Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.1.1.17 (ornithine decarboxylase)
6,351 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thyrotropin (TSH) injected intraperitoneally caused a significant rise in the activity of L-ornithine decarboxylase of rat thyroid within 4 hr. TSH-releasing hormone (TRH) also increased the activity of this enzyme in a dose-related manner and of putrescine-activated S-adenosyl-L-methionine decarboxylase, probably through the increased secretion of TSH from the pituitary. Administration of methylthiouracil (MTU) in the drinking water to rats resulted in an increase of these two enzymes in the thyroid. Maximal activation was observed 4 days after the initiation of MTU treatment for both enzymes. The intracellular level of putrescine and spermidine increased during the rapid phase of thyroid enlargement caused by MTU treatment. The spermine concentration, however, was relatively constant during the treatment. The RNA/DNA ratio followed a pattern very similar to that exhibited by the spermidine/spermine ratio. These results indicate that TSH stimulates the biosynthesis of polyamines by increasing the activity of the decarboxylases in the thyroid. The findings further suggest that polyamines play a role in the regulation of thyroid growth and nucleic acid metabolism.
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PMID:Thyroid function and polyamines. II. Thyrotropin stimulation of polyamine biosynthesis in the rat thyroid. 81 58

A comparison was made between rats fed diets containing either 5% casein or 25% casein, both being supplemented with DL-methionine, from the first day of pregnancy. Livers of dams killed on days 7, 14, and 21 and whole fetuses on days 12, 14, and 21 were weighed, analyzed for protein, RNA and DNA content and assayed for ornithine decarboxylase (ODC) and S-adenosyl-L-methionine decarboxylase (SAMD). Free and total alkaline ribonuclease activity were also measured in the maternal livers. Malnutrition reduced the characteristic increase in content of DNA, RNA and protein in the maternal liver and fetus. In control rats total hepatic RNase activity increased and free RNase activity decreased during late pregnancy. In the deprived group, total activity decreased and free activity increased during late pregnancy. Liver and fetal ODC and SAMD activities were reduced by undernutrition. These studies show that malnutrition reduced both growth and the accretion of RNA in livers and fetuses of rat dams. These changes coincide with a reduced activity of polyamine synthesizing enzymes suggesting that there is a functional relationship between polyamines and RNA. High hepatic free RNase activity in malnourished dams may help to limit any build up in RNA content.
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PMID:Effects of malnutrition on some aspects of RNA metabolism in the maternal liver and fetal tissues at different stages of pregnancy in the rat. 89 66

1. Ehrlich ascites-carcinoma cells contained relatively high concentrations of spermidine and spermine, but the putrescine content of the washed cells was less than 10% of that of higher polyamines. 2. Ascites-tumour cells likewise exhibited high activities of L-ornithine decarboxylase (EC 4.1.1.17), S-adenosyl-L-methionine decarboxylase (EC 4.1.1.50), spermidine synthase (EC 2.5.1.16) and spermine synthase. 3. During the first days after the inoculation, the polyamine pattern of the ascites cells was characterized by a high molar ratio of spermidine to spermine, which markedly decreased on aging of the cells. 4. Various diamines injected into mice bearing ascites cells rapidly and powerfully decreased ornithine decarboxylase activity in the carcinoma cells, apparently through a mechanism that was not a direct inhibition of the enzyme in vitro. Cadaverine (1,5-diaminopentane) and 1,6-diaminohexane were the most potent inhibitors of ornithine decarboxylase among the amines tested. 5. Chronic treatment of the mice with diamines resulted in a virtually complete disappearance of ornithine decarboxylase activity, and after 24h a significant decline in spermidine accumulation. 6. Cadaverine appeared to be an especially suitable compound for use as an inhibitor of the synthesis of higher polyamines, at least in Ehrlich ascites cells, since this diamine also acted as a competitive inhibitor for putrescine in the spermidine synthase reaction without being incorporated into the higher polyamines.
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PMID:Polyamines and their biosynthetic enzymes in Ehrlich ascites-carcinoma cells. Modification of tumour polyamine pattern by diamines. 90 22

The activities of L-ornithine decarboxylase (EC 4.1.1.17) and S-adenosyl-L-methionine decarboxylase (EC 4.1.50) fluctuate markedly in rat ovary during the normal oestrous cycle. Ovarian ornithine and adenosylmethionine decarboxylases also showed profound changes during pregnancy of the rat. Both enzyme activities were remarkably low in the ovary through the first 11 days of pregnancy, but sharply increased at the time the placenta is formed in the rat. The enzyme activities remained elevated almost until term. It appears that the stimulated of polyamine synthesis in rat ovary, as reflected by the enhanced decarboxylation of ornithine and adenosylmethionine, is associated with the growth of the ovarian tissue rather than the secretory function of the corpus luteum during pregnancy.
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PMID:Decarboxylation of ornithine and adenosymethionine in rat ovary during pregnancy. 94 68

The hepatic synthesis and accumulation of S-adenosylhomocysteine, S-adenosylmethionine and polyamines were studied in normal and vitamin B-6-deficient male albino rats. A method involving a single chromatography on a phosphocellulose column was developed for the determination of S-adenosylhomocysteine and S-adenosylmethionine from tissue samples. Feeding the rat with pyridoxine-deficient diet for 3 or 6 weeks resulted in a four- to five-fold increase in the concentration of S-adenosylhomocysteine, whereas that of S-adenosylmethionine was only slighly elevated. The concentration of putrescine was decreased to half, that of spermidine was somewhat decreased and that of spermine remained fairly constant. The activities of L-ornithine decarboxylase, S-adenosyl-L-methionine decarboxylase, L-methionine adenosyltransferase and S-adenosyl-L-homocysteine hydrolase were moderately increased. S-Adenosylmethionine decarboxylase showed no requirement for pyridoxal 5'-phosphate. The major effect of pyridoxine deficiency of S-adenosylmethionine metabolism seems to be a block in the utilization of S-adenosylhomocysteine, resulting in the accumulation of this metabolite to a concentration that may inhibit biological methylation reactions.
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PMID:A new method for the assay of tissue. S-adenosylhomocysteine and S-adenosylmethione. Effect of pyridoxine deficiency on the metabolism of S-adenosylhomocysteine, S-adenosylmethionine and polyamines in rat liver. 100 58

The effects of DL-alpha-hydrazino-delta-aminovaleric acid (DL-HAVA) on polyamine metabolism in isoproterenol(IPR)-stimulated mouse parotid glands were investigated both in vitro and in vivo. Using partially enzyme preparations, it was found that DL-HAVA strongly inhibited ornithine decarboxylase (EC 4.1.1.17) by competing with L-ornithine. Other enzymes metabolizing ornithine and pyridoxal phosphate-dependent enzymes were at least 2-3 orders of magnitude less sensitive to DL-HAVA than ornithine decarboxylase. Administration of DL-HAVA greatly depressed the increases in both the putrescine level and putrescine formation from L-ornithine induced by IPR in the mouse parotid glands. Under the same conditions, the stimulation of DNA synthesis and subsequent cell proliferation in the glands were also suppressed. However, the IPR-dependent increases in S-adenosyl-L-methionine decarboxylase (EC 4.1.1.50) activity, synthesis and the tissue concentration of spermidine, and RNA synthesis in the parotid glands were not affected appreciably by DL-HAVA. The inhibition of DNA synthesis by DL-HAVA was effectively prevented by putrescine, but not by spermidine or 1,7-diaminoheptane, given at the same time when DL-HAVA inhibited stimulation of putrescine formation by IPR. From these results, it is proposed that putrescine is involved in cell proliferation besides being a precursor of spermidine. The effects of methylglyoxal bis(guanylhydrazone) (MGBG), an inhibitor of S-adenosyl-L-methionine decarboxylase, on the metabolism of polyamines and nucleic acids in growing parotid glands were also examined.
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PMID:Effect of DL-alpha-hydrazino-delta-aminovaleric acid, an inhibitor of ornithine decarboxylase, on polyamine metabolism in isoproterenol-stimulated mouse parotid glands. 115 Jun 42

To investigate whether the metabolism of the polyamines putrescine, spermidine and spermine is related to cellular growth rate, we have measured the activities of L-ornithine decarboxylase and S-adenosyl-L-methionine decarboxylase as well as the levels of the polyamines in rat brain tumor cells at various stages of a 7-day in vitro growth period and correlated them with the continuous changes in specific growth rate ([dN[t]/dt]/N[t]). L-Ornithine decarboxylase and S-adenosyl-L-methionine decarboxylase both exhibited their maximal activities at the time of most rapid growth. A high positive correlation between the activities of these enzymes and the specific growth rate of the tumor cells during the entire growth period was demonstrated statistically. The pattern of fluctuation of the spermidine content during the culture cycle was similar to those of the enzyme activities and likewise showed a high positive correlation with the specific growth rate of the tumor cells during the entire growth period. The putrescine content exhibited a low positive correlation, whereas the spermine content exhibited a somewhat higher, but negative correlation with the specific growth rate. The high correlation between the specific growth rate of the tumor cells and the synthesis of the polyamines indicates that these events are primarily associated with processes involved in cell replication. Putrescine and spermidine are thought to participate in the regulation of cellular growth rate; a high content may augment, and a low content may restrain, cellular growth rate.
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PMID:Polyamine metabolism in a rat brain tumor cell line: its relationship to the growth rate. 120 31

The polyamine biosynthetic pathway has attracted much interest as a therapeutic target. Many studies have shown the potential value of inhibitors of the first enzyme in the biosynthetic pathway, ornithine decarboxylase, which forms putrescine. In order to convert putrescine into the polyamines, spermidine and spermine, the aminopropyl donor, decarboxylated S-adenosylmethionine, is needed. Therefore, S-adenosylmethionine decarboxylase (AdoMetDC, EC 4.1.1.50) is essential for polyamine synthesis. Early studies of the inhibition of this enzyme were carried out with compounds such as methylglyoxal bis(guanylhydrazone) that lack specificity and also lack potency since they are competitive inhibitors whose effects are overcome by a compensatory increase in the amount of the target enzyme. Recently, powerful irreversible inhibitors of AdoMetDC have become available including 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine, an enzyme activated inhibitor and 5'-deoxy-5'-[(3-hydrazinopropyl)methylamino]adenosine which binds to the active site and forms a covalent bond with the pyruvate prosthetic group. This review describes the current state of knowledge of the structure and properties of AdoMetDC, the available inhibitors of this enzyme, their mechanism of action and their effects on polyamines and on the growth of tumors and protozoan parasites. These effects indicate that AdoMetDC inhibitors may be of therapeutic value either alone or in combination with ornithine decarboxylase inhibitors and that further trials of these compounds should be considered.
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PMID:S-adenosylmethionine decarboxylase as an enzyme target for therapy. 130 96

We reported recently that administration of ([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine (MDL 73811), an enzyme-activated irreversible inhibitor of S-adenosyl-L-methionine decarboxylase (AdoMetDC; EC 4.1.1.50), a key enzyme in the synthesis of spermidine, cures African trypanosome infections in mice. The precise mechanism of action of MDL 73811 was not clear because a rapid disappearance of trypanosomes from the bloodstream of treated rats occurred before significant depletion of spermidine. Administration of MDL 73811 to Trypanosoma brucei brucei-infected rats resulted in a 70% decrease in parasitaemia within 1 h and a complete disappearance of parasites by 5 h. The reduction in parasitaemia was accompanied by complete inhibition of AdoMetDC activity by 10 min after injection of MDL 73811; inhibition was sustained for at least 4 h. Polyamine levels in trypanosomes were unaffected during the first 1 h in which the marked decrease in parasitaemia was observed, but parasite AdoMet levels increased 20-fold within this time. In contrast, exposure of cultured mammalian cells to MDL 73811 resulted in only a 1.5-2-fold increase in AdoMet levels over a 6 h time course. Experiments with inhibitors of ornithine decarboxylase (ODC) also suggested that the increased AdoMet levels might be an important factor for antitrypanosomal efficacy. Trypanosomes taken from rats treated for 36 h with eflornithine, an inhibitor of ODC, were depleted of putrescine and had markedly decreased spermidine levels. These organisms also had less than 10% of control AdoMetDC activity, and had elevated decarboxy AdoMet (greater than 4000-fold) and AdoMet (up to 50-fold) levels. The methyl ester of alpha-monofluromethyl-3,4-dehydro-ornithine (delta-MFMO-CH3), which cures murine T. b. brucei infections, and the ethyl ester analogue of this compound (delta-MFMO-C2H5), which does not cure this infection, become ODC inhibitors upon hydrolysis and thus were tested for their effects on trypanosomal polyamines, AdoMet and decarboxy AdoMet levels. Although both esters of delta-MFMO depleted trypanosomal polyamines, AdoMet and decarboxy AdoMet levels were elevated in T. b. brucei from infected mice treated with delta-MFMO-CH3 but not in parasites from mice treated with the delta-MFMO-C2H5. These data suggest that inhibition of AdoMetDC, either directly with MDL 73811 or indirectly with inhibitors of ODC, apparently leads to a trypanosome-specific elevation of AdoMet. It is possible that major changes in AdoMet, rather than changes in polyamines, may be responsible for the antitrypanosomal effects of these drugs.
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PMID:Antitrypanosomal effects of polyamine biosynthesis inhibitors correlate with increases in Trypanosoma brucei brucei S-adenosyl-L-methionine. 167

Follicle stimulating hormone (FSH) modulates testicular function via Sertoli cells. The effect of FSH on S-adenosyl-L-methionine decarboxylase (AdoMetDC) activity was investigated in cultured Sertoli cells isolated from 18-day-old rats. In contrast to our previous finding that FSH inhibited Sertoli cell ornithine decarboxylase (ODC) activity, FSH stimulated AdoMetDC activity 160 to 300% above the level of the control cells during the initial 2 to 6 hours of treatment. The stimulated enzyme activity declined to 20 to 30% below the control values by 12 hours of exposure to FSH, and then rebounded to 120 to 125% of control values. To determine whether or not the initial opposite effects of FSH on AdoMetDC and on ODC activities are mediated by the same mechanism, various agents which increase intracellular cAMP level were used. All agents studied stimulated Sertoli cell AdoMetDC activity at 5 hours after their inclusion while they significantly inhibited ODC activity. In the presence of FSH, the stimulatory effect of these agents on AdoMetDC was either equal to or slightly greater than that caused by FSH or either agent alone. The combination of dbcGMP with FSH or with dbcAMP resulted in a synergistic or additive effect on AdoMetDC, as well as ODC, activity. The data suggest that the action of FSH on AdoMetDC activity in Sertoli cells is also mediated through cAMP, as concluded previously for ODC activity. Regardless of the effects of FSH on both enzymes, ODC always exhibited a relatively greater activity than did AdoMetDC in cultured rat Sertoli cells.
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PMID:Differential effects of FSH on the activities of S-adenosyl-L-methionine decarboxylase and ornithine decarboxylase in Rat sertoli cells. 217 45


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