Selective regulation of polyamine metabolism with methylated polyamine analogues

Abstract

Polyamine metabolism is intimately linked to the physiological state of the cell. Low polyamines levels promote growth cessation, while increased concentrations are often associated with rapid proliferation or cancer. Delicately balanced biosynthesis, catabolism, uptake and excretion are very important for maintaining the intracellular polyamine homeostasis, and deregulated polyamine metabolism is associated with imbalanced metabolic red/ox state. Although many cellular targets of polyamines have been described, the precise molecular mechanisms in these interactions are largely unknown. Polyamines are readily interconvertible which complicate studies on the functions of the individual polyamines. Thus, non-metabolizable polyamine analogues, like carbon-methylated analogues, are needed to circumvent that problem. This review focuses on methylated putrescine, spermidine and spermine analogues in which at least one hydrogen atom attached to polyamine carbon backbone has been replaced by a methyl group. These analogues allow the regulation of both metabolic and catabolic fates of the parent molecule. Substituting the natural polyamines with methylated analogue(s) offers means to study either the functions of an individual polyamine or the effects of altered polyamine metabolism on cell physiology. In general, gem-dimethylated analogues are considered to be non-metabolizable by polyamine catabolizing enzymes spermidine/spermine-N¹-acetyltransferase and acetylpolyamine oxidase and they support short-term cellular proliferation in many experimental models. Monomethylation renders the analogues chiral, offering some advantage over gem-dimethylated analogues in the specific regulation of polyamine metabolism. Thus, methylated polyamine analogues are practical tools to meet existing biological challenges in solving the physiological functions of polyamines.

Molecular Basis of the ‘Anti-Aging' Effect of Spermidine and Other Natural Polyamines - A Mini-Review

“…We should study the effects of all polyamines, on their own and in combination, as well as for instance methylated analogues. These analogues are metabolically more stable, some of them cannot be converted into other polyamines and each has different biochemical properties that could help us tease out the exact roles of polyamines in aging [26,27]. …”

Targeting polyamine metabolism for cancer therapy and prevention

“…Similarly, the biologically stable class of polyamines originally synthesized by Coward and colleagues [150], the α-methylated polyamines, has seen a resurgence in interest [92]. Although all of the classes of analogs have interesting features that have aided in a better understanding of natural polyamine regulation and function, none have thus far made a significant impact in the clinic.…”

Polyamines and transglutaminases: biological, clinical, and biotechnological perspectives

“…Thus, non-metabolizable analogues, like carbon-methylated polyamine analogues, are needed to circumvent that problem. Keinänen et al (2013) have reviewed methylated putrescine, spermidine, and spermine analogues in which at least one hydrogen atom attached to polyamine carbon backbone has been replaced by a methyl group. The authors observed that methylated polyamine analogues allow the regulation of both metabolic and catabolic fates of the parent molecule in vitro and in vivo.…”