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Journal of Assisted Reproduction and... Mar 2019The aging-related decline in fertility is an increasingly pressing medical and economic issue in modern society where women are delaying family building. Increasingly... (Review)
Review
The aging-related decline in fertility is an increasingly pressing medical and economic issue in modern society where women are delaying family building. Increasingly sophisticated, costly, and often increasingly invasive, assisted reproductive clinical protocols and laboratory technologies (ART) have helped many older women achieve their reproductive goals. Current ART procedures have not been able to address the fundamental problem of oocyte aging, the increased rate of egg aneuploidy, and the decline of developmental potential of the eggs. Oocyte maturation, which is triggered by luteinizing hormone (LH) in vivo or by injection of human chorionic gonadotropin (hCG) in an in vitro fertilization (IVF) clinic, is the critical stage at which the majority of egg aneuploidies arise and when much of an egg's developmental potential is established. Our proposed strategy focuses on improving egg quality in older women by restoring a robust oocyte maturation process. We have identified putrescine deficiency as one of the causes of poor egg quality in an aged mouse model. Putrescine is a biogenic polyamine naturally produced in peri-ovulatory ovaries. Peri-ovulatory putrescine supplementation has reduced egg aneuploidy, improved embryo quality, and reduced miscarriage rates in aged mice. In this paper, we review the literature on putrescine, its occurrence and physiology in living organisms, and its unique role in oocyte maturation. Preliminary human data demonstrates that there is a maternal aging-related deficiency in ovarian ornithine decarboxylase (ODC), the enzyme responsible for putrescine production. We argue that peri-ovulatory putrescine supplementation holds great promise as a natural and effective therapy for infertility in women of advanced maternal age, applicable in natural conception and in combination with current ART therapies.
Topics: Abortion, Spontaneous; Adult; Aging; Female; Fertilization in Vitro; Humans; Infertility, Female; Middle Aged; Oocytes; Oogenesis; Ornithine Decarboxylase; Ovary; Pregnancy; Putrescine; Reproduction
PubMed: 30467617
DOI: 10.1007/s10815-018-1327-x -
Medical Sciences (Basel, Switzerland) Jun 2021Putrescine, spermine, and spermidine are the important polyamines (PAs), found in all living organisms. PAs are formed by the decarboxylation of amino acids, and they... (Review)
Review
Putrescine, spermine, and spermidine are the important polyamines (PAs), found in all living organisms. PAs are formed by the decarboxylation of amino acids, and they facilitate cell growth and development via different cellular responses. PAs are the integrated part of the cellular and genetic metabolism and help in transcription, translation, signaling, and post-translational modifications. At the cellular level, PA concentration may influence the condition of various diseases in the body. For instance, a high PA level is detrimental to patients suffering from aging, cognitive impairment, and cancer. The levels of PAs decline with age in humans, which is associated with different health disorders. On the other hand, PAs reduce the risk of many cardiovascular diseases and increase longevity, when taken in an optimum quantity. Therefore, a controlled diet is an easy way to maintain the level of PAs in the body. Based on the nutritional intake of PAs, healthy cell functioning can be maintained. Moreover, several diseases can also be controlled to a higher extend via maintaining the metabolism of PAs. The present review discusses the types, important functions, and metabolism of PAs in humans. It also highlights the nutritional role of PAs in the prevention of various diseases.
Topics: Disease Management; Humans; Polyamines; Putrescine; Spermidine; Spermine
PubMed: 34207607
DOI: 10.3390/medsci9020044 -
Science Advances Oct 2023Spermidine, a ubiquitous polyamine, is known to be required for critical physiological functions in bacteria. Two principal pathways are known for spermidine...
Spermidine, a ubiquitous polyamine, is known to be required for critical physiological functions in bacteria. Two principal pathways are known for spermidine biosynthesis, both of which involve aminopropylation of putrescine. Here, we identified a spermidine biosynthetic pathway via a previously unknown metabolite, carboxyaminopropylagmatine (CAPA), in a model cyanobacterium sp. PCC 6803 through an approach combining C and N tracers, metabolomics, and genetic and biochemical characterization. The CAPA pathway starts with reductive condensation of agmatine and l-aspartate-β-semialdehyde into CAPA by a previously unknown CAPA dehydrogenase, followed by decarboxylation of CAPA to form aminopropylagmatine, and ends with conversion of aminopropylagmatine to spermidine by an aminopropylagmatine ureohydrolase. Thus, the pathway does not involve putrescine and depends on l-aspartate-β-semialdehyde as the aminopropyl group donor. Genomic, biochemical, and metagenomic analyses showed that the CAPA-pathway genes are widespread in 15 different phyla of bacteria distributed in marine, freshwater, and other ecosystems.
Topics: Spermidine; Putrescine; Biosynthetic Pathways; Aspartic Acid; Ecosystem; Cyanobacteria
PubMed: 37878710
DOI: 10.1126/sciadv.adj9075 -
MSystems Aug 2022Fusobacterium nucleatum is a common constituent of the oral microbiota in both periodontal health and disease. Previously, we discovered ornithine cross-feeding between...
Fusobacterium nucleatum is a common constituent of the oral microbiota in both periodontal health and disease. Previously, we discovered ornithine cross-feeding between F. nucleatum and Streptococcus gordonii, where S. gordonii secretes ornithine via an arginine-ornithine antiporter (ArcD), which in turn supports the growth and biofilm development of F. nucleatum; however, broader metabolic aspects of F. nucleatum within polymicrobial communities and their impact on periodontal pathogenesis have not been addressed. Here, we show that when cocultured with S. gordonii, F. nucleatum increased amino acid availability to enhance the production of butyrate and putrescine, a polyamine produced by ornithine decarboxylation. Coculture with Veillonella parvula, another common inhabitant of the oral microbiota, also increased lysine availability, promoting cadaverine production by F. nucleatum. We confirmed that ArcD-dependent S. gordonii-excreted ornithine induces synergistic putrescine production, and mass spectrometry imaging revealed that this metabolic capability creates a putrescine-rich microenvironment on the surface of F. nucleatum biofilms. We further demonstrated that polyamines caused significant changes in the biofilm phenotype of a periodontal pathogen, Porphyromonas gingivalis, with putrescine accelerating the biofilm life cycle of maturation and dispersal. This phenomenon was also observed with putrescine derived from S. gordonii-F. nucleatum coculture. Lastly, analysis of plaque samples revealed cooccurrence of P. gingivalis with genetic modules for putrescine production by S. gordonii and F. nucleatum. Overall, our results highlight the ability of F. nucleatum to induce synergistic polyamine production within multispecies consortia and provide insight into how the trophic web in oral biofilm ecosystems can eventually shape disease-associated communities. Periodontitis is caused by a pathogenic shift in subgingival biofilm ecosystems, which is accompanied by alterations in microbiome composition and function, including changes in the metabolic activity of the biofilm, which comprises multiple commensals and pathogens. While Fusobacterium nucleatum is a common constituent of the supra- and subgingival biofilms, its metabolic integration within polymicrobial communities and the impact on periodontal pathogenesis are poorly understood. Here, we report that amino acids supplied by other commensal bacteria induce polyamine production by F. nucleatum, creating polyamine-rich microenvironments. Polyamines reportedly have diverse functions in bacterial physiology and possible involvement in periodontal pathogenesis. We show that the F. nucleatum-integrated trophic network yielding putrescine from arginine through ornithine accelerates the biofilm life cycle of Porphyromonas gingivalis, a periodontal pathogen, from the planktonic state through biofilm formation to dispersal. This work provides insight into how cooperative metabolism within oral biofilms can tip the balance toward periodontitis.
Topics: Humans; Fusobacterium nucleatum; Putrescine; Biofilms; Periodontitis; Porphyromonas gingivalis; Microbiota; Arginine; Ornithine
PubMed: 35852319
DOI: 10.1128/msystems.00170-22 -
International Journal of Molecular... May 2023Putrescine is a bioactive polyamine. Its retinal concentration is strictly controlled to maintain a healthy sense of vision. The present study investigated putrescine...
Putrescine is a bioactive polyamine. Its retinal concentration is strictly controlled to maintain a healthy sense of vision. The present study investigated putrescine transport at the blood-retinal barrier (BRB) to gain a better understanding of the mechanisms of putrescine regulation in the retina. Our microdialysis study showed that the elimination rate constant during the terminal phase was significantly greater (1.90-fold) than that of [C]D-mannitol, which is a bulk flow marker. The difference in the apparent elimination rate constants of [H]putrescine and [C]D-mannitol was significantly decreased by unlabeled putrescine and spermine, suggesting active putrescine transport from the retina to the blood across the BRB. Our study using model cell lines of the inner and outer BRB showed that [H]putrescine transport was time-, temperature-, and concentration-dependent, suggesting the involvement of carrier-mediated processes in putrescine transport at the inner and outer BRB. [H]Putrescine transport was significantly reduced under Na-free, Cl-free, and K-replacement conditions, and attenuated by polyamines or organic cations such as choline, a choline transporter-like protein (CTL) substrate. Rat CTL1 cRNA-injected oocytes exhibited marked alterations in [H]putrescine uptake, and CTL1 knockdown significantly reduced [H]putrescine uptake in model cell lines, suggesting the possible participation of CTL1 in putrescine transport at the BRB.
Topics: Rats; Animals; Blood-Retinal Barrier; Putrescine; Rats, Wistar; Retina; Biological Transport; Polyamines; Mannitol
PubMed: 37240348
DOI: 10.3390/ijms24109003 -
Nature Communications Oct 2023The broad bioactivities of nonribosomal peptides rely on increasing structural diversity. Genome mining of the Burkholderiales strain Schlegelella brevitalea DSM 7029...
The broad bioactivities of nonribosomal peptides rely on increasing structural diversity. Genome mining of the Burkholderiales strain Schlegelella brevitalea DSM 7029 leads to the identification of a class of dodecapeptides, glidonins, that feature diverse N-terminal modifications and a uniform putrescine moiety at the C-terminus. The N-terminal diversity originates from the wide substrate selectivity of the initiation module. The C-terminal putrescine moiety is introduced by the unusual termination module 13, the condensation domain directly catalyzes the assembly of putrescine into the peptidyl backbone, and other domains are essential for stabilizing the protein structure. Swapping of this module to another two nonribosomal peptide synthetases leads to the addition of a putrescine to the C-terminus of related nonribosomal peptides, improving their hydrophilicity and bioactivity. This study elucidates the mechanism for putrescine addition and provides further insights to generate diverse and improved nonribosomal peptides by introducing a C-terminal putrescine.
Topics: Putrescine; Peptides; Peptide Synthases
PubMed: 37857663
DOI: 10.1038/s41467-023-42387-z -
Pharmacological Research Oct 2016Spermine and spermidine are natural polyamines that are produced mainly via decarboxylation of l-ornithine and the sequential transfer of aminopropyl groups from... (Review)
Review
Spermine and spermidine are natural polyamines that are produced mainly via decarboxylation of l-ornithine and the sequential transfer of aminopropyl groups from S-adenosylmethionine to putrescine by spermidine synthase and spermine synthase. Spermine and spermidine interact with intracellular and extracellular acidic residues of different nature, including nucleic acids, phospholipids, acidic proteins, carboxyl- and sulfate-containing polysaccharides. Therefore, multiple actions have been suggested for these polycations, including modulation of the activity of ionic channels, protein synthesis, protein kinases, and cell proliferation/death, within others. In this review we summarize these neurochemical/neurophysiological/morphological findings, particularly those that have been implicated in the improving and deleterious effects of spermine and spermidine on learning and memory of naïve animals in shock-motivated and nonshock-motivated tasks, from a historical perspective. The interaction with the opioid system, the facilitation and disruption of morphine-induced reward and the effect of polyamines and putative polyamine antagonists on animal models of cognitive diseases, such as Alzheimer's, Huntington, acute neuroinflammation and brain trauma are also reviewed and discussed. The increased production of polyamines in Alzheimer's disease and the biphasic nature of the effects of polyamines on memory and on the NMDA receptor are also considered. In light of the current literature on polyamines, which include the description of an inborn error of the metabolism characterized by mild-to moderate mental retardation and polyamine metabolism alterations in suicide completers, we can anticipate that polyamine targets may be important for the development of novel strategies and approaches for understanding the etiopathogenesis of important central disorders and their pharmacological treatment.
Topics: Animals; Binding Sites; Cognitive Dysfunction; Humans; Learning; Memory; Putrescine; Rats; Spermidine; Spermine
PubMed: 27015893
DOI: 10.1016/j.phrs.2016.03.023 -
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 -
Microbiology Spectrum Jun 2022Pseudomonas aeruginosa is a vital opportunistic human bacterial pathogen that causes acute and chronic infections. In this study, we set to determine whether the...
Pseudomonas aeruginosa is a vital opportunistic human bacterial pathogen that causes acute and chronic infections. In this study, we set to determine whether the endogenous spermidine biosynthesis plays a role in regulation of type III secretion system (T3SS). The results showed that deletion of and , which encode putrescine biosynthesis, did not seem to affect cellular spermidine level and the T3SS gene expression. In contrast, mutation of and encoding spermidine biosynthesis led to significantly decreased spermidine production and expression of T3SS genes. We also showed that endogenous spermidine could auto-induce the transcriptional expression of and its full functionality required the transporter SpuDEFGH. Cytotoxicity analysis showed that mutants Δ and Δ were substantially attenuated in virulence compared with their wild-type strain PAO1. Our data imply a possibility that spermidine biosynthesis in P. aeruginosa may not use putrescine as a substrate, and that spermidine signaling pathway may interact with other two T3SS regulatory mechanisms in certain degree, i.e., cAMP-Vfr and GacS/GacA signaling systems. Taken together, these results specify the role of endogenous spermidine in regulation of T3SS in P. aeruginosa and provide useful clues for design and development antimicrobial therapies. Type III secretion system (T3SS) is one of the pivotal virulence factors of Pseudomonas aeruginosa responsible for evading phagocytosis, and secreting and translocating effectors into host cells. Previous studies underline the complicated and elaborate regulatory mechanisms of T3SS for the accurate, fast, and malicious pathogenicity of P. aeruginosa. Among these regulatory mechanisms, our previous study indicated that the spermidine from the host was vital to the host-pathogen interaction. However, the role of endogenous spermidine synthesized by P. aeruginosa on the regulation of T3SS expression is largely unknown. Here we reveal the role and regulatory network of endogenous spermidine synthesis in regulation of T3SS and bacterial virulence, showing that the spermidine is an important interspecies signal for modulating the virulence of P. aeruginosa through regulating T3SS expression.
Topics: Bacterial Proteins; Gene Expression Regulation, Bacterial; Pseudomonas aeruginosa; Putrescine; Spermidine; Type III Secretion Systems; Virulence Factors
PubMed: 35435755
DOI: 10.1128/spectrum.00644-22 -
Molecules and Cells Dec 2022Exogenous polyamines are able to induce life span and improve glucose homeostasis and insulin sensitivity. However, the effects of exogenous polyamines on adipocyte...
Exogenous polyamines are able to induce life span and improve glucose homeostasis and insulin sensitivity. However, the effects of exogenous polyamines on adipocyte differentiation and which polyamine transporters mediate them have not been elucidated yet. Here, we identified for the first time that exogenous polyamines can clearly stimulate adipocyte differentiation through polyamine transporters, solute carrier family 3 member A2 (SLC3A2) and SLC7A1. Exogenous polyamines markedly promote 3T3-L1 adipocyte differentiation by increasing the intracellular lipid accumulation and the expression of both adipogenic and lipogenic genes in a concentration-dependent manner. In particular, exogenous putrescine mainly regulates adipocyte differentiation in the early and intermediate stages. Moreover, we have assessed the expression of polyamine transporter genes in 3T3-L1 preadipocytes and adipocytes. Interestingly, the putrescine-induced adipocyte differentiation was found to be significantly suppressed in response to a treatment with a polyamine transporter inhibitor (AMXT-1501). Furthermore, knockdown experiments using siRNA that specifically targeted SLC3A2 or SLC7A2, revealed that both SLC3A2 and SLC7A2 act as important transporters in the cellular importing of exogenous putrescine. Thus, the exogenous putrescine entering the adipocytes via cellular transporters is involved in adipogenesis through a modulation of both the mitotic clonal expansion and the expression of master transcription factors. Taken together, these results suggest that exogenous polyamines (such as putrescine) entering the adipocytes through polyamine transporters, can stimulate adipogenesis.
Topics: Animals; Mice; 3T3-L1 Cells; Adipocytes; Adipogenesis; Cell Differentiation; Fusion Regulatory Protein 1, Heavy Chain; Polyamines; Putrescine; Amino Acid Transport Systems, Basic
PubMed: 36572564
DOI: 10.14348/molcells.2022.0123