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⇱ The crystal structure of spermidine synthase with a multisubstrate adduct inhibitor | Nature Structural & Molecular Biology

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Abstract

Polyamines are essential in all branches of life. Spermidine synthase (putrescine aminopropyltransferase, PAPT) catalyzes the biosynthesis of spermidine, a ubiquitous polyamine. The crystal structure of the PAPT from Thermotoga maritima (TmPAPT) has been solved to 1.5 Γ… resolution in the presence and absence of AdoDATO (S-adenosyl-1,8-diamino-3-thiooctane), a compound containing both substrate and product moieties. This, the first structure of an aminopropyltransferase, reveals deep cavities for binding substrate and cofactor, and a loop that envelops the active site. The AdoDATO binding site is lined with residues conserved in PAPT enzymes from bacteria to humans, suggesting a universal catalytic mechanism. Other conserved residues act sterically to provide a structural basis for polyamine specificity. The enzyme is tetrameric; each monomer consists of a C-terminal domain with a Rossmann-like fold and an N-terminal Ξ²-stranded domain. The tetramer is assembled using a novel barrel-type oligomerization motif.

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Figure 1
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Figure 2: Overall structure of TmPAPT monomer and architecture of the tetramer.
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Figure 3: Sequence alignment of TmPAPT with plant and human PAPTs and with PNMT.
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Figure 4: Interaction of AdoDATO with TmPAPT.
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Acknowledgements

We wish to thank all members of the SBC at ANL for their help in conducting experiments and L. Keller for help in preparation of this manuscript. This work was supported by the National Institutes of Health; the U.S. Department of Energy, Office of Biological and Environmental Research; the Ontario Research and Development Challenge Fund; and National Institutes of Health. A.M.E. and C.H.A. are CIHR Investigators. The submitted manuscript has been created by the University of Chicago as Operator of Argonne National Laboratory ('Argonne') under contract with the U.S. Department of Energy. The U.S. Government retains for itself, and others acting on its behalf, a paid-up, nonexclusive, irrevocable worldwide license in said article to reproduce, prepare derivative works, distribute copies to the public, and perform publicly and display publicly, by or on behalf of the Government.

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Authors and Affiliations

  1. Biosciences Division and Structural Biology Center, Argonne National Laboratory, 9700 South Cass Ave., Bldg. 202, Argonne, 60439, Illinois, USA

    Sergey Korolev & Andrzej Joachimiak

  2. Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, P.O. Box 850, 500 University Drive, Hershey, 17033, Pennsylvania, USA

    Yoshihiko Ikeguchi & Anthony E. Pegg

  3. Banting and Best Department of Medical Research, 112 College St., Toronto, M5G 1L6, Ontario, Canada

    Tatiana Skarina, Steven Beasley, Cheryl Arrowsmith, Aled Edwards & Alexei Savchenko

  4. Clinical Genomics Centre/Proteomics, University Health Network, 101 College St., Toronto, M5G 1L7, Ontario, Canada

    Aled Edwards

Authors
  1. Sergey Korolev
  2. Yoshihiko Ikeguchi
  3. Tatiana Skarina
  4. Steven Beasley
  5. Cheryl Arrowsmith
  6. Aled Edwards
  7. Andrzej Joachimiak
  8. Anthony E. Pegg
  9. Alexei Savchenko

Corresponding authors

Correspondence to Aled Edwards, Andrzej Joachimiak or Anthony E. Pegg.

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Korolev, S., Ikeguchi, Y., Skarina, T. et al. The crystal structure of spermidine synthase with a multisubstrate adduct inhibitor. Nat Struct Mol Biol 9, 27–31 (2002). https://doi.org/10.1038/nsb737

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  • DOI: https://doi.org/10.1038/nsb737

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