Metabolism of an alkyl polyamine analog by a polyamine oxidase from the microsporidian Encephalitozoon cuniculi

Antimicrob Agents Chemother. 2009 Jun;53(6):2599-604. doi: 10.1128/AAC.00267-08. Epub 2009 Feb 17.

Abstract

Encephalitozoon cuniculi is a microsporidium responsible for systemic illness in mammals. In the course of developing leads to new therapy for microsporidiosis, we found that a bis(phenylbenzyl)3-7-3 analog of spermine, 1,15-bis{N-[o-(phenyl)benzylamino}-4,12-diazapentadecane (BW-1), was a substrate for an E. cuniculi amine oxidase activity. The primary natural substrate for this oxidase activity was N'-acetylspermine, but BW-1 had activity comparable to that of the substrate. As the sole substrate, BW-1 gave linear reaction rates over 15 min and K(m) of 2 microM. In the presence of N'-acetylspermine, BW-1 acted as a competitive inhibitor of oxidase activity and may be a subversive substrate, resulting in increased peroxide production. By use of (13)C-labeled BW-1 as a substrate and nuclear magnetic resonance analysis, two products were determined to be oxidative metabolites, a hydrated aldehyde or dicarboxylate and 2(phenyl)benzylamine. These products were detected after exposure of (13)C-labeled BW-1 to E. cuniculi preemergent spore preparations and to uninfected host cells. In previous studies, BW-1 was curative in a rodent model of infection with E. cuniculi. The results in this study demonstrate competitive inhibition of oxidase activity by BW-1 and support further studies of this oxidase activity by the parasite and host.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Encephalitozoon cuniculi / metabolism*
  • Magnetic Resonance Spectroscopy
  • Oxidoreductases Acting on CH-NH Group Donors / physiology*
  • Polyamine Oxidase
  • Polyamines / metabolism*
  • Rabbits

Substances

  • 1,15-bis(N-(o-phenyl)benzylamino)-4,12-diazapentadecane
  • Polyamines
  • Oxidoreductases Acting on CH-NH Group Donors