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Diphthamide biosynthesis requires an organic radical generated by an iron–sulphur enzyme

Author

Listed:
  • Yang Zhang

    (Cornell University, Ithaca, New York 14853, USA)

  • Xuling Zhu

    (Cornell University, Ithaca, New York 14853, USA)

  • Andrew T. Torelli

    (Cornell University, Ithaca, New York 14853, USA)

  • Michael Lee

    (The Pennsylvania State University, University Park, Pennsylvania 16802, USA)

  • Boris Dzikovski

    (Cornell University, Ithaca, New York 14853, USA)

  • Rachel M. Koralewski

    (Cornell University, Ithaca, New York 14853, USA)

  • Eileen Wang

    (Cornell University, Ithaca, New York 14853, USA)

  • Jack Freed

    (Cornell University, Ithaca, New York 14853, USA)

  • Carsten Krebs

    (The Pennsylvania State University, University Park, Pennsylvania 16802, USA
    The Pennsylvania State University, University Park, Pennsylvania 16802, USA)

  • Steven E. Ealick

    (Cornell University, Ithaca, New York 14853, USA)

  • Hening Lin

    (Cornell University, Ithaca, New York 14853, USA)

Abstract

Archaeal and eukaryotic translation elongation factor 2 contain a unique post-translationally modified histidine residue called diphthamide, which is the target of diphtheria toxin. The biosynthesis of diphthamide was proposed to involve three steps, with the first being the formation of a C–C bond between the histidine residue and the 3-amino-3-carboxypropyl group of S-adenosyl-l-methionine (SAM). However, further details of the biosynthesis remain unknown. Here we present structural and biochemical evidence showing that the first step of diphthamide biosynthesis in the archaeon Pyrococcus horikoshii uses a novel iron–sulphur-cluster enzyme, Dph2. Dph2 is a homodimer and each of its monomers can bind a [4Fe–4S] cluster. Biochemical data suggest that unlike the enzymes in the radical SAM superfamily, Dph2 does not form the canonical 5′-deoxyadenosyl radical. Instead, it breaks the Cγ,Met–S bond of SAM and generates a 3-amino-3-carboxypropyl radical. Our results suggest that P. horikoshii Dph2 represents a previously unknown, SAM-dependent, [4Fe–4S]-containing enzyme that catalyses unprecedented chemistry.

Suggested Citation

  • Yang Zhang & Xuling Zhu & Andrew T. Torelli & Michael Lee & Boris Dzikovski & Rachel M. Koralewski & Eileen Wang & Jack Freed & Carsten Krebs & Steven E. Ealick & Hening Lin, 2010. "Diphthamide biosynthesis requires an organic radical generated by an iron–sulphur enzyme," Nature, Nature, vol. 465(7300), pages 891-896, June.
    • Handle: RePEc:nat:nature:v:465:y:2010:i:7300:d:10.1038_nature09138
    DOI: 10.1038/nature09138
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    Cited by:

    1. Hongliang Zhang & Julia Quintana & Koray Ütkür & Lorenz Adrian & Harmen Hawer & Klaus Mayer & Xiaodi Gong & Leonardo Castanedo & Anna Schulten & Nadežda Janina & Marcus Peters & Markus Wirtz & Ulrich , 2022. "Translational fidelity and growth of Arabidopsis require stress-sensitive diphthamide biosynthesis," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Marie C. Schoelmerich & Heleen T. Ouboter & Rohan Sachdeva & Petar I. Penev & Yuki Amano & Jacob West-Roberts & Cornelia U. Welte & Jillian F. Banfield, 2022. "A widespread group of large plasmids in methanotrophic Methanoperedens archaea," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

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