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Abstract
The biogenic polyamines, spermine (Spm) and spermidine, are organic polycations present in millimolar concentrations in all eukaryotic cells participating in the regulation of vital cellular functions including proliferation and differentiation. The design and biochemical evaluation of polyamine analogues are cornerstones of polyamine research. Here we synthesized and studied novel C-methylated Spm analogues: 2,11-dimethylspermine (2,11-Me2Spm), 3,10-dimethylspermine (3,10-Me2Spm), 2-methylspermine, and 2,2-dimethylspermine. The tested analogues overcame growth arrest induced by a 72 h treatment with α-difluoromethylornithine, an ornithine decarboxylase (ODC) inhibitor, and entered into DU145 cells via the polyamine transporter. 3,10-Me2Spm was a poor substrate of spermine oxidase and spermidine/spermine-N1-acetyltransferase (SSAT) when compared with 2,11-Me2Spm, thus resembling 1,12-dimethylspermine, which lacks the substrate properties required for the SSAT reaction. The antizyme (OAZ1)-mediated downregulation of ODC and inhibition of polyamine transport are crucial in the maintenance of polyamine homeostasis. Interestingly, 3,10-Me2Spm was found to be the first Spm analogue that did not induce OAZ1 and, consequently, was a weak downregulator of ODC activity in DU145 cells.
Highlights
The biogenic polyamines, spermine (Spm, 1), spermidine (Spd), and their precursor putrescine (Put), are present in micromolar to millimolar concentrations in all eukaryotic cells, which a priori determines the diversity of their functions, many of which are vitally important.[1,2] The investigation of the individual cellular functions of Spm and Spd is complicated by the ability of polyamines to replace each other in many functions; Spm is readily interconverted into Spd.[1−4]Spd is vitally important because in addition to its many cellular functions, it is the sole donor of the aminobutyl group for the hypusination of a specific Lys residue of eukaryotic translation initiation factor 5A
The correct spatial organization of the key part(s) of the analogue is of crucial importance, and the recognition is affected by the presence of even a comparatively small methyl group
The present results provide new insights into the structural limitations that should be taken into consideration during the design of the drugs to treat Snyder−
Summary
Spd is vitally important because in addition to its many cellular functions, it is the sole donor of the aminobutyl group for the hypusination of a specific Lys residue of eukaryotic translation initiation factor 5A (eIF5A, which is an important elongation factor). This post-translational modification is crucial to allow this protein to function in protein synthesis by promoting the translation of polyproline motifs and some other ribosome-pausing sites.[5] Respectively, when cellular polyamine levels decrease, the hypusination of eIF5a is affected last, as demonstrated in a mutant strain of S. cerevisiae, which has a limited pool of Spd.[6] This milestone finding explains why. It is clear that Spm and an appropriate
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