Abstract
The biogenic polyamines, spermine, spermidine (Spd) and putrescine (Put) are present at micro-millimolar concentrations in eukaryotic and prokaryotic cells (many prokaryotes have no spermine), participating in the regulation of cellular proliferation and differentiation. In mammalian cells Put is formed exclusively from L-ornithine by ornithine decarboxylase (ODC) and many potent ODC inhibitors are known. In bacteria, plants, and fungi Put is synthesized also from agmatine, which is formed from L-arginine by arginine decarboxylase (ADC). Here we demonstrate that the isosteric hydroxylamine analogue of agmatine (AO-Agm) is a new and very potent (IC50 3•10−8 M) inhibitor of E. coli ADC. It was almost two orders of magnitude less potent towards E. coli ODC. AO-Agm decreased polyamine pools and inhibited the growth of DU145 prostate cancer cells only at high concentration (1 mM). Growth inhibitory analysis of the Acremonium chrysogenum demonstrated that the wild type (WT) strain synthesized Put only from L-ornithine, while the cephalosporin C high-yielding strain, in which the polyamine pool is increased, could use both ODC and ADC to produce Put. Thus, AO-Agm is an important addition to the set of existing inhibitors of the enzymes of polyamine biosynthesis, and an important instrument for investigating polyamine biochemistry.
Highlights
The biogenic polyamines, spermine (Spm) and spermidine (Spd), are organic polycations present at micro-millimolar concentrations in eukaryotic and prokaryotic cells where they participate in the regulation of vital cellular functions including proliferation and differentiation [1,2,3]
We demonstrate that the isosteric hydroxylamine analogue of agmatine (AO-Agm) is a new and very potent (IC50 310−8 M) inhibitor of E. coli arginine decarboxylase (ADC)
Growth inhibitory analysis of the Acremonium chrysogenum demonstrated that the wild type (WT) strain synthesized Put only from L-ornithine, while the cephalosporin C high-yielding strain, in which the polyamine pool is increased, could use both ornithine decarboxylase (ODC) and ADC to produce Put
Summary
The biogenic polyamines, spermine (Spm) and spermidine (Spd), are organic polycations present at micro-millimolar concentrations in eukaryotic and prokaryotic cells (in many of prokaryotes Spm is absent) where they participate in the regulation of vital cellular functions including proliferation and differentiation [1,2,3]. There is still a need for specific inhibitors and inducers of the key enzymes of polyamine metabolism, as well as functionally active mimetics of Spm and Spd [8,9,10,11,12]. Ornithine decarboxylase (ODC) is the key and the rate-limiting enzyme of polyamine biosynthesis, since putrescine (Put), formed from the decarboxylation of L-ornithine (L-Orn), gives rise to Spd and Spm [2,4]. Α-(Difluoromethyl)ornithine (DFMO) was synthesized in 1978 [13], and is the best-known and most widely used of the ODC inhibitors, serving for many years as the “gold standard inhibitor” of polyamine research [8,12]. DFMO has fungicidal activity; this was demonstrated for the first time when it conferred protection on bean plants against infection by uredospores of the bean rust fungus Uromyces phaseoli Linnaeus in greenhouse experiments [16]
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