Physiology of the natural polyamines putrescine, spermidine and spermine.
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The biochemistry and biological function of the naturally occurring polyamines, putrescine, spermidine, and spermine, have been reviewed with special reference to animal organisms. These compounds are universally distributed in all living material. Their biosynthesis from ornithine and methionine is accurately controlled and may fluctuate according to the metabolic needs of the cell. Polyamines strongly and specifically interact with nucleic acids in vitro. It appears that under physiological conditions a substantial portion of cellular polyamines is noncovalently bound to nucleic acids and nucleic acid-containing structures such as ribosomes. Polyamines are able to stimulate protein and ribonucleic acid synthesis in vitro. In several systems characterized by rapid growth polyamines and ribonucleic acid accumulate in parrallel. Evidence that polyamines may have an essential role in protein and/or nucleic acid synthesis is substantiated by recent observations on polyamine-deficient bacterial mutants, although no specific function has been established with certainty as yet. Some clinical applications of polyamine research related to cancer are also discussed briefly.Keywords:
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The addition of arginine to cultures of Escherichia coli K12 deficient in agmatine ureohydrolase (EC 3.5.3.7) results in polyamine depletion and a striking inhibition of nucleic acid accumulation and growth. The omission of lysine from these cultures leads to a further decrease in growth rate and nucleic acid synthesis. In arginine-inhibited cells the addition of putrescine or spermidine, in the presence or absence of lysine, restores the control rate of growth and nucleic acid accumulation. Under the same conditions of arginine inhibition in the absence of lysine, the addition of cadaverine alone stimu- lates growth rate and RNA synthesis. The addition of lysine to polyamine-depleted cultures results in cadaverine production and in the appearance of a new spermidine analogue, containing lysine carbon. The new compound 1has been identified as N-3-aminopropyl-l,5-diaminopen- tane.
Polyamine
Auxotrophy
Agmatine
Lysine decarboxylase
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The biochemistry and biological function of the naturally occurring polyamines, putrescine, spermidine, and spermine, have been reviewed with special reference to animal organisms. These compounds are universally distributed in all living material. Their biosynthesis from ornithine and methionine is accurately controlled and may fluctuate according to the metabolic needs of the cell. Polyamines strongly and specifically interact with nucleic acids in vitro. It appears that under physiological conditions a substantial portion of cellular polyamines is noncovalently bound to nucleic acids and nucleic acid-containing structures such as ribosomes. Polyamines are able to stimulate protein and ribonucleic acid synthesis in vitro. In several systems characterized by rapid growth polyamines and ribonucleic acid accumulate in parrallel. Evidence that polyamines may have an essential role in protein and/or nucleic acid synthesis is substantiated by recent observations on polyamine-deficient bacterial mutants, although no specific function has been established with certainty as yet. Some clinical applications of polyamine research related to cancer are also discussed briefly.
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ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXT.alpha.-Methyl polyamines: metabolically stable spermidine and spermine mimics capable of supporting growth in cells depleted of polyaminesJohn R. Lakanen, James K. Coward, and Anthony E. PeggCite this: J. Med. Chem. 1992, 35, 4, 724–734Publication Date (Print):February 1, 1992Publication History Published online1 May 2002Published inissue 1 February 1992https://pubs.acs.org/doi/10.1021/jm00082a013https://doi.org/10.1021/jm00082a013research-articleACS PublicationsRequest reuse permissionsArticle Views535Altmetric-Citations50LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
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Bacillus alcalophilus, an obligately alkalophilic bacterium, grow at pH 11 with an intracellular pH greater than 9.5. Polyamines are positively charged at physiological pH, but less than 50% of polyamines will be charged at pH 9.5 and above. In view of the importance of polycationic nature of polyamines in their physiological functions, it is of interest to study the polyamine metabolism in B. alcalophilus, an unusual organism that grow at very high pH. Spermidine is the major polyamine in this organism, accounts for more than 90% of total polyamine. The level of spermidine fluctuates between 10 to 30 nmol per mg protein during growth. In contrast, putrescine and spermine levels stay constant during entire period of growth. No ornithine decarboxylase (DC) activity can be detected in B. alcalophilus under all conditions examined. When (/sup 3/H)arginine was added to the bacterial culture, the distribution of radioactivity in polyamine pool was 3% for putrescine, 94% for spermidine, and 3% for spermine, suggesting the presence of arginine pathway for polyamine biosynthesis. B. alcalophilus appears to possess a polyamine transport system that is Na/sup +/-dependent. Putrescine uptake in B. alcalophilus is sensitive to the inhibition of gramicidine S (10 ..mu..M) and valinomycin (2..mu..M).
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Arginine decarboxylase
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The acetyl derivatives of polyamines, N1-acetylspermine (N1-AcSPM) and N1-acetylspermidine (N1-AcSPD), are in vitro better substrates of tissue polyamine oxidase than the corresponding non-acetylated polyamines. Rat hepatoma tissue culture (HTC) cells, depleted of their putrescine (PUT) and spermidine (SPD) content by the use of DL-alpha-difluoromethylornithine (DFMeOrn), an irreversible inhibitor of L-ornithine decarboxylase, were used to study in situ the catabolism of these acetyl derivatives of polyamines. Normal intracellular spermidine content was restored by the addition of N1-acetylspermidine to polyamine-deficient cells. Addition of spermine (SPM) did not restore the spermidine content, although this polyamine elevated the spermine content of the cells. N1-Acetylspermidine reestablished normal spermidine levels of the cells and elevated the cellular putrescine content more efficiently and more rapidly than spermidine. Monoacetylputrescine and N1, N12-diacetylspermine (di-AcSPM) were ineffective in restoring putrescine and spermidine contents. These findings support the concept that N1-acetylspermine and N1-acetylspermidine are natural substrates of tissue polyamine oxidase and suggest poor membrane permeability of monoacetylputrescine (AcPUT) and N1, N12-diacetylspermine. Furthermore, they indicate that acetylation of polyamines by the cytosolic acetyl CoA: polyamine N1-acetyltransferase is the rate-limiting step of polyamine catabolism in rat hepatoma cells. Growth inhibition by DL-alpha-difluoromethylornithine was reversed by N1-acetylspermine and N1-acetylspermidine but not by monoacetylputrescine and N1, N12-diacetylspermine. These results suggest again that the antiproliferative effect of DL-alpha-dilfuoromethylornithine is related to inhibition of polyamine biosynthesis.
Polyamine oxidase
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The polyamines putrescine, spermidine and spermine represent a group of naturally occurring compounds exerting a bewildering number of biological effects, yet despite several decades of intensive research work, their exact physiological function remains obscure. Chemically these compounds are organic aliphatic cations with two (putrescine), three (spermidine) or four (spermine) amino or imino groups that are fully protonated at physiological pH values. Early studies showed that the polyamines are closely connected to the proliferation of animal cells. Their biosynthesis is accomplished by a concerted action of four different enzymes: ornithine decarboxylase, adenosylmethionine decarboxylase, spermidine synthase and spermine synthase. Out of these four enzymes, the two decarboxylases represent unique mammalian enzymes with an extremely short half life and dramatic inducibility in response to growth promoting stimuli. The regulation of ornithine decarboxylase, and to some extent also that of adenosylmethionine decarboxylase, is complex, showing features that do not always fit into the generally accepted rules of molecular biology. The development and introduction of specific inhibitors to the biosynthetic enzymes of the polyamines have revealed that an undisturbed synthesis of the polyamines is a prerequisite for animal cell proliferation to occur. The biosynthesis of the polyamines thus offers a meaningful target for the treatment of certain hyperproliferative diseases, most notably cancer. Although most experimental cancer models responds strikingly to treatment with polyamine antimetabolites—namely, inhibitors of various polyamine synthesizing enzymes—a real breakthrough in the treatment of human cancer has not yet occurred. It is, however, highly likely that the concept is viable. An especially interesting approach is the chemoprevention of cancer with polyamine antimetabolites, a process that appears to work in many experimental animal models. Meanwhile, the inhibition of polyamine accumulation has shown great promise in the treatment of human parasitic diseases, such as African trypanosomiasis.
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Several biochemical parameters, including that of polyamine content, accompanying the growth of the cyanobacterium Anacystis nidulans were studied. At all stages of growth under autotrophic conditions, the organisms were found to be rich in spermidine and lacking in spermine, as is typical of procaryotic organisms. The cells were quite low in putrescine, and no unusual polyamine was observed to be present as a major component. Conjugated polyamines were not detected in the cultures. At maximal culture density, the levels of spermidine, DNA, RNA, protein, and chlorophyll were also maximal. Shortly after the inception of the stationary phase, the spermidine content of the cells was the first parameter observed to decrease in cultures which were shortly to become yellow. Spermidine lost from the cells was not recovered in the medium in a free or conjugated form. This indication of degradation of spermidine was studied by the addition of polyamines to growing cultures. Exogenous spermidine and spermine were found to be metabolized rapidly by the organisms, of which diaminopropane was one product. Putrescine was found to be markedly toxic, whereas spermidine, some other triamines, and spermine were much less toxic.
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