Inhibition of polyamine and spermine oxidases by polyamine analogues

Marzia Bianchi, Fabio Polticelli, Paolo Ascenzi, Maurizio Botta, Rodolfo Federico, Paolo Mariottini, Alessandra Cona

Research output: Contribution to journalArticlepeer-review

Abstract

Polyamine oxidase (PAO) and spermine oxidase (SMO) are involved in the catabolism of polyamines - basic regulators of cell growth and proliferation. The discovery of selective inhibitors of PAO and SMO represents an important tool in studying the involvement of these enzymes in polyamine homeostasis and a starting point for the development of novel antineoplastic drugs. Here, a comparative study on murine PAO (mPAO) and SMO (mSMO) inhibition by the polyamine analogues 1,8-diaminooctane, 1,12-diaminododecane, N-prenylagmatine (G3), guazatine and N,N1-bis(2,3-butadienyl)-1,4-butanediamine (MDL72527) is reported. Interestingly, 1,12-Diaminododecane and G3 behave as specific inhibitors of mPAO, values of Ki for mPAO inhibition being lower than those for mSMO inactivation by several orders of magnitude. The analysis of molecular models of mPAO and mSMO indicates a significant reduction of the hydrophobic pocket located in maize PAO (MPAO) at the wider catalytic tunnel opening. This observation provides a rationale to explain the lower affinity displayed by G3, guazatine and MDL72527 for mPAO and mSMO as compared to MPAO. The different behaviour displayed by 1,12-diaminododecane towards mPAO and mSMO reveals the occurrence of basic differences in the ligand binding mode of the two enzymes, the first enzyme interacting mainly with substrate secondary amino groups and the second one with substrate primary amino groups. Thus, the data reported here provide the basis for the development of novel and selective inhibitors able to discriminate between mammalian SMO and PAO activities.

Original languageEnglish
Pages (from-to)1115-1123
Number of pages9
JournalFEBS Journal
Volume273
Issue number6
DOIs
Publication statusPublished - Mar 2006

Keywords

  • Polyamine analogue inhibitors
  • Polyamine oxidase
  • Polyamines
  • Spermine oxidase

ASJC Scopus subject areas

  • Biochemistry

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