Unforeseen Possibilities To Investigate the Regulation of Polyamine Metabolism Revealed by Novel C-Methylated Spermine Derivatives

Хомутов, М. А.; Hyvönen, Mervi T.; Simonian, A. R.; Formanovsky, A. A.; Михура, И. В.; Chizhov, Alexander O.; Kochetkov, Sergey N.; Alhonen, Leena; Vepsäläinen, Jouko; Keinänen, Tuomo A.; Khomutov, Alex R.

doi:10.1021/acs.jmedchem.9b01666

Cited by 9 publications

(11 citation statements)

References 49 publications

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“…Additionally, 1,12-Me 2 SPM may serve as a lead compound for the design of related molecules with improved safety profiles. In particular, recent analyses of structurally similar compounds have indicated that positioning of the methyl groups of these compounds alters their biochemical properties with regard to polyamine metabolic (38). Thus, the results reported in this study provide proof of principle that dimethylated SPM mimetics are effective in decreasing SPD levels in SRS-affected cells as well as in multiple tissues in vivo, paving the way for further discovery and development in the understanding and treatment of SRS.…”

Section: Dimethylspermine Reduces Spermidine Accumulation In Srssupporting

confidence: 59%

(R,R)-1,12-Dimethylspermine can mitigate abnormal spermidine accumulation in Snyder–Robinson syndrome

Murray-Stewart

Хомутов

Foley

et al. 2020

Journal of Biological Chemistry

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Snyder–Robinson syndrome (SRS) is an X-linked intellectual disability syndrome caused by a loss-of-function mutation in the spermine synthase (SMS) gene. Primarily affecting males, the main manifestations of SRS include osteoporosis, hypotonic stature, seizures, cognitive impairment, and developmental delay. Because there is no cure for SRS, treatment plans focus on alleviating symptoms rather than targeting the underlying causes. Biochemically, the cells of individuals with SRS accumulate excess spermidine, whereas spermine levels are reduced. We recently demonstrated that SRS patient-derived lymphoblastoid cells are capable of transporting exogenous spermine and its analogs into the cell and, in response, decreasing excess spermidine pools to normal levels. However, dietary supplementation of spermine does not appear to benefit SRS patients or mouse models. Here, we investigated the potential use of a metabolically stable spermine mimetic, (R,R)-1,12-dimethylspermine (Me2SPM), to reduce the intracellular spermidine pools of SRS patient-derived cells. Me2SPM can functionally substitute for the native polyamines in supporting cell growth while stimulating polyamine homeostatic control mechanisms. We found that both lymphoblasts and fibroblasts from SRS patients can accumulate Me2SPM, resulting in significantly decreased spermidine levels with no adverse effects on growth. Me2SPM administration to mice revealed that Me2SPM significantly decreases spermidine levels in multiple tissues. Importantly, Me2SPM was detectable in brain tissue, the organ most affected in SRS, and was associated with changes in polyamine metabolic enzymes. These findings indicate that the (R,R)-diastereomer of 1,12-Me2SPM represents a promising lead compound in developing a treatment aimed at targeting the molecular mechanisms underlying SRS pathology.

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Section: Dimethylspermine Reduces Spermidine Accumulation In Srssupporting

confidence: 59%

(R,R)-1,12-Dimethylspermine can mitigate abnormal spermidine accumulation in Snyder–Robinson syndrome

Murray-Stewart

Хомутов

Foley

et al. 2020

Journal of Biological Chemistry

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“…The ability of racemic 1,12-Me2Spm, 2,11-Me2Spm and 3,10-Me2Spm ( Fig. 2B ) to serve as substrates for SMOX decreased as the methyl group was positioned closer to the secondary (N4) amino group, and for 3,10-Me2Spm, kinetic parameters were impossible to determine [ 19 ]. This is likely because the methyl group at the third position of the Spm backbone may restrict the proton splitting at the C3 carbon atom and influence the formation of the Shiff base, a key intermediate of the SMOX reaction.…”

Section: Resultsmentioning

confidence: 99%

“…2B ) towards SMOX and PAOX. Rac -2,11-Me2Spm was a comparatively poor substrate of SMOX, having a Vmax of 124 pmol/min/μg protein and a Km of 121 μM, while the activity of PAOX was inhibited for 60% only at the 500 μM concentration, when a fixed 50 μM concentration of the substrate N 1-Ac-Spd was used in the PAOX assay [ 19 ].…”

Section: Resultsmentioning

confidence: 99%

Identification of a novel substrate-derived spermine oxidase inhibitor

et al. 2020

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Homeostasis of the biogenic polyamines spermine (Spm) and spermidine (Spd), present in M-mM concentrations in all eukaryotic cells, is precisely regulated by coordinated activities of the enzymes of polyamine 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 essential role in regulating polyamine homeostasis by catalyzing the back-conversion of Spm to Spd. The development 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-diamino-2,11-bis(methylidene)-4,9-diazadodecane (2,11-Met2-Spm) has, under standard assay conditions, an IC50 value of 169 M towards SMOX and is an interesting instrument and lead compound for studying polyamine catabolism.

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“…Mutant and genetically modified microorganisms and cell lines, as well as transgenic animals have been widely used for these purposes during the last decades [7]. However, 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].…”

Section: Introductionmentioning

confidence: 99%

Hydroxylamine Analogue of Agmatine: Magic Bullet for Arginine Decarboxylase

et al. 2020

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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.

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Unforeseen Possibilities To Investigate the Regulation of Polyamine Metabolism Revealed by Novel C-Methylated Spermine Derivatives

Cited by 9 publications

References 49 publications

(R,R)-1,12-Dimethylspermine can mitigate abnormal spermidine accumulation in Snyder–Robinson syndrome

(R,R)-1,12-Dimethylspermine can mitigate abnormal spermidine accumulation in Snyder–Robinson syndrome

Identification of a novel substrate-derived spermine oxidase inhibitor

Hydroxylamine Analogue of Agmatine: Magic Bullet for Arginine Decarboxylase

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