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)

DL-alpha-Hydrazino-delta-aminovaleric acid (DL-HAVA) is a potent and fairly specific inhibitor of ornithine decarboxylase (EC 4.1.1.17). Its effect on polyamine metabolism and cell proliferation was investigated in sarcoma-180, inoculated into the axillary region of mice. In the tumor tissues, the activities of ornithine and S-adenosyl-L-methionine decarboxylases and the putrescine level were much higher in the early stage of growth than those in normal mouse liver. Administration of DL-HAVA greatly depressed the putrescine level and putrescine formation from L-ornithine. It also suppressed DNA synthesis and increase in weight of the tumor tissue. However, it had little effect on RNA synthesis or the tissue concentration of spermidine and spermine. The inhibition of DNA synthesis and subsequent tumor development by DL-HAVA was effectively prevented by putrescine, but not by cadaverine or 1,7-diaminoheptane. From these results it is concluded that the suppression of DNA synthesis and neoplastic growth by DL-HAVA is due to decrease in the putrescine level by inhibition of ornithine decarboxylase.
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PMID:Effect of DL-alpha-hydrazino-delta-aminovaleric acid, an inhibitor of ornithine decarboxylase, on polyamine metabolism and growth of mouse sarcoma-180. 102 52

A biphasic increase of putrescine concentration occurs in rat hepatoma tissue culture cells induced to proliferate. DL-alpha-Methyl ornithine, a competitive inhibitor of ornithine decarboxylase ( L-ornithine carboxylyase, EC 4.1.1.7) of hepatoma tissue culture cells, blocks the usual increases of putrescine and spermidine concentrations in these cells, and causes a rapid fall in the levels of putrescine which is followed by a striking decrease of spermidine. In parallel with the depletion of these amines, incorporation of [3H]thymidine into DNA and cell proliferation are inhibited. Addition of putrescine, spermidine, or spermine results in an immediate resumption of cell proliferation. Cell proliferation is also restored by L-ornithine presumably due to in situ competitive inhibition of ornithine decarboxylase. These findings of hepatoma tissue culture cells support the concept that polyamines play an essential function in the cell division processes.
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PMID:Alpha-methyl ornithine, a potent competitive inhibitor of ornithine decarboxylase, blocks proliferation of rat hepatoma cells in culture. 106 34

Putrescine, the end-product of ornithine decarboxylase (ODC: L-ornithine carboxylyase, EC; 4.1.1.17) action, induces the synthesis of a protein(s), in L1210, neuroblastoma, and H-35 cells as well as in rat liver, which inhibits ODC activity. Spermidine and spermine, distal products of ODC activity, also induce the synthesis of a similar protein in H-35 cells. These ODC-inhibitors are heat-labile, trypsin-sensitive, and their induction is dependent upon protein synthesis. They have short half-lives which range from 18 to 66 min; these half-lives are similar to those of the ODC derived from the same source. They are noncompetitive inhibitors of ODC activity with an apparent molecular weight of 26,500. Each inhibitor crossreacts with the ODC's of the other cells and forms an enzyme-inhibitor complex which is stable during Sephadex chromatography; however, after treatment with ammonium sulfate, enzyme and inhibitor activities can be dissociated and recovered intact from the same column. We propose the name antizyme for proteins whose synthesis is induced by the proximal or distal products of the enzyme they inhibit.
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PMID:Induction of a protein inhibitor to ornithine decarboxylase by the end products of its reaction. 106 59

Ornithine levels rise progressively in the liver of partially hepatectomized rats, probably as a consequence of the increased flow of metabolites through the urea cycle. Ammonia and urea concentrations in the blood and liber of partially hepatectomized animals are not significantly different from those of sham-operated rats. However, in regenerating livers, the ability to remove ammonia from the blood is close to its maximal limit. Ammonia overload leads to the production of large amounts of orotic acid and causes a marked elevation of hepatic ornithine decarboxylase activity. Among the pyrimidine precursors dihydroorotic acid injections increase the activity of the enzyme while orotic acid is without effect. A peak of labeled material that corresponds to dihydroorotic acid was identified by partition chromatography of acid-soluble extracts of livers of partially hepatectomized rats previously given injections of [14-C2 bicarbonate. The labeling of dihydroorotic acid from [14-C] bicarbibate is increased in the liver of rats given injections of ornithine. Despite the difficulties involved in studies of ornithine decarbozylase activity in vivo, our results suggest that mutual interactions between urea, pyrimidine, and polyamine synthesis take place during liver regeneration.
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PMID:Possible interactions between the urea cycle and synthesis of pyrimidines and polyamines in regenerating liver. 110 4

The effects of purified growth hormone and its CNBr fragments on somatomedin induction and on the stimulation of hepatic and renal ornithine decarboxylase (L-ornithine carboxylase, EC 4.1.1.17) activity in rats have been investigated. At the doses tested, none of the CNBr fragments induced somatomedin as evidenced by lack of an effect on sulfate, leucine, and thymidine incorporation into cartilage of hypophysectomized rats. However, the largest fragment, consisting of two peptides corresponding to Residues 6-124 and 150-179 linked by a disulfide bridge, stimulated both renal and hepatic ornithine decarboxylase activity in hypophysectomized rats and the activity of the hepatic enzyme in intact animals. A smaller CNBr fragment corresponding to Residues 125-149 slightly stimulated the activity of renal ornithine decarboxylase but failed to increase activity of the hepatic enzyme. A similar slight stimulation of the activity of the renal, but not the hepatic, enzyme was produced by a large carboxyl-terminal fragment (molecular weight 8000) prepared by proteolytic cleavage of partially purified ovine growth hormone. Circular dichroic spectra of the CNBr fragments demonstrated that the largest fragment retained much of the ordered secondary structure of intact growth hormone while two smaller CNBr fragments were devoid of ordered secondary structure. These observations indicate that different biological activities of growth hormone may be dissociated by fragmentation of the parent molecule.
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PMID:Evidence for structural dissociation of two biologic actions of growth hormone. 111 89

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

Alpha-Methyl-(+/-)-ornithine hydrochloride was not a substrate for ornithine decarboxylase from rat prostate glands. It produced equal inhibition of ornithine decarboxylase obtained from rat prostate glands, spleens of mice inoculated with L1210 leukemic cells, and regenerating rat liver indicating its lack of selectivity for any of these tissues. In these three tissues the inhibition was competitive with L-ornithine. A number of alpha-alkyl- and alpha-aralkyl-substituted analogs of (+/-)-ornithine were synthesized and evaluated in vitro as inhibitors of the enzyme L-ornithine decarboxylase obtained from prostate glands of rats. These compounds were obtained by the reaction of alkyl iodide or benzyl bromide with the anion obtained by treatment of 3-(benzalimino)piperidin-2-one with sodium hydride. The following alpha-substituted analogs of (+/-)-ornithine were obtained: ethyl, n-propyl, n-butyl, n-hexyl, n-octyl, and benzyl. The synthesized compounds were found to be much less active than alpha-methyl-(+/-)-ornithine as competitive inhibitors of ornithine decarboxylase in vitro. The most active compound in the series was alpha-n-octyl-(+/-)-ornithine which was 60-fold less active than alpha-methyl-(+/-)-ornithine and the least active analog was alpha-n-butyl-(+/-)-ornithine which was 270-fold less active than the alpha-methyl-(+/-)-ornithine.
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PMID:Potential inhibitors of polyamine biosynthesis. 2. alpha-Alkyl- and benzyl-(+/-)-ornithine. 115 75

(+/-)-5-Amino-2-hydrazino-2-methylpentanoic acid [alpha-hydrazino-alpha-methyl-(+/-)-ornithine] was obtained from 1-phthalimidopentan-4-one by treatment with hydrazine and KCN followed by acid hydrolysis. The title compound was found in vitro to be a potent competitive inhibitor of ornithine decarboxylase obtained from the prostate glands of rats. This inhibition was abolished at high concentrations of pyridoxal phosphate. The title compound also blocked the increase in putrescine levels normally observed in bovine lymphocytes transformed by conconavalin A.
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PMID:Inhibitors of polyamine biosynthesis. 3. (+/-)-5-Amino-2-hydrazine-2-methylpentanoic acid, an inhibitor of ornithine decarboxylase. 115 17

Addition of putrescine of spermidine prevents the increase in ornithine decarboxylase activity in cultures of 3T3 cells brought about by pituitary growth factors and results in a rapid, specific, and reversible reduction of enzyme activity in cultures previously stimulated by the growth factors. These effects are not due to polyamine toxicity and do not require other organic medium components. The amines apparently share a single carrier-mediated transport system in 3T3 cells. Methylglyoxal bis(guanylhydrazone), an inhibitor of spermidine synthesis from putrescine was found to also inhibit uptake of each amine. Studies with this drug indicate that each amine is effective without further metabolism. Since ornithine decarboxylase activity decays more rapidly in the presence of each polyamine after addition of camptothecin, the major locus of amine action appears to be in the cytoplasm. However, direct inhibition of the enzyme in vivo by assimilated amines appears to account for at most a small part of the reduction in activity, a conclusion supported by the inability to recover activity in vitro. Also, neither amine seems to act by accelerating enzyme inactivation. When amines are removed from the medium, the subsequent recovery of enzyme activity is totally prevented by trichodermin, an inhibitor of protein synthesis, but is only slightly reduced by camptothecin. It is suggested that both putrescine and spermidine reduce ornithine decarboxylase activity by selectively inhibiting translation.
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PMID:Regulation of ornithine decarboxylase in 3T3 cells by putrescine and spermidine: indirect evidence for translational control. 117 9

The synthesis of several N-(5'-phosphopyridoxyl)-amino acids is described. These compounds, analogs of the Schiff base intermediate involved in enzyme-catalyzed decarboxylation, are potent inhibitors of the cognate amino acid decarboxylases. Kinetic studies using partially purified rat liver ornithine decarboxylase, have shown that N-(5'-phosphopyridoxyl)-ornithine inhibits the enzyme in a non-competitive manner with respect to both ornithine and pyridoxal-5'-phosphate. These findings suggest that the inhibitor binds to the holoenzyme active site in place of the Schiff base intermediate.
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PMID:Stable multisubstrate adducts as enzyme inhibitors. Potent inhibition of ornithine decarboxylase by N-(5'-phosphopyridoxyl)-ornithine. 117 45


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