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==== Class C sub-family ====
==== 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 <ref name=":1" /><ref name=":2" /> and are cobalamin-independent.<ref name=":6"/>
* Class C enzymes are reported to play roles in biosynthesis of complex natural products and secondary metabolites. These enzymes methylate heteroaromatic substrates <ref name=":1" /><ref name=":2" /> and are cobalamin-independent.<ref name=":6">{{cite journal|vauthors=Mahanta N, Hudson GA, Mitchell DA|date=October 2017|title=Radical S-Adenosylmethionine Enzymes Involved in RiPP Biosynthesis|journal=Biochemistry|volume=56|issue=40|pages=5229–5244|doi=10.1021/acs.biochem.7b00771|pmc=5634935|pmid=28895719}}</ref>
* These enzymes contain both the radical SAM motif and exhibit striking sequence similarity to [[Coproporphyrinogen III oxidase|coproporhyrinogen III oxidase]] (HemN), a radical SAM enzyme involved in heme biosynthesis <ref name=":0" /><ref name=":2" />
* These enzymes contain both the radical SAM motif and exhibit striking sequence similarity to [[Coproporphyrinogen III oxidase|coproporhyrinogen III oxidase]] (HemN), a radical SAM enzyme involved in heme biosynthesis <ref name=":0" /><ref name=":2" />
* Recently, detailed mechanistic investigation on two important class C radical SAM methylases have been reported:
* Recently, detailed mechanistic investigation on two important class C radical SAM methylases have been reported:
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=== Peptide modifications ===
=== 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.<ref>{{cite journal | vauthors = Flühe L, Marahiel MA | title = Radical S-adenosylmethionine enzyme catalyzed thioether bond formation in sactipeptide biosynthesis | journal = Current Opinion in Chemical Biology | volume = 17 | issue = 4 | pages = 605–12 | date = August 2013 | pmid = 23891473 | doi = 10.1016/j.cbpa.2013.06.031 }}</ref> Another common name for this peptide class is [[ribosomally synthesized and post-translationally modified peptides]] (RiPPs).<ref name="Benjdia 2017"/><ref>{{cite journal | vauthors = Davis KM, Schramma KR, Hansen WA, Bacik JP, Khare SD, Seyedsayamdost MR, Ando N | title = Structures of the peptide-modifying radical SAM enzyme SuiB elucidate the basis of substrate recognition | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 39 | pages = 10420–10425 | date = September 2017 | pmid = 28893989 | doi = 10.1073/pnas.1703663114 | pmc = 5625900 | doi-access = free }}</ref>
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.<ref>{{Cite journal|last=Balty|first=Clémence|last2=Guillot|first2=Alain|last3=Fradale|first3=Laura|last4=Brewee|first4=Clémence|last5=Boulay|first5=Mylène|last6=Kubiak|first6=Xavier|last7=Benjdia|first7=Alhosna|last8=Berteau|first8=Olivier|date=2019-10|title=Ruminococcin C, an anti-clostridial sactipeptide produced by a prominent member of the human microbiota Ruminococcus gnavus|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925820350079|journal=Journal of Biological Chemistry|language=en|volume=294|issue=40|pages=14512–14525|doi=10.1074/jbc.RA119.009416|pmc=PMC6779426|pmid=31337708}}</ref><ref>{{cite journal | vauthors = Flühe L, Marahiel MA | title = Radical S-adenosylmethionine enzyme catalyzed thioether bond formation in sactipeptide biosynthesis | journal = Current Opinion in Chemical Biology | volume = 17 | issue = 4 | pages = 605–12 | date = August 2013 | pmid = 23891473 | doi = 10.1016/j.cbpa.2013.06.031 }}</ref> Another common name for this peptide class is [[ribosomally synthesized and post-translationally modified peptides]] (RiPPs).<ref name="Benjdia 2017"/><ref>{{Cite journal|last=Benjdia|first=Alhosna|last2=Balty|first2=Clémence|last3=Berteau|first3=Olivier|date=2017-11-08|title=Radical SAM Enzymes in the Biosynthesis of Ribosomally Synthesized and Post-translationally Modified Peptides (RiPPs)|url=http://journal.frontiersin.org/article/10.3389/fchem.2017.00087/full|journal=Frontiers in Chemistry|volume=5|pages=87|doi=10.3389/fchem.2017.00087|issn=2296-2646|pmc=PMC5682303|pmid=29167789}}</ref>


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.<ref>{{cite journal | vauthors = Haft DH | title = Bioinformatic evidence for a widely distributed, ribosomally produced electron carrier precursor, its maturation proteins, and its nicotinoprotein redox partners | journal = BMC Genomics | volume = 12 | issue = 1 | pages = 21 | date = January 2011 | pmid = 21223593 | doi = 10.1186/1471-2164-12-21 | pmc = 3023750 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Haft DH, Basu MK | title = Biological systems discovery in silico: radical S-adenosylmethionine protein families and their target peptides for posttranslational modification | journal = Journal of Bacteriology | volume = 193 | issue = 11 | pages = 2745–55 | date = June 2011 | pmid = 21478363 | doi = 10.1128/jb.00040-11 | pmc = 3133131 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Grell TA, Goldman PJ, Drennan CL | title = SPASM and twitch domains in S-adenosylmethionine (SAM) radical enzymes | journal = The Journal of Biological Chemistry | volume = 290 | issue = 7 | pages = 3964–71 | date = February 2015 | pmid = 25477505 | pmc = 4326806 | doi = 10.1074/jbc.R114.581249 }}</ref>
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.<ref>{{cite journal | vauthors = Haft DH | title = Bioinformatic evidence for a widely distributed, ribosomally produced electron carrier precursor, its maturation proteins, and its nicotinoprotein redox partners | journal = BMC Genomics | volume = 12 | issue = 1 | pages = 21 | date = January 2011 | pmid = 21223593 | doi = 10.1186/1471-2164-12-21 | pmc = 3023750 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Haft DH, Basu MK | title = Biological systems discovery in silico: radical S-adenosylmethionine protein families and their target peptides for posttranslational modification | journal = Journal of Bacteriology | volume = 193 | issue = 11 | pages = 2745–55 | date = June 2011 | pmid = 21478363 | doi = 10.1128/jb.00040-11 | pmc = 3133131 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Grell TA, Goldman PJ, Drennan CL | title = SPASM and twitch domains in S-adenosylmethionine (SAM) radical enzymes | journal = The Journal of Biological Chemistry | volume = 290 | issue = 7 | pages = 3964–71 | date = February 2015 | pmid = 25477505 | pmc = 4326806 | doi = 10.1074/jbc.R114.581249 }}</ref>
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The following examples are representative enzymes that can catalyze peptide modifications to generate specific natural products or cofactors.
The following examples are representative enzymes that can catalyze peptide modifications to generate specific natural products or cofactors.


# TsrM in [[thiostrepton]] biosynthesis<ref>{{Cite journal|last=Pierre|first=Stéphane|last2=Guillot|first2=Alain|last3=Benjdia|first3=Alhosna|last4=Sandström|first4=Corine|last5=Langella|first5=Philippe|last6=Berteau|first6=Olivier|date=2012-12|title=Thiostrepton tryptophan methyltransferase expands the chemistry of radical SAM enzymes|url=http://www.nature.com/articles/nchembio.1091|journal=Nature Chemical Biology|language=en|volume=8|issue=12|pages=957–959|doi=10.1038/nchembio.1091|issn=1552-4450}}</ref><ref>{{Cite journal|last=Benjdia|first=Alhosna|last2=Pierre|first2=Stéphane|last3=Gherasim|first3=Carmen|last4=Guillot|first4=Alain|last5=Carmona|first5=Manon|last6=Amara|first6=Patricia|last7=Banerjee|first7=Ruma|last8=Berteau|first8=Olivier|date=2015-12|title=The thiostrepton A tryptophan methyltransferase TsrM catalyses a cob(II)alamin-dependent methyl transfer reaction|url=http://www.nature.com/articles/ncomms9377|journal=Nature Communications|language=en|volume=6|issue=1|pages=8377|doi=10.1038/ncomms9377|issn=2041-1723|pmc=PMC4632189|pmid=26456915}}</ref>
# TsrM in [[thiostrepton]] biosynthesis<ref name=":6">{{cite journal | vauthors = Mahanta N, Hudson GA, Mitchell DA | title = Radical S-Adenosylmethionine Enzymes Involved in RiPP Biosynthesis | journal = Biochemistry | volume = 56 | issue = 40 | pages = 5229–5244 | date = October 2017 | pmid = 28895719 | pmc = 5634935 | doi = 10.1021/acs.biochem.7b00771 }}</ref>
# PoyD<ref>{{Cite journal|last=Benjdia|first=Alhosna|last2=Balty|first2=Clémence|last3=Berteau|first3=Olivier|date=2017-11-08|title=Radical SAM Enzymes in the Biosynthesis of Ribosomally Synthesized and Post-translationally Modified Peptides (RiPPs)|url=http://journal.frontiersin.org/article/10.3389/fchem.2017.00087/full|journal=Frontiers in Chemistry|volume=5|pages=87|doi=10.3389/fchem.2017.00087|issn=2296-2646|pmc=PMC5682303|pmid=29167789}}</ref> and PoyC<ref>{{Cite journal|last=Parent|first=Aubérie|last2=Guillot|first2=Alain|last3=Benjdia|first3=Alhosna|last4=Chartier|first4=Gwladys|last5=Leprince|first5=Jérôme|last6=Berteau|first6=Olivier|date=2016-12-07|title=The B 12 -Radical SAM Enzyme PoyC Catalyzes Valine C β -Methylation during Polytheonamide Biosynthesis|url=https://pubs.acs.org/doi/10.1021/jacs.6b06697|journal=Journal of the American Chemical Society|language=en|volume=138|issue=48|pages=15515–15518|doi=10.1021/jacs.6b06697|issn=0002-7863|pmc=PMC5410653|pmid=27934015}}</ref> in polytheonamide biosynthesis
# PoyD and PoyC in polytheonamide biosynthesis<ref name=":6" />
# TbtI in thiomuracin biosynthesis<ref name=":6" />
# TbtI in thiomuracin biosynthesis<ref name=":6" />
# NosN in [[nosiheptide]] biosynthesis<ref name=":7">{{cite journal | vauthors = Yokoyama K, Lilla EA | title = C-C bond forming radical SAM enzymes involved in the construction of carbon skeletons of cofactors and natural products | journal = Natural Product Reports | volume = 35 | issue = 7 | pages = 660–694 | date = July 2018 | pmid = 29633774 | pmc = 6051890 | doi = 10.1039/c8np00006a }}</ref>
# NosN in [[nosiheptide]] biosynthesis<ref name=":7">{{cite journal | vauthors = Yokoyama K, Lilla EA | title = C-C bond forming radical SAM enzymes involved in the construction of carbon skeletons of cofactors and natural products | journal = Natural Product Reports | volume = 35 | issue = 7 | pages = 660–694 | date = July 2018 | pmid = 29633774 | pmc = 6051890 | doi = 10.1039/c8np00006a }}</ref>
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# OxsB in oxetanocin biosynthesis<ref name=":7" />
# OxsB in oxetanocin biosynthesis<ref name=":7" />
# BchE in anaerobic [[bacteriochlorophyll]] biosynthesis<ref name=":7" />
# BchE in anaerobic [[bacteriochlorophyll]] biosynthesis<ref name=":7" />
# F0 synthases in F420 cofactor biosynthesis<ref>{{Cite journal|last=Philmus|first=Benjamin|last2=Decamps|first2=Laure|last3=Berteau|first3=Olivier|last4=Begley|first4=Tadhg P.|date=2015-04-29|title=Biosynthetic Versatility and Coordinated Action of 5′-Deoxyadenosyl Radicals in Deazaflavin Biosynthesis|url=https://pubs.acs.org/doi/10.1021/ja513287k|journal=Journal of the American Chemical Society|language=en|volume=137|issue=16|pages=5406–5413|doi=10.1021/ja513287k|issn=0002-7863|pmc=PMC4416281|pmid=25781338}}</ref><ref>{{Cite journal|last=Decamps|first=Laure|last2=Philmus|first2=Benjamin|last3=Benjdia|first3=Alhosna|last4=White|first4=Robert|last5=Begley|first5=Tadhg P.|last6=Berteau|first6=Olivier|date=2012-11-07|title=Biosynthesis of F 0 , Precursor of the F 420 Cofactor, Requires a Unique Two Radical-SAM Domain Enzyme and Tyrosine as Substrate|url=https://pubs.acs.org/doi/10.1021/ja307762b|journal=Journal of the American Chemical Society|language=en|volume=134|issue=44|pages=18173–18176|doi=10.1021/ja307762b|issn=0002-7863}}</ref>
# F0 synthases in F420 cofactor biosynthesis<ref name=":7" />
# MqnE and MqnC in [[Vitamin K2|menaquinone]] biosynthesis<ref name=":7" /><ref name=":8" />
# MqnE and MqnC in [[Vitamin K2|menaquinone]] biosynthesis<ref name=":7" /><ref name=":8" />
# QhpD in post-translational processing of quinohemoprotein amine dehydrogenase<ref>{{cite journal | vauthors = Nakai T, Ito H, Kobayashi K, Takahashi Y, Hori H, Tsubaki M, Tanizawa K, Okajima T | display-authors = 6 | title = The Radical S-Adenosyl-L-methionine Enzyme QhpD Catalyzes Sequential Formation of Intra-protein Sulfur-to-Methylene Carbon Thioether Bonds | journal = The Journal of Biological Chemistry | volume = 290 | issue = 17 | pages = 11144–66 | date = April 2015 | pmid = 25778402 | doi = 10.1074/jbc.M115.638320 | pmc = 4409272 | doi-access = free }}</ref>
# QhpD in post-translational processing of quinohemoprotein amine dehydrogenase<ref>{{cite journal | vauthors = Nakai T, Ito H, Kobayashi K, Takahashi Y, Hori H, Tsubaki M, Tanizawa K, Okajima T | display-authors = 6 | title = The Radical S-Adenosyl-L-methionine Enzyme QhpD Catalyzes Sequential Formation of Intra-protein Sulfur-to-Methylene Carbon Thioether Bonds | journal = The Journal of Biological Chemistry | volume = 290 | issue = 17 | pages = 11144–66 | date = April 2015 | pmid = 25778402 | doi = 10.1074/jbc.M115.638320 | pmc = 4409272 | doi-access = free }}</ref>


=== Epimerization ===
=== Epimerization ===
Radical SAM [[Epimerase and racemase|epimerases]] are responsible for the [[Regioselectivity|regioselective]] introduction of [[D-Amino acid|D-amino acids]] into RiPPs. Two well-known enzymes have been thoroughly described in RiPP biosynthetic pathways.
Radical SAM [[Epimerase and racemase|epimerases]] are responsible for the [[Regioselectivity|regioselective]] introduction of [[D-Amino acid|D-amino acids]] into RiPPs<ref>{{Cite journal|last=Benjdia|first=Alhosna|last2=Guillot|first2=Alain|last3=Ruffié|first3=Pauline|last4=Leprince|first4=Jérôme|last5=Berteau|first5=Olivier|date=2017-07|title=Post-translational modification of ribosomally synthesized peptides by a radical SAM epimerase in Bacillus subtilis|url=http://www.nature.com/articles/nchem.2714|journal=Nature Chemistry|language=en|volume=9|issue=7|pages=698–707|doi=10.1038/nchem.2714|issn=1755-4330|pmc=PMC6485343|pmid=28644475}}</ref>. 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.<ref name=":6" /> Polytheoamide is a natural potent cytoxic agent by forming pores in membranes.<ref>{{cite journal | vauthors = Itoh H, Inoue M | title = Structural permutation of potent cytotoxin, polytheonamide B: discovery of cytotoxic Peptide with altered activity | journal = ACS Medicinal Chemistry Letters | volume = 4 | issue = 1 | pages = 52–6 | date = January 2013 | pmid = 24900563 | pmc = 4027433 | doi = 10.1021/ml300264c }}</ref> This peptide cytotoxin is naturally produced by uncultivated bacteria that exist as symbionts in a marine sponge.<ref>{{cite journal | vauthors = Freeman MF, Helf MJ, Bhushan A, Morinaka BI, Piel J | title = Seven enzymes create extraordinary molecular complexity in an uncultivated bacterium | journal = Nature Chemistry | volume = 9 | issue = 4 | pages = 387–395 | date = April 2017 | pmid = 28338684 | doi = 10.1038/nchem.2666 | bibcode = 2017NatCh...9..387F | url = https://www.nature.com/articles/nchem.2666 }}</ref>
* PoyD installs numerous D-stereocenters in enzyme PoyA to ultimately help facilitate polytheonamide biosynthesis.<ref name=":6" /><ref>{{Cite journal|last=Parent|first=Aubérie|last2=Benjdia|first2=Alhosna|last3=Guillot|first3=Alain|last4=Kubiak|first4=Xavier|last5=Balty|first5=Clémence|last6=Lefranc|first6=Benjamin|last7=Leprince|first7=Jérôme|last8=Berteau|first8=Olivier|date=2018-02-21|title=Mechanistic Investigations of PoyD, a Radical S -Adenosyl- l -methionine Enzyme Catalyzing Iterative and Directional Epimerizations in Polytheonamide A Biosynthesis|url=https://pubs.acs.org/doi/10.1021/jacs.7b08402|journal=Journal of the American Chemical Society|language=en|volume=140|issue=7|pages=2469–2477|doi=10.1021/jacs.7b08402|issn=0002-7863|pmc=PMC5824343|pmid=29253341}}</ref> Polytheoamide is a natural potent cytoxic agent by forming pores in membranes.<ref>{{cite journal | vauthors = Itoh H, Inoue M | title = Structural permutation of potent cytotoxin, polytheonamide B: discovery of cytotoxic Peptide with altered activity | journal = ACS Medicinal Chemistry Letters | volume = 4 | issue = 1 | pages = 52–6 | date = January 2013 | pmid = 24900563 | pmc = 4027433 | doi = 10.1021/ml300264c }}</ref> This peptide cytotoxin is naturally produced by uncultivated bacteria that exist as symbionts in a marine sponge.<ref>{{cite journal | vauthors = Freeman MF, Helf MJ, Bhushan A, Morinaka BI, Piel J | title = Seven enzymes create extraordinary molecular complexity in an uncultivated bacterium | journal = Nature Chemistry | volume = 9 | issue = 4 | pages = 387–395 | date = April 2017 | pmid = 28338684 | doi = 10.1038/nchem.2666 | bibcode = 2017NatCh...9..387F | url = https://www.nature.com/articles/nchem.2666 }}</ref>
* YydG epimerase modifies two amino acid positions on YydF in Gram-positive ''[[Bacillus subtilis]]''.<ref name=":6" /> A recent study has reported the extrinsically added YydF mediates subsequent dissipation of membrane potential via membrane permeabilization, resulting in death of the organism.<ref>{{cite journal | vauthors = Popp PF, Benjdia A, Strahl H, Berteau O, Mascher T | title = Bacillus subtilis and Causes Severe Membrane Perturbations | language = en | journal = Frontiers in Microbiology | volume = 11 | pages = 151 | date = 2020 | pmid = 32117169 | doi = 10.3389/fmicb.2020.00151 | pmc = 7026026 | doi-access = free }}</ref>
* YydG epimerase modifies two amino acid positions on YydF in Gram-positive ''[[Bacillus subtilis]]''.<ref>{{Cite journal|last=Benjdia|first=Alhosna|last2=Balty|first2=Clémence|last3=Berteau|first3=Olivier|date=2017-11-08|title=Radical SAM Enzymes in the Biosynthesis of Ribosomally Synthesized and Post-translationally Modified Peptides (RiPPs)|url=http://journal.frontiersin.org/article/10.3389/fchem.2017.00087/full|journal=Frontiers in Chemistry|volume=5|pages=87|doi=10.3389/fchem.2017.00087|issn=2296-2646|pmc=PMC5682303|pmid=29167789}}</ref><ref>{{Cite journal|last=Benjdia|first=Alhosna|last2=Guillot|first2=Alain|last3=Ruffié|first3=Pauline|last4=Leprince|first4=Jérôme|last5=Berteau|first5=Olivier|date=2017-07|title=Post-translational modification of ribosomally synthesized peptides by a radical SAM epimerase in Bacillus subtilis|url=http://www.nature.com/articles/nchem.2714|journal=Nature Chemistry|language=en|volume=9|issue=7|pages=698–707|doi=10.1038/nchem.2714|issn=1755-4330|pmc=PMC6485343|pmid=28644475}}</ref> A recent study has reported the extrinsically added YydF mediates subsequent dissipation of membrane potential via membrane permeabilization, resulting in death of the organism.<ref>{{cite journal | vauthors = Popp PF, Benjdia A, Strahl H, Berteau O, Mascher T | title = Bacillus subtilis and Causes Severe Membrane Perturbations | language = en | journal = Frontiers in Microbiology | volume = 11 | pages = 151 | date = 2020 | pmid = 32117169 | doi = 10.3389/fmicb.2020.00151 | pmc = 7026026 | doi-access = free }}</ref>


=== Complex carbon skeleton rearrangements ===
=== 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.
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 lyase|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.<ref name=":9">{{cite journal | vauthors = Wang J, Woldring RP, Román-Meléndez GD, McClain AM, Alzua BR, Marsh EN | title = Recent advances in radical SAM enzymology: new structures and mechanisms | journal = ACS Chemical Biology | volume = 9 | issue = 9 | pages = 1929–38 | date = September 2014 | pmid = 25009947 | pmc = 4168785 | doi = 10.1021/cb5004674 }}</ref><ref>{{cite journal | vauthors = Yang L, Li L | title = Spore photoproduct lyase: the known, the controversial, and the unknown | journal = The Journal of Biological Chemistry | volume = 290 | issue = 7 | pages = 4003–9 | date = February 2015 | pmid = 25477522 | pmc = 4326811 | doi = 10.1074/jbc.R114.573675 }}</ref>
* DNA [[Spore photoproduct lyase|spore photoproduct lysase]] (SPL) is a radical SAM that can repair DNA [[thymine dimers]] (spore product, SP) caused by UV radiation<ref>{{Cite journal|last=Benjdia|first=Alhosna|last2=Heil|first2=Korbinian|last3=Barends|first3=Thomas R. M.|last4=Carell|first4=Thomas|last5=Schlichting|first5=Ilme|date=2012-10|title=Structural insights into recognition and repair of UV-DNA damage by Spore Photoproduct Lyase, a radical SAM enzyme|url=https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gks603|journal=Nucleic Acids Research|language=en|volume=40|issue=18|pages=9308–9318|doi=10.1093/nar/gks603|issn=1362-4962|pmc=PMC3467042|pmid=22761404}}</ref>. 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.<ref>{{Cite journal|last=Chandor|first=Alexia|last2=Berteau|first2=Olivier|last3=Douki|first3=Thierry|last4=Gasparutto|first4=Didier|last5=Sanakis|first5=Yannis|last6=Ollagnier-de-Choudens|first6=Sandrine|last7=Atta|first7=Mohamed|last8=Fontecave|first8=Marc|date=2006-09|title=Dinucleotide Spore Photoproduct, a Minimal Substrate of the DNA Repair Spore Photoproduct Lyase Enzyme from Bacillus subtilis|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925819348690|journal=Journal of Biological Chemistry|language=en|volume=281|issue=37|pages=26922–26931|doi=10.1074/jbc.M602297200}}</ref><ref name=":9">{{cite journal | vauthors = Wang J, Woldring RP, Román-Meléndez GD, McClain AM, Alzua BR, Marsh EN | title = Recent advances in radical SAM enzymology: new structures and mechanisms | journal = ACS Chemical Biology | volume = 9 | issue = 9 | pages = 1929–38 | date = September 2014 | pmid = 25009947 | pmc = 4168785 | doi = 10.1021/cb5004674 }}</ref><ref>{{cite journal | vauthors = Yang L, Li L | title = Spore photoproduct lyase: the known, the controversial, and the unknown | journal = The Journal of Biological Chemistry | volume = 290 | issue = 7 | pages = 4003–9 | date = February 2015 | pmid = 25477522 | pmc = 4326811 | doi = 10.1074/jbc.R114.573675 }}</ref><ref>{{Cite journal|last=Chandor-Proust|first=Alexia|last2=Berteau|first2=Olivier|last3=Douki|first3=Thierry|last4=Gasparutto|first4=Didier|last5=Ollagnier-de-Choudens|first5=Sandrine|last6=Fontecave|first6=Marc|last7=Atta|first7=Mohamed|date=2008-12|title=DNA Repair and Free Radicals, New Insights into the Mechanism of Spore Photoproduct Lyase Revealed by Single Amino Acid Substitution|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925820496449|journal=Journal of Biological Chemistry|language=en|volume=283|issue=52|pages=36361–36368|doi=10.1074/jbc.M806503200|pmc=PMC2662300|pmid=18957420}}</ref><ref>{{Cite journal|last=Benjdia|first=Alhosna|date=2012-12|title=DNA photolyases and SP lyase: structure and mechanism of light-dependent and independent DNA lyases|url=https://linkinghub.elsevier.com/retrieve/pii/S0959440X12001613|journal=Current Opinion in Structural Biology|language=en|volume=22|issue=6|pages=711–720|doi=10.1016/j.sbi.2012.10.002}}</ref>
* HydG is a radical SAM responsible for generating [[Carbon monoxide|CO]] and [[Cyanide|CN<sup>−</sup>]] ligands in the [Fe-Fe]-hydrogenase (HydA) in various anaerobic bacteria.<ref name=":9" />
* HydG is a radical SAM responsible for generating [[Carbon monoxide|CO]] and [[Cyanide|CN<sup>−</sup>]] ligands in the [Fe-Fe]-hydrogenase (HydA) in various anaerobic bacteria.<ref name=":9" />
* Radical SAM MoaA and MoaC are involved in converting GTP into cyclic pyranopterin monophosphate (cPMP). Overall, both play important roles in [[molybdopterin]]<nowiki/>biosynthesis.<ref name=":9" />
* Radical SAM MoaA and MoaC are involved in converting GTP into cyclic pyranopterin monophosphate (cPMP). Overall, both play important roles in [[molybdopterin]]<nowiki/>biosynthesis.<ref name=":9" />

Revision as of 18:30, 24 March 2021

Radical_SAM
Identifiers
SymbolRadical_SAM
PfamPF04055
InterProIPR007197
SCOP2102114 / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

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.

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 ([1]). 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]
  2. Radical S-Adenosylmethionine Enzymes: [3]
  3. Radical S-Adenosylmethionine (SAM) Enzymes in Cofactor Biosynthesis: A Treasure Trove of Complex Organic Radical Rearrangement Reactions: [4]
  4. Molecular architectures and functions of radical enzymes and their (re)activating proteins: [5]

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][34] Another common name for this peptide class is ribosomally synthesized and post-translationally modified peptides (RiPPs).[6][35]

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.[36][37][38]

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

  1. TsrM in thiostrepton biosynthesis[39][40]
  2. PoyD[41] and PoyC[42] in polytheonamide biosynthesis
  3. TbtI in thiomuracin biosynthesis[15]
  4. NosN in nosiheptide biosynthesis[43]
  5. MoaA in molybdopterin biosynthesis[43][44]
  6. PqqE in pyrroloquinoline quinone biosynthesis[43]
  7. TunB in tunicamycin biosynthesis[43]
  8. OxsB in oxetanocin biosynthesis[43]
  9. BchE in anaerobic bacteriochlorophyll biosynthesis[43]
  10. F0 synthases in F420 cofactor biosynthesis[45][46]
  11. MqnE and MqnC in menaquinone biosynthesis[43][44]
  12. QhpD in post-translational processing of quinohemoprotein amine dehydrogenase[47]

Epimerization

Radical SAM epimerases are responsible for the regioselective introduction of D-amino acids into RiPPs[48]. 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][49] Polytheoamide is a natural potent cytoxic agent by forming pores in membranes.[50] This peptide cytotoxin is naturally produced by uncultivated bacteria that exist as symbionts in a marine sponge.[51]
  • YydG epimerase modifies two amino acid positions on YydF in Gram-positive Bacillus subtilis.[52][53] 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.

  • DNA spore photoproduct lysase (SPL) is a radical SAM that can repair DNA thymine dimers (spore product, SP) caused by UV radiation[55]. 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.[56][18][57][58][59]
  • 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.[60]
  • 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.[61]

Clinical considerations

  • Deficiency in human tRNA methylthiotransferase eMtaB has been shown to be responsible for abnormal insulin synthesis and predisposition to type 2 diabetes.[62]
  • Mutations in human GTP cyclase MoaA has been reported to lead to molybdenum cofactor deficiency, a usually fatal disease accompanied by severe neurological symptoms.[63]
  • Mutations in human wybutosine-tRNA modifying enzyme Tyw1 promotes retrovirus infection.[64]
  • Alterations in human tRNA-modifying enzyme Elp3 results in progression into amyotrophic lateral sclerosis (ALS).[64]
  • Mutations in human antiviral RSAD1 has been shown to be associated with congenital heart disease.[64]
  • Mutations in human sulfurtransferase LipA has been implicated in glycine encephalopathy, pyruvate dehydrogenase and lipoic acid synthetase deficiency.[64]
  • Mutations in human methylthiotransferase MiaB are related to impaired cardiac and respiratory functions.[64]

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.[65][66] 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.[67]
  • 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.[68]
  • 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.[69]

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)
  • 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 [70]
  • 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) [71]
  • 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) [72]
  • Dph2 (PF01866) - diphthamide biosynthesis enzyme Dph2 (protein modification - diphthamide in translation elongation factor 2) (note different radical production, a 3-amino-3-carboxypropyl radical) [73]
  • PhnJ (PF06007) - phosphonate metabolism protein PhnJ (C-P phosphonate bond cleavage) [74]

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