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Journal of Experimental & Clinical... Oct 2011Increased polyamine concentrations in the blood and urine of cancer patients reflect the enhanced levels of polyamine synthesis in cancer tissues arising from increased... (Review)
Review
Increased polyamine concentrations in the blood and urine of cancer patients reflect the enhanced levels of polyamine synthesis in cancer tissues arising from increased activity of enzymes responsible for polyamine synthesis. In addition to their de novo polyamine synthesis, cells can take up polyamines from extracellular sources, such as cancer tissues, food, and intestinal microbiota. Because polyamines are indispensable for cell growth, increased polyamine availability enhances cell growth. However, the malignant potential of cancer is determined by its capability to invade to surrounding tissues and metastasize to distant organs. The mechanisms by which increased polyamine levels enhance the malignant potential of cancer cells and decrease anti-tumor immunity are reviewed. Cancer cells with a greater capability to synthesize polyamines are associated with increased production of proteinases, such as serine proteinase, matrix metalloproteinases, cathepsins, and plasminogen activator, which can degrade surrounding tissues. Although cancer tissues produce vascular growth factors, their deregulated growth induces hypoxia, which in turn enhances polyamine uptake by cancer cells to further augment cell migration and suppress CD44 expression. Increased polyamine uptake by immune cells also results in reduced cytokine production needed for anti-tumor activities and decreases expression of adhesion molecules involved in anti-tumor immunity, such as CD11a and CD56. Immune cells in an environment with increased polyamine levels lose anti-tumor immune functions, such as lymphokine activated killer activities. Recent investigations revealed that increased polyamine availability enhances the capability of cancer cells to invade and metastasize to new tissues while diminishing immune cells' anti-tumor immune functions.
Topics: Humans; Neoplasms; Polyamines
PubMed: 21988863
DOI: 10.1186/1756-9966-30-95 -
Biomolecules May 2023The biogenic polyamines, spermidine (Spd) and spermine (Spm), are present at millimolar concentrations in all eukaryotic cells, where they participate in the regulation...
The biogenic polyamines, spermidine (Spd) and spermine (Spm), are present at millimolar concentrations in all eukaryotic cells, where they participate in the regulation of vitally important cellular functions. Polyamine analogs and derivatives are a traditional and important instrument for the investigation of the cellular functions of polyamines, enzymes of their metabolism, and the regulation of the biosynthesis of antizyme-a key downregulator of polyamine homeostasis. Here, we describe convenient gram-scale syntheses of a set of -methylated analogs of Spd. The biochemical properties of these compounds and the possibility for the regulation of their activity by moving a methyl group along the polyamine backbone and by changing the stereochemistry of the chiral center(s) are discussed.
Topics: Spermidine; Polyamines; Spermine; Biogenic Polyamines; Homeostasis
PubMed: 37371496
DOI: 10.3390/biom13060916 -
Journal of Alzheimer's Disease : JAD 2024A hypothesis of Alzheimer's disease etiology is proposed describing how cellular stress induces excessive polyamine synthesis and recycling which can disrupt nucleoli....
A hypothesis of Alzheimer's disease etiology is proposed describing how cellular stress induces excessive polyamine synthesis and recycling which can disrupt nucleoli. Polyamines are essential in nucleolar functions, such as RNA folding and ribonucleoprotein assembly. Changes in the nucleolar pool of anionic RNA and cationic polyamines acting as counterions can cause significant nucleolar dynamics. Polyamine synthesis reduces S-adenosylmethionine which, at low levels, triggers tau phosphorylation. Also, polyamine recycling reduces acetyl-CoA needed for acetylcholine, which is low in Alzheimer's disease. Extraordinary nucleolar expansion and/or contraction can disrupt epigenetic control in peri-nucleolar chromatin, such as chromosome 14 with the presenilin-1 gene; chromosome 21 with the amyloid precursor protein gene; chromosome 17 with the tau gene; chromosome 19 with the APOE4 gene; and the inactive X chromosome (Xi; aka "nucleolar satellite") with normally silent spermine synthase (polyamine synthesis) and spermidine/spermine-N1-acetyltransferase (polyamine recycling) alleles. Chromosomes 17, 19 and the Xi have high concentrations of Alu elements which can be transcribed by RNA polymerase III if positioned nucleosomes are displaced from the Alu elements. A sudden flood of Alu RNA transcripts can competitively bind nucleolin which is usually bound to Alu sequences in structural RNAs that stabilize the nucleolar heterochromatic shell. This Alu competition leads to loss of nucleolar integrity with leaking of nucleolar polyamines that cause aggregation of phosphorylated tau. The hypothesis was developed with key word searches (e.g., PubMed) using relevant terms (e.g., Alzheimer's, lupus, nucleolin) based on a systems biology approach and exploring autoimmune disease tautology, gaining synergistic insights from other diseases.
Topics: Humans; Polyamines; Alzheimer Disease; Cell Nucleolus; Autoimmune Diseases; RNA
PubMed: 38489184
DOI: 10.3233/JAD-231184 -
Cell Host & Microbe Aug 2016Polyamines are small, positively charged molecules derived from ornithine and synthesized through an intricately regulated enzymatic pathway. Within cells, they are...
Polyamines are small, positively charged molecules derived from ornithine and synthesized through an intricately regulated enzymatic pathway. Within cells, they are abundant and play several roles in diverse processes. We find that polyamines are required for the life cycle of the RNA viruses chikungunya virus (CHIKV) and Zika virus (ZIKV). Depletion of spermidine and spermine via type I interferon signaling-mediated induction of spermidine/spermine N1-acetyltransferase (SAT1), a key catabolic enzyme in the polyamine pathway, restricts CHIKV and ZIKV replication. Polyamine depletion restricts these viruses in vitro and in vivo, due to impairment of viral translation and RNA replication. The restriction is released by exogenous replenishment of polyamines, further supporting a role for these molecules in virus replication. Thus, SAT1 and, more broadly, polyamine depletion restrict viral replication and suggest promising avenues for antiviral therapies.
Topics: Acetyltransferases; Chikungunya virus; Polyamines; Spermidine; Spermine; Virus Replication; Zika Virus
PubMed: 27427208
DOI: 10.1016/j.chom.2016.06.011 -
Microbiology (Reading, England) Dec 2021Polyamines constitute a group of organic polycations positively charged at physiological pH. They are involved in a large variety of biological processes, including the...
Polyamines constitute a group of organic polycations positively charged at physiological pH. They are involved in a large variety of biological processes, including the protection against physiological stress. In this study, we show that the genome of , a commensal bacterium of the intestine and the vagina and one of the most common agents responsible of neonate infections, does not encode proteins homologous to the specific enzymes involved in the known polyamine synthetic pathways. This lack of biosynthetic capability was verified experimentally by TLC analysis of the intracellular content of grown in the absence of polyamines. However, similar analyses showed that the polyamines spermidine, spermine and putrescine can be imported from the growth media into the bacteria. We found that all strains of possess the genes encoding the polyamine ABC transporter PotABCD. We demonstrated that these genes form an operon with , a gene involved in folate biosynthesis, , a gene involved in peptidoglycan biosynthesis, and with , a gene encoding a Cl/H antiporter involved in resistance to acid stress in . Transcription of the operon is induced by peroxide-induced oxidative stress but not by acidic stress. Spermidine and spermine were found to be inducers of transcription at pH 7.4 whereas putrescine induces this expression only during peroxide-induced oxidative stress. Using a deletion mutant of , we were nevertheless unable to associate phenotypic traits to the PotABCD transporter, probably due to the existence of one or more as yet identified transporters with a redundant action.
Topics: Biological Transport; Humans; Infant, Newborn; Membrane Transport Proteins; Polyamines; Putrescine; Spermidine; Streptococcus agalactiae
PubMed: 34910617
DOI: 10.1099/mic.0.001124 -
The Journal of Biological Chemistry Aug 2023Polyamines are positively charged alkylamines ubiquitous among eukaryotes, prokaryotes, and archaea. Humans obtain polyamines through dietary intake, metabolic...
Polyamines are positively charged alkylamines ubiquitous among eukaryotes, prokaryotes, and archaea. Humans obtain polyamines through dietary intake, metabolic production, or uptake of polyamines made by gut microbes. The polyamine biosynthetic pathway used by most gut microbes differs from that used by human cells. This alternative pathway employs carboxyspermidine dehydrogenase (CASDH), an enzyme with limited characterization. Here, we solved a 1.94 Å X-ray crystal structure of Bacteroides fragilis CASDH by molecular replacement. BfCASDH is composed of three domains with a fold similar to saccharopine dehydrogenase but with a distinct active site arrangement. Using steady-state methods, we determined k and k/K for BfCASDH and Clostridium leptum CASDH using putrescine, diaminopropane, aspartate semi-aldehyde, NADH, and NADPH as substrates. These data revealed evidence of cooperativity in BfCASDH. Putrescine is the likely polyamine substrate and NADPH is the coenzyme used to complete the reaction, forming carboxyspermidine as a product. These data provide the first kinetic characterization of CASDH-a key enzyme in the production of microbial polyamines.
Topics: Humans; NADP; Oxidoreductases; Polyamines; Putrescine; Spermidine; Bacteroides fragilis
PubMed: 37437886
DOI: 10.1016/j.jbc.2023.105033 -
Science Advances Jan 2018The study of metabolism has provided remarkable information about the biological basis and therapeutic weaknesses of cancer cells. Classic biochemistry established the... (Review)
Review
The study of metabolism has provided remarkable information about the biological basis and therapeutic weaknesses of cancer cells. Classic biochemistry established the importance of metabolic alterations in tumor biology and revealed the importance of various metabolite families to the tumorigenic process. We have evidence of the central role of polyamines, small polycatonic metabolites, in cell proliferation and cancer growth from these studies. However, how cancer cells activate this metabolic pathway and the molecular cues behind the oncogenic action of polyamines has remained largely obscure. In contrast to the view of metabolites as fuel (anabolic intermediates) for cancer cells, polyamines are better defined as the oil that lubricates the cancer engine because they affect the activity of biological processes. Modern research has brought back to the limelight this metabolic pathway, providing a strong link between genetic, metabolic, and signaling events in cancer. In this review, we enumerate and discuss current views of the regulation and activity of polyamine metabolism in tumor cell biology.
Topics: Animals; Chromatin Assembly and Disassembly; Humans; Neoplasms; Polyamines; Signal Transduction
PubMed: 29376126
DOI: 10.1126/sciadv.aar2606 -
The FEBS Journal Mar 2006Polyamine oxidase (PAO) and spermine oxidase (SMO) are involved in the catabolism of polyamines--basic regulators of cell growth and proliferation. The discovery of... (Comparative Study)
Comparative Study
Polyamine oxidase (PAO) and spermine oxidase (SMO) are involved in the catabolism of polyamines--basic regulators of cell growth and proliferation. The discovery of selective inhibitors of PAO and SMO represents an important tool in studying the involvement of these enzymes in polyamine homeostasis and a starting point for the development of novel antineoplastic drugs. Here, a comparative study on murine PAO (mPAO) and SMO (mSMO) inhibition by the polyamine analogues 1,8-diaminooctane, 1,12-diaminododecane, N-prenylagmatine (G3), guazatine and N,N1-bis(2,3-butadienyl)-1,4-butanediamine (MDL72527) is reported. Interestingly, 1,12-Diaminododecane and G3 behave as specific inhibitors of mPAO, values of K(i) for mPAO inhibition being lower than those for mSMO inactivation by several orders of magnitude. The analysis of molecular models of mPAO and mSMO indicates a significant reduction of the hydrophobic pocket located in maize PAO (MPAO) at the wider catalytic tunnel opening. This observation provides a rationale to explain the lower affinity displayed by G3, guazatine and MDL72527 for mPAO and mSMO as compared to MPAO. The different behaviour displayed by 1,12-diaminododecane towards mPAO and mSMO reveals the occurrence of basic differences in the ligand binding mode of the two enzymes, the first enzyme interacting mainly with substrate secondary amino groups and the second one with substrate primary amino groups. Thus, the data reported here provide the basis for the development of novel and selective inhibitors able to discriminate between mammalian SMO and PAO activities.
Topics: Amino Acid Sequence; Animals; Catalysis; Catalytic Domain; Cloning, Molecular; Dose-Response Relationship, Drug; Enzyme Inhibitors; Mice; Models, Molecular; Molecular Sequence Data; Molecular Structure; Oxidation-Reduction; Oxidoreductases Acting on CH-NH Group Donors; Polyamines; Substrate Specificity; Polyamine Oxidase
PubMed: 16519678
DOI: 10.1111/j.1742-4658.2006.05137.x -
International Journal of Molecular... May 2022Spermidine/spermine N-acetyltransferase (SSAT) functions as a critical enzyme in maintaining the homeostasis of polyamines, including spermine, spermidine, and... (Review)
Review
Spermidine/spermine N-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.
Topics: Acetyltransferases; Animals; Humans; Mammals; Neoplasms; Polyamines; Spermidine; Spermine
PubMed: 35682610
DOI: 10.3390/ijms23115926 -
Science Advances Dec 2020Robust and effective T cell-mediated immune responses require proper allocation of metabolic resources through metabolic pathways to sustain the energetically costly...
Robust and effective T cell-mediated immune responses require proper allocation of metabolic resources through metabolic pathways to sustain the energetically costly immune response. As an essential class of polycationic metabolites ubiquitously present in all living organisms, the polyamine pool is tightly regulated by biosynthesis and salvage pathway. We demonstrated that arginine is a major carbon donor and glutamine is a minor carbon donor for polyamine biosynthesis in T cells. Accordingly, the dependence of T cells can be partially relieved by replenishing the polyamine pool. In response to the blockage of biosynthesis, T cells can rapidly restore the polyamine pool through a compensatory increase in extracellular polyamine uptake, indicating a layer of metabolic plasticity. Simultaneously blocking synthesis and uptake depletes the intracellular polyamine pool, inhibits T cell proliferation, and suppresses T cell inflammation, indicating the potential therapeutic value of targeting the polyamine pool for managing inflammatory and autoimmune diseases.
Topics: Arginine; Carbon; Cell Proliferation; Homeostasis; Polyamines
PubMed: 33328226
DOI: 10.1126/sciadv.abc4275