Effects of certain 5'-substituted adenosines on polyamine synthesis: selective inhibitors of spermine synthase

Biochemistry ◽  
1986 ◽  
Vol 25 (14) ◽  
pp. 4091-4097 ◽  
Author(s):  
Anthony E. Pegg ◽  
James K. Coward ◽  
Ratnakar R. Talekar ◽  
John A. Secrist
Keyword(s):  
Selective Inhibitors ◽  
Polyamine Synthesis ◽  
Spermine Synthase

Effects of inhibitors of spermidine synthase and spermine synthase on polyamine synthesis in rat tissues

1993 ◽  
Vol 45 (9) ◽  
pp. 1897-1903 ◽  
Author(s):  
Akira Shirahata ◽  
Norio Takahashi ◽  
Takanobu Beppu ◽  
Harumi Hosoda ◽  
Keijiro Samejima
Keyword(s):  
Rat Tissues ◽  
Spermidine Synthase ◽  
Polyamine Synthesis ◽  
Spermine Synthase

scholarly journals Studies of non-metabolizable polyamines that support growth of SV-3T3 cells depleted of natural polyamines by exposure to α-difluoromethylornithine

1988 ◽  
Vol 254 (2) ◽  
pp. 373-378 ◽  
Author(s):  
S Nagarajan ◽  
B Ganem ◽  
A E Pegg
Keyword(s):  
Cell Growth ◽  
Physiological Role ◽  
3T3 Cells ◽  
Polyamine Synthesis ◽  
Spermine Synthase ◽  
Support Cell ◽  
Polyamine Derivatives ◽  
Metabolic Interconversion

A number of synthetic polyamine derivatives that included five achiral gem-dimethylspermidines and two analogous tetramethylated spermines were tested for their abilities to serve as substrates for enzymes metabolizing polyamines and for their capacities to substitute for the natural polyamines in cell growth. It was found that none of the compounds were effective substrates for spermine synthase, and only one, namely 8,8-dimethylspermidine, was a substrate for spermidine/spermine N1-acetyltransferase. However, all of the spermidine derivatives and 1,1,12,12-tetramethylspermine were able to support the growth of SV-3T3 cells in which endogenous polyamine synthesis was prevented by the addition of alpha-difluoromethylornithine. These results suggest that either spermidine or spermine can support cell growth without the need for metabolic interconversion. In contrast with the result with 1,1,12,12-tetramethylspermine, 3,3,10,10-tetramethylspermine did not restore growth of polyamine-depleted SV-3T3 cells. Comparison of the properties of these derivatives may prove valuable in understanding the physiological role of polyamines.

scholarly journals Studies of inhibition of rat spermidine synthase and spermine synthase

1980 ◽  
Vol 187 (2) ◽  
pp. 419-428 ◽  
Author(s):  
Hiroshige Hibasami ◽  
Ronald T. Borchardt ◽  
Shiang Yuan Chen ◽  
James K. Coward ◽  
Anthony E. Pegg
Keyword(s):  
Amino Acid ◽  
Ventral Prostate ◽  
Amino Group ◽  
Spermidine Synthase ◽  
Polyamine Synthesis ◽  
Weak Inhibitor ◽  
Spermine Synthase ◽  
Rat Ventral Prostate ◽  
Potential Inhibitors ◽  
Derivatives Of

1. S-Adenosyl-l-methionine, S-adenosyl-l-homocysteine, 5′-methylthioadenosine and a number of analogues having changes in the base, sugar or amino acid portions of the molecule were tested as potential inhibitors of spermidine synthase and spermine synthase from rat ventral prostate. 2. S-Adenosyl-l-methionine was inhibitory to these reactions, as were other nucleosides containing a sulphonium centre. The most active of these were S-adenosyl-l-ethionine, S-adenosyl-4-methylthiobutyric acid, S-adenosyl-d-methionine and S-tubercidinylmethionine, which were all comparable in activity with S-adenosylmethionine itself, producing 70–98% inhibition at 1mm concentrations. Spermine synthase was somewhat more sensitive than spermidine synthase. 3. 5′-Methylthioadenosine, 5′-ethylthioadenosine and 5′-methylthiotubercidin were all powerful inhibitors of both enzymes, giving 50% inhibition of spermine synthase at 10–15μm and 50% inhibition of spermidine synthase at 30–45μm. 4. S-Adenosyl-l-homocysteine was a weak inhibitor of spermine synthase and practically inactive against spermidine synthase. Analogues of S-adenosylhomocysteine lacking either the carboxy or the amino group of the amino acid portion were somewhat more active, as were derivatives in which the ribose ring had been opened by oxidation. The sulphoxide and sulphone derivatives of decarboxylated S-adenosyl-l-homocysteine and the sulphone of S-adenosyl-l-homocysteine were quite potent inhibitors and were particularly active against spermidine synthase (giving 50% inhibition at 380, 50 and 20μm respectively). 5. These results are discussed in terms of the possible regulation of polyamine synthesis by endogenous nucleosides and the possible value of some of the inhibitory substances in experimental manipulations of polyamine concentrations. It is suggested that 5′-methylthiotubercidin and the sulphone of S-adenosylhomocysteine or of S-adenosyl-3-thiopropylamine may be particularly valuable in this respect.

scholarly journals Inhibition of the synthesis of polyamines and macromolecules by 5′-methylthioadenosine and 5′-alkylthiotubercidins in BHK21 cells

1982 ◽  
Vol 204 (3) ◽  
pp. 697-703 ◽  
Author(s):  
Aarne Raina ◽  
Kyllikki Tuomi ◽  
Raija-Leena Pajula
Keyword(s):  
Growth Inhibition ◽  
Spermidine Synthase ◽  
Baby Hamster Kidney ◽  
Polyamine Synthesis ◽  
Adenosylmethionine Decarboxylase ◽  
Spermine Synthase ◽  
Target Sites ◽  
Polyamine Content ◽  
Exogenous Spermidine

5′-Methylthioadenosine and four 5′-alkylthiotubercidins were tested for their ability to inhibit polyamine synthesis in vitro and to decrease polyamine concentration and prevent growth of baby-hamster-kidney (BHK21) cells. 5′-Methylthioadenosine and 5′-methylthiotubercidin decreased the activity of spermidine synthase from brain to roughly the same extent, whereas brain spermine synthase was much more strongly inhibited by 5′-methylthioadenosine compared with 5′-methylthiotubercidin. These nucleoside derivatives also inhibited the growth of BHK21 cells and increased the concentration of putrescine. 5′-Methylthioadenosine decreased cellular spermine concentration, whereas 5′-methylthiotubercidin lowered the concentration of spermidine. The activities of ornithine decarboxylase and S-adenosylmethionine decarboxylase were enhanced in cells grown in the presence of 5′-methylthiotubercidin. The growth inhibition produced by these nucleoside derivatives was not reversed by exogenous spermidine or spermine. 5′-Ethylthiotubercidin, 5′-propylthiotubercidin and 5′-isopropylthiotubercidin did not appreciably inhibit spermidine or spermine synthase in vitro or decrease the cellular polyamine content, but effectively prevented the growth of BHK21 cells. All nucleoside derivatives at concentrations of 0.2–1 mm caused a rapid inhibition of protein synthesis. It is concluded that the growth inhibition produced by 5′-methylthioadenosine and 5′-alkylthiotubercidins was not primarily due to polyamine depletion but other target sites, for instance the cellular nucleotide pool, cell membranes etc. must be considered.

Effect of polyamine depletion on caspase activation: a study with spermine synthase-deficient cells

2001 ◽  
Vol 355 (1) ◽  
pp. 199-206 ◽  
Author(s):  
Claudio STEFANELLI ◽  
Carla PIGNATTI ◽  
Benedetta TANTINI ◽  
Monia FATTORI ◽  
Ivana STANIC ◽  
...  
Keyword(s):  
Uv Irradiation ◽  
Normal Male ◽  
Caspase Activity ◽  
Caspase Activation ◽  
Embryonic Fibroblasts ◽  
Polyamine Synthesis ◽  
Spermine Synthase ◽  
Cell Processes ◽  
Mutant Male

Activation of the caspase proteases represents a central point in apoptosis. The requirement for spermine for the processes leading to caspase activation has been studied in transformed embryonic fibroblasts obtained from gyro (Gy) mutant male mice. These cells lack spermine synthase activity and thus provide a valuable model to study the role of spermine in cell processes. Gy fibroblasts do not contain spermine and have a higher spermidine content. However, when compared with fibroblasts obtained from normal male littermates (N cells), Gy fibroblasts were observed to grow normally. The lack of spermine did not affect the expression of Bcl-2, and caspases 3 and 9 were activated by etoposide in both N and Gy cells, indicating that spermine is dispensable for caspase activation. Spermine deficiency did not significantly influence caspase activity in cells treated with etoposide, cycloheximide or staurosporine, but sensitized the cells to UV irradiation, which triggered significantly higher caspase activity in Gy cells compared with N cells. α-Difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis that is able to deplete cells of putrescine and spermidine, but usually does not influence spermine content, was able to produce a more complete polyamine depletion in Gy cells. This depletion, which included spermine deficiency, dramatically increased caspase activation and cell death in Gy fibroblasts exposed to UV irradiation. On the other hand, in either N or Gy cells, DFMO treatment did not influence caspase activity triggered by staurosporine, but inhibited it when the inducers were cycloheximide or etoposide. In Gy cells depleted of polyamines by DFMO, polyamine replenishment with either spermidine or spermine was sufficient to restore caspase activity induced by etoposide, indicating that, in this model, polyamines have an interchangeable role in supporting caspase activation. Therefore, spermine is not required for such activation, and the effect and specificity of polyamine depletion on caspase activity may be very different, depending on the role of polyamines in the specific death pathways engaged by different stimuli. Some inducers of apoptosis, for example etoposide, absolutely require polyamines for caspase activation, yet the lack of polyamines, particularly spermine, strongly increases caspase activation when induced by UV irradiation.

scholarly journals Effect of analogues of 5′-methylthioadenosine on cellular metabolism. Inactivation of S-adenosylhomocysteine hydrolase by 5′-isobutylthioadenosine

1983 ◽  
Vol 210 (2) ◽  
pp. 429-435 ◽  
Author(s):  
F Della Ragione ◽  
A E Pegg
Keyword(s):  
Convenient Method ◽  
Cellular Metabolism ◽  
Spermidine Synthase ◽  
Polyamine Synthesis ◽  
Adenosylhomocysteine Hydrolase ◽  
Methylthioadenosine Phosphorylase ◽  
Spermine Synthase ◽  
Irreversible Inhibition

The effects of a number of nucleosides related to 5′-methylthioadenosine on the activities of S-adenosylhomocysteine hydrolase, 5′-methylthioadenosine phosphorylase, spermidine synthase and spermine synthase were investigated. Both 5′-methylthioadenosine and 5′-isobutylthioadenosine gave rise to an enzyme-activated irreversible inhibition of S-adenosylhomocysteine hydrolase, but 5′-methylthiotubercidin (5′-methylthio-7-deaza-adenosine), 5′-deoxy-5′-chloroformycin, 5′-ethylthio-2-fluoro-adenosine and 1,N6-etheno-5′-methylthioadenosine were totally ineffective in producing this inactivation. Of the nucleosides tested, only 5′-methylthioadenosine, 5′-methylthiotubercidin and 5′-isobutylthioadenosine were inhibitory towards the aminopropyltransferases responsible for the synthesis of spermine and spermidine. 5′-Methylthiotubercidin, 5′-deoxy-5′-chloroformycin and 5′-isobutylthioadenosine were inhibitors of the degradation of 5′-methylthioadenosine by 5′-methylthioadenosine phosphorylase, but only 5′-isobutylthioadenosine was also a substrate for this enzyme. These results suggest that the effects of 5′-isobutylthioadenosine of the cell may result from the combination of inhibitory actions on polyamine synthesis, 5′-methylthioadenosine degradation and S-adenosylhomocysteine degradation. The resulting increased concentrations of S-adenosylhomocysteine could bring about inhibition of methyltransferase reactions. A new convenient method for the assay of S-adenosylhomocysteine hydrolase in the direction of synthesis is described.

scholarly journals Increase in S-adenosylmethionine decarboxylase in SV-3T3 cells treated with S-methyl-5′-methylthioadenosine

1987 ◽  
Vol 244 (1) ◽  
pp. 49-54 ◽  
Author(s):  
A E Pegg ◽  
R Wechter ◽  
A Pajunen
Keyword(s):  
Translation Efficiency ◽  
3T3 Cells ◽  
Enzyme Protein ◽  
Polyamine Synthesis ◽  
Adenosylmethionine Decarboxylase ◽  
Spermine Synthase ◽  
Additional Stabilization ◽  
Key Enzyme ◽  
Translatable Mrna ◽  
Synthase Inhibitor

Treatment of SV-3T3 cells with the spermine synthase inhibitor S-methyl-5′-methylthioadenosine [AdoS+(CH3)2] led to a large increase in the activity of S-adenosylmethionine decarboxylase (AdoMetDC) without affecting ornithine decarboxylase. The elevation of AdoMetDC activity was due to an increased amount of enzyme protein, as demonstrated by radioimmunoassay and by immunoblotting. The increase in AdoMetDC protein was caused by at least three factors: an increase in the amount of translatable mRNA, an increased translation efficiency of the mRNA and an increase in the half-life of the protein. The depletion of spermine brought about by AdoS+(CH3)2 appeared to be responsible for the increased synthesis of AdoMetDC and for part of the decrease in its rate of degradation. An additional stabilization of the enzyme protein was probably due to the binding of AdoS+(CH3)2, which is also a weak inhibitor of AdoMetDC. These results demonstrate the importance of cellular spermine concentrations in regulating the activity of AdoMetDC, which is a key enzyme controlling polyamine synthesis.

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