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1
Lee, Jung Yeop, Brian K. Janes, Karla D. Passalacqua, Brian F. Pfleger, Nicholas H. Bergman, Haichuan Liu, Kristina Håkansson, et al. "Biosynthetic Analysis of the Petrobactin Siderophore Pathway from Bacillusanthracis." Journal of Bacteriology 189, no. 5 (December 22, 2006): 1698–710. http://dx.doi.org/10.1128/jb.01526-06.
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ABSTRACT The asbABCDEF gene cluster from Bacillus anthracis is responsible for biosynthesis of petrobactin, a catecholate siderophore that functions in both iron acquisition and virulence in a murine model of anthrax. We initiated studies to determine the biosynthetic details of petrobactin assembly based on mutational analysis of the asb operon, identification of accumulated intermediates, and addition of exogenous siderophores to asb mutant strains. As a starting point, in-frame deletions of each of the genes in the asb locus (asbABCDEF) were constructed. The individual mutations resulted in complete abrogation of petrobactin biosynthesis when strains were grown on iron-depleted medium. However, in vitro analysis showed that each asb mutant grew to a very limited extent as vegetative cells in iron-depleted medium. In contrast, none of the B. anthracis asb mutant strains were able to outgrow from spores under the same culture conditions. Provision of exogenous petrobactin was able to rescue the growth defect in each asb mutant strain. Taken together, these data provide compelling evidence that AsbA performs the penultimate step in the biosynthesis of petrobactin, involving condensation of 3,4-dihydroxybenzoyl spermidine with citrate to form 3,4-dihydroxybenzoyl spermidinyl citrate. As a final step, the data reveal that AsbB catalyzes condensation of a second molecule of 3,4-dihydroxybenzoyl spermidine with 3,4-dihydroxybenzoyl spermidinyl citrate to form the mature siderophore. This work sets the stage for detailed biochemical studies with this unique acyl carrier protein-dependent, nonribosomal peptide synthetase-independent biosynthetic system.
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Ponasik, J. A., C. Strickland, C. Faerman, S. Savvides, P. A. Karplus, and B. Ganem. "Kukoamine A and other hydrophobic acylpolyamines: potent and selective inhibitors of Crithidia fasciculata trypanothione reductase." Biochemical Journal 311, no. 2 (October 15, 1995): 371–75. http://dx.doi.org/10.1042/bj3110371.
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The enzyme trypanothione reductase (TR), together with its substrate, the glutathione-spermidine conjugate trypanothione, plays an essential role in protecting parasitic trypanosomatids against oxidative stress and is a target for drug design. Here we show that a naturally occurring spermine derivative, the antihypertensive agent kukoamine A [N1N12-bis(dihydrocaffeoyl)-spermine] inhibits TR as a mixed inhibitor (Ki = 1.8 microM, Kii = 13 microM). Kukoamine shows no significant inhibition of human glutathione reductase (Ki > 10 mM) and thus provides a novel selective drug lead. The corresponding N1N8-bis(dihydrocaffeoyl)spermidine derivative was synthesized and acted as a purely competitive inhibitor with Ki = 7.5 microM. A series of mono- and di-acylated spermines and spermidines were synthesized to gain an insight into the effect of polyamine chain length, the nature and position of the acyl substituent and the importance of conformational mobility. These compounds inhibited TR with Ki values ranging from 11 to 607 microM.
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Alves da Costa Ribeiro Quintans, Isadora Louise, Juliana Alves da Costa Ribeiro Souza, and Michael K. Deyholos. "Orbitides and free polyamines have similarly limited fungicidal activity against three common pathogens of flax in vitro." FACETS 7 (January 1, 2022): 843–52. http://dx.doi.org/10.1139/facets-2021-0201.
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Fusarium oxysporum f. sp. lini and Septoria linicola are causes of fusarium wilt and pasmo in flax ( Linum usitatissimum). Members of a third fungal genus, Alternaria spp., have also been found in fiber and linseed varieties of flax, and are a source of post-harvest spoilage and mycotoxins in a wide range of crops. We performed a microdilution assay and calculated the median effective concentration (EC50) to compare the potency of cyclolinopeptides (CLPs), two polyamines (spermidine and spermine), and the fungicide carbendazimin in the control of three fungi that have potential pathogenic activity ( F. oxysporum, S. linicola, and Alternaria spp), of which the first two are particulary significant causes of disease in flax. For carbendazim, all EC50 values were <0.6 μg/mL. The observed EC50 ranged from 111 to 340 μg/mL for a mixture of six unique CLPs, 109 to 778 μg/mL for spermine, and 21 to 272 μg/mL for spermidine. Spermidine was most effective against Alternaria sp., with an EC50 of 21 μg/mL. The results presented here showed that polyamines and CLPs possess limited antifungal activities against several fungi, with spermidines the most effective naturally occurring compound tested. Our findings do not support the hypothesis that CLPs act as potent antifungals against the three species of pathogens tested.
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Mercier, A. J., S. Farragher, B. Schmor, M. Kamau, and J. Atkinson. "Effect of a plant-derived spider toxin analogue on crayfish neuromuscular junctions." Canadian Journal of Zoology 76, no. 11 (November 1, 1998): 2103–7. http://dx.doi.org/10.1139/z98-142.
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N8-Coumaroyl spermidine (N8-CS) is an example of hydroxycinnamic acid - polyamine conjugates found in certain plants. Because of its structural similarity to some spider toxins, N8-CS was tested for its ability to block arthropod neuromuscular synapses. It inhibited chemical synaptic transmission at crayfish (Procambarus clarkii) neuromuscular junctions, the IC50 being approximately 200 µM. Its effect was at least partially reversed by washing with physiological saline. Joro spider toxin, a structurally similar compound, also blocked crayfish neuromuscular synapses but its effect was irreversible. These results suggest that plant-derived cinnamoyl spermidines might have paralytic properties similar to those of spider toxins.
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Perrin, Jennifer, Natalja Kulagina, Marianne Unlubayir, Thibaut Munsch, Inês Carqueijeiro, Thomas Dugé de Bernonville, Johan-Owen De Craene, et al. "Exploiting Spermidine N-Hydroxycinnamoyltransferase Diversity and Substrate Promiscuity to Produce Various Trihydroxycinnamoyl Spermidines and Analogues in Engineered Yeast." ACS Synthetic Biology 10, no. 2 (January 15, 2021): 286–96. http://dx.doi.org/10.1021/acssynbio.0c00391.
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Hamana, Koei, and Shigeru Matsuzaki. "Polyamine distribution patterns serve as a phenotypic marker in the chemotaxonomy of the Proteobacteria." Canadian Journal of Microbiology 39, no. 3 (March 1, 1993): 304–10. http://dx.doi.org/10.1139/m93-043.
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Polyamines of various genera of the class Proteobacteria were analyzed by high-performance liquid chromatography to determine if they can serve as taxonomic markers. The major polyamine of Zymomonas was homospermidine, whereas the Acetobacter–Gluconobacter complex contained spermidine, suggesting the presence of two different polyamine distribution patterns in the alpha subclass. Both the homospermidine-dominant type and the spermidine-dominant type were found in heterogeneous Sphingomonas species. Typical species belonging to the gamma subclass have their own unique polyamine pattern in Xanthomonas (spermidine), Azomonas (putrescine), Frateuria (spermidine), Alteromonas (putrescine–spermidine or spermidine), Shewanella (putrescine), Marinomonas (putrescine–spermidine or spermidine), Halomonas (putrescine–spermidine or spermidine), and Deleya (spermidine). Cadaverine was sporadically distributed in some species in these genera. Some strains classified into Rhizobacter, Zoogloea, Azomonas, or Alteromonas contained 2-hydroxyputrescine found exclusively in the beta subclass. Polyamine distribution patterns are genus- and (or) species-specific and can serve as a phenotypic marker in the chemotaxonomy of the Proteobacteria.Key words: polyamine, chemotaxonomy, Proteobacteria.
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Higashi, Kyohei, Hiroyuki Ishigure, Risa Demizu, Takeshi Uemura, Kunihiko Nishino, Akihito Yamaguchi, Keiko Kashiwagi, and Kazuei Igarashi. "Identification of a Spermidine Excretion Protein Complex (MdtJI) in Escherichia coli." Journal of Bacteriology 190, no. 3 (November 26, 2007): 872–78. http://dx.doi.org/10.1128/jb.01505-07.
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ABSTRACT A spermidine excretion protein in Escherichia coli was looked for among 33 putative drug exporters thus far identified. Cell toxicity and inhibition of growth due to overaccumulation of spermidine were examined in an E. coli strain deficient in spermidine acetyltransferase, an enzyme that metabolizes spermidine. Toxicity and inhibition of cell growth by spermidine were recovered in cells transformed with pUCmdtJI or pMWmdtJI, encoding MdtJ and MdtI, which belong to the small multidrug resistance family of drug exporters. Both mdtJ and mdtI are necessary for recovery from the toxicity of overaccumulated spermidine. It was also found that the level of mdtJI mRNA was increased by spermidine. The spermidine content in cells cultured in the presence of 2 mM spermidine was decreased, and excretion of spermidine from cells was enhanced by MdtJI, indicating that the MdtJI complex can catalyze excretion of spermidine from cells. It was found that Tyr4, Trp5, Glu15, Tyr45, Tyr61, and Glu82 in MdtJ and Glu5, Glu19, Asp60, Trp68, and Trp81 in MdtI are involved in the excretion activity of MdtJI.
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Elejalde-Palmett, Carolina, Thomas Dugé de Bernonville, Gaëlle Glevarec, Olivier Pichon, Nicolas Papon, Vincent Courdavault, Benoit St-Pierre, Nathalie Giglioli-Guivarc’h, Arnaud Lanoue, and Sébastien Besseau. "Characterization of a spermidine hydroxycinnamoyltransferase inMalus domesticahighlights the evolutionary conservation of trihydroxycinnamoyl spermidines in pollen coat of core Eudicotyledons." Journal of Experimental Botany 66, no. 22 (September 12, 2015): 7271–85. http://dx.doi.org/10.1093/jxb/erv423.
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Erwin, B. G., and A. E. Pegg. "Regulation of spermidine/spermine N1-acetyltransferase in L6 cells by polyamines and related compounds." Biochemical Journal 238, no. 2 (September 1, 1986): 581–87. http://dx.doi.org/10.1042/bj2380581.
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Exposure of rat L6 cells in culture to exogenous polyamines led to a very large increase in the activity of spermidine/spermine N1-acetyltransferase. Spermine was more potent than spermidine in bringing about this increase, but in both cases the elevated acetyltransferase activity increased the cellular conversion of spermidine into putrescine. The N1-acetyltransferase turned over very rapidly in the L6 cells, with a half-life of 9 min after spermidine and 18 min after spermine. A wide variety of synthetic polyamine analogues also brought about a substantial induction of spermidine/spermine N1-acetyltransferase activity. These included sym-norspermidine, sym-norspermine, sym-homospermidine, N4-substituted spermidine derivatives, 1,3,6-triaminohexane, 1,4,7-triaminoheptane and deoxyspergualin, which were comparable with spermidine in their potency, and N1N8-bis(ethyl)spermidine, N1N9-bis(ethyl)homospermidine, methylglyoxal bis(guanylhydrazone), ethylglyoxal bis(guanylhydrazone) and 1,1′-[(methylethanediylidene)dinitrilo]bis(3-amino-guanidine), which were even more active than spermidine. It is suggested that these polyamine analogues may bring about a decrease in cellular polyamines not only by inhibiting biosynthesis but by stimulating the degradation of spermidine into putrescine.
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Liao, Chen-Yu, Oona M. P. Kummert, Amanda M. Bair, Nora Alavi, Josef Alavi, Delana M. Miller, Isha Bagga, et al. "The Autophagy Inducer Spermidine Protects Against Metabolic Dysfunction During Overnutrition." Journals of Gerontology: Series A 76, no. 10 (June 1, 2021): 1714–25. http://dx.doi.org/10.1093/gerona/glab145.
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Abstract Autophagy, a process catabolizing intracellular components to maintain energy homeostasis, impacts aging and metabolism. Spermidine, a natural polyamine and autophagy activator, extends life span across a variety of species, including mice. In addition to protecting cardiac and liver tissue, spermidine also affects adipose tissue through unexplored mechanisms. Here, we examined spermidine in the links between autophagy and systemic metabolism. Consistently, daily injection of spermidine delivered even at late life is sufficient to cause a trend in life-span extension in wild-type mice. We further found that spermidine has minimal metabolic effects in young and old mice under normal nutrition. However, spermidine counteracts high-fat diet (HFD)-induced obesity by increasing lipolysis in visceral fat. Mechanistically, spermidine increases the hepatokine fibroblast growth factor 21 (FGF21) expression in liver without reducing food intake. Spermidine also modulates FGF21 in adipose tissues, elevating FGF21 expression in subcutaneous fat, but reducing it in visceral fat. Despite this, FGF21 is not required for spermidine action, since Fgf21−/− mice were still protected from HFD. Furthermore, the enhanced lipolysis by spermidine was also independent of autophagy in adipose tissue, given that adipose-specific autophagy-deficient (Beclin-1flox/+Fabp4-cre) mice remained spermidine-responsive under HFD. Our results suggest that the metabolic effects of spermidine occur through systemic changes in metabolism, involving multiple mechanistic pathways.
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IGNATENKO, Natalia A., Jennifer L. FISH, L. Richard SHASSETZ, Dale P. WOOLRIDGE, and Eugene W. GERNER. "Expression of the human spermidine/spermine N1-acetyltransferase in spermidine acetylation-deficient Escherichia coli." Biochemical Journal 319, no. 2 (October 15, 1996): 435–40. http://dx.doi.org/10.1042/bj3190435.
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A cDNA encoding the human spermidine/spermine N1-acetyltransferase (N1SSAT) was conditionally expressed in a strain of Escherichia coli deficient in spermidine-acetylating activity. Conditional expression of this cDNA was performed under the control of the lac promoter, by addition of the non-hydrolysable lactose analogue isopropyl β-D-thiogalactoside. Expression of the N1SSAT cDNA oriented in the sense direction resulted in the acetylation of spermidine at the N1 but not the N8 position and a decrease in endogenous spermidine contents and growth rates in these bacteria. When this cDNA was expressed in the anti-sense orientation, spermidine acetylation was not detected and endogenous spermidine contents and growth rates were unaffected. Increasing the endogenous N1-acetylspermidine concentration by addition of this amine to the culture medium did not suppress growth, and increasing endogenous spermidine pools by exogenous addition was not sufficient to restore optimal growth in cells expressing the human N1SSAT. Exogenous spermidine, but neither N1- nor N8-acetylspermidine, stimulated cell growth in strains unable to synthesize spermidine. These results suggest that one physiological consequence of spermidine acetylation in E. coli is growth inhibition. The mechanism of this inhibition seems to involve the formation of acetylspermidine, and is not simply due to a decrease in the intracellular concentration of non-acetylated spermidine.
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Ohashi, Koji, Masaaki Kageyama, Katsuhiko Shinomiya, Yukie Fujita-Koyama, Shin-ichiro Hirai, Osamu Katsuta, and Masatsugu Nakamura. "Spermidine Oxidation-Mediated Degeneration of Retinal Pigment Epithelium in Rats." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–13. http://dx.doi.org/10.1155/2017/4128061.
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Retinal pigment epithelium (RPE) degeneration is a crucial event in dry age-related macular degeneration and gyrate atrophy. The polyamine spermidine has been shown to induce RPE cell death in vitro. The present study aimed to establish a novel in vivo model of spermidine-induced RPE degeneration and to determine whether spermidine-induced RPE cell death involves oxidative mechanisms. In this study, spermidine caused ARPE-19 cell death in a concentration-dependent manner. This effect was prevented by removal of serum from the culture medium or treatment with amine oxidase inhibitors, N-acetylcysteine (NAC), or aldehyde dehydrogenase (ALDH). Intravitreal injection of spermidine into rats significantly increased the permeability of the blood-retinal barrier and decreased the amplitudes of scotopic electroretinogram a- and b-waves. Histological analysis revealed that spermidine induced vacuolation, atrophy, and dropout of RPE cells, leading to the disruption of photoreceptor outer segments. Simultaneous intravitreal administration of NAC and ALDH with spermidine prominently inhibited the functional and morphological changes induced by spermidine. In conclusion, this study demonstrated that the intravitreal administration of spermidine induced RPE cell dysfunction and death followed by photoreceptor degeneration in rats. These effects of spermidine are thought to be mediated by oxidative stress and a toxic aldehyde generated during spermidine oxidation.
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Porter, C. W., F. G. Berger, A. E. Pegg, B. Ganis, and R. J. Bergeron. "Regulation of ornithine decarboxylase activity by spermidine and the spermidine analogue N1N8-bis(ethyl)spermidine." Biochemical Journal 242, no. 2 (March 1, 1987): 433–40. http://dx.doi.org/10.1042/bj2420433.
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Polyamine biosynthesis in intact cells can be exquisitely controlled with exogenous polyamines through the regulation of rate-limiting biosynthetic enzymes, particularly ornithine decarboxylase (ODC). In an attempt to exploit this phenomenon as an antiproliferative strategy, certain polyamine analogues have been identified [Porter, Cavanaugh, Stolowich, Ganis, Kelly & Bergeron (1985) Cancer Res. 45, 2050-2057] which lower ODC activity in intact cells, have no direct inhibitory effects on ODC, are incapable of substituting for spermidine (SPD) in supporting cell growth, and are growth-inhibitory at micromolar concentrations. In the present study, the most effective of these analogues, N1N8-bis(ethyl)SPD (BES), is compared with SPD in its ability to regulate ODC activity in intact L1210 cells and in the mechanism(s) by which this is accomplished. With respect to time and dose-dependence of ODC suppression, both polyamines closely paralleled one another in their response curves, although BES was slightly less effective than SPD. Conditions of minimal treatment leading to near-maximal ODC suppression (70-80%) were determined and found to be 3 microM for 2 h with either SPD or BES. After such treatment, ODC activity was fully recovered within 2-4 h when cells were re-seeded in drug-free media. By assessing BES or [3H]SPD concentrations in treated and recovered cells, it was possible to deduce that an intracellular accumulation of BES or SPD equivalent to less than 6.5% of the combined cellular polyamine pool was sufficient to invoke ODC regulatory mechanisms. Decreases in ODC activity after BES or SPD treatment were closely paralleled by concomitant decreases in ODC protein. Since cellular ODC mRNA was not similarly decreased by either BES or SPD, it was concluded that translational and/or post-translational mechanisms, such as increased degradation of ODC protein or decreased translation of ODC mRNA, were probably responsible for regulation of enzyme activity. Experimental evidence indicated that neither of these mechanisms seemed to be mediated by cyclic AMP or ODC-antizyme induction. On the basis of the consistent similarities between BES and SPD in all parameters studied, it is concluded that the analogue most probably acts by the same mechanisms as SPD in regulating polyamine biosynthesis.
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Kauppinen, L., S. Myöhänen, M. Halmekytö, L. Alhonen, and J. Jänne. "Transgenic mice over-expressing the human spermidine synthase gene." Biochemical Journal 293, no. 2 (July 15, 1993): 513–16. http://dx.doi.org/10.1042/bj2930513.
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We have generated a transgenic mouse line harbouring the functional (chromosome-1-derived) human spermidine synthase (EC 2.5.1.16) gene in their genome. The transgenic animals expressed the human gene-derived mRNA, as revealed by reverse-transcriptase/PCR analysis, in all tissues studied and displayed tissue spermidine synthase activity that was 2-6 times that in their syngenic littermates. The elevated spermidine synthase activity, however, had virtually no effect on tissue putrescine, spermidine or spermine levels. The view that the accumulation of spermidine and spermine is possibly controlled by S-adenosylmethionine decarboxylase was further supported by the finding that tissue spermidine and spermine contents also remained practically normal in hybrid transgenic mice over-expressing both human ornithine decarboxylase and spermidine synthase genes.
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Limsuwun, Kornvika, and Pamela G. Jones. "Spermidine Acetyltransferase Is Required To Prevent Spermidine Toxicity at Low Temperatures in Escherichia coli." Journal of Bacteriology 182, no. 19 (October 1, 2000): 5373–80. http://dx.doi.org/10.1128/jb.182.19.5373-5380.2000.
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ABSTRACT Polyamines are required for optimal growth in most cells; however, polyamine accumulation leads to inhibition of cellular growth. To reduce intracellular polyamine levels, spermidine is monoacetylated in both prokaryotes and eukaryotes. In Escherichia coli, thespeG gene encodes the spermidine acetyltransferase, which transfers the acetyl group to either the N-1 or N-8 position. In addition to polyamine accumulation, stress conditions, such as cold shock, cause an increase in the level of spermidine acetylation, suggesting an adaptive role for reduced polyamine levels under stressful growth conditions. The effect of spermidine accumulation on the growth of E. coli at low temperature was examined using a speG mutant. At 37°C, growth of the speGmutant was normal in the presence of 0.5 or 1 mM spermidine. However, following a shift to 7°C, the addition of 0.5 or 1 mM spermidine resulted in inhibition of cellular growth or cell lysis, respectively. Furthermore, at 7°C, spermidine accumulation resulted in a decrease in total protein synthesis accompanied by an increase in the synthesis of the major cold shock proteins CspA, CspB, and CspG. However, the addition of 50 mM Mg2+ restored growth and protein synthesis in the presence of 0.5 mM spermidine. The results indicate that the level of spermidine acetylation increases at low temperature to prevent spermidine toxicity. The data suggest that the excess spermidine replaces the ribosome-bound Mg2+, resulting in ribosome inactivation at low temperatures.
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LEE, Chang Hoon, and Myung Hee PARK. "Human deoxyhypusine synthase: interrelationship between binding of NAD and substrates." Biochemical Journal 352, no. 3 (December 8, 2000): 851–57. http://dx.doi.org/10.1042/bj3520851.
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Deoxyhypusine synthase catalyses the NAD-dependent transfer of the butylamine moiety from the polyamine, spermidine, to a specific lysine residue of a single cellular protein, eukaryotic translation-initiation factor 5A (eIF5A) precursor. The native enzyme exists as a tetramer of four identical subunits and contains four binding sites for NAD. The binding of spermidine and NAD was studied by a filtration assay. [3H]Spermidine binding to the enzyme was not detectable alone or in the presence of the eIF5A precursor, but was detected only in the presence of NAD or NADH, suggesting that a NAD/NADH-induced conformational change is required for the binding of spermidine. A strong NAD-dependent binding was also observed with a spermidine analogue, N1-guanyl-1,7-diamino[3H]heptane (GC7), but not with [14C]putrescine or [14C]spermine. Although [3H]NAD binding to the enzyme occurred in the absence of spermidine, its affinity for the enzyme was markedly enhanced by spermidine, GC7 and also by the eIF5A precursor. The maximum binding for NAD and spermidine was estimated to be ≈ 4 molecules each/enzyme tetramer. The dependence of spermidine binding on NAD and the modulation of binding of NAD by spermidine and the eIF5A precursor suggest intricate relationships between the binding of cofactor and the substrates, and provide new insights into the reaction mechanism.
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Jiang, Dongmei, Guilin Mo, Yilong Jiang, and Bo Kang. "Exogenous spermidine affects polyamine metabolism in the mouse hypothalamus." Open Life Sciences 16, no. 1 (January 1, 2021): 39–45. http://dx.doi.org/10.1515/biol-2021-0006.
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Abstract Spermidine is important for the hypothalamic control of pituitary secretion of hormones involved in neuroendocrine functions in mammals. In this study, the effect of exogenous spermidine on the expression of genes and proteins related to polyamine metabolism and polyamine levels was examined. The results indicated that treatment with spermidine at 0.05 mg/g (BW) significantly increased the levels of Oaz1 mRNA and protein expression and decreased putrescine content in mouse hypothalamus (p < 0.05). The administration with spermidine at 0.10 mg/g significantly increased the levels of Oaz1, Oaz2, and Odc expression in mouse hypothalamus (p < 0.05). Treatment with spermidine at 0.05 mg/g significantly increased the levels of Ssat mRNA expression and reduced the level of Smo mRNA expression in mouse hypothalamus (p < 0.05). Putrescine concentrations in the hypothalamus after the administration of spermidine at 0.10 and 0.15 mg/g were significantly higher than those in the control group (p < 0.05). The concentration of both spermidine and spermine in the hypothalamus after the administration of spermidine at 0.15 mg/g was decreased significantly (p < 0.05). In summary, our results indicate that exogenous spermidine affects polyamine homeostasis in the mouse hypothalamus by modulating the expression of genes and proteins related to polyamine metabolism.
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Pankoke, Sophia, Christiane Pfarrer, Silke Glage, Christian Mühlfeld, and Julia Schipke. "Oral Supplementation with the Polyamine Spermidine Affects Hepatic but Not Pulmonary Lipid Metabolism in Lean but Not Obese Mice." Nutrients 14, no. 20 (October 15, 2022): 4318. http://dx.doi.org/10.3390/nu14204318.
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The polyamine spermidine is discussed as a caloric restriction mimetic and therapeutic option for obesity and related comorbidities. This study tested oral spermidine supplementation with regard to the systemic, hepatic and pulmonary lipid metabolism under different diet conditions. Male C57BL/6 mice were fed a purified control (CD), high sucrose (HSD) or high fat (HFD) diet with (-S) or without spermidine for 30 weeks. In CD-fed mice, spermidine decreased body and adipose tissue weights and reduced hepatic lipid content. The HSD induced hepatic lipid synthesis and accumulation and hypercholesterolemia. This was not affected by spermidine supplementation, but body weight and blood glucose were lower in HSD-S compared to HSD. HFD-fed mice showed higher body and fat depot weights, prediabetes, hypercholesterolemia and severe liver steatosis, which were not altered by spermidine. Within the liver, spermidine diminished hepatic expression of lipogenic transcription factors SREBF1 and 2 under HSD and HFD and affected the expression of other lipid-related enzymes. In contrast, diet and spermidine exerted only minor effects on pulmonary parameters. Thus, oral spermidine supplementation affects lipid metabolism in a diet-dependent manner, with significant reductions in body fat and weight under physiological nutrition and positive effects on weight and blood glucose under high sucrose intake, but no impact on dietary fat-related parameters.
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NISHIKAWA, Yuji, Siddhartha KAR, Laurie WIEST, Anthony E. PEGG, and Brian I. CARR. "Inhibition of spermidine synthase gene expression by transforming growth factor-β1 in hepatoma cells." Biochemical Journal 321, no. 2 (January 15, 1997): 537–43. http://dx.doi.org/10.1042/bj3210537.
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We screened genes responsive to transforming growth factor-α (TGF-α1) protein in a human hepatoma cell line (Hep3B) using a PCR-mediated differential display technique, in order to investigate the mechanisms involved in TGF-α-induced growth suppression. We found a gene that was down-regulated by TGF-α1 to be completely identical in an approx. 620 bp segment to the gene for the enzyme spermidine synthase, which mediates the conversion of putrescine into spermidine. Both spermidine synthase mRNA expression and its enzyme activity were decreased after TGF-α1 treatment of Hep3B cells. The inhibition of spermidine synthase gene expression by TGF-α1 protein was also observed in other hepatoma cell lines. The expression of genes for other biosynthetic enzymes in polyamine metabolism (ornithine decarboxylase and S-adenosylmethionine decarboxylase) was also inhibited to the same extent as for spermidine synthase, while the gene expression of spermidine/spermine N1-acetyltransferase, a catabolic enzyme, was relatively resistant to TGF-α1. Spermine levels in Hep3B cells were decreased by TGF-α1 treatment, although the levels of spermidine and putrescine were unchanged, probably due to compensation by remaining spermidine/spermine N1-acetyltransferase activity. Exogenously added spermidine or spermine, but not putrescine, partially antagonized the growth-inhibitory effects of TGF-α1 on Hep3B cells. Our data suggest that down-regulation of gene expression of the enzymes involved in polyamine metabolism, including spermidine synthase, may be associated with the mechanism of TGF-α-induced growth suppression.
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Kumagai, J., R. Jain, and L. R. Johnson. "Characteristics of spermidine uptake by isolated rat enterocytes." American Journal of Physiology-Gastrointestinal and Liver Physiology 256, no. 5 (May 1, 1989): G905—G910. http://dx.doi.org/10.1152/ajpgi.1989.256.5.g905.
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Eukaryotic cells require polyamines for growth. The supply of polyamines to growing cells may be increased either by new synthesis or increased uptake. We have recently shown that putrescine uptake by isolated rat enterocytes is energy dependent, saturable, and ouabain insensitive. Although putrescine uptake was inhibited by putrescine and cadaverine, it was not inhibited by equal concentrations of spermine and spermidine. These data indicated that a carrier mechanism separate from that putrescine existed for spermidine and spermine. In the current study spermidine uptake by isolated enterocytes was saturable, temperature dependent, and inhibited by 1 mM KCN. Kinetic analysis resulted in a Km = 2.51 x 10(-6) M and a Vmax = 3.57 x 10(-12) mol.10(6) cells-1.15 min-1. Spermidine uptake was 70% inhibited by 1 mM ouabain. Replacement of sodium by choline, lithium, tetramethylammonium, or N-methyl-D-glucamine also inhibited spermidine uptake. Replacement of Na+ by mannitol or sucrose, however, depressed uptake but not significantly. Spermidine uptake was inhibited by 1 mM ouabain. Spermidine uptake was inhibited by relatively low concentrations of spermine and high concentrations of putrescine; while putrescine uptake was inhibited by relatively high concentrations of both spermine and spermidine. Kinetic data indicated that spermidine and spermine share a carrier that is distinct from the one mediating the uptake of putrescine. While spermidine uptake does not appear to depend on Na+ cotransport, it may be dependent on the electrical gradient established by the Na+-K+-ATPase.
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Kvietys, P. R., R. D. Specian, and G. Cepinskas. "Polyamines attenuate jejunal mucosal injury induced by oleic acid." American Journal of Physiology-Gastrointestinal and Liver Physiology 263, no. 2 (August 1, 1992): G224—G229. http://dx.doi.org/10.1152/ajpgi.1992.263.2.g224.
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Effects of putrescine, spermidine, and spermine on lipid-induced injury to jejunal mucosa were assessed in anesthetized rats. Mucosal epithelial integrity was continuously monitored by measuring blood-to-lumen clearance of 51Cr-labeled EDTA. Perfusion of jejunal lumen with emulsified lipid (20 mM sodium taurocholate and 40 mM oleic acid) increased 51Cr-EDTA clearance. Addition of spermidine (0.5 mM), but not putrescine (2.0 mM) or spermine (0.25 mM), to the lipid perfusate reduced the increment in 51Cr-EDTA clearance. Histological evaluation of jejunal mucosa indicated that the epithelial lining of the villous tips was damaged by emulsified oleic acid and that this injury was ameliorated by spermidine. Pretreatment of jejunal mucosa with spermidine did not prevent disruption of mucosal integrity induced by a subsequent perfusion with emulsified lipids. Intravenous infusion of spermidine to achieve an extracellular concentration of 0.5 mM did not prevent the lipid-induced increase in 51Cr-EDTA. Spermidine also ameliorated lipid-induced disruption of Caco-2 cell monolayers in culture; this protective effect was dose dependent and was observed only when spermidine was applied to the apical aspect of the monolayers. These findings indicate that spermidine must be present on the apical portion of the epithelial cell during lipid insult. Substitution of lysine or arginine for spermidine did not reduce the extent of lipid-induced injury to jejunal mucosa, indicating that spermidine's protective effects cannot simply be attributed to its cationic nature. Spermidine did not alter the turbidity of a micellar oleic acid solution, indicating that spermidine was not removing oleic acid from the soluble phase.(ABSTRACT TRUNCATED AT 250 WORDS)
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Niechcial, Anna, Matthias Butter, Salomon Manz, Nicole Obialo, Katharina Bäbler, Lisa van der Lely, Silvia Lang, et al. "Presence of PTPN2 SNP rs1893217 Enhances the Anti-inflammatory Effect of Spermidine." Inflammatory Bowel Diseases 26, no. 7 (February 7, 2020): 1038–49. http://dx.doi.org/10.1093/ibd/izaa013.
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Abstract Background The single nucleotide polymorphism (SNP) rs1893217 within the gene locus encoding PTPN2 represents a risk factor for inflammatory bowel disease (IBD). Our previous work demonstrated reduced PTPN2 activity and subsequently increased inflammatory signaling upon presence of SNP rs1893217. The naturally occurring polyamine spermidine reduces pro-inflammatory signaling via induction of PTPN2 activity; however, the effect of SNP rs1893217 on the anti-inflammatory potential of spermidine is still unknown. Here, we investigated how presence of SNP rs1893217 affects treatment efficacy of spermidine and whether it might serve as a potential biomarker for spermidine treatment. Methods Human T84 (wild-type [WT] for PTPN2 SNP rs1893217) and HT29 (heterozygous for PTPN2 SNP rs1893217) intestinal epithelial cells (IECs) were treated with several polyamines from the putrescine-spermidine pathway. T84 and HT29 IECs, THP-1 monocytes (WT and transfected with a lentiviral vector expressing PTPN2 SNP rs1893217) and genotyped, patient-derived peripheral blood mononuclear cells were challenged with IFN-γ and/or spermidine. Results Among the analyzed polyamines, spermidine was the most efficient activator of PTPN2 phosphatase activity, regardless of the PTPN2 genotype. Spermidine suppressed IFN-γ-induced STAT1 and STAT3 phosphorylation, along with decreased mRNA expression of ICAM-1, NOD2, and IFNG in IECs and monocytes. Of note, these effects were clearly more pronounced when the disease-associated PTPN2 C-variant in SNP rs1893217 was present. Conclusions Our data demonstrate that spermidine is the most potent polyamine in the putrescine-spermine axis for inducing PTPN2 enzymatic activity. The anti-inflammatory effect of spermidine is potentiated in the presence of SNP rs1893217, and this SNP might thus be a useful biomarker for possible spermidine-treatment in IBD patients.
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Jiang, Dong-Mei, Ze-Long Wang, Jia-Di Yang, Xin Wang, Chun-Yang Niu, Cheng-Weng Ji, Wei-Kang Ling, et al. "Effects of Spermidine on Mouse Gut Morphology, Metabolites, and Microbial Diversity." Nutrients 15, no. 3 (February 1, 2023): 744. http://dx.doi.org/10.3390/nu15030744.
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Spermidine is a class of biologically active organic small molecules that play an important role in maintaining intestinal homeostasis. The specific objective of this study was to explore the effects of spermidine on intestinal morphology, metabolites, and microbial diversity in mice. We showed that 0.3 mmol/L of spermidine significantly promoted the growth of ileal villi (p < 0.05), and 3.0 mmol/L of spermidine significantly increased the body weight of mice and promoted the growth of jejunum villi (p < 0.05). The 16S rDNA sequencing results indicated that 3.0 mmol/L of spermidine affected the balance of the intestinal flora by increasing the abundance of intestinal Lactic acid bacteria and reducing the abundance of harmful bacteria (Turicibacter and Alistipes). Additionally, spermidine affects the levels of microbial metabolites such as succinic acid and Pantetheine. In summary, spermidine affects intestinal morphology and regulates intestinal flora and metabolites, and this study has provided a new understanding of spermidine’s effects on the intestinal tract.
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Kim, Da Hye, Jeong-Hwan Kim, Hyun Hwangbo, So Young Kim, Seon Yeong Ji, Min Yeong Kim, Hee-Jae Cha, et al. "Spermidine Attenuates Oxidative Stress-Induced Apoptosis via Blocking Ca2+ Overload in Retinal Pigment Epithelial Cells Independently of ROS." International Journal of Molecular Sciences 22, no. 3 (January 29, 2021): 1361. http://dx.doi.org/10.3390/ijms22031361.
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Retinal pigment epithelial (RPE) cells occupy the outer layer of the retina and perform various biological functions. Oxidative damage to RPE cells is a major risk factor for retinal degeneration that ultimately leads to vision loss. In this study, we investigated the role of spermidine in a hydrogen peroxide (H2O2)-induced oxidative stress model using human RPE cells. Our findings showed that 300 μM H2O2 increased cytotoxicity, apoptosis, and cell cycle arrest in the G2/M phase, whereas these effects were markedly suppressed by 10 μM spermidine. Furthermore, spermidine significantly reduced H2O2-induced mitochondrial dysfunction including mitochondrial membrane potential and mitochondrial activity. Although spermidine displays antioxidant properties, the generation of intracellular reactive oxygen species (ROS) upon H2O2 insult was not regulated by spermidine. Spermidine did suppress the increase in cytosolic Ca2+ levels resulting from endoplasmic reticulum stress in H2O2-stimulated human RPE cells. Treatment with a cytosolic Ca2+ chelator markedly reversed H2O2-induced cellular dysfunction. Overall, spermidine protected against H2O2-induced cellular damage by blocking the increase of intracellular Ca2+ independently of ROS. These results suggest that spermidine protects RPE cells from oxidative stress, which could be a useful treatment for retinal diseases.
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Raj, V. Samuel, Hideyuki Tomitori, Madoka Yoshida, Auayporn Apirakaramwong, Keiko Kashiwagi, Koji Takio, Akira Ishihama, and Kazuei Igarashi. "Properties of a Revertant of Escherichia coli Viable in the Presence of Spermidine Accumulation: Increase in l-Glycerol 3-Phosphate." Journal of Bacteriology 183, no. 15 (August 1, 2001): 4493–98. http://dx.doi.org/10.1128/jb.183.15.4493-4498.2001.
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ABSTRACT Escherichia coli CAG2242 cells are deficient in thespeG gene encoding spermidine acetyltransferase. When these cells were cultured in the presence of 0.5 to 4 mM spermidine, their viability was greatly decreased through the inhibition of protein synthesis by overaccumulation of spermidine. When the cells were cultured with a high concentration of spermidine (4 mM), a revertant strain was obtained. We found that a 55-kDa protein, glycerol kinase, was overexpressed in the revertant and that synthesis of a ribosome modulation factor and the RNA polymerase ς38 subunit, factors important for cell viability, was increased in the revertant. Levels of l-glycerol 3-phosphate also increased in the revertant. Transformation of glpFK, which encodes a glycerol diffusion facilitator (glpF) and glycerol kinase (glpK), to E. coli CAG2242 partially prevented the cell death caused by accumulation of spermidine. It was also found that l-glycerol 3-phosphate inhibited spermidine binding to ribosomes and attenuated the inhibition of protein synthesis caused by high concentrations of spermidine. These results indicate that l-glycerol 3-phosphate reduces the binding of excess amounts of spermidine to ribosomes so that protein synthesis is recovered.
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Caffaratti, Clément, Caroline Plazy, Valérie Cunin, Bertrand Toussaint, and Audrey Le Gouellec. "Bioengineering of Escherichia coli Nissle 1917 for Production and Excretion of Spermidine, a Key Metabolite in Human Health." Metabolites 12, no. 11 (November 2, 2022): 1061. http://dx.doi.org/10.3390/metabo12111061.
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Microbiota-derived metabolites have biological importance for their host. Spermidine, a metabolite described for its protective effect in age-related diseases, is now studied for its role in the resolution of inflammation and gut homeostasis. Strategies to modulate its production in the gastrointestinal tract are of interest to increase host spermidine intakes. Here, we show that metabolic engineering can be used to increase spermidine production by the probiotic Escherichia coli Nissle 1917 (EcN), used in humans. First, we found that increasing the expression of genes involved in polyamine biosynthesis, namely the S-adenosylmethionine synthase speD and the spermidine synthase speE, resulted in an increase in spermidine produced and excreted by our engineered bacteria. The major drawback of this first attempt was the production of acetylated forms of spermidine. Next, we propose to solve this problem by increasing the expression of the spermidine exporter system MdtI/MdtJ. This second strategy had a major impact on the spermidine profile found in the culture supernatant. Our results demonstrate, for the first time, the feasibility of rationally engineering bacterial probiotic strains to increase their ability to deliver the microbiota-derived metabolite, spermidine. This work illustrates how metabolomic and synthetic biology can be used to design and improve engineered Live Biotherapeutic Products that have the potential to be used in personalized medicine.
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Liu, S. M., A. Murray, A. C. Schlink, G. Mata, and D. G. Masters. "The effects of intradermal injections of spermidine on the growth rate of fibres and mitosis of wool follicles in Merino lambs." Animal Science 75, no. 1 (April 2002): 33–40. http://dx.doi.org/10.1017/s1357729800052802.
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AbstractPolyamines (putrescine, spermidine and spermine) are required for optimal growth in all cells, and are essential for cell proliferation and growth of cultured wool follicles, with an optimal concentration of spermidine required for the fibre elongation. The effects of a local supply of exogenous spermidine on the rate of cell division in the wool follicles, the length growth rate and diameter of fibres were therefore examined in Merino lambs. Three groups of eight lambs (40 kg) were given food at 1·2 ✕ maintenance. Spermidine was injected intradermally into a small patch (3 ✕ 3 cm) on the left flank three times per day for 7 days at one of three concentrations: 1·38, 2·75 or 4·58 џmol in 0·8 ml volume. The same volume of saline was injected into the contralateral side as a control. The concentration of spermidine in the skin patch 3 h after injection on day 7 increased by proportionately 018, 0·33 or 0·41 (P < 0001) respectively. The rates of cell division in the follicle bulb 3 h after the spermidine injection were proportionately 0104, 0184 and 0·283 higher compared with the contralateral side (P = 0078 overall) for the low, medium and high doses of spermidine respectively and differed between the three doses (P < 005). The fibre length growth rate, as measured using autoradiography, was proportionately 0099, 0117 and 0156 higher than that of the contralateral side (P < 0001 overall) for the low, medium and high doses of spermidine respectively, but differences between doses were not significant (P > 005). Spermidine injection did not result in a significant change in fibre diameter during the treatment period. The ratio of fibre length growth rate to fibre diameter was increased by the injection of spermidine (P < 0001). The results suggest that injecting extra spermidine into the skin altered spermidine homeostasis in the skin, stimulated cell proliferation and resulted in increased fibre growth.
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Sha, Qun, Carl Romano, Anatoli N. Lopatin, and Colin G. Nichols. "Spermidine Release fromXenopusOocytes." Journal of Biological Chemistry 271, no. 7 (February 16, 1996): 3392–97. http://dx.doi.org/10.1074/jbc.271.7.3392.
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Pekar, Thomas, Aribert Wendzel, Walter Flak, Alexandra Kremer, Susanne Pauschenwein-Frantsich, Anna Gschaider, Felix Wantke, and Reinhart Jarisch. "Spermidine in dementia." Wiener klinische Wochenschrift 132, no. 1-2 (December 12, 2019): 42–46. http://dx.doi.org/10.1007/s00508-019-01588-7.
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SummaryPrevious studies have highlighted that spermidine has the ability to trigger the important process of dissolving amyloid-beta plaques by autophagy. This manuscript focuses on the correlation of serum spermidine levels between age and between performance in mini-mental state examinations. It will serve as a premise for an ongoing multicentric placebo-controlled study, which focuses on the effect of oral spermidine supplementation on memory performance. Memory tests were carried out on 80 subjects aged 60–96 years old in 6 nursing homes in Styria. Blood samples were taken for the determination of spermidine concentration. The results showed a significant correlation between the spermidine concentration and the mini-mental state examination score (p = 0.025). On the basis of the dependence demonstrated it can be concluded that spermidine might be suitable as a biomarker for the diagnosis of neurocognitive changes (senile dementia or Alzheimer’s disease).
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Zhang, Huawei, and Shannon Wing Ngor Au. "Helicobacter pylori does not use spermidine synthase to produce spermidine." Biochemical and Biophysical Research Communications 490, no. 3 (August 2017): 861–67. http://dx.doi.org/10.1016/j.bbrc.2017.06.132.
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Chan, Ying Ying, and Kim Lee Chua. "Growth-related changes in intracellular spermidine and its effect on efflux pump expression and quorum sensing in Burkholderia pseudomallei." Microbiology 156, no. 4 (April 1, 2010): 1144–54. http://dx.doi.org/10.1099/mic.0.032888-0.
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The Burkholderia pseudomallei BpeAB-OprB resistance-nodulation-division (RND) family pump effluxes aminoglycoside and macrolide antibiotics as well as acylhomoserine lactones (AHLs) involved in quorum sensing. Expression of bpeA–lacZ was cell density-dependent and was inducible in the presence of these compounds. Intracellular levels of spermidine and N-acetylspermidine increased with cell density in wild-type B. pseudomallei KHW, but were always lower in the bpeAB pump mutant at all growth phases. The significance of changes in intracellular spermidine on efflux pump expression was demonstrated by the disruption of the binding of the BpeR repressor protein to the bpeABoprB regulatory region in vitro in the presence of increasing spermidine concentrations. This was supported by dose-dependent activation of bpeA–lacZ transcription in vivo in the presence of exogenous spermidine and N-acetylspermidine, thus implicating the involvement of the BpeAB-OprB pump in spermidine homeostasis in B. pseudomallei. Consequently, inhibition of intracellular spermidine synthesis reduced the efflux of AHLs by BpeAB-OprB. Other potential therapeutic applications of spermidine synthase inhibitors include the reduction of swimming motility and biofilm formation by B. pseudomallei.
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Gerner, E. W., T. A. Kurtts, D. J. M. Fuller, and R. A. Casero. "Stress induction of the spermidine/spermine N1-acetyltransferase by a post-transcriptional mechanism in mammalian cells." Biochemical Journal 294, no. 2 (September 1, 1993): 491–95. http://dx.doi.org/10.1042/bj2940491.
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Heat shock and diethyldithiocarbamate stimulate polyamine catabolism in animal cells by a mechanism involving the induction of spermidine/spermine N1-acetyltransferase (N1-SSAT) activity. Steady-state levels of RNA encoding this enzyme remain essentially unchanged during periods after these stresses when N1-SSAT activity is increased by 3.5-10-fold or more in three different cell lines of hamster and human origin. Depletion of intracellular spermidine pools by alpha-difluoromethylornithine (DFMO) inhibits stress induction of N1-SSAT activity. Exogenous spermidine can restore stress inducibility of N1-SSAT to DFMO-treated cells, and induce this enzyme activity in non-heat-shocked but polyamine-depleted cells. Acetylation at N1 suppresses the ability of spermidine to induce N1-SSAT activity, relative to this same modification at N8. Fluorinated spermidine analogues, which decrease the pKa values of the amine groups at positions 4 and 8, neither induce nor inhibit N1-SSAT activity in DFMO-treated cells. These data demonstrate that certain stresses induce N1-SSAT by a spermidine-dependent post-transcriptional mechanism. The mode of induction is affected by both the propyl and butyl moieties of spermidine.
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Orr, Gary R., Deborah W. Danz, Gabriele Pontoni, P. C. Prabhakaran, Steven J. Gould, and James K. Coward. "Synthesis of chirally deuteriated (S-adenosyl-S-methylsulfonio)propylamines and spermidines. Elucidation of the stereochemical course of putrescine aminopropyltransferase (spermidine synthase)." Journal of the American Chemical Society 110, no. 17 (August 1988): 5791–99. http://dx.doi.org/10.1021/ja00225a034.
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Byers, T. L., B. Ganem, and A. E. Pegg. "Cytostasis induced in L1210 murine leukaemia cells by the S-adenosyl-l-methionine decarboxylase inhibitor 5′-([(Z)-4-amino-2-butenyl]methylamino)-5′-deoxyadenosine may be due to hypusine depletion." Biochemical Journal 287, no. 3 (November 1, 1992): 717–24. http://dx.doi.org/10.1042/bj2870717.
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The effects of inhibition of the capacity to form spermidine and spermine on cell growth were investigated using murine leukaemia L1210 cells and 5′-([(Z)-4-amino-2-butenyl]methylamino)-5′-deoxyadenosine (MDL 73811, AbeAdo), an enzyme-activated irreversible inhibitor of S-adenosyl-L-methionine decarboxylase. Putrescine levels were increased 80-fold, and spermidine and spermine levels were greatly reduced after a 3-day exposure to a maximally inhibitory dose of 10 microM-AbeAdo. Addition of AbeAdo to the culture medium inhibited the growth of L1210 cells measured 3 days later in a dose-dependent manner, but, even at a dose of 10 microM, which was maximally effective, exposure to AbeAdo was not immediately cytostatic. However, the growth rate of L1210 cells chronically exposed to 10 microM-AbeAdo declined steadily until day 12, when the cells stopped growing. L1210 cells exposed to AbeAdo for 12 days could not be rescued from cytostasis by removal of the drug from the culture, but could be rescued by exposure to exogenous spermidine or spermine, indicating that the growth-inhibitory effects of AbeAdo were a result of spermidine and/or spermine depletion. It is suggested that elevated intracellular putrescine in AbeAdo-treated cells sustained limited growth in the absence of physiological levels of spermidine and spermine until certain critical and specific physiological role(s) fulfilled by spermidine (and/or spermine) became deficient resulting in cytostasis. N-(3-Aminopropyl)-1,4-diamino-cis-but-2-ene, a spermidine analogue that is a substrate for deoxyhypusine synthase, was able to mimic the effects of spermidine in reversing AbeAdo-induced cytostasis. Spermidine analogues such as 5,5-dimethylspermidine, which are not substrates for deoxyhypusine synthase, were not active in this way. These results provide evidence that the formation of hypusine in the protein-synthesis initiation factor eIF-5A may be a critical role of spermidine essential for cell growth.
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Chibucos, M. Constantine, and Paul F. Morris. "Levels of Polyamines and Kinetic Characterization of Their Uptake in the Soybean Pathogen Phytophthora sojae." Applied and Environmental Microbiology 72, no. 5 (May 2006): 3350–56. http://dx.doi.org/10.1128/aem.72.5.3350-3356.2006.
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ABSTRACT Polyamines are ubiquitous biologically active aliphatic cations that are at least transiently available in the soil from decaying organic matter. Our objectives in this study were to characterize polyamine uptake kinetics in Phytophthora sojae zoospores and to quantify endogenous polyamines in hyphae, zoospores, and soybean roots. Zoospores contained 10 times more free putrescine than spermidine, while hyphae contained only 4 times as much free putrescine as spermidine. Zoospores contained no conjugated putrescine, but conjugated spermidine was present. Hyphae contained both conjugated putrescine and spermidine at levels comparable to the hyphal free putrescine and spermidine levels. In soybean roots, cadaverine was the most abundant polyamine, but only putrescine efflux was detected. The selective efflux of putrescine suggests that the regulation of polyamine availability is part of the overall plant strategy to influence microbial growth in the rhizosphere. In zoospores, uptake experiments with [1,4-14C]putrescine and [1,4-14C]spermidine confirmed the existence of high-affinity polyamine transport for both polyamines. Putrescine uptake was reduced by high levels of exogenous spermidine, but spermidine uptake was not reduced by exogenous putrescine. These observations suggest that P. sojae zoospores express at least two high-affinity polyamine transporters, one that is spermidine specific and a second that is putrescine specific or putrescine preferential. Disruption of polyamine uptake or metabolism has major effects on a wide range of cellular activities in other organisms and has been proposed as a potential control strategy for Phytophthora. Inhibition of polyamine uptake may be a means of reducing the fitness of the zoospore along with subsequent developmental stages that precede infection.
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Smigielski, AJ, ME Muir, and BJ Wallace. "Studies on the Accumulation of Putrescine and Spermidine in Escherichia coli." Australian Journal of Biological Sciences 38, no. 4 (1985): 383. http://dx.doi.org/10.1071/bi9850383.
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The rate of accumulation of the polyamines spermidine and putrescine by E. coli depended on growth rate. Spermidine ac~umulation was faster in chemostat cultures with high dilution rates than in those with low dilution rates and was slower in bacteria that had been grown for several generations with either putrescine or spermidine, suggesting that the spermidine-uptake system was repressed by exogenous polyamines. The uptake of spermidine required metabolic energy. Thus accumulation occurred in an energy-starved unc strain only upon addition of glucose (or D-lactate to a smaller extent). With glucose present accumulation occurred in an unc, frd strain under anaerobic conditions, suggesting that ATP drives uptake. However, accumulation was generally sensitive to carbonylcyanide m-chlorophenylhydrazone (CCCP), indicating that the proton motive force was involved in uptake. Unlike spermidine, putrescine accumulation was faster in slow-growing than in fast-growing cultures. This may have been due to greater efflux of putrescine at faster growth rates. Accumulation of putrescine was faster following prolonged growth with either putrescine or spermidine, suggesting induction of the putrescine-uptake system by exogenous polyamines. Like spermidine accumulation, putrescine accumulation required metabolic energy. Accumulation was insensitive to CCCP and occurred only when glucose was added to energy-starved unc bacteria, suggesting that high-energy bonds may drive the uptake of putrescine.
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Gröber, Uwe. "Das Polyamin Spermidin." Zeitschrift für Orthomolekulare Medizin 19, no. 02 (June 2021): 31–33. http://dx.doi.org/10.1055/a-1521-0541.
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ZusammenfassungSpermidin ist ein Polyamin, das im Körper gebildet und mit der Nahrung zugeführt wird. Es ist in eine Vielzahl zellulärer Prozesse involviert und kann z. B. den zellulären Recyclingprozess der Autophagie aktivieren. Studienergebnisse zeigen zudem, dass die Polyamine Spermidin und Spermin die Infektion von Zellen mit SARS-CoV-2 konzentrationsabhängig hemmen kann. Allerdings ist die Datenlage noch unzureichend. Darüber hinaus gibt einen Zusammenhang zwischen Spermidin und reduziertem Mortalitätsrisiko sowie der Verbesserung der kognitiven Leistungsfähigkeit bei älteren Menschen.
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Madeo, Frank, and Tobias Eisenberg. "Spermidin als Demenzprotektor." Zeitschrift für Komplementärmedizin 12, no. 05 (September 2020): 38–40. http://dx.doi.org/10.1055/a-1228-2009.
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SummarySpermidin ist eine natürliche im Organismus vorkommendeSubstanz des Aminosäurestoffwechsels. In Untersuchungenkonnte eine Aktivierung der Autophagiedurch Spermidin gezeigt werden. Dieser zelluläre Recyclingprozesswird v.a. durch Fasten ausgelöst und hatbelegte gesundheitsfördernde Wirkungen.Experimentelle und klinische Studien geben vielversprechendeHinweise für einen möglichen Einsatz von Spermidinzur Demenzprävention. Eine klinische Studiekonnte eine Korrelation des Spermidinspiegels mit derkognitiven Leistungsfähigkeit zeigen. Eine weitere Untersuchungdeutet auf eine verbesserte Gehirngesundheitbei Spermidinaufnahme mit der Nahrung hin.Weitere Untersuchungen sind notwendig, um das Potenzialdieser körpereigenen Substanz insbesondere zurProtektion von Demenzerkrankungen zu erhärten.
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Sharma, Priyanka, and Rishi Kumar Jaiswal. "SPERMIDINE MAINTAINS TELOMERE LENGTH AND DELAYS AGING." Central Asian Journal of Medical Hypotheses and Ethics 2, no. 1 (April 2, 2021): 51–58. http://dx.doi.org/10.47316/cajmhe.2021.2.1.08.
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Spermidine, a natural polyamine, has been noticed for its anti-aging properties. Supplementation of this drug prolongs lifespan and diminishes the incidence of age-related pathology. In the human population, spermidine levels decrease as aging progresses, and a potential link between diminished endogenous spermidine levels and age-related declination has been studied. At the cellular level, autophagy is the prime mode of action of spermidine known to decline with the progress of aging, similarly contributing to the accretion of impaired macromolecules and organelles through aging. Epidemiological statistics support the concept, suggesting that elevated uptake of polyamine delays aging. Here, we overview the effect of autophagy on cellular processes and age-associated diseases, emphasizing the importance of these events to the hallmarks of aging.
There are numerous factors like shortening telomere, oxidative stress, mitochondrial damage, and impaired intracellular calcium signaling, which are influenced by the aging process. We hypothesize that spermidine supplements in the diet increase the telomere length. The proposed hypothesis also brings to light the differentially regulated genes involved in telomere maintenance and aging after spermidine treatment. Knowing the role of spermidine in telomere maintenance would help us understand the molecular mechanism of spermidine's effect on aging.
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Pegg, A. E., and B. G. Erwin. "Induction of spermidine/spermine N1-acetyltransferase in rat tissues by polyamines." Biochemical Journal 231, no. 2 (October 15, 1985): 285–89. http://dx.doi.org/10.1042/bj2310285.
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Treatment of rats with spermidine, spermine or sym-norspermidine led to a substantial induction of spermidine/spermine N1-acetyltransferase activity in liver, kidney and lung. The increase in this enzyme, which was determined independently of other acetylases by using a specific antiserum, accounted for all of the increased acetylase activity in extracts from rats treated with these polyamines. Spermine was the most active inducer, and the greatest effect was seen in liver. Liver spermidine/spermine N1-acetyltransferase activity was increased about 300-fold within 6 h of treatment with 0.3 mmol/kg doses of spermine; activity in kidney increased 30-fold and activity in the lung 15-fold under these conditions. The increased spermidine/spermine N1-acetyltransferase activity led to a large increase in the liver putrescine content and a decline in spermidine. These changes are due to the oxidation by polyamine oxidase of the N1-acetylspermidine formed by the acetyltransferase. Our results indicated that spermidine was the preferred substrate in vivo of the acetylase/oxidase pathway for the conversion of the higher polyamines into putrescine. The induction of the spermidine/spermine N1-acetyltransferase by polyamines may provide a mechanism by which excess polyamines can be removed.
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WOOLRIDGE, Dale P., Jesse D. MARTINEZ, David E. STRINGER, and Eugene W. GERNER. "Characterization of a novel spermidine/spermine acetyltransferase, BltD, from Bacillus subtilis." Biochemical Journal 340, no. 3 (June 8, 1999): 753–58. http://dx.doi.org/10.1042/bj3400753.
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Overexpression of the BltD gene in Bacillus subtilis causes acetylation of the polyamines spermidine and spermine. BltD is co-regulated with another gene, Blt, which encodes a multidrug export protein whose overexpression facilitates spermidine export [Woolridge, Vazquez-Laslop, Markham, Chevalier, Gerner and Neyfakh (1997) J. Biol. Chem. 272, 8864-8866]. Here we show that BltD acetylates both spermidine and spermine at primary propyl amine moieties, with spermine being the preferred substrate. In the presence of saturating concentrations of acetyl CoA, BltD rapidly acetylates spermine at both the N1 and N12 positions. The Km (app) values for spermine, spermidine and N1-acetylspermine are ≤ 67, 200 and 1200 μM, respectively. Diamines ranging from 1,3-diaminopropane to 1,12-diaminododecane, monoacetylputrescine and N8-acetylspermidine were not substrates for BltD. Putrescine (1,4-diaminobutane) and N8-acetylspermidine were competitive inhibitors of spermidine acetylation by BltD, with Ki values of 0.25 and 5.76 mM, respectively. CoA competitively inhibited both spermidine and acetyl-CoA interactions with BltD. These data and other results indicate that the mechanism of spermidine and spermine acetylation by BltD is a random-order mechanism of bi-molecular kinetics.
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Baek, Ae Rin, Jisu Hong, Ki Sung Song, An Soo Jang, Do Jin Kim, Su Sie Chin, and Sung Woo Park. "Spermidine attenuates bleomycin-induced lung fibrosis by inducing autophagy and inhibiting endoplasmic reticulum stress (ERS)-induced cell death in mice." Experimental & Molecular Medicine 52, no. 12 (December 2020): 2034–45. http://dx.doi.org/10.1038/s12276-020-00545-z.
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AbstractSpermidine is an endogenous biological polyamine that plays various longevity-extending roles and exerts antioxidative, antiaging, and cell growth-promoting effects. We previously reported that spermidine levels were significantly reduced in idiopathic pulmonary fibrosis (IPF) of the lung. The present study assessed the potential beneficial effects of spermidine on lung fibrosis and investigated the possible mechanism. Lung fibrosis was established in mice using bleomycin (BLM), and exogenous spermidine was administered daily by intraperitoneal injection (50 mg/kg in phosphate-buffered saline). BLM-induced alveolar epithelial cells showed significant increases in apoptosis and endoplasmic reticulum stress (ERS)-related mediators, and spermidine attenuated BLM-induced apoptosis and activation of the ERS-related pathway. Senescence-associated β-gal staining and decreased expression of p16 and p21 showed that spermidine ameliorated BLM-induced premature cellular senescence. In addition, spermidine enhanced beclin-1-dependent autophagy and autophagy modulators in IPF fibroblasts and BLM-induced mouse lungs, in which inflammation and collagen deposition were significantly decreased. This beneficial effect was related to the antiapoptotic downregulation of the ERS pathway, antisenescence effects, and autophagy activation. Our findings suggest that spermidine could be a therapeutic agent for IPF treatment.
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Desiderio, M. A., S. Mattei, G. Biondi, and M. P. Colombo. "Cytosolic and nuclear spermidine acetyltransferases in growing NIH 3T3 fibroblasts stimulated with serum or polyamines: relationship to polyamine-biosynthetic decarboxylases and histone acetyltransferase." Biochemical Journal 293, no. 2 (July 15, 1993): 475–79. http://dx.doi.org/10.1042/bj2930475.
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The expression (mRNA level of enzymic activity) of cytosolic and nuclear spermidine acetyltransferases was studied in NIH 3T3 fibroblasts, either (1) serum-starved and stimulated to grow by serum refeeding, or (2) treated with inhibitors of ornithine decarboxylase (ODC) (MDL 72.175) and S-adenosylmethionine decarboxylase (AdoMetDC) (MDL 73.811) and stimulated to grow by spermidine. Expression of the known growth-regulated genes for ODC, AdoMetDC and histone acetyltransferase was also examined. The mRNA for spermidine/spermine N1-acetyltransferase (SAT) accumulated after serum refeeding (between 6 and 16 h) and even more after spermidine addition (16 h). Histone acetyltransferase activity increased after both growth stimuli, whereas spermidine N8-acetyltransferase activity remained unchanged. After serum stimulation, the ODC mRNA level and activity rose between 6 and 16 h, whereas AdoMetDC mRNA accumulation occurred later (16 h) than the increase in enzyme activity (6 h). Stimulation of ODC and AdoMetDC activities was suppressed by the inhibitors added alone or in combination with spermidine, whereas mRNA accumulation was down-regulated by spermidine. These results indicate that the expression of SAT was growth-controlled and that SAT mRNA level was regulated by polyamines.
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Zhang, Min, Bang Li, Zuliang Wan, Xiaofei Chen, Chang Liu, Chunjuan Liu, and Yufei Zhou. "Exogenous Spermidine Promotes Germination of Aged Sorghum Seeds by Mediating Sugar Metabolism." Plants 11, no. 21 (October 26, 2022): 2853. http://dx.doi.org/10.3390/plants11212853.
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Starch, a substance stored in seeds, is the main source of energy for germination in sorghum seeds. However, as the seeds age, the catabolism of seed starch is affected, thereby seriously damaging germination ability. In this study, we aimed to understand how exogenous spermidine promoted germination in aged sorghum seed. Our phenotypic analysis indicated that exogenous spermidine not only significantly improved the germination rate, germination potential, germination index, and vigor index of aged seeds, but also increased the root and shoot length after germination. Further, physiological analysis showed that exogenous spermidine increased the content of soluble sugar by upregulating the activity of amylase and sucrose invertase. Exogenous spermidine also improved the activities of key enzymes in glycolysis, the tricarboxylic acid cycle, and the pentose phosphate pathway of aged sorghum seeds. Interestingly, exogenous spermidine protected the mitochondrial structure of aged seeds, which was consistent with the increase in the respiration rate and ATP content during seed germination. Moreover, qRT-PCR analysis revealed that exogenous spermidine induced the expression of key genes related to starch and sugar metabolism in aged sorghum seeds. In conclusion, our study demonstrated that exogenous spermidine promoted aged sorghum seed germination by regulating starch and sugar metabolism.
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Korbas, Agata, Jan Kubiś, Magdalena Rybus-Zając, and Tamara Chadzinikolau. "Spermidine Modify Antioxidant Activity in Cucumber Exposed to Salinity Stress." Agronomy 12, no. 7 (June 28, 2022): 1554. http://dx.doi.org/10.3390/agronomy12071554.
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The effects of short-term 48 h long NaCl-stress and spermidine level modification on polyamines level and antioxidant status in cucumber (Cucumis sativus cv. Dar) leaves were investigated. Seedlings kept in nutrient solutions treated with 50 mM NaCl for 48 h exhibited reduced relative water content and accumulation of free polyamines, especially spermidine. Salinity stress caused an increase in superoxide radicals and hydrogen peroxide generation during the salinity-induced increase in antioxidant enzyme activities. Spermidine application before stress resulted in a marked increase in spermidine and spermine contents in the leaves of salt-stressed cucumber seedlings. Additionally, increased spermidine/spermine level mobilised the antioxidant enzyme’s activity and limited reactive oxygen species content. Polyamine synthesis inhibitor (MGBG) slightly decreased spermidine and spermine levels during salinity and reversed the antioxidant activity mobilisation. These results showed that Spd modifications significantly improved PAs, enhancing salinity stress tolerance by detoxifying ROS. Our findings determined the implication of PAs for improving the salinity tolerance of important vegetable species.
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Han, Wentao, Haoyu Li, and Baihua Chen. "Research Progress and Potential Applications of Spermidine in Ocular Diseases." Pharmaceutics 14, no. 7 (July 19, 2022): 1500. http://dx.doi.org/10.3390/pharmaceutics14071500.
Full textAbstract:
Spermidine, a natural polyamine, exists in almost all human tissues, exhibiting broad properties like anti-aging, autophagy induction, anti-inflammation, anti-oxidation, cell proliferation activation, and ion channel regulation. Considering that spermidine is already present in human nutrition, recent studies targeting supplementing exogenous sources of this polyamine appear feasible. The protective role of spermidine in various systems has been illuminated in the literature, while recent progress of spermidine administration in ocular diseases remains to be clarified. This study shows the current landscape of studies on spermidine and its potential to become a promising therapeutic agent to treat ocular diseases: glaucoma, optic nerve injury, age-related macular degeneration (AMD), cataracts, dry eye syndrome, and bacterial keratitis. It also has the potential to become a potent biomarker to predict keratoconus (KC), cataracts, uveitis, glaucoma, proliferative diabetic retinopathy (PDR), proliferative vitreoretinopathy (PVR), and retinopathy of prematurity (ROP). We also summarize the routes of administration and the effects of spermidine at different doses.
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Lee, Hyesook, Da Hye Kim, Hyun Hwangbo, So Young Kim, Seon Yeong Ji, Min Yeong Kim, Jung-Hyun Shim, et al. "The Protective Effect of Topical Spermidine on Dry Eye Disease with Retinal Damage Induced by Diesel Particulate Matter2.5." Pharmaceutics 13, no. 9 (September 10, 2021): 1439. http://dx.doi.org/10.3390/pharmaceutics13091439.
Full textAbstract:
Air pollutants, especially ambient fine particulate matter2.5, may contribute to various ocular surface disorders, including dry eye disease, keratitis and conjunctivitis. A natural polyamine spermidine has a protective effect on the retina and optic nerve; however, no study has been conducted on the application of spermidine in particulate matter2.5-induced dry eye disease. In the present study, we investigated the effect of spermidine eye drops in topically exposed particulate matter2.5-induced dry eye models of Sprague-Dawley rats, by hematological, biochemical and histological evaluation. Spermidine eye drops attenuated the particulate matter2.5 exposure-induced reduction of tear secretion and corneal epithelial damage. Furthermore, spermidine protected against conjunctival goblet cell loss and retinal ganglion cell loss induced by particulate matter2.5. Additionally, spermidine markedly prevented particulate matter2.5-induced infiltration of cluster of differentiation3+ and cluster of differentiation4+ T lymphocytes and F4/80+ macrophages on lacrimal gland. Moreover, over expression of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-6 and interleukin-17 in the lacrimal gland and cornea. Meanwhile, the levels of serum total cholesterol and low-density lipoprotein cholesterol were markedly increased by topical exposure to particulate matter2.5, but this change in the lipid profile was decreased by spermidine. Taken together, spermidine may have protective effects against particulate matter2.5-induced dry eye symptoms via stabilization of the tear film and suppression of inflammation and may in part contribute to improving retinal function and lipid metabolism disorder.
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LEE, Chang Hoon, Patrick Y. UM, and Myung Hee PARK. "Structure–function studies of human deoxyhypusine synthase: identification of amino acid residues critical for the binding of spermidine and NAD." Biochemical Journal 355, no. 3 (April 24, 2001): 841–49. http://dx.doi.org/10.1042/bj3550841.
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Deoxyhypusine synthase catalyses the first step in the biosynthesis of hypusine [Nε-(4-amino-2-hydroxybutyl)lysine]. The crystal structure of human deoxyhypusine synthase in complex with NAD revealed four NAD-binding sites per enzyme tetramer, and led to a prediction of the spermidine-binding pocket. We have replaced each of the seven amino acid residues at the predicted spermidine-binding site, and eleven residues that contact NAD, on an individual basis with alanine. Of the amino acid residues at the spermidine site, substitution of Asp-243, Trp-327, His-288, Asp-316 or Glu-323 with alanine caused an almost complete loss of spermidine binding and enzyme activity; only the mutation Tyr-305 → Ala showed partial binding and activity. His-288 → Ala was also deficient in terms of binding NAD. NAD binding was significantly reduced in all of the NAD-site mutant enzymes, except for Glu-137 → Ala, which showed a normal binding of NAD, but was totally lacking in spermidine binding. Of the NAD-site mutant enzymes, Asp-342 → Ala, Asp-313 → Ala and Asp-238 → Ala displayed the lowest binding of NAD. These enzymes and His-288Ala also showed a reduced binding of spermidine, presumably because spermidine binding is dependent on NAD. These findings permit the positive identification of amino acid residues critical for binding of spermidine and NAD, and provide a new insight into the complex molecular interactions involved in the deoxyhypusine synthase reaction.
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Kingsbury, Joanne M., Zhonghui Yang, Tonya M. Ganous, Gary M. Cox, and John H. McCusker. "Novel Chimeric Spermidine Synthase-Saccharopine Dehydrogenase Gene (SPE3-LYS9) in the Human Pathogen Cryptococcus neoformans." Eukaryotic Cell 3, no. 3 (June 2004): 752–63. http://dx.doi.org/10.1128/ec.3.3.752-763.2004.
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ABSTRACT The Cryptococcus neoformans LYS9 gene (encoding saccharopine dehydrogenase) was cloned and found to be part of an evolutionarily conserved chimera with SPE3 (encoding spermidine synthase). spe3-lys9, spe3-LYS9, and SPE3-lys9 mutants were constructed, and these were auxotrophic for lysine and spermidine, spermidine, and lysine, respectively. Thus, SPE3-LYS9 encodes functional spermidine synthase and saccharopine dehydrogenase gene products. In contrast to Saccharomyces cerevisiae spe3 mutants, the polyamine auxotrophy of C. neoformans spe3-LYS9 mutants was not satisfied by spermine. In vitro phenotypes of spe3-LYS9 mutants included reduced capsule and melanin production and growth rate, while SPE3-lys9 mutants grew slowly at 30°C, were temperature sensitive in rich medium, and died upon lysine starvation. Consistent with the importance of saccharopine dehydrogenase and spermidine synthase in vitro, spe3-lys9 mutants were avirulent and unable to survive in vivo and both functions individually contributed to virulence. SPE3-LYS9 mRNA levels showed little evidence of being influenced by exogenous spermidine or lysine or starvation for spermidine or lysine; thus, any regulation is likely to be posttranscriptional. Expression in S. cerevisiae of the full-length C. neoformans SPE3-LYS9 cDNA complemented a lys9 mutant but not a spe3 mutant. However, expression in S. cerevisiae of a truncated gene product, consisting of only C. neoformans SPE3, complemented a spe3 mutant, suggesting possible modes of regulation. Therefore, we identified and describe a novel chimeric SPE3-LYS9 gene, which may link spermidine and lysine biosynthesis in C. neoformans.
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THOMAS, T. J., Gayathri D. KULKARNI, Norma J. GREENFIELD, Akira SHIRAHATA, and Thresia THOMAS. "Structural specificity effects of trivalent polyamine analogues on the stabilization and conformational plasticity of triplex DNA." Biochemical Journal 319, no. 2 (October 15, 1996): 591–99. http://dx.doi.org/10.1042/bj3190591.
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Natural polyamines, i.e. putrescine, spermidine and spermine, are excellent promoters of triplex DNA. Using melting temperature (Tm) measurements and CD spectroscopy, we found that structural alterations on spermidine backbone, including methylation, or acetylation at the N1-, N4- and/or N8-positions had a profound influence on the stability and conformation of poly(dA).2poly(dT) triplex. The conformation of the polynucleotide complex underwent sequential changes from B-DNA to triplex DNA as the concentration of spermidine increased from 0 to 50 µM in a buffer containing 10 mM sodium cacodylate and 1 mM EDTA (pH 7.2). At 60 µM spermidine, the CD spectrum of triplex DNA was comparable with that of Ψ-DNA, with a strong positive band centred around 260 nm. A negative band was also found at 295 nm. At higher concentrations of spermidine, however, the intensity of the positive band progressively decreased and the peak intensity was found at a 1:0.3 molar ratio of DNA phosphate:spermidine. Temperature-dependent CD analysis showed that the Ψ-DNA structure melted to single-stranded DNA at temperatures above the Tm determined from the absorbance versus temperature profile. Comparable effects were exerted on the conformation of triplex DNA by Co(NH3)63+, an inorganic trivalent cation. Substitution of the N4-hydrogen of spermidine by a cyclohexyl ring or the fusion of the N4-nitrogen in a cyclic ring system, as in piperidine, enhanced the ability of spermidine analogues to stabilize triplex and Ψ-DNA forms over a wider concentration range compared with spermidine. These data demonstrate a differential effect of trivalent cations in stabilizing triplex DNA and provoking unusual conformations such as Ψ-DNA. Synthetic homologues of spermidine that stabilize triplex DNA over a wider range of concentrations than that stabilized by spermidine itself might have potential therapeutic applications in the development of an anti-gene strategy against several diseases, including cancer and AIDS.