The functional role of polyamines in eukaryotic cells

Igarashi, Kazuei; Kashiwagi, Keiko

doi:10.1016/j.biocel.2018.12.012

Cited by 104 publications

(66 citation statements)

References 104 publications

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“…ODC catalyzes the conversion of L-ornithine into putrescine, which is then metabolized to spermidine by spermidine synthase and spermine by spermine synthase (260). At physiological pH polyamines are positively charged and bind to acidic sites in DNA and RNA, controlling gene expression (261). Moreover, polyamines have antioxidative properties, bind to K + channels, NMDA receptors, and modulate the activity of various enzymes (261).…”

Section: Polyaminesmentioning

confidence: 99%

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Myeloid Cell-Derived Arginase in Cancer Immune Response

et al. 2020

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Amino acid metabolism is a critical regulator of the immune response, and its modulating becomes a promising approach in various forms of immunotherapy. Insufficient concentrations of essential amino acids restrict T-cells activation and proliferation. However, only arginases, that degrade L-arginine, as well as enzymes that hydrolyze L-tryptophan are substantially increased in cancer. Two arginase isoforms, ARG1 and ARG2, have been found to be present in tumors and their increased activity usually correlates with more advanced disease and worse clinical prognosis. Nearly all types of myeloid cells were reported to produce arginases and the increased numbers of various populations of myeloid-derived suppressor cells and macrophages correlate with inferior clinical outcomes of cancer patients. Here, we describe the role of arginases produced by myeloid cells in regulating various populations of immune cells, discuss molecular mechanisms of immunoregulatory processes involving L-arginine metabolism and outline therapeutic approaches to mitigate the negative effects of arginases on antitumor immune response. Development of potent arginase inhibitors, with improved pharmacokinetic properties, may lead to the elaboration of novel therapeutic strategies based on targeting immunoregulatory pathways controlled by L-arginine degradation.

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Section: Polyaminesmentioning

confidence: 99%

“…At physiological pH polyamines are positively charged and bind to acidic sites in DNA and RNA, controlling gene expression (261). Moreover, polyamines have antioxidative properties, bind to K + channels, NMDA receptors, and modulate the activity of various enzymes (261).…”

Section: Polyaminesmentioning

confidence: 99%

Myeloid Cell-Derived Arginase in Cancer Immune Response

et al. 2020

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“…Another physiologically relevant polyamine is PUT, a diamine synthesised in the polyamine synthesis pathway [50]. Ornithine and agmatine are precursors of PUT that are produced in ornithine decarboxylase (ODC)-or agmatinase (AGMAT)-catalysed reactions respectively.…”

Section: Dhs Binds Spermine and Putrescinementioning

confidence: 99%

Half Way to Hypusine—Structural Basis for Substrate Recognition by Human Deoxyhypusine Synthase

2020

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Deoxyhypusine synthase (DHS) is a transferase enabling the formation of deoxyhypusine, which is the first, rate-limiting step of a unique post-translational modification: hypusination. DHS catalyses the transfer of a 4-aminobutyl moiety of polyamine spermidine to a specific lysine of eukaryotic translation factor 5A (eIF5A) precursor in a nicotinamide adenine dinucleotide (NAD)-dependent manner. This modification occurs exclusively on one protein, eIF5A, and it is essential for cell proliferation. Malfunctions of the hypusination pathway, including those caused by mutations within the DHS encoding gene, are associated with conditions such as cancer or neurodegeneration. Here, we present a series of high-resolution crystal structures of human DHS. Structures were determined as the apoprotein, as well as ligand-bound states at high-resolutions ranging from 1.41 to 1.69 Å. By solving DHS in complex with its natural substrate spermidine (SPD), we identified the mode of substrate recognition. We also observed that other polyamines, namely spermine (SPM) and putrescine, bind DHS in a similar manner as SPD. Moreover, we performed activity assays showing that SPM could to some extent serve as an alternative DHS substrate. In contrast to previous studies, we demonstrate that no conformational changes occur in the DHS structure upon spermidine-binding. By combining mutagenesis and a light-scattering approach, we show that a conserved “ball-and-chain” motif is indispensable to assembling a functional DHS tetramer. Our study substantially advances our knowledge of the substrate recognition mechanism by DHS and may aid the design of pharmacological compounds for potential applications in cancer therapy.

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“…AMD1 decarboxylated S-adenosylmethionine, which provide aminopropyl for putrescine conversion to spermidine and spermine [27]. Spermidine, one of natural polyamines, is not only a major inducer of growth and proliferation in eukaryotic cell, but also has signi cant mitigative and protective effects against the development of neurodegenerative diseases and impaired cognitive ability [28]. Numerous studies have showed that spermidine treatment could attenuate oxidative stress, neuroin ammation and possess promising neuroprotective effect against degenerative changes [29,30].…”

Section: Discussionmentioning

confidence: 99%

S-adenosylmethionine Decarboxylase 1 Participates in PM2.5 Exposure Induced Neuronal Apoptosis via Mitochondria-Mediated Pathway

Zhu

Shou

et al. 2020

Preprint

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Background: Fine particle (Particulate matter 2.5, PM2.5), as the primary ambient pollutant, is considered harmful to some neurodegenerative diseases, while the specific biochemical mechanism underlying is still unrevealed. Neuronal apoptosis is believed the crucial event in neurodegenerative pathogenesis, but evidence supporting neuronal apoptosis as PM2.5 induced neuronal injury is insufficient. S-adenosylmethionine decarboxylase 1 (AMD1) and its related spermidine synthesis have been shown to participate in cellular apoptosis, but its role in PM2.5 exposure induced neuronal apoptosis was rarely reported. To better understand contribution of AMD1 activity and spermidine in PM2.5 exposure induced neuronal apoptosis, may provide novel therapeutic and preventive targets for air pollution associated neurodegenerative diseases.Methods: In the current work, sixteen C57BL/6 male mice were randomly divided into ambient PM2.5 chamber or filtered air chamber, and the mouse model of whole-body ambient PM2.5 chronic exposure was established. Behavioral and cognitive ability, together with corresponding biomedical index were recorded and tested to evaluated neurotoxicity by PM2.5 exposure in mice. In parallel, PC12 cells and primary hippocampal neurons were applied for PM2.5 treatment to explore the possible cellular and molecular mechanism which may be critically involved in the process. AMD1 activity and cellular spermidine content were modulated by pharmacological approach to examine their participation in PM2.5 triggered neuronal apoptosis, followed by better examination of typical index for mitochondrial membrane potential and mitochondrial-mediated apoptosis pathway signaling.Results: Chronic ambient PM2.5 exposure attenuated spatial learning and memory ability, and triggered neuronal apoptosis together with increased expression of apoptosis-related Bax/Bcl-2 and cleaved caspase-3. PM2.5 exposure impaired AMD1 expression and spermidine synthesis. AMD1 inhibition could mimick PM2.5 exposure induced neuronal apoptosis. Spermidine supplementation rescued against neurotoxicity and inhibited PM2.5 induced apoptosis, in which mitochondrial pathway signaling.Conclusions: Chronic real-time exposure to ambient PM2.5 led to the reduced the ability of spatial learning and memory in mice. Neuronal apoptosis was the key event in the process of neurodegenerative development induced by PM2.5 exposure. AMD1 and spermidine participated in neuronal apoptosis induced by PM2.5 exposure, which was at least partially dependent on mitochondria mediated pathway.

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The functional role of polyamines in eukaryotic cells

Cited by 104 publications

References 104 publications

Myeloid Cell-Derived Arginase in Cancer Immune Response

Myeloid Cell-Derived Arginase in Cancer Immune Response

Half Way to Hypusine—Structural Basis for Substrate Recognition by Human Deoxyhypusine Synthase

S-adenosylmethionine Decarboxylase 1 Participates in PM2.5 Exposure Induced Neuronal Apoptosis via Mitochondria-Mediated Pathway

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