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PubMed2003

Yeast Fms1 is a FAD-utilizing polyamine oxidase.

In this report we show that recombinant Saccharomyces cerevisiae Fms1 protein is a polyamine oxidase that binds FAD with an FAD:Fms1 stoichiometry of 1:1. Biochemical characterization of Fms1 shows that it can oxidize spermine, N(1)-acetylspermine, N(1)-acetylspermidine, and N(8)-acetylspermidine, but not spermidine. The products of spermine oxidation are spermidine and 3-aminopropanal. A kinetic analysis revealed that spermine, N(1)-acetylspermine, and N(1)-acetylspermidine are oxidized with similar efficiencies, while N(8)-acetylspermidine is a poor substrate. The data support a previous report, suggesting that Fms1 is responsible for the production of beta-alanine from spermine for the synthesis of pantothenic acid.

Acetylation↗
PubMed1993

Elevated ornithine decarboxylase activity, polyamines and cell proliferation in neoplastic and vacuolated liver cells of winter flounder (Pleuronectes americanus)

Liver neoplasms, including hepatocellular and cholangiocellular tumors, commonly occur in winter flounder (Pleuronectes americanus) caught from some chemically contaminated areas such as Boston Harbor. Hydropically vacuolated cells, very often associated with neoplasia in winter flounder liver, appear to represent the first cellular abnormality in animals that later develop frank neoplasms. The proliferative capacity of hydropically vacuolated cells was studied by analyzing both ornithine decarboxylase (ODC) activity and bromodeoxyuridine (BrdU) labeling indices. Liver of winter flounder with vacuolated cellular lesions had ODC activity more than 5- to 12-fold greater than that in liver that lacked such vacuolation, whether caught from Boston Harbor or Georges Bank. Large focal areas of hydropically vacuolated cells dissected from severely affected livers had ODC activity as high or higher than surrounding parenchymal tissue. Significant elevations in hepatic polyamine levels and ratios of putrescine/spermidine were also present in all Boston Harbor animals studied, especially those exhibiting vacuolated cellular lesions, as compared to Georges Bank fish. BrdU labeling techniques indicate that hydropically vacuolated cells, along with perivacuolar small basophilic cells and neoplastic cholangiocytes, appear to have the capacity to synthesize DNA and undergo mitosis. The frequent association of hydropically vacuolated cells with hepatic neoplasia, along with high ODC activity and DNA synthesis capability, suggest that the vacuolated cells and/or perivacuolar basophilic cells may be integral to the development of some neoplastic phenotypes in winter flounder liver.

Animals↗
PubMed1994

Inhibition of ornithine decarboxylase does not prevent intestinal smooth muscle hyperplasia in the rat.

The objective of this research is to examine the relationship between intestinal smooth muscle cell proliferation and polyamine metabolism. Proliferation of muscle is induced by serosal application of benzyldimethyltetradecylammonium chloride (BAC) to a segment of rat jejunum. This treatment destroys all of the longitudinal muscle, one-half of the circular muscle, and the myenteric and extrinsic nerves. The remaining muscle cells undergo mitosis and, by 15 days, the number of muscle cells is increased in both the longitudinal and circular muscle layers. Within 12 h after BAC treatment, there is an increase in the activity of ornithine decarboxylase (ODC) that returns to preinjury levels by 4 days. The smooth muscle content of the three polyamines putrescine, spermidine, and spermine is increased 6 h after injury, returning to preinjury levels within 1 day. DL-alpha-Difluoromethylornithine (DFMO), an irreversible inhibitor of ODC, prevents the transient increases in both ODC activity and the three polyamines in the smooth muscle. In addition to preventing the transient increases in the three polyamines, DMFO has different effects on smooth muscle content of putrescine, spermidine, and spermine. Putrescine content is permanently depleted by DFMO. Spermidine and spermine content is initially decreased within 24 h by DFMO administration. In contrast to the persistent depletion of putrescine by DFMO, spermidine and spermine return to preinjury levels by 2 days. The maximal peak in DNA synthesis occurs 2 days after injury. In DFMO-administered animals, the maximal DNA synthesis occurs 5 days after injury. The increases in smooth muscle wet weight and DNA content 15 days after injury are not affected by DFMO.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

[Effects of zinc and boron nutrition on balsam pear (Momordica charantia) yield and quality, and polyamines, hormone, and senescence of its leaves].

Field trial and physiological determination on the effects of zinc and boron nutrition on balsam pear (Momordica charantia) yield and quality and on polyamines, hormone, and senescence of its leaves showed that application of ZnSO4.7H2O and Na2B4o7.10H2O on Zn and B deficient soils could increase balsam pear yield and its contents of protein, Vc and 17 sorts of amino acids, especially the contents of essential amino acids for human body, but decrease the NO3(-)-N content. The reason was that Zn and B could increase polyamines (PAs), putrescine (Put), spermidine (Spd), spermine (Spm), indole acetic acid (IAA), gibberellic acid (GA3) and ascorbic acid (ASA) contents and superoxide dismutase (SOD), peroxidase (POD) and catalase(CAT) activities, and reduce malondialdehyde (MDA), abscisic acid (ABA) contents in leaves, which inhibited membrane lipid peroxidation. The results also showed that there was a significant positive correlation between yields and PAs, Put, Spd, Spm, GA3, SOD, POD, CAT, but a significant negative correlation with MDA and ABA contents in leaves. There was a significant positive correlation between MDA and ABA, but a significant negative correlation with PAs, Put, Spd, Spm, IAA, GA3, ASA, SOD, POD, and CAT.

Aging↗
PubMedDate not supplied

[Distribution of polyamines in Escherichia coli and their role in potassium exchange between the cell and the environment during aerobiosis-anaerobiosis transitions].

The transition of E. coli cells to anaerobiosis is accompanied by the onset of two cellular cation flows in different directions: potassium is released into the environment, and putrescine enters the cells. If aerobic conditions are reestablished, the cation flows change directions. Under anaerobiosis, the cell components bind putrescine. Investigation of the chemical interactions resulting in putrescine binding and metabolic conversion under anaerobic conditions revealed DNA to be the main target in this process. The driving forces and mechanisms of cation transfer are discussed, and the involvement of putrescine in topological changes in the DNA and the development of adaptive cell responses to anaerobiosis is considered.

Adaptation, Physiological↗
PubMed2005

A dual upstream open reading frame-based autoregulatory circuit controlling polyamine-responsive translation.

A novel form of translational regulation is described for the key polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (AdoMetDC). Plant AdoMetDC mRNA 5' leaders contain two highly conserved overlapping upstream open reading frames (uORFs): the 5' tiny and 3' small uORFs. We demonstrate that the small uORF-encoded peptide is responsible for constitutively repressing downstream translation of the AdoMetDC proenzyme ORF in the absence of increased polyamine levels. This first example of a sequence-dependent uORF to be described in plants is also functional in Saccharomyces cerevisiae. The tiny uORF is required for normal polyamine-responsive AdoMetDC mRNA translation, and we propose that this is achieved by control of ribosomal recognition of the occluded small uORF, either by ribosomal leaky scanning or by programmed -1 frameshifting. In vitro expression demonstrated that both the tiny and the small uORFs are translated. This tiny/small uORF configuration is highly conserved from moss to Arabidopsis thaliana, and a more diverged tiny/small uORF arrangement is found in the AdoMetDC mRNA 5' leader of the single-celled green alga Chlamydomonas reinhardtii, indicating an ancient origin for the uORFs.

Adenosylmethionine Decarboxylase↗
PubMed1996

Activation of ornithine decarboxylase and accumulation of putrescine after traumatic brain injury.

Activation of ornithine decarboxylase (ODC), the initial enzyme in polyamine synthesis, and accumulation of putrescine are thought to mediate pathological processes in the ischemic and traumatized brain. Past studies have separately investigated either ODC or polyamines after head injury. The purpose of the present study was to quantify both ODC activity and polyamines in the rat parietal cortex before and after controlled cortical impact injury. Adult, male rats underwent a right craniectomy and were subjected to a 5 m/sec, 2-mm deformation impact injury. Rats were sacrificed 1, 4, 8, and 24 h postimpact and tissues from the injured (right) and contralateral (left) hemisphere were analyzed for ODC and polyamines. ODC activity was determined by measuring the decarboxylation of [14C]ornithine to putrescine. Putrescine, spermidine, and spermine were determined by high performance liquid chromatography. Cortical impact induced a 10- to 20-fold increase in ODC activity and a 4- to 5-fold increase in putrescine in the ipsilateral cortex. Spermidine and spermine did not significantly increase in the ipsilateral (right) cortex compared to controls (right cortex). In contrast, there was a slight increase in spermidine content in the contralateral (left) cortex after injury. The delayed increase in ODC activity and accumulation of putrescine may mediate pathophysiological changes observed after head injury.

Animals↗
PubMed1995

Autoregulatory frameshifting in decoding mammalian ornithine decarboxylase antizyme.

Rat antizyme gene expression requires programmed, ribosomal frameshifting. A novel autoregulatory mechanism enables modulation of frameshifting according to the cellular concentration of polyamines. Antizyme binds to, and destabilizes, ornithine decarboxylase, a key enzyme in polyamine synthesis. Rapid degradation ensues, thus completing a regulatory circuit. In vitro experiments with a fusion construct using reticulocyte lysates demonstrate polyamine-dependent expression with a frameshift efficiency of 19% at the optimal concentration of spermidine. The frameshift is +1 and occurs at the codon just preceding the terminator of the initiating frame. Both the termination codon of the initiating frame and a pseudoknot downstream in the mRNA have a stimulatory effect. The shift site sequence, UCC-UGA-U, is not similar to other known frameshift sites. The mechanism does not seem to involve re-pairing of peptidyl-tRNA in the new frame but rather reading or occlusion of a fourth base.

Amino Acid Sequence↗
PubMed1995

Antidepressant-like actions of the polyamine site NMDA antagonist, eliprodil (SL-82.0715).

Functional N-methyl-D-aspartate (NMDA) antagonists including competitive antagonists, glycine partial agonists, and use-dependent channel blockers exhibit antidepressant-like actions in preclinical models. The present study examined the effects of eliprodil (SL-82.0715), an NMDA antagonist acting at polyamine sites, in behavioral and neurochemical tests predictive of antidepressant activity. In mice, eliprodil produced a dose-dependent reduction in immobility in the forced swim test, but was inactive in the tail suspension test. Chronic treatment with eliprodil produced both a significant downregulation of beta-adrenoceptors and a reduction in the potency of glycine to inhibit [3H]5,7-dichlorokynurenic acid binding to strychnine-insensitive glycine receptors in neocortical membranes. In toto, these data indicate that like other NMDA antagonists, eliprodil possesses antidepressant-like actions in preclinical tests predictive of clinical efficacy.

Adrenergic Uptake Inhibitors↗
PubMed2001

Tumour promoter mediated altered expression and regulation of ornithine decarboxylase and S-adenosylmethionine decarboxylase in H-ras-transformed fibrosarcoma cell lines.

Alterations in cellular growth are important in the progression of malignant disease. Cell growth regulation by tumour promoters can be complex. The present study demonstrates a novel link between alterations in phorbol ester tumour promoter mediated regulation during malignant conversion and the expression of ornithine decarboxylase and S-adenosylmethionine decarboxylase, key rate-limiting and regulatory activities in the biosynthesis of polyamines. H-ras-transformed mouse 10 T 1/2 cell lines exhibiting increasing malignant potential were investigated for possible phorbol ester tumour promoter mediated changes in ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMDC) gene expression. Selective induction of ODC and SAMDC gene expression was observed, since in contrast to nontransformed parental 10 T1/2 cells, ras-transformed cells capable of benign tumour formation (NR3 cells) and ras-transformed cells capable of metastasis formation (C2 cells) exhibited marked alterations in the levels of ODC and SAMDC gene expression. Increased ODC gene and SAMDC gene expression in response to phorbol-12-myristate-13-acetate (PMA) treatment was found to involve transcriptional events in both NR3 cells and in C2 cells. Post-transcriptional events also played a role in the regulation of ODC gene expression in NR3 cells and in C2 cells, and in the regulation of SAMDC gene expression in C2 cells but not in NR3 cells. In NR3 cells, alterations in ODC and in SAMDC gene expression was an event requiring de novo protein synthesis, whereas in highly malignant C2 cells, protein synthesis inhibition following cycloheximide treatment in cooperation with PMA resulted in an augmentation of both ODC and SAMDC gene expression. Evidence is presented to suggest that the PMA-mediated alterations in ODC and in SAMDC gene expression in NR3 cells and in C2 cells involved protein kinase C - mediated events. The status of the cellular polyamine levels was also an important determinant of the PMA-mediated alterations that occurred in ODC and in SAMDC expression in these H-ras transformed cells. Collectively, these results suggest that PMA can modulate ODC and SAMDC expression in H-ras transformed cells and that the mechanisms involved in the PMA- mediated regulation of ODC and SAMDC gene expression changes as a function of H-ras mediated cellular transformation and malignant progression. This study further suggests a mechanism of PMA stimulation of transformed cells wherein early alterations in the regulatory control of ODC and SAMDC gene expression are important and critical.

Adenosylmethionine Decarboxylase↗
PubMed1993

Studies on the mechanism by which prolactin stimulates alpha-aminoisobutyric acid uptake into cultured mouse mammary tissues.

Studies were carried out to determine the possible roles of the polyamines, cyclic nucleotides, icosanoid products, and protein kinase C in the prolactin regulation of amino acid transport in cultured mammary gland explants derived from 12-14 day pregnant mice. Elevated cyclic AMP concentrations impaired the PRL stimulation of AIB transport. DBcAMP as well as the phosphodiesterase inhibitors theophylline and methyl isobutylxanthine, when added to the cultures, attenuated or abolished the PRL responses. 8-Bromo cyclic GMP elicited a modest stimulation of AIB transport. Ongoing polyamine synthesis appears to be necessary for PRL to effect a stimulation of AIB transport since methylglyoxal bis(guanyl hydrazone), an inhibitor of S-adenosyl methionine decarboxylase, abolishes the PRL response; specificity of this effect was established by its reversal with the addition of spermidine to the culture medium. Ongoing icosanoid product synthesis also appears to be required for the PRL stimulation of AIB transport since indomethacin abolishes the PRL response. Finally, the inhibition of the PRL response by the protein kinase C inhibitor H-7 suggests that the activation of kinase C activity may also be involved in the PRL stimulation of AIB transport.

1-Methyl-3-isobutylxanthine↗
PubMed1993

The effect of hepatic ischemia-reperfusion on polyamine metabolism in some organs of the rat.

Hepatic ischemia was produced by clamping the portal venous and hepatic arterial blood supply to the left lateral and median lobes of the rat liver. Hepatic ornithine decarboxylase (ODC) and spermidine/spermine N1-acetyltransferase (SAT) activities in ischemic and nonischemic regions were increased and, respectively, peaked by 6 hr and 3 hr after 1 hr of hepatic ischemia. Hepatic putrescine contents in ischemic and nonischemic regions were increased and peaked by 6 hr. However, hepatic spermidine and spermine were not increased. an increase in ODC activity was also observed in the spleen and the kidney after 1 hr of hepatic ischemia. [3H]thymidine incorporation into DNA was observed in the liver and the spleen--however it was not observed in the kidney--after hepatic ischemia.

Animals↗
PubMed1992

Seizure activity-induced changes in polyamine metabolism and neuronal pathology during the postnatal period in rat brain.

Systemic injection of kainic acid (KA) does not cause neuronal pathology in limbic structures in rat brain prior to postnatal day (PND) 21. The present study tested if the development of the pathogenic response is associated with the maturation of a link between seizure activity and polyamine metabolism. Pathology was assessed with histological techniques and with the binding of [3H]Ro5-4864, a ligand for the peripheral type benzodiazepine binding sites (PTBBS), a marker of glial cell proliferation. In agreement with previous results, peripherally administered kainate at doses sufficient to induce intense behavioral seizures produced a loss of Nissl staining in hippocampus after PND 21 but not at earlier ages. The pattern of neuronal damage observed after PND 21 resembled that found in adult animals: extensive losses of Nissl staining in area CA3 of hippocampus and in piriform cortex, more modest effects in CA1 and sparing of the granule cells of the dentate gyrus. Similarly, no increase in [3H]Ro5-4864 binding as a result of KA administration was observed in hippocampus and piriform cortex until PND 21. Ornithine decarboxylase (ODC) activity and putrescine levels were high in the neonatal brain and decreased to reach adult values by PND 21. KA-induced seizure activity did not significantly alter both variables until PND 21. After PND 21, ODC activity and putrescine levels markedly increased 16 h after KA-induced seizure activity in hippocampus and piriform cortex. The magnitude of the effects increased between PND 21 and PND 30, at which point the changes in both parameters were comparable to those found in adults. Polyamines stimulate the activity of the calcium-dependent proteases calpain in brain fractions and may increase calpain-mediated proteolysis in situ. In accord with this, kainate-induced breakdown of spectrin, a preferred substrate of calpain, measured 16 h after KA injection followed a developmental curve parallel to that for kainate-induced increases in putrescine levels. These results indicate that the onset of vulnerability to seizure activity triggered by kainic acid is correlated with the development of an ODC/polyamine response to the seizures and further support a critical role for the ODC/polyamine pathway in neuronal pathology following a variety of insults.

Animals↗
PubMed2006

Importance of bile acids for novel oral absorption system containing polyamines to improve intestinal absorption.

The synergetic improving effect of bile acids with spermine (SPM), a major polyamine, on the absorption of rebamipide, a poorly soluble and poorly absorbable drug (BCS Class IV), was evaluated in rats and beagle dogs. Although the absorption of rebamipide was improved by the addition of polyamines alone in normal rats, it was not improved in bile duct ligated (BDL) rats. The combinatorial use of sodium taurocholate (STC), a bile acid, with SPM improved the absorption of rebamipide even in BDL rats. In the beagle dogs, the oral administration of SPM alone did not enhance the absorption of rebamipide, but the combinatorial use of STC with SPM improved the absorption as well as in the BDL rats. These results indicate that bile acids are indispensable for the novel formulation containing SPM to improve the absorption of rebamipide after oral administration.

Alanine↗
PubMed1997

The inhibitory effect of vitamin E on pulmonary polyamine biosynthesis, cell proliferation and carcinogenesis in mice.

We investigated the modulating effect of vitamin E on pulmonary polyamine biosynthesis, cell proliferation and carcinogenesis in mice treated with urethane. Pulmonary ornithine decarboxylase induction and subsequent polyamine accumulation were observed during the initiation and promotion phases of the urethane-induced lung carcinogenesis in mice. The increases of ODC activity and polyamine level during both phases were almost inhibited when a high vitamin E diet was provided. The urethane-increased level of pulmonary proliferating cell nuclear antigen as a marker of cell proliferation during the carcinogenesis was inhibited by vitamin E treatment. Also, vitamin E suppressed the urethane-induced elevation of pulmonary cyclooxygenase activity as a marker of tumor promotion. In conjugation with these events, vitamin E reduced the development of lung tumors in mice treated with urethane. These results indicated that vitamin E could act as a useful chemopreventive agent against lung carcinogenesis in mice due to the regulation of cell proliferation.

Animals↗
PubMed1989

The role of polyamines in interferon and retinoic acid mediated synergistic antiproliferative action.

Retinoic acid alone has no effect on the human breast cancer cell line BT-20 but can amplify the antiproliferative action of interferon-gamma (IFN-gamma). In our system ornithine decarboxylase (ODC) activity correlates well with growth rate; it was investigated whether the antiproliferative effects of IFN-gamma and IFN-gamma plus retinoic acid could be attributed to suppression of ODC activity. The ODC inhibitor difluoromethylornithine (DFMO), which is active as a single agent did not enhance growth inhibition induced by the biological response modifiers. The substitution of the BT-20 cells with putrescine, the product of the enzymatic reaction mediated by ODC, reversed DFMO induced antiproliferative action. On the other hand putrescine did not affect the proliferation of BT-20 cells treated with interferon alone or in combination with retinoic acid.

Biogenic Polyamines↗
PubMed2004

Polyamine uptake in cultured cerebellar granule neurons.

In the present study, we have examined the transport of polyamines in cultured cerebellar granule cells. Our results suggest the existence of two different transporters for polyamines in these neurons. Putrescine and spermidine uptake (K ap m = 2.17 and 1.39 microM, respectively), were affected when extracellular sodium was replaced with choline (about 30% inhibition over controls) or sucrose (about 2.5-fold potentiation over controls). By contrast, the substitution of sodium by choline or sucrose did not modify spermine uptake (K ap m = 13.53 microM) in cerebellar granule cells. Accordingly, alteration of membrane potential with ouabain was able to block putrescine (50% inhibition) and spermidine (60% inhibition) uptake but not spermine uptake. These results indicate that putrescine and spermidine transport in cerebellar granule cells is membrane potential dependent, whereas spermine uptake is not modulated by membrane potential.

Animals↗
PubMed2002

Gene expression profiling reveals alterations of specific metabolic pathways in schizophrenia.

Dysfunction of the dorsal prefrontal cortex (PFC) in schizophrenia may be associated with alterations in the regulation of brain metabolism. To determine whether abnormal expression of genes encoding proteins involved in cellular metabolism contributes to this dysfunction, we used cDNA microarrays to perform gene expression profiling of all major metabolic pathways in postmortem samples of PFC area 9 from 10 subjects with schizophrenia and 10 matched control subjects. Genes comprising 71 metabolic pathways were assessed in each pair, and only five pathways showed consistent changes (decreases) in subjects with schizophrenia. Reductions in expression were identified for genes involved in the regulation of ornithine and polyamine metabolism, the mitochondrial malate shuttle system, the transcarboxylic acid cycle, aspartate and alanine metabolism, and ubiquitin metabolism. Interestingly, although most of the metabolic genes that were consistently decreased across subjects with schizophrenia were not similarly decreased in haloperidol-treated monkeys, the transcript encoding the cytosolic form of malate dehydrogenase displayed prominent drug-associated increases in expression compared with untreated animals. These molecular analyses implicate a highly specific pattern of metabolic alterations in the PFC of subjects with schizophrenia and raise the possibility that antipsychotic medications may exert a therapeutic effect, in part, by normalizing some of these changes.

Adult↗