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)

An early increase in ornithine decarboxylase (ODC) activity and polyamine levels in rat cerebral capillaries was previously implicated in the mediation of blood-brain barrier (BBB) breakdown in cold-injured brain. A time course study in rat cerebrum indicated that cold injury evokes a biphasic increase in ODC activity and polyamine levels in perilesional cortex. ODC activity rose sharply (fourfold) within 1 min, remained elevated for 5 min, and then returned to the basal level by 10 min. A transient rise in polyamine concentration followed in the rank order of putrescine greater than spermidine greater than spermine. A secondary rise in ODC activity commenced in perilesional tissue at 2-6 h and peaked (8.8-fold) at 48 h. Major increases in the content of putrescine (330%), spermidine (103%), and spermine (50%) developed at 48-72 h. alpha-Difluoromethylornithine (DFMO), a specific irreversible inhibitor of ODC, suppressed the evoked increase in ODC activity and abolished the associated increase in content of polyamines, findings indicating that the accumulation of polyamines in cryoinjured brain reflects enhanced synthesis resulting from an ODC-mediated increase in putrescine content. Cycloheximide and actinomycin D were without effect on the early increase in ODC activity but inhibited the delayed increase in ODC activity, an observation suggesting that the initial increase in activity reflects an activation of a cryptic ODC via a posttranslational process, whereas the delayed increase in activity results from ODC synthesis mainly under transcriptional control.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Blood-brain barrier breakdown in cold-injured brain is linked to a biphasic stimulation of ornithine decarboxylase activity and polyamine synthesis: both are coordinately inhibited by verapamil, dexamethasone, and aspirin. 249 56

The intracisternal injection of either all-trans-retinoic acid or [alpha]-difluoromethylornithine (DFMO) into the brain of 9-day-old mice blocked (greater than 90%) phorbol ester-induced ornithine decarboxylase (ODC, EC 4.1.1.17) activity in a concentration-dependent fashion; this inhibition was not evident with the use of the biologically impotent furyl analog of retinoic acid. In a similar manner, retinoic acid reduced the soluble protein kinase-C (PK-C) activity by 60% as well as total EGTA-sensitive kinase activity (66%) associated with the plasma membrane. Sixty-six percent of the retinoic acid-induced loss of PK-C activity in the soluble fraction could be accounted for by the translocation of PK-C to the plasma membrane as measured by the specific binding of 12-O-[3H]tetradecanylphorbol-13-acetate (TPA). DFMO and furyl-retinoic acid were not effective in altering PK-C activity or TPA binding to PK-C. In the presence of retinoic acid, however, there was a 2.3-fold increase in specific [3H]TPA binding in the plasma membrane fraction, which was 3.4-fold greater than that lost from the cytosol. Because retinoids do not directly affect TPA binding to PK-C, the data suggest that (i) the presence of retinoic acid results in the exposure of heretofore cryptic TPA-binding sites in the membrane, where this binding is most likely related to the alteration of membrane structure and (ii) de novo ODC induction is not required for retinoid-dependent inhibition of PK-C, although the TPA induction of PK-C appears to be necessary with regard to ODC induction.
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PMID:The in vivo inhibition of mouse brain protein kinase-C by retinoic acid. 300 83

Ornithine decarboxylase was present in a cryptic, complexed form in an amount approximately equivalent to that of free ornithine decarboxylase activity in adult rat heart. Addition of isoproterenol (10 mg/kg) caused a notable rise in ornithine decarboxylase activity and a simultaneous decrease in the amount of the complexed enzyme. During the period of ornithine decarboxylase decay, when cardiac putrescine content had reached high values, the level of the complex increased above that of the control. Administration of putrescine (1.5 mmol/kg, twice) or dexamethasone (4 mg/kg) produced a decrease of heart ornithine decarboxylase activity, while it did not remarkably affect the level of complexed ornithine decarboxylase, therefore raising significantly the ratio of bound to total ornithine decarboxylase. Putrescine also elicited the appearance of free antizyme, concomitantly with the disappearance of free ornithine decarboxylase activity after 3-4 h of treatment. These results indicate that a significant amount of ornithine decarboxylase occurs in an inactive form in the heart under physiological conditions and that its absolute and relative levels may vary following stimuli which affect heart ornithine decarboxylase activity.
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PMID:Modulation of ornithine decarboxylase activity and ornithine decarboxylase-antizyme complex in rat heart by hormone and putrescine treatment. 373 Apr 19

The increase in spermidine N-acetyltransferase activity in rat liver produced by carbon tetrachloride was completely prevented by simultaneous treatment with inhibitors of protein and nucleic acid synthesis suggesting that the increase results from the synthesis of new protein rather than the release of the enzyme from a cryptic inactive form. Treatment with cycloheximide 2 h after carbon tetrachloride also completely blocked the rise in spermidine N-acetyltransferase seen 4 h later. Such treatment completely prevented the fall in spermidine and rise in putrescine in the liver 6 h after carbon tetrachloride confirming the importance of the induction of spermidine N-acetyltransferase in the conversion of spermidine into putrescine. When cycloheximide was administered to rats in which spermidine N-acetyltransferase activity had been stimulated by prior treatment with carbon tetrachloride or thioacetamide, the activity was lost rapidly showing that the enzyme protein has a rapid rate of turnover. The half-life for the enzyme in thioacetamide-treated rats was 40 min, whereas the half-life for ornithine decarboxylase (which is well known to turn over very rapidly) was 27 min. In carbon tetrachloride-treated rats the rate or protein degradation was reduced and the half-life of spermidine N-acetyltransferase was 155 min and that for ornithine decarboxylase was 65 min. It appears that three of the enzymes involved in the synthesis and interconversion of putrescine and spermidine namely, ornithine decarboxylase, S-adenosylmethionine decarboxylase and spermidine N-acetyltransferase have rapid rates of turnover and that polyamine levels are regulated by changes in the amount of these enzymes.
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PMID:Effect of inhibitors of protein synthesis on rat liver spermidine N-acetyltransferase. 616 99

Ornithine decarboxylase (ODC) is the ratelimiting enzyme in the biosynthesis of polyamines, which are required for optimal cell growth and proliferation. ODC is overexpressed in many tumors and, conversely, its overexpression induces transformation. We have previously reported that ODC mRNA alternative splicing relieves the translation repression normally imposed by a long and structured 5' untranslated region (UTR), and that the ODC 5' UTR contains an internal ribosome entry site (IRES). Here we show that ODC IRES activity is enhanced following inclusion of alternative sequences generated by splicing at cryptic acceptor sites. Furthermore, the alternative ODC IRES is more sensitive to cell-cycledependent changes in the rate of translation. These findings uncover a new biological property of differentially spliced transcripts. This is the first example of alternative splicing that modulates mRNA translation through the cell cycle in a cap-independent manner.
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PMID:Alternative splicing facilitates internal ribosome entry on the ornithine decarboxylase mRNA. 1590 64

Polyamines are organic polycations essential for cell growth and differentiation; their aberrant accumulation is often associated with diseases, including many types of cancer. To maintain polyamine homeostasis, the catalytic activity and protein abundance of ornithine decarboxylase (ODC), the committed enzyme for polyamine biosynthesis, are reciprocally controlled by the regulatory proteins antizyme isoform 1 (Az1) and antizyme inhibitor (AzIN). Az1 suppresses polyamine production by inhibiting the assembly of the functional ODC homodimer and, most uniquely, by targeting ODC for ubiquitin-independent proteolytic destruction by the 26S proteasome. In contrast, AzIN positively regulates polyamine levels by competing with ODC for Az1 binding. The structural basis of the Az1-mediated regulation of polyamine homeostasis has remained elusive. Here we report crystal structures of human Az1 complexed with either ODC or AzIN. Structural analysis revealed that Az1 sterically blocks ODC homodimerization. Moreover, Az1 binding triggers ODC degradation by inducing the exposure of a cryptic proteasome-interacting surface of ODC, which illustrates how a substrate protein may be primed upon association with Az1 for ubiquitin-independent proteasome recognition. Dynamic and functional analyses further indicated that the Az1-induced binding and degradation of ODC by proteasome can be decoupled, with the intrinsically disordered C-terminal tail fragment of ODC being required only for degradation but not binding. Finally, the AzIN-Az1 structure suggests how AzIN may effectively compete with ODC for Az1 to restore polyamine production. Taken together, our findings offer structural insights into the Az-mediated regulation of polyamine homeostasis and proteasomal degradation.
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PMID:Structural basis of antizyme-mediated regulation of polyamine homeostasis. 2630 48