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Structural basis for non-radical catalysis by TsrM, a radical SAM methylase.

Knox HL, Chen PY, Blaszczyk AJ, Mukherjee A, Grove TL, Schwalm EL, Wang B, Drennan CL, Booker SJ
Nat Chem Biol 17 485-491 (2021)
Cited: 23 times
EuropePMC logo PMID: 33462497

Abstract

Tryptophan 2C methyltransferase (TsrM) methylates C2 of the indole ring of L-tryptophan during biosynthesis of the quinaldic acid moiety of thiostrepton. TsrM is annotated as a cobalamin-dependent radical S-adenosylmethionine (SAM) methylase; however, TsrM does not reductively cleave SAM to the universal 5'-deoxyadenosyl 5'-radical intermediate, a hallmark of radical SAM (RS) enzymes. Herein, we report structures of TsrM from Kitasatospora setae, which are the first structures of a cobalamin-dependent radical SAM methylase. Unexpectedly, the structures show an essential arginine residue that resides in the proximal coordination sphere of the cobalamin cofactor, and a [4Fe-4S] cluster that is ligated by a glutamyl residue and three cysteines in a canonical CXXXCXXC RS motif. Structures in the presence of substrates suggest a substrate-assisted mechanism of catalysis, wherein the carboxylate group of SAM serves as a general base to deprotonate N1 of the tryptophan substrate, facilitating the formation of a C2 carbanion.

Reviews - 6wtf mentioned but not cited (2)

  1. Computational Approaches: An Underutilized Tool in the Quest to Elucidate Radical SAM Dynamics. Blue TC, Davis KM. Molecules 26 2590 (2021)
  2. Structure and Catalytic Mechanism of Radical SAM Methylases. Nguyen TQ, Nicolet Y. Life (Basel) 12 1732 (2022)

Articles - 6wtf mentioned but not cited (4)

  1. Structural basis for non-radical catalysis by TsrM, a radical SAM methylase. Knox HL, Chen PY, Blaszczyk AJ, Mukherjee A, Grove TL, Schwalm EL, Wang B, Drennan CL, Booker SJ. Nat Chem Biol 17 485-491 (2021)
  2. Structure of a B12-dependent radical SAM enzyme in carbapenem biosynthesis. Knox HL, Sinner EK, Townsend CA, Boal AK, Booker SJ. Nature 602 343-348 (2022)
  3. Crystallographic snapshots of a B12-dependent radical SAM methyltransferase. Fyfe CD, Bernardo-García N, Fradale L, Grimaldi S, Guillot A, Brewee C, Chavas LMG, Legrand P, Benjdia A, Berteau O. Nature 602 336-342 (2022)
  4. The Atypical Cobalamin-Dependent S-Adenosyl-l-Methionine Nonradical Methylase TsrM and Its Radical Counterparts. Ulrich EC, Drennan CL. J Am Chem Soc 144 5673-5684 (2022)


Reviews citing this publication (4)

  1. Cobalamin-Dependent Radical S-Adenosylmethionine Enzymes: Capitalizing on Old Motifs for New Functions. Bridwell-Rabb J, Li B, Drennan CL. ACS Bio Med Chem Au 2 173-186 (2022)
  2. Methyltransferases: Functions and Applications. Abdelraheem E, Thair B, Varela RF, Jockmann E, Popadić D, Hailes HC, Ward JM, Iribarren AM, Lewkowicz ES, Andexer JN, Hagedoorn PL, Hanefeld U. Chembiochem 23 e202200212 (2022)
  3. Structural insights into auxiliary cofactor usage by radical S-adenosylmethionine enzymes. Jeyachandran VR, Boal AK. Curr Opin Chem Biol 68 102153 (2022)
  4. Functional Diversity of HemN-like Proteins. Cheng J, Liu WQ, Zhu X, Zhang Q. ACS Bio Med Chem Au 2 109-119 (2022)

Articles citing this publication (13)

  1. Structural Insight into the Substrate Scope of Viperin and Viperin-like Enzymes from Three Domains of Life. Lachowicz JC, Gizzi AS, Almo SC, Grove TL. Biochemistry 60 2116-2129 (2021)
  2. Evolution of Methods for the Study of Cobalamin-Dependent Radical SAM Enzymes. Sinner EK, Marous DR, Townsend CA. ACS Bio Med Chem Au 2 4-10 (2022)
  3. A Cobalamin-Dependent Radical SAM Enzyme Catalyzes the Unique Cα -Methylation of Glutamine in Methyl-Coenzyme M Reductase. Gagsteiger J, Jahn S, Heidinger L, Gericke L, Andexer JN, Friedrich T, Loenarz C, Layer G. Angew Chem Int Ed Engl 61 e202204198 (2022)
  4. Human Mat2A Uses an Ordered Kinetic Mechanism and Is Stabilized but Not Regulated by Mat2B. Bailey J, Douglas H, Masino L, de Carvalho LPS, Argyrou A. Biochemistry 60 3621-3632 (2021)
  5. Overall Retention of Methyl Stereochemistry during B12-Dependent Radical SAM Methyl Transfer in Fosfomycin Biosynthesis. McLaughlin MI, Pallitsch K, Wallner G, van der Donk WA, Hammerschmidt F. Biochemistry 60 1587-1596 (2021)
  6. Purification and characterization of sequential cobalamin-dependent radical SAM methylases ThnK and TokK in carbapenem β-lactam antibiotic biosynthesis. Sinner EK, Townsend CA. Methods Enzymol 669 29-44 (2022)
  7. Stereochemical course of cobalamin-dependent radical SAM methylation by TokK and ThnK. Lichstrahl MS, Townsend CA, Sinner EK. RSC Chem Biol 3 1028-1034 (2022)
  8. Cobalamin Riboswitches Are Broadly Sensitive to Corrinoid Cofactors to Enable an Efficient Gene Regulatory Strategy. Kennedy KJ, Widner FJ, Sokolovskaya OM, Innocent LV, Procknow RR, Mok KC, Taga ME. mBio 13 e0112122 (2022)
  9. Editorial Twenty Years of Radical SAM! The Genesis of the Superfamily. Booker SJ, Lloyd CT. ACS Bio Med Chem Au 2 538-547 (2022)
  10. Two Radical SAM Enzymes Are Necessary and Sufficient for the In Vitro Production of the Oxetane Nucleoside Antiviral Agent Albucidin. Fan PH, Geng Y, Romo AJ, Zhong A, Zhang J, Yeh YC, Lee YH, Liu HW. Angew Chem Int Ed Engl 61 e202210362 (2022)
  11. Changing Fates of the Substrate Radicals Generated in the Active Sites of the B12-Dependent Radical SAM Enzymes OxsB and AlsB. Lee YH, Yeh YC, Fan PH, Zhong A, Ruszczycky MW, Liu HW. J Am Chem Soc 145 3656-3664 (2023)
  12. Spectroscopic and Computational Investigation of the Epoxyqueuosine Reductase QueG Reveals Intriguing Similarities with the Reductive Dehalogenase PceA. Greenhalgh ED, Kincannon W, Bandarian V, Brunold TC. Biochemistry 61 195-205 (2022)
  13. Studies of GenK and OxsB, two B12-dependent radical SAM enzymes involved in natural product biosynthesis. Lee YH, Liu HW. Methods Enzymol 669 71-90 (2022)


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