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  • 02/22/17 - 12:00 PM to 1:00 PM

    Special Seminar: Professor K. Kristoffer Andersson

    Special Seminar

"Inhibition of Class IA Ribonucleotide Reductase, and a Comparison of the Dimanganese Active Sites of Class IB Ribonucleotide Reductase and Manganese Catalase"

Marie Lofstad, Lars H. Böttger, Marta Hammerstad, Åsmund Kjendseth Røhr, Hans-Petter Hersleth, Mirela F. Zaltariov, Vladimir B. Arion, Edward I. Solomon, and K. Kristoffer Andersson

Ribonucleotide reductases (RNRs) are enzymes that convert RNA building blocks into DNA building blocks1. The reductive reaction by RNRs requires a cysteine thiyl radical, which, in the case of class Ia or Ib RNRs, is initiated by an FeIII2- or MnIII2-tyrosyl radical (Y•) cofactor in the R2 subunit of RNR. During enzymatic turnover, the cofactor is activated by oxygen, and generates a Y• that is transported from the smaller R2 subunit to the large catalytic subunit R1 of RNR, where DNA building blocks are formed.

The small subunit of class Ia RNRs can be inhibited by several small compounds2,3, through the inhibition of the active FeIII2- Y• cofactor. We have performed interaction studies and Kd measurements of a mammalian R2 protein with several newly synthesized compounds, and studied their potential inhibitory effect on the protein with EPR, showing promising results.

Manganese catalase (MnCAT) enzymes4,5,6 contain an active site that is similar in structure to the MnIII2 form of NrdF (the R2 subunit in class Ib RNR), characterized by a carboxylate-bridged MnIII-O-MnIII cofactor. However, it catalyzes a different reaction–the degradation of hydrogen peroxide to dioxygen and water. A still unresolved question is how these enzymes containing similar active sites can catalyze different reactions. A variety of spectroscopic methods have been used to try to resolve this question. Samples containing NrdF with active MnIII-O-MnIII cofactor have been prepared and studied by circular dichroism (CD) and magnetic CD (MCD) spectroscopy6. The data show both similar and distinct features as compared to MnCAT.

  1. A.B. Tomter; G. Zoppelaro; N.H. Andersen; H.-P. Hersleth; M. Hammerstad; Å.K. Røhr; G.K. Sandvik;  G.E. Nilsson; C.B. Bell; A.L. Barra; E. Blasco; L. Le Pape; E.I. Solomon; and K.K. Andersson. Coord. Chem. Rev. (2013), 257, 3 
  2. Popovic-Bijelic A; C.R. Kowol; M.E.S. Lind; J. Luo; F. Himo; A.E. Enyedy; V.B. Arion; and A. Gräslund. (2011) J. Inorg. Biochem. 105, 1422
  3. Zaltariov, M.-F.; Hammerstad, M.; Arabshahi, H.; Jovanovic, K.; Richter, K.; Cazacu, M.; Shova, S.; Balan, M.; Andersen, N.H.; Radulovic, S.; Reynisson, J.; Andersson, K. K.; Arion, V.B. Inorg. Chem. (submitted) 
  4. T.C. Brunold; D.R. Gamelin; T.L. Stemmler; S.K. Mandal; W.H. Armstrong; J.E. Penner-Hahn; and E. I. Solomon. J. Am. Chem. Soc. (1998), 120, 8724
  5. K.K. Andersson et al., Chem. Comm. (submitted) 
  6. Marie Lofstad, Ph.D. thesis (2017) ISSN 1501-7710: 1808/2017

Professor Andersson

Professor Andersson’s research is centered on radical-proteins, metalloproteins, oxygen activation, radical/electron transfer, redoxproteins, protein structure combined with functional and advanced spectroscopic studies. He studies several protein cofactors with iron (in e.g. heme protein, non heme iron proteins); copper proteins; manganese proteins; cobalt substituted protein; flavin and biopterin containing proteins; tyrosyl-radicals; with enzymatic, cryobiochemical, optical and magnetic methods. His research group performs 3D structure determination by X-ray crystallography together with single-crystal light absorption and Raman spectroscopy. He has edited a book titled, “Ribonucleotide reductase,” and reviews.

  • Event Details

    Location: 401/402 Walter Library
    Host: Professor Connie Lu and the Center for Metals in Biocatalysis