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10 pages, 1293 KiB

Open AccessArticle

Alkaline Stress Causes Changes in Polyamine Biosynthesis in Thermus thermophilus

by Teruyuki Kobayashi, Akihiko Sakamoto, Keiko Kashiwagi, Kazuei Igarashi, Toshiyuki Moriya, Tairo Oshima and Yusuke Terui

Int. J. Mol. Sci. 2022, 23(21), 13523; https://doi.org/10.3390/ijms232113523 - 4 Nov 2022

Cited by 4 | Viewed by 2147

Abstract

An extreme thermophile, Thermus thermophilus, produces 16 different polyamines including long-chain and branched-chain polyamines. The composition and content of polyamines in the thermophile cells change not only with growth temperature but also with pH changes. In particular, cell growth decreased greatly at [...] Read more.

An extreme thermophile, Thermus thermophilus, produces 16 different polyamines including long-chain and branched-chain polyamines. The composition and content of polyamines in the thermophile cells change not only with growth temperature but also with pH changes. In particular, cell growth decreased greatly at alkaline medium together with significant changes in the composition and content of polyamines. The amounts of tetraamines (spermine and its homologs) markedly decreased at alkaline pH. Thus, we knocked out the speE gene, which is involved in the biosynthesis of tetraamines, and changes of composition of polyamines with pH changes in the mutant cells were studied. Cell growth in the ΔspeE strain was decreased compared with that of the wild-type strain for all pHs, suggesting that tetraamines are important for cell proliferation. Interestingly, the amount of spermidine decreased and that of putrescine increased in wild-type cells at elevated pH, although T. thermophilus lacks a putrescine synthesizing pathway. In addition, polyamines possessing a diaminobutane moiety, such as spermine, decreased greatly at high pH. We assessed whether the speB gene encoding aminopropylagmatine ureohydrolase (TtSpeB) is directly involved in the synthesis of putrescine. The catalytic assay of the purified enzyme indicated that TtSpeB accepts agmatine as its substrate and produces putrescine due to the change in substrate specificity at high pH. These results suggest that pH stress was exacerbated upon intracellular depletion of polyamines possessing a diaminobutane moiety induced by unusual changes in polyamine biosynthesis under high pH conditions. Full article

(This article belongs to the Special Issue Modes of Action of Polyamine Metabolism)

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18 pages, 2296 KiB

Open AccessArticle

Hypusinated eIF5A Promotes Ribosomal Frameshifting during Decoding of ODC Antizyme mRNA in Saccharomyces cerevisiae

by Kai Halwas, Lennard-Maximilian Döring, Franziska Valentina Oehlert and R. Jürgen Dohmen

Int. J. Mol. Sci. 2022, 23(21), 12972; https://doi.org/10.3390/ijms232112972 - 26 Oct 2022

Cited by 3 | Viewed by 2582

Abstract

Polyamines are essential biogenic poly-cations with important roles in many cellular processes and diseases such as cancer. A rate-limiting step early in the biosynthesis of polyamines is the conversion of ornithine to putrescine by the homodimeric enzyme ornithine decarboxylase (ODC). In a conserved [...] Read more.

Polyamines are essential biogenic poly-cations with important roles in many cellular processes and diseases such as cancer. A rate-limiting step early in the biosynthesis of polyamines is the conversion of ornithine to putrescine by the homodimeric enzyme ornithine decarboxylase (ODC). In a conserved mechanism of posttranslational regulation, ODC antizyme (OAZ) binds to ODC monomers promoting their ubiquitin-independent degradation by the proteasome. Decoding of OAZ mRNA is unusual in that it involves polyamine-regulated bypassing of an internal translation termination (STOP) codon by a ribosomal frameshift (RFS) event. Using Saccharomyces cerevisiae, we earlier showed that high polyamine concentrations lead to increased efficiency of OAZ1 mRNA translation by binding to nascent Oaz1 polypeptide. The binding of polyamines prevents stalling of the ribosomes on OAZ1 mRNA caused by nascent Oaz1 polypeptide thereby promoting synthesis of full-length Oaz1. Polyamine depletion, however, also inhibits RFS during the decoding of constructs bearing the OAZ1 shift site lacking sequences encoding the Oaz1 parts implicated in polyamine binding. Polyamine depletion is known to impair hypusine modification of translation factor eIF5A. Using a novel set of conditional mutants impaired in the function of eIF5A/Hyp2 or its hypusination, we show here that hypusinated eIF5A is required for efficient translation across the OAZ1 RFS site. These findings identify eIF5A as a part of Oaz1 regulation, and thereby of polyamine synthesis. Additional experiments with DFMO, however, show that depletion of polyamines inhibits translation across the OAZ1 RFS site not only by reducing Hyp2 hypusination, but in addition, and even earlier, by affecting RFS more directly. Full article

(This article belongs to the Special Issue Modes of Action of Polyamine Metabolism)

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16 pages, 6892 KiB

Open AccessArticle

Improvement of Drought Tolerance by Exogenous Spermidine in Germinating Wheat (Triticum aestivum L.) Plants Is Accompanied with Changes in Metabolite Composition

by Fatemeh Gholizadeh, Tibor Janda, Orsolya Kinga Gondor, Magda Pál, Gabriella Szalai, Amirali Sadeghi and Aras Turkoglu

Int. J. Mol. Sci. 2022, 23(16), 9047; https://doi.org/10.3390/ijms23169047 - 12 Aug 2022

Cited by 10 | Viewed by 2191

Abstract

Drought is one of the most important environmental factors reducing the yield and production of crops, including wheat. Polyamines are closely associated with plant stress tolerance. The present study investigated the mechanisms through seed germination with spermidine protecting wheat varieties from drought stress. [...] Read more.

Drought is one of the most important environmental factors reducing the yield and production of crops, including wheat. Polyamines are closely associated with plant stress tolerance. The present study investigated the mechanisms through seed germination with spermidine protecting wheat varieties from drought stress. In the first experiment, the effects of spermidine on the germination of wheat varieties, namely Rakhshan, Mihan, Sirvan and Pishgam, were investigated in three drought levels, namely 0, −2, and −4 MPa induced by polyethylene glycol 6000. Analysis of variance indicated that spermidine, drought stress and interaction between varieties and drought stress were significant for all traits, and with severity of stress, all traits significantly decreased. In the second experiment, detailed gene expression and non-targeted metabolomics analyses were carried out using the Rakhshan and Mihan varieties after germination, with or without spermidine treatment and/or drought stress. According to the biomass parameters, the Mihan variety showed relatively better growth compared to the other variety, but the Rakhshan one showed more pronounced responses at gene expression level to exogenous spermidine than the Mihan variety. Overall, these results showed that spermidine increased the drought tolerance of wheat at the germination stage, due to specific role of polyamine metabolism in the development of effective responses under drought stress. Full article

(This article belongs to the Special Issue Modes of Action of Polyamine Metabolism)

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22 pages, 3116 KiB

Open AccessArticle

Light Spectral Composition Modifies Polyamine Metabolism in Young Wheat Plants

by Magda Pál, Kamirán Áron Hamow, Altafur Rahman, Imre Majláth, Judit Tajti, Orsolya Kinga Gondor, Mohamed Ahres, Fatemeh Gholizadeh, Gabriella Szalai and Tibor Janda

Int. J. Mol. Sci. 2022, 23(15), 8394; https://doi.org/10.3390/ijms23158394 - 29 Jul 2022

Cited by 8 | Viewed by 1872

Abstract

Although light-emitting diode (LED) technology has extended the research on targeted photomorphogenic, physiological, and biochemical responses in plants, there is not enough direct information about how light affects polyamine metabolism. In this study, the effect of three spectral compositions (referred to by their [...] Read more.

Although light-emitting diode (LED) technology has extended the research on targeted photomorphogenic, physiological, and biochemical responses in plants, there is not enough direct information about how light affects polyamine metabolism. In this study, the effect of three spectral compositions (referred to by their most typical characteristic: blue, red, and the combination of blue and red [pink] lights) on polyamine metabolism was compared to those obtained under white light conditions at the same light intensity. Although light quality induced pronounced differences in plant morphology, pigment contents, and the expression of polyamine metabolism-related genes, endogenous polyamine levels did not differ substantially. When exogenous polyamines were applied, their roborative effect were detected under all light conditions, but these beneficial changes were correlated with an increase in polyamine content and polyamine metabolism-related gene expression only under blue light. The effect of the polyamines on leaf gene expression under red light was the opposite, with a decreasing tendency. Results suggest that light quality may optimize plant growth through the adjustment of polyamine metabolism at the gene expression level. Polyamine treatments induced different strategies in fine-tuning of polyamine metabolism, which were induced for optimal plant growth and development under different spectral compositions. Full article

(This article belongs to the Special Issue Modes of Action of Polyamine Metabolism)

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11 pages, 2846 KiB

Open AccessArticle

Putrescine Intensifies Glu/GABA Exchange Mechanism and Promotes Early Termination of Seizures

by Zsolt Kovács, Serguei N. Skatchkov, Zsolt Szabó, Saif Qahtan, Miguel P. Méndez-González, Christian J. Malpica-Nieves, Misty J. Eaton, Julianna Kardos and László Héja

Int. J. Mol. Sci. 2022, 23(15), 8191; https://doi.org/10.3390/ijms23158191 - 25 Jul 2022

Cited by 8 | Viewed by 2536

Abstract

Endogenous anticonvulsant mechanisms represent a reliable and currently underdeveloped strategy against recurrent seizures and may recall novel original therapeutics. Here, we investigated whether the intensification of the astroglial Glu-GABA exchange mechanism by application of the GABA precursor putrescine (PUT) may be effective against [...] Read more.

Endogenous anticonvulsant mechanisms represent a reliable and currently underdeveloped strategy against recurrent seizures and may recall novel original therapeutics. Here, we investigated whether the intensification of the astroglial Glu-GABA exchange mechanism by application of the GABA precursor putrescine (PUT) may be effective against convulsive and non-convulsive seizures. We explored the potential of PUT to inhibit spontaneous spike-and-wave discharges (SWDs) in WAG/Rij rats, a genetic model of absence epilepsy. Significant shortening of SWDs in response to intraperitoneally applied PUT has been observed, which could be antagonized by blocking GAT-2/3-mediated astrocytic GABA release with the specific inhibitor SNAP-5114. Direct application of exogenous GABA also reduced SWD duration, suggesting that PUT-triggered astroglial GABA release through GAT-2/3 may be a critical step in limiting seizure duration. PUT application also dose-dependently shortened seizure-like events (SLEs) in the low-[Mg²⁺] in vitro model of temporal lobe epilepsy. SNAP-5114 reversed the antiepileptic effect of PUT in the in vitro model as well, further confirming that PUT reduces seizure duration by triggering glial GABA release. In accordance, we observed that PUT specifically reduces the frequency of excitatory synaptic potentials, suggesting that it specifically acts at excitatory synapses. We also identified that PUT specifically eliminated the tonic depolarization-induced desynchronization of SLEs. Since PUT is an important source of glial GABA and we previously showed significant GABA release, it is suggested that the astroglial Glu-GABA exchange mechanism plays a key role in limiting ictal discharges, potentially opening up novel pathways to control seizure propagation and generalization. Full article

(This article belongs to the Special Issue Modes of Action of Polyamine Metabolism)

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17 pages, 3199 KiB

Open AccessArticle

Role of Polyamine-Induced Dimerization of Antizyme in Its Cellular Functions

by Mervi T. Hyvönen, Olga A. Smirnova, Vladimir A. Mitkevich, Vera L. Tunitskaya, Maxim Khomutov, Dmitry S. Karpov, Sergey P. Korolev, Merja R. Häkkinen, Marko Pietilä, Marina B. Gottikh, Jouko Vepsäläinen, Leena Alhonen, Alexander A. Makarov, Sergey N. Kochetkov, Heather M. Wallace, Tuomo A. Keinänen and Alex R. Khomutov

Int. J. Mol. Sci. 2022, 23(9), 4614; https://doi.org/10.3390/ijms23094614 - 21 Apr 2022

Cited by 7 | Viewed by 2838

Abstract

The polyamines, spermine (Spm) and spermidine (Spd), are important for cell growth and function. Their homeostasis is strictly controlled, and a key downregulator of the polyamine pool is the polyamine-inducible protein, antizyme 1 (OAZ1). OAZ1 inhibits polyamine uptake and targets ornithine decarboxylase (ODC), [...] Read more.

The polyamines, spermine (Spm) and spermidine (Spd), are important for cell growth and function. Their homeostasis is strictly controlled, and a key downregulator of the polyamine pool is the polyamine-inducible protein, antizyme 1 (OAZ1). OAZ1 inhibits polyamine uptake and targets ornithine decarboxylase (ODC), the rate-limiting enzyme of polyamine biosynthesis, for proteasomal degradation. Here we report, for the first time, that polyamines induce dimerization of mouse recombinant full-length OAZ1, forming an (OAZ1)₂-Polyamine complex. Dimerization could be modulated by functionally active C-methylated spermidine mimetics (MeSpds) by changing the position of the methyl group along the Spd backbone—2-MeSpd was a poor inducer as opposed to 1-MeSpd, 3-MeSpd, and Spd, which were good inducers. Importantly, the ability of compounds to inhibit polyamine uptake correlated with the efficiency of the (OAZ1)₂-Polyamine complex formation. Thus, the (OAZ1)₂-Polyamine complex may be needed to inhibit polyamine uptake. The efficiency of polyamine-induced ribosomal +1 frameshifting of OAZ1 mRNA could also be differentially modulated by MeSpds—2-MeSpd was a poor inducer of OAZ1 biosynthesis and hence a poor downregulator of ODC activity unlike the other MeSpds. These findings offer new insight into the OAZ1-mediated regulation of polyamine homeostasis and provide the chemical tools to study it. Full article

(This article belongs to the Special Issue Modes of Action of Polyamine Metabolism)

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23 pages, 3483 KiB

Open AccessArticle

A Second Gamma-Glutamylpolyamine Synthetase, GlnA2, Is Involved in Polyamine Catabolism in Streptomyces coelicolor

by Sergii Krysenko, Nicole Okoniewski, Merle Nentwich, Arne Matthews, Moritz Bäuerle, Alina Zinser, Tobias Busche, Andreas Kulik, Stephanie Gursch, Annika Kemeny, Agnieszka Bera and Wolfgang Wohlleben

Int. J. Mol. Sci. 2022, 23(7), 3752; https://doi.org/10.3390/ijms23073752 - 29 Mar 2022

Cited by 10 | Viewed by 3265

Abstract

Streptomyces coelicolor is a soil bacterium living in a habitat with very changeable nutrient availability. This organism possesses a complex nitrogen metabolism and is able to utilize the polyamines putrescine, cadaverine, spermidine, and spermine and the monoamine ethanolamine. We demonstrated that GlnA2 (SCO2241) [...] Read more.

Streptomyces coelicolor is a soil bacterium living in a habitat with very changeable nutrient availability. This organism possesses a complex nitrogen metabolism and is able to utilize the polyamines putrescine, cadaverine, spermidine, and spermine and the monoamine ethanolamine. We demonstrated that GlnA2 (SCO2241) facilitates S. coelicolor to survive under high toxic polyamine concentrations. GlnA2 is a gamma-glutamylpolyamine synthetase, an enzyme catalyzing the first step in polyamine catabolism. The role of GlnA2 was confirmed in phenotypical studies with a glnA2 deletion mutant as well as in transcriptional and biochemical analyses. Among all GS-like enzymes in S. coelicolor, GlnA2 possesses the highest specificity towards short-chain polyamines (putrescine and cadaverine), while its functional homolog GlnA3 (SCO6962) prefers long-chain polyamines (spermidine and spermine) and GlnA4 (SCO1613) accepts only monoamines. The genome-wide RNAseq analysis in the presence of the polyamines putrescine, cadaverine, spermidine, or spermine revealed indication of the occurrence of different routes for polyamine catabolism in S. coelicolor involving GlnA2 and GlnA3. Furthermore, GlnA2 and GlnA3 are differently regulated. From our results, we can propose a complemented model of polyamine catabolism in S. coelicolor, which involves the gamma-glutamylation pathway as well as other alternative utilization pathways. Full article

(This article belongs to the Special Issue Modes of Action of Polyamine Metabolism)

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27 pages, 3641 KiB

Open AccessArticle

Polyamine Metabolism under Different Light Regimes in Wheat

by Orsolya Kinga Gondor, Judit Tajti, Kamirán Áron Hamow, Imre Majláth, Gabriella Szalai, Tibor Janda and Magda Pál

Int. J. Mol. Sci. 2021, 22(21), 11717; https://doi.org/10.3390/ijms222111717 - 29 Oct 2021

Cited by 23 | Viewed by 2912

Abstract

Although the relationship between polyamines and photosynthesis has been investigated at several levels, the main aim of this experiment was to test light-intensity-dependent influence of polyamine metabolism with or without exogenous polyamines. First, the effect of the duration of the daily illumination, then [...] Read more.

Although the relationship between polyamines and photosynthesis has been investigated at several levels, the main aim of this experiment was to test light-intensity-dependent influence of polyamine metabolism with or without exogenous polyamines. First, the effect of the duration of the daily illumination, then the effects of different light intensities (50, 250, and 500 μmol m^–2 s^–1) on the polyamine metabolism at metabolite and gene expression levels were investigated. In the second experiment, polyamine treatments, namely putrescine, spermidine and spermine, were also applied. The different light quantities induced different changes in the polyamine metabolism. In the leaves, light distinctly induced the putrescine level and reduced the 1,3-diaminopropane content. Leaves and roots responded differently to the polyamine treatments. Polyamines improved photosynthesis under lower light conditions. Exogenous polyamine treatments influenced the polyamine metabolism differently under individual light regimes. The fine-tuning of the synthesis, back-conversion and terminal catabolism could be responsible for the observed different polyamine metabolism-modulating strategies, leading to successful adaptation to different light conditions. Full article

(This article belongs to the Special Issue Modes of Action of Polyamine Metabolism)

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Review

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13 pages, 1568 KiB

Open AccessReview

The Association between Spermidine/Spermine N¹-Acetyltransferase (SSAT) and Human Malignancies

by Ryan Tsz-Hei Tse, Xiaofan Ding, Christine Yim-Ping Wong, Carol Ka-Lo Cheng, Peter Ka-Fung Chiu and Chi-Fai Ng

Int. J. Mol. Sci. 2022, 23(11), 5926; https://doi.org/10.3390/ijms23115926 - 25 May 2022

Cited by 8 | Viewed by 3915

Abstract

Spermidine/spermine N¹-acetyltransferase (SSAT) functions as a critical enzyme in maintaining the homeostasis of polyamines, including spermine, spermidine, and putrescine, in mammalian cells. SSAT is a catalytic enzyme that indirectly regulates cellular physiologies and pathways through interaction with endogenous and exogenous polyamines. [...] Read more.

Spermidine/spermine N¹-acetyltransferase (SSAT) functions as a critical enzyme in maintaining the homeostasis of polyamines, including spermine, spermidine, and putrescine, in mammalian cells. SSAT is a catalytic enzyme that indirectly regulates cellular physiologies and pathways through interaction with endogenous and exogenous polyamines. Normally, SSAT exhibits only at a low cellular level, but upon tumorigenesis, the expression, protein level, and activities of SSAT are altered. The alterations induce cellular damages, including oxidative stress, cell cycle arrest, DNA dynamics, and proliferation by influencing cellular mechanisms and signaling pathways. The expression of SSAT has been reported in various studies to be altered in different cancers, and it has been correlated with tumor development and progression. Tumor grades and stages are associated with the expression levels of SSAT. SSAT can be utilized as a target for substrate binding, and excreted metabolites may be used as a novel cancer biomarker. There is also potential for SSAT to be developed as a therapeutic target. Polyamine analogs could increase SSAT expression and increase the cytotoxicity of chemotherapy to tumor cells. Drugs targeting polyamines and SSAT expression have the potential to be developed into new cancer treatments in the future. Full article

(This article belongs to the Special Issue Modes of Action of Polyamine Metabolism)

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23 pages, 1172 KiB

Open AccessReview

Putrescine: A Key Metabolite Involved in Plant Development, Tolerance and Resistance Responses to Stress

by Ana Isabel González-Hernández, Loredana Scalschi, Begonya Vicedo, Emilio Luis Marcos-Barbero, Rosa Morcuende and Gemma Camañes

Int. J. Mol. Sci. 2022, 23(6), 2971; https://doi.org/10.3390/ijms23062971 - 10 Mar 2022

Cited by 60 | Viewed by 7312

Abstract

Putrescine (Put) is the starting point of the polyamines (PAs) pathway and the most common PA in higher plants. It is synthesized by two main pathways (from ornithine and arginine), but recently a third pathway from citrulline was reported in sesame plants. There [...] Read more.

Putrescine (Put) is the starting point of the polyamines (PAs) pathway and the most common PA in higher plants. It is synthesized by two main pathways (from ornithine and arginine), but recently a third pathway from citrulline was reported in sesame plants. There is strong evidence that Put may play a crucial role not only in plant growth and development but also in the tolerance responses to the major stresses affecting crop production. The main strategies to investigate the involvement of PA in plant systems are based on the application of competitive inhibitors, exogenous PAs treatments, and the most efficient approaches based on mutant and transgenic plants. Thus, in this article, the recent advances in understanding the role of this metabolite in plant growth promotion and protection against abiotic and biotic stresses will be discussed to provide an overview for future research. Full article

(This article belongs to the Special Issue Modes of Action of Polyamine Metabolism)

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11 pages, 3710 KiB

Open AccessReview

The Potential Role of Spermine and Its Acetylated Derivative in Human Malignancies

by Ryan Tsz-Hei Tse, Christine Yim-Ping Wong, Peter Ka-Fung Chiu and Chi-Fai Ng

Int. J. Mol. Sci. 2022, 23(3), 1258; https://doi.org/10.3390/ijms23031258 - 23 Jan 2022

Cited by 23 | Viewed by 4580

Abstract

Polyamines are essential biomolecules for normal cellular metabolism in humans. The roles of polyamines in cancer development have been widely discussed in recent years. Among all, spermine alongside with its acetylated derivative, N¹, N¹²-Diacetylspermine, demonstrate a relationship with the [...] Read more.

Polyamines are essential biomolecules for normal cellular metabolism in humans. The roles of polyamines in cancer development have been widely discussed in recent years. Among all, spermine alongside with its acetylated derivative, N¹, N¹²-Diacetylspermine, demonstrate a relationship with the diagnosis and staging of various cancers, including lung, breast, liver, colorectal and urogenital. Numerous studies have reported the level of spermine in different body fluids and organ tissues in patients with different types of cancers. Currently, the role and the underlying mechanisms of spermine in cancer development and progression are still under investigation. This review summarized the roles of spermine in cancer development and as a diagnostic, prognostic and therapeutic tool in various cancers. Full article

(This article belongs to the Special Issue Modes of Action of Polyamine Metabolism)

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