scholarly journals Selective regulation of S-adenosylmethionine decarboxylase activity by the spermine analogue 6-spermyne

1988 ◽  
Vol 254 (2) ◽  
pp. 337-342 ◽  
Author(s):  
C W Porter ◽  
J McManis ◽  
D Lee ◽  
R J Bergeron
Keyword(s):  
Binding Sites ◽  
Enzyme Activities ◽  
Decarboxylase Activity ◽  
Polyamine Biosynthesis ◽  
Adenosylmethionine Decarboxylase ◽  
L1210 Cells ◽  
Initial Decrease ◽  
Function Correlation ◽  
Apparent Ability ◽  
Interesting Structure

Polyamine-biosynthesis activity is known to be negatively regulated by intracellular polyamine pools. Accordingly, treatment of cultured L1210 cells with 10 microM-spermine rapidly and significantly lowered ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC) activities in a sequential manner. By contrast, treatment for 48 h with 10 microM of the unsaturated spermine analogue 6-spermyne lowered AdoMetDC activity, but not ODC activity. An initial decrease in ODC activity at 2 h was attributed to a transient increase in free intracellular spermidine and spermine brought about through their displacement by the analogue. Thereafter, ODC activity recovered steadily to control values as 6-spermyne pools increased and spermidine and spermine pools decreased owing to analogue suppression of AdoMetDC activity. The apparent ability of 6-spermyne to regulate AdoMetDC, but not ODC, activity suggests an interesting structure-function correlation and demonstrates that the typical co-regulation of these enzyme activities can be dissociated. This, in turn, may reflect the existence of independent regulatory binding sites for the two enzymes.

scholarly journals Role of pyridoxal phosphate in mammalian polyamine biosynthesis. Lack of requirement for mammalian S-adenosylmethionine decarboxylase activity

1977 ◽  
Vol 166 (1) ◽  
pp. 81-88 ◽  
Author(s):  
A E Pegg
Keyword(s):  
Ornithine Decarboxylase ◽  
Pyridoxal Phosphate ◽  
Vitamin B ◽  
Decarboxylase Activity ◽  
Deficient Diet ◽  
Polyamine Biosynthesis ◽  
Adenosylmethionine Decarboxylase ◽  
Ornithine Decarboxylase Activity

1. Polyamine concentrations were decreased in rats fed on a diet deficient in vitamin B-6. 2. Ornithine decarboxylase activity was decreased by vitamin B-6 deficiency when assayed in tissue extracts without addition of pyridoxal phosphate, but was greater than in control extracts when pyridoxal phosphate was present in saturating amounts. 3. In contrast, the activity of S-adenosylmethionine decarboxylase was not enhanced by pyridoxal phosphate addition even when dialysed extracts were prepared from tissues of young rats suckled by mothers fed on the vitamin B-6-deficient diet. 4. S-Adenosylmethionine decarboxylase activities were increased by administration of methylglyoxal bis(guanylhydrazone) (1,1′-[(methylethanediylidine)dinitrilo]diguanidine) to similar extents in both control and vitamin B-6-deficient animals. 5. The spectrum of highly purified liver S-adenosylmethionine decarboxylase did not indicate the presence of pyridoxal phosphate. After inactivation of the enzyme by reaction with NaB3H4, radioactivity was incorporated into the enzyme, but was not present as a reduced derivative of pyridoxal phosphate. 6. It is concluded that the decreased concentrations of polyamines in rats fed on a diet containing vitamin B-6 may be due to decreased activity or ornithine decarboxylase or may be caused by an unknown mechanism responding to growth retardation produced by the vitamin deficiency. In either case, measurements of S-adenosylmethionine decarboxylase and ornithine decarboxylase activity under optimum conditions in vitro do not correlate with the polyamine concentrations in vivo.

scholarly journals Regulation of S-adenosylmethionine decarboxylase activity by alterations in the intracellular polyamine content

1992 ◽  
Vol 288 (2) ◽  
pp. 511-518 ◽  
Author(s):  
L M Shantz ◽  
I Holm ◽  
O A Jänne ◽  
A E Pegg
Keyword(s):  
Cho Cells ◽  
Translational Regulation ◽  
Decarboxylase Activity ◽  
Origin Of Replication ◽  
Sv40 Promoter ◽  
Polyamine Biosynthesis ◽  
Adenosylmethionine Decarboxylase ◽  
Mammalian Cell Lines ◽  
Sv40 Origin ◽  
Polyamine Content

The effects of addition of exogenous spermidine and spermine and of two inhibitors of polyamine biosynthesis, alpha-difluoromethylornithine (DFMO), which decreases spermidine concentrations, and n-butyl-1,3-diaminopropane, which depletes spermine, on the expression of S-adenosylmethionine decarboxylase (AdoMetDC) activity were studied in mammalian cell lines (HT29, CHO and COS-7). AdoMetDC levels were inversely related to the polyamine content, and spermine was the more potent repressor of AdoMetDC activity, but only spermidine affected the amount of AdoMetDC mRNA. Transfection of COS-7 cells or CHO cells with plasmid constructs containing a chloramphenicol acetyltransferase (CAT) reporter gene driven by portions of the AdoMetDC promoter region indicated that CAT expression was altered by spermidine, but not by spermine, suggesting that there is a spermidine-responsive element in this promoter. Transient transfection of COS-7 cells with pSAMh1, a plasmid containing the AdoMetDC cDNA in a vector with the SV40 promoter and origin of replication, led to a large increase in AdoMetDC expression. Although treatment of COS-7 cells with n-butyl-1,3-diaminopropane greatly increased endogenous AdoMetDC activity, the spermine depletion brought about by this inhibitor did not stimulate AdoMetDC expression from pSAMh1. The pSAMh1 cDNA is missing 72 nucleotides from the 5′ end of the AdoMetDC mRNA, and it is possible that translational regulation by spermine involves this region. The expression of AdoMetDC from pSAMh1 in COS-7 cells was greatly inhibited by DFMO treatment, although endogenous AdoMetDC activity was increased. The expression of other plasmids containing the SV40 origin of replication was also inhibited by DFMO in COS-7 cells, but not in CHO cells. DFMO treatment did not interfere with the expression of plasmids driven by the RSV promoter. These results suggest that low spermidine levels interfere with the replication of plasmids containing the SV40 origin of replication.

scholarly journals Polyamine homoeostasis as a drug target in pathogenic protozoa: peculiarities and possibilities

2011 ◽  
Vol 438 (2) ◽  
pp. 229-244 ◽  
Author(s):  
Lyn-Marie Birkholtz ◽  
Marni Williams ◽  
Jandeli Niemand ◽  
Abraham I. Louw ◽  
Lo Persson ◽  
...  
Keyword(s):  
Drug Targets ◽  
Current Knowledge ◽  
New Drugs ◽  
Polyamine Metabolism ◽  
Decarboxylase Activity ◽  
Polyamine Biosynthesis ◽  
Adenosylmethionine Decarboxylase ◽  
Thiol Metabolism ◽  
Potential Drug Targets ◽  
Unique Compound

New drugs are urgently needed for the treatment of tropical and subtropical parasitic diseases, such as African sleeping sickness, Chagas' disease, leishmaniasis and malaria. Enzymes in polyamine biosynthesis and thiol metabolism, as well as polyamine transporters, are potential drug targets within these organisms. In the present review, the current knowledge of unique properties of polyamine metabolism in these parasites is outlined. These properties include prozyme regulation of AdoMetDC (S-adenosylmethionine decarboxylase) activity in trypanosomatids, co-expression of ODC (ornithine decarboxylase) and AdoMetDC activities in a single protein in plasmodia, and formation of trypanothione, a unique compound linking polyamine and thiol metabolism in trypanosomatids. Particularly interesting features within polyamine metabolism in these parasites are highlighted for their potential in selective therapeutic strategies.

scholarly journals Altered polyamine metabolism in the PRO/Re strain of inbred mice

1976 ◽  
Vol 158 (3) ◽  
pp. 529-533 ◽  
Author(s):  
C A Manen ◽  
R L Blake ◽  
D H Russell
Keyword(s):  
Biosynthetic Pathway ◽  
Inbred Mice ◽  
Proline Accumulation ◽  
Polyamine Metabolism ◽  
Decarboxylase Activity ◽  
Polyamine Biosynthesis ◽  
Male And Female ◽  
Adenosylmethionine Decarboxylase ◽  
Significant Difference ◽  
High Concentrations

The PRO/Re strain of inbred mice are characterized by abnormally high concentrations of proline in both blood (hyperprolinaemia) and urine (prolinuria). They excrete increased amounts of polyamines in their urine. Male PRO/Re mice excreted putrescine at 175% and spermidine at 300% the amount of male C57BL/6J controls. Female PRO/Re mice excreted putrescine at 115% and spermidine at 150% of the amount in the urine of female controls. Examination of the enzymes involved in polyamine biosynthesis revealed that ornithine decarboxylase, the initial enzyme in the polyamine-biosynthetic pathway, was increased by 150% in the kidneys and by 100% in the liver of male PRO/Re mice. There was no significant difference between PRO/Re and C57BL/6J male mice for either putrescine- or spermidine-stimulated S-adenosylmethionine decarboxylase activity. Female PRO/Re mice showed no significant difference from female C57BL/6J mice for any of the enzymes examined. When the concentrations of the polyamines in the tissues of the PRO/Re mice were determined, spermidine and spermine concentrations in the kidneys of the male PRO/Re mice were twice those of the controls. Spermidine concentration in the livers of both male and female PRO/Re mice was approx. 130% that of the controls. Polyamine concentrations in the brains were similar in controls and mutants. The increased polyamine biosynthesis and excretion in the PRO/Re mutant mice may be a mechanism to decrease the extent of proline accumulation.

scholarly journals Role of propylamine transferases in hormone-induced stimulation of polyamine biosynthesis

1980 ◽  
Vol 192 (1) ◽  
pp. 59-63 ◽  
Author(s):  
Kirsti Käpyaho ◽  
Hannu Pösö ◽  
Juhani Jänne
Keyword(s):  
Seminal Vesicle ◽  
Ornithine Decarboxylase ◽  
Ovarian Tissue ◽  
Ventral Prostate ◽  
Decarboxylase Activity ◽  
Spermidine Synthase ◽  
Polyamine Biosynthesis ◽  
Adenosylmethionine Decarboxylase ◽  
Spermine Synthase ◽  
Stimulation Of

The effect of various hormones on the activities of the four enzymes engaged with the biosynthesis of the polyamines has been investigated in the rat. Human choriogonadotropin induced a dramatic, yet transient, stimulation of l-ornithine decarboxylase (EC 4.1.1.17) activity in rat ovary, with no or only marginal changes in the activities of S-adenosyl-l-methionine decarboxylase (EC 4.1.1.50), spermidine synthase (aminopropyltransferase; EC 2.5.1.16) or spermine synthase. A single injection of oestradiol into immature rats maximally induced uterine ornithine decarboxylase at 4h after the injection. This early stimulation of ornithine decarboxylase activity was accompanied by a distinct enhancement of adenosylmethionine decarboxylase activity and a decrease in the activities of spermidine synthase and spermine synthase. In the seminal vesicle of castrated rats, testosterone treatment elicited a striking and persistent stimulation of ornithine decarboxylase and adenosylmethionine decarboxylase activities. The activity of spermidine synthase likewise rapidly increased between the first and the second day after the commencement of the hormone treatment, whereas the activity of spermine synthase remained virtually unchanged during the whole period of observation. Testosterone-induced changes in polyamine formation in the ventral prostate were comparable with those found in the seminal vesicle, with the possible exception of a more pronounced stimulation of spermidine synthase activity. It thus appears that an enhancement in one or both of the propylamine transferase (aminopropyltransferase) activities in response to hormone administration is an indicator of hormone-dependent growth (uterus and the male accessory sexual glands), and is not necessarily associated with non-proliferative hormonal responses, such as gonadotropin-induced luteinization of the ovarian tissue.

scholarly journals Decarboxylases for polyamine biosynthesis in Drosophila melanogaster larvae

1976 ◽  
Vol 154 (1) ◽  
pp. 31-33 ◽  
Author(s):  
C V Byus ◽  
E J Herbst
Keyword(s):  
Drosophila Melanogaster ◽  
Larval Development ◽  
Ornithine Decarboxylase ◽  
Enzyme Activities ◽  
Polyamine Biosynthesis ◽  
Adenosylmethionine Decarboxylase ◽  
Larval Stages ◽  
Early Stages ◽  
Adenosyl Methionine ◽  
Stimulation Of

Ornithine decarboxylase (L-ornithine carboxy-lase, EC 4.1.1.17) and S-adenosyl-methionine decarboxylase (S-adenosyl-L-methionine carboxy-lase, EC 4.1.1.50) were assayed in Drosophilia melanogaster larvae. The highest enzyme activities were detected in 24 and 48 h larvae, with diminishing activities in subsequent larval stages. Stimulation of S-adenosylmethionine decarboxylase by putrescine was demonstrable in late but not in early stages of larval development.

scholarly journals Glyoxal bis(guanylhydrazone) as an inhibitor of polyamine biosynthesis in tumour cells

1984 ◽  
Vol 221 (2) ◽  
pp. 483-488 ◽  
Author(s):  
P Seppänen ◽  
R Fagerström ◽  
L Alhonen-Hongisto ◽  
H Elo ◽  
P Lumme ◽  
...  
Keyword(s):  
Ornithine Decarboxylase ◽  
Parent Compound ◽  
Competitive Inhibitor ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Experimental Conditions ◽  
Polyamine Biosynthesis ◽  
Adenosylmethionine Decarboxylase ◽  
L1210 Cells ◽  
In Cells

Glyoxal bis(guanylhydrazone), the parent compound of methylglyoxal bis(guanylhydrazone), was synthesized and tested for its ability to inhibit the biosynthesis of polyamines. It was found to be a powerful competitive inhibitor of adenosylmethionine decarboxylase (EC 4.1.1.50), yet the lack of the methyl group at the glyoxal portion increased the apparent Ki value for the enzyme by about 30-fold in comparison with methylglyoxal bis(guanylhydrazone). Glyoxal bis(guanylhydrazone) inhibited diamine oxidase (EC 1.4.3.6) activity as effectively as did methylglyoxal bis(guanylhydrazone). The cellular accumulation curves of glyoxal bis(guanylhydrazone) in L1210 cells were practically superimposable with those of methylglyoxal bis(guanylhydrazone), and the uptake of both compounds was distinctly stimulated by a prior treatment with 2-difluoromethylornithine. The drug decreased the concentration of spermidine in a dose-dependent manner and, in contrast with methylglyoxal bis(guanylhydrazone), without a concomitant accumulation of putrescine. The fact that putrescine concentrations were decreased in cells exposed to glyoxal bis(guanylhydrazone) was, at least in part, attributable to an inhibition of ornithine decarboxylase (EC 4.1.1.17) activity in cells treated with the compound. Under these experimental conditions equivalent concentrations of methylglyoxal bis(guanylhydrazone) [1,1′-[(methylethanediylidine)dinitrilo]diguanidine] elicited large increases in the enzyme activity. When combined with difluoromethylornithine, glyoxal bis(guanylhydrazone) potentiated the growth-inhibitory effect of that drug. Taking into consideration the proven anti-leukaemic activity of glyoxal bis(guanylhydrazone), its effectiveness to inhibit spermidine biosynthesis (without raising the concentration of putrescine) as well as its suitability for combined use with inhibitors of ornithine decarboxylase, this drug is apparently worthy of further testing in tumour-bearing animals, especially in combination with difluoromethylornithine or related inhibitors of ornithine decarboxylase.

scholarly journals Regulation of ornithine decarboxylase activity by spermidine and the spermidine analogue N1N8-bis(ethyl)spermidine

1987 ◽  
Vol 242 (2) ◽  
pp. 433-440 ◽  
Author(s):  
C W Porter ◽  
F G Berger ◽  
A E Pegg ◽  
B Ganis ◽  
R J Bergeron
Keyword(s):  
Ornithine Decarboxylase ◽  
Supporting Cell ◽  
Dose Dependence ◽  
Decarboxylase Activity ◽  
Response Curves ◽  
Polyamine Biosynthesis ◽  
Intact Cells ◽  
Polyamine Analogues ◽  
L1210 Cells ◽  
Minimal Treatment

Polyamine biosynthesis in intact cells can be exquisitely controlled with exogenous polyamines through the regulation of rate-limiting biosynthetic enzymes, particularly ornithine decarboxylase (ODC). In an attempt to exploit this phenomenon as an antiproliferative strategy, certain polyamine analogues have been identified [Porter, Cavanaugh, Stolowich, Ganis, Kelly & Bergeron (1985) Cancer Res. 45, 2050-2057] which lower ODC activity in intact cells, have no direct inhibitory effects on ODC, are incapable of substituting for spermidine (SPD) in supporting cell growth, and are growth-inhibitory at micromolar concentrations. In the present study, the most effective of these analogues, N1N8-bis(ethyl)SPD (BES), is compared with SPD in its ability to regulate ODC activity in intact L1210 cells and in the mechanism(s) by which this is accomplished. With respect to time and dose-dependence of ODC suppression, both polyamines closely paralleled one another in their response curves, although BES was slightly less effective than SPD. Conditions of minimal treatment leading to near-maximal ODC suppression (70-80%) were determined and found to be 3 microM for 2 h with either SPD or BES. After such treatment, ODC activity was fully recovered within 2-4 h when cells were re-seeded in drug-free media. By assessing BES or [3H]SPD concentrations in treated and recovered cells, it was possible to deduce that an intracellular accumulation of BES or SPD equivalent to less than 6.5% of the combined cellular polyamine pool was sufficient to invoke ODC regulatory mechanisms. Decreases in ODC activity after BES or SPD treatment were closely paralleled by concomitant decreases in ODC protein. Since cellular ODC mRNA was not similarly decreased by either BES or SPD, it was concluded that translational and/or post-translational mechanisms, such as increased degradation of ODC protein or decreased translation of ODC mRNA, were probably responsible for regulation of enzyme activity. Experimental evidence indicated that neither of these mechanisms seemed to be mediated by cyclic AMP or ODC-antizyme induction. On the basis of the consistent similarities between BES and SPD in all parameters studied, it is concluded that the analogue most probably acts by the same mechanisms as SPD in regulating polyamine biosynthesis.

scholarly journals Overexpression of arginine decarboxylase in transgenic plants

1997 ◽  
Vol 325 (2) ◽  
pp. 331-337 ◽  
Author(s):  
Daniel BURTIN ◽  
Anthony J. MICHAEL
Keyword(s):  
Transgenic Plants ◽  
Arginine Decarboxylase ◽  
Polyamine Metabolism ◽  
Morphological Development ◽  
Polyamine Biosynthesis ◽  
Adenosylmethionine Decarboxylase ◽  
Two Generations ◽  
Key Enzyme ◽  
Polyamine Conjugate ◽  
And Control

The activity of arginine decarboxylase (ADC), a key enzyme in plant polyamine biosynthesis, was manipulated in two generations of transgenic tobacco plants. Second-generation transgenic plants overexpressing an oat ADC cDNA contained high levels of oat ADC transcript relative to tobacco ADC, possessed elevated ADC enzyme activity and accumulated 10–20-fold more agmatine, the direct product of ADC. In the presence of high levels of the precursor agmatine, no increase in the levels of the polyamines putrescine, spermidine and spermine was detected in the transgenic plants. Similarly, the activities of ornithine decarboxylase and S-adenosylmethionine decarboxylase were unchanged. No diversion of polyamine metabolism into the hydroxycinnamic acid–polyamine conjugate pool or into the tobacco alkaloid nicotine was detected. Activity of the catabolic enzyme diamine oxidase was the same in transgenic and control plants. The elevated ADC activity and agmatine production were subjected to a metabolic/physical block preventing increased, i.e. deregulated, polyamine accumulation. Overaccumulation of agmatine in the transgenic plants did not affect morphological development.

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