Author/Authors :
Dunston, T.T Sidney Kimmel Comprehensive Cancer Center - The Johns Hopkins University School of Medicine, Baltimore, USA , Khomutov, M.A Engelhardt Institute of Molecular Biology - Russian Academy of Sciences, Moscow, Russia , Gabelli, S.B Sidney Kimmel Comprehensive Cancer Center - The Johns Hopkins University School of Medicine, Baltimore, USA , Stewart, T.M Sidney Kimmel Comprehensive Cancer Center - The Johns Hopkins University School of Medicine, Baltimore, USA , Foley, J.R Sidney Kimmel Comprehensive Cancer Center - The Johns Hopkins University School of Medicine, Baltimore, USA , Kochetkov, S.N Engelhardt Institute of Molecular Biology - Russian Academy of Sciences, Moscow, Russia , Khomutov, A.R Engelhardt Institute of Molecular Biology - Russian Academy of Sciences, Moscow, Russia , Casero, R.A Sidney Kimmel Comprehensive Cancer Center - The Johns Hopkins University School of Medicine, Baltimore, USA
Abstract :
Homeostasis of the biogenic polyamines spermine (Spm) and spermidine (Spd), present in μM-mM concentrations in all eukaryotic cells, is precisely regulated by coordinated activities of the enzymes of poly-amine synthesis, degradation, and transport, in order to sustain normal cell growth and viability. Spermine oxidase (SMOX) is the key and most recently discovered enzyme of polyamine metabolism that plays an es-sential role in regulating polyamine homeostasis by catalyzing the back-conversion of Spm to Spd. The deve-lopment of many types of epithelial cancer is associated with inflammation, and disease-related inflammatory stimuli induce SMOX. MDL72527 is widely used in vitro and in vivo as an irreversible inhibitor of SMOX, but it is also potent towards N1-acetylpolyamine oxidase. Although SMOX has high substrate specificity, Spm analogues have not been systematically studied as enzyme inhibitors. Here we demonstrate that 1,12-diami-no-2,11-bis(methylidene)-4,9-diazadodecane (2,11-Met2-Spm) has, under standard assay conditions, an IC50value of 169 μM towards SMOX and is an interesting instrument and lead compound for studying polyamine catabolism.
Keywords :
2,11-Met2-Spm , spermine analogues , MDL72527 , inhibitors , Spermine oxidase
