A 30 Å long U-shaped catalytic tunnel in the crystal structure of polyamine oxidase

Claudia Binda, Alessandro Coda, Riccardo Angelini, Rodolfo Federico, Paolo Ascenzi, Andrea Mattevi

Research output: Contribution to journalArticle

Abstract

Background: Polyamines are essential for cell growth and differentiation; compounds interfering with their metabolism are potential anticancer agents. Polyamine oxidase (PAO) plays a central role in polyamine homeostasis. The enzyme utilises an FAD cofactor to catalyse the oxidation of the secondary amino groups of spermine and spermidine. Results: The first crystal structure of a polyamine oxidase has been determined to a resolution of 1.9 Å. PAO from Zea mays contains two domains, which define a remarkable 30 Å long U-shaped catalytic tunnel at their interface. The structure of PAO in complex with the inhibitor MDL72527 reveals the residues forming the catalytic machinery and unusual enzyme-inhibitor CH···O hydrogen bonds. A ring of glutamate and aspartate residues surrounding one of the two tunnel openings contributes to the steering of the substrate towards the inside of the tunnel. Conclusions: PAO specifically oxidises substrates that have both primary and secondary amino groups. The complex with MDL72527 shows that the primary amino groups are essential for the proper alignment of the substrate with respect to the flavin. Conservation of an N-terminal sequence motif indicates that PAO is a member of a novel family of flavoenzymes. Among these, monoamine oxidase displays significant sequence homology with PAO, suggesting a similar overall folding topology.

Original languageEnglish
Pages (from-to)265-276
Number of pages12
JournalStructure
Volume7
Issue number3
DOIs
Publication statusPublished - Mar 1999

Keywords

  • Enzyme catalysis
  • Flavoenzymes
  • Monoamine oxidase
  • Polyamine oxidase
  • X-ray crystallography

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

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    Binda, C., Coda, A., Angelini, R., Federico, R., Ascenzi, P., & Mattevi, A. (1999). A 30 Å long U-shaped catalytic tunnel in the crystal structure of polyamine oxidase. Structure, 7(3), 265-276. https://doi.org/10.1016/S0969-2126(99)80037-9