicb.2020.00151. PMC 7026026. PMID 32117169.
  44. Yang L, Li L (February 2015). "Spore photoproduct lyase: the known, the controversial, and the unknown". The Journal of Biological Chemistry. 290 (7): 4003–9. doi:10.1074/jbc.R114.573675. PMC 4326811. PMID 25477522.
  45. Yokogawa T, Nomura Y, Yasuda A, Ogino H, Hiura K, Nakada S, et al. (December 2019). "Identification of a radical SAM enzyme involved in the synthesis of archaeosine". Nature Chemical Biology. 15 (12): 1148–1155. doi:10.1038/s41589-019-0390-7. PMID 31740832.
  46. Honarmand Ebrahimi K (April 2018). "A unifying view of the broad-spectrum antiviral activity of RSAD2 (viperin) based on its radical-SAM chemistry". Metallomics : Integrated Biometal Science. 10 (4): 539–552. doi:10.1039/C7MT00341B. PMID 29568838.
  47. Wei FY, Suzuki T, Watanabe S, Kimura S, Kaitsuka T, Fujimura A, Matsui H, Atta M, Michiue H, Fontecave M, Yamagata K, Suzuki T, Tomizawa K (September 2011). "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. doi:10.1172/JCI58056. PMC 3163968. PMID 21841312.
  48. Hänzelmann P, Schindelin H (August 2004). "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. Bibcode:2004PNAS..10112870H. doi:10.1073/pnas.0404624101. PMC 516487. PMID 15317939.
  49. Landgraf BJ, McCarthy EL, Booker SJ (June 2016). "Radical S-Adenosylmethionine Enzymes in Human Health and Disease". Annual Review of Biochemistry. 85 (1): 485–514. doi:10.1146/annurev-biochem-060713-035504. PMID 27145839.
  50. Letzel AC, Pidot SJ, Hertweck C (November 2014). "Genome mining for ribosomally synthesized and post-translationally modified peptides (RiPPs) in anaerobic bacteria". BMC Genomics. 15 (1): 983. doi:10.1186/1471-2164-15-983. PMC 4289311. PMID 25407095.
  51. Papagianni M (September 2003). "Ribosomally synthesized peptides with antimicrobial properties: biosynthesis, structure, function, and applications". Biotechnology Advances. 21 (6): 465–99. doi:10.1016/s0734-9750(03)00077-6. PMID 14499150.
  52. Joshi S, Fedoseyenko D, Mahanta N, Ducati RG, Feng M, Schramm VL, Begley TP (March 2019). "H. pylori: Inhibition of the Radical SAM Enzyme MqnE in Menaquinone Biosynthesis". ACS Medicinal Chemistry Letters. 10 (3): 363–366. doi:10.1021/acsmedchemlett.8b00649. PMC 6421580. PMID 30891141.
  53. Feng J, Wu J, Dai N, Lin S, Xu HH, Deng Z, He X (2013-07-18). "Discovery and characterization of BlsE, a radical S-adenosyl-L-methionine decarboxylase involved in the blasticidin S biosynthetic pathway". PLOS ONE. 8 (7): e68545. Bibcode:2013PLoSO...868545F. doi:10.1371/journal.pone.0068545. PMC 3715490. PMID 23874663.
  54. Honarmand Ebrahimi K, Rowbotham JS, McCullagh J, James WS (January 2020). "Mechanism of Diol Dehydration by a Promiscuous Radical-SAM Enzyme Homologue of the Antiviral Enzyme Viperin (RSAD2)". ChemBioChem. n/a (n/a): 1605–1612. doi:10.1002/cbic.201900776. PMID 31951306.
  55. 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.
  56. 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.
  57. 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.
  58. 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. Bibcode:2010Natur.465..891Z. doi:10.1038/nature09138. PMC 3006227. PMID 20559380.
  59. Kamat SS, Williams HJ, Raushel FM (November 2011). "Intermediates in the transformation of phosphonates to phosphate by bacteria". Nature. 480 (7378): 570–3. Bibcode:2011Natur.480..570K. doi:10.1038/nature10622. PMC 3245791. PMID 22089136.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.