Equilibrium between active and inactive forms of rat liver ornithine decarboxylase mediated by L‐ornithine and salts

Solano, F.; Peñafiel, Rafael; Solano, María Emilia; Lozano, JoséA.

doi:10.1016/0014-5793(85)81311-9

Cited by 32 publications

(16 citation statements)

References 21 publications

(21 reference statements)

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“…Two active sites are located at the interface between the subunits and each active site is made up of amino acid residues from both subunits [122,123]. This is consistent with a previous observation using gel-filtration chromatography that the active ODC dimer is dissociated into inactive monomers by the addition of high concentrations of salts [68,124,125]. The two subunits dissociate and reassociate unusually rapidly, so that randomization is complete within 5 min under physiological conditions [123].…”

Section: Tentative Model Of Antizyme-stimulated Odc Degradationsupporting

confidence: 82%

Rapid and regulated degradation of ornithine decarboxylase

Hayashi

Murakami

1995

Biochemical Journal

194

131

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Section: Tentative Model Of Antizyme-stimulated Odc Degradationsupporting

confidence: 82%

Rapid and regulated degradation of ornithine decarboxylase

Hayashi

Murakami

1995

Biochemical Journal

194

131

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“…In its active form, mammalian ODC is a homodimer, while the monomer retains no enzymic activity [21]. In a study demonstrating that ODC subunits are recognized by the proteolytic machinery only in cis [22], we suggested the possibility that ODC is recognized and degraded whereas its subunits are in a transient monomeric state.…”

Section: Interaction With Antizyme Results In Monomerization Of Odcmentioning

confidence: 85%

A Unified Pathway for the Degradation of Ornithine Decarboxylase in Reticulocyte Lysate Requires Interaction with the Polyamine‐Induced Protein, Ornithine Decarboxylase Antizyme

Mamroud‐Kidron

Omer‐Itsicovich

Bercovich

et al. 1994

European Journal of Biochemistry

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Recent studies have provided convincing evidence to add to a number of earlier observations suggesting that the rapid intracellular degradation of mammalian ornithine decarboxylase (ODC) is further accelerated by the action of ornithine decarboxylase antizyme (ODC-Az), a polyamineinduced protein. However, the mechanism whereby ODC-Az exerts its effect in this proteolytic process is mostly unknown. Here, by using reticulocyte-lysate-based synthesis and degradation systems, we demonstrate that interaction of ODC-Az with ODC results in two related outcomes: (a) ODC is inactivated as a result of its monomerization, and (b) ODC degradation is dramatically accelerated. While ODC inactivation requires the integrity of the ODC-Az binding site of ODC and the ODC binding site of ODC-Az, acceleration in ODC degradation also requires the previously characterized carboxyl-terminal destabilizing segment of ODC and a specific segment of ODC-Az that may be functionally distinct from that required for ODC binding. Interestingly, an active ODC variant with a mutant ODC-Az binding site is stable under basal degradation conditions. This, together with the ability of anti-(ODC-Az) antibody to specifically inhibit the basal degradation of ODC in the lysate, suggests that ODC-Az is an essential general mediator of ODC degradation. Based on these observations, we propose a model for the degradation of ODC which always require interaction with antizyme.Short intracellular half-life is a characteristic feature shared by highly regulated proteins, which enables their efficient modulation by upstream cellular regulatory mechanisms [l]. Ornithine decarboxylase (ODC) is a highly regulated enzyme in the biosynthesis of polyamines, which is one of the most labile cellular proteins [l]. Studies performed, both in intact cells and in vitro in a reticulocyte-lysate-based degradation system, revealed that ODC is degraded via a non-lysosomal, ATP-dependent, but ubiquitin-independent, proteolytic pathway [2, 31. Furthermore, genetically engineered ODC variants revealed that the integrity of a segment, encompassing the most carboxyl-terminal 37 amino acids of mouse ODC is required for maintaining its rapid degradation both in cells [4, 51 and in vitro [5].Recent studies have suggested that ODC degradation may be mediated by two distinct proteolytic machinery's [6, 71. According to these studies, the first proteolytic machinery is engaged in degrading ODC under basal metabolic conditions [6, 71 ; the second, that is stimulated by high concentration of polyamines, requires interaction of ODC with a small protein, termed ornithine decarboxylase antizyme (ODC-Az) [6, 71. ODC-Az is a 26-kDa protein that is induced in cells by polyamines [S-lo]. It binds ODC with high affinity and Correspondence to C. Kahana, Department of Molecular Genetics and Virology, The Weizmann Institute of Science, IL-Rehovot IL-76100, IsraelAbbreviations. ODC, ornithine decarboxylase; ODC-Az, ornithine decarboxylase antizyme ; GST, glutathione S-transferase. inhibits its activity ...

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“…Although the exact binding modes of these compounds are unknown, it is unlikely to be at the active site, because addition of substrate increases the potency of the inhibitor. It is known that binding of ornithine stabilizes the dimerization of ODC (54). This suggests that the benzthiazoles bind to the ODC homodimer.…”

Section: Discussionmentioning

confidence: 99%

Discovery of Potent and Selective Inhibitors of Trypanosoma brucei Ornithine Decarboxylase

Smithson

Lee

Shelat

et al. 2010

Journal of Biological Chemistry

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Human African trypanosomiasis, caused by the eukaryotic parasite Trypanosoma brucei, is a serious health problem in much of central Africa. The only validated molecular target for treatment of human African trypanosomiasis is ornithine decarboxylase (ODC), which catalyzes the first step in polyamine metabolism. Here, we describe the use of an enzymatic high throughput screen of 316,114 unique molecules to identify potent and selective inhibitors of ODC. This screen identified four novel families of ODC inhibitors, including the first inhibitors selective for the parasitic enzyme. These compounds display unique binding modes, suggesting the presence of allosteric regulatory sites on the enzyme. Docking of a subset of these inhibitors, coupled with mutagenesis, also supports the existence of these allosteric sites.

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Equilibrium between active and inactive forms of rat liver ornithine decarboxylase mediated by L‐ornithine and salts

Cited by 32 publications

References 21 publications

Rapid and regulated degradation of ornithine decarboxylase

Rapid and regulated degradation of ornithine decarboxylase

A Unified Pathway for the Degradation of Ornithine Decarboxylase in Reticulocyte Lysate Requires Interaction with the Polyamine‐Induced Protein, Ornithine Decarboxylase Antizyme

Discovery of Potent and Selective Inhibitors of Trypanosoma brucei Ornithine Decarboxylase

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