Conformational changes in ornithine decarboxylase enable recognition by antizyme

Mitchell, John L.A.; Chen, Hong J.

doi:10.1016/0167-4838(90)90109-s

Cited by 51 publications

(49 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The two subunits dissociate and reassociate unusually rapidly, so that randomization is complete within 5 min under physiological conditions [123]. Antizyme binds preferentially to the ODC monomer [126]. The rapid dissociation and reassociation of the ODC subunits should be advantageous for antizyme binding, fixing the enzyme in the inactive monomer form and eliciting its by 26 S proteasome conformational change to expose its C-terminus, which is susceptible to degradation ( Figure 6).…”

Section: Tentative Model Of Antizyme-stimulated Odc Degradationmentioning

confidence: 99%

Rapid and regulated degradation of ornithine decarboxylase

Hayashi

Murakami

1995

Biochemical Journal

194

131

View full text Add to dashboard Cite

Section: Tentative Model Of Antizyme-stimulated Odc Degradationmentioning

confidence: 99%

Rapid and regulated degradation of ornithine decarboxylase

Hayashi

Murakami

1995

Biochemical Journal

194

131

View full text Add to dashboard Cite

“…ODC activity was assayed by measuring the release of 14CO2 from L-[14C]ornithine as described previously [9]. One unit is defined as the release of 1 nmol of 14C02/h.…”

Section: Introductionmentioning

confidence: 99%

“…Since excessive polyamines are detrimental to normal cell function [4], both polyamine biosynthesis and transport are tightly feedback-regulated. Substantial progress has been made in understanding feedback repression of polyamine biosynthesis, which appears to centre around the polyamine-stimulated production of a labile protein, antizyme, that binds specifically and reversibly to the initial enzyme in polyamine synthesis, ornithine decarboxylase (ODC) [5][6][7][8][9][10]. Experiments in vitro have revealed that this ODC-antizyme complex is sensitive to rapid degradation by the 26 S proteasome [11,12].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Feedback repression of polyamine transport is mediated by antizyme in mammalian tissue-culture cells

Mitchell

Judd

Bareyal-Leyser

et al. 1994

Biochemical Journal

208

156

View full text Add to dashboard Cite

Antizyme, a spermidine-induced protein that binds and stimulates ornithine decarboxylase degradation, is now shown also to mediate the rapid feedback inhibition of polyamine uptake into mammalian cells. Using a cell line (HZ7) transfected with truncated antizyme cDNA, and mutant ornithine decarboxylase cell lines, we demonstrate that this newly discovered action of antizyme is distinct from its role in modulating polyamine biosynthesis.

show abstract

“…This delicate regulatory process is fine-tuned by the different affinity that these two proteins have toward Az. As opposed to ODC monomers that are known to bind Az, ODC dimers do not interact with Az (Mitchell and Chen 1990). Active ODC dimers have been shown to be in rapid equilibrium with inactive monomers, providing a pool of monomers, which are needed for ODC regulation by Az.…”

Section: Biochemical Studies Demonstrate That Azi Exists As a Monomermentioning

confidence: 99%

Crystallographic and biochemical studies revealing the structural basis for antizyme inhibitor function

et al. 2008

View full text Add to dashboard Cite

Antizyme inhibitor (AzI) regulates cellular polyamine homeostasis by binding to the polyamine-induced protein, Antizyme (Az), with greater affinity than ornithine decarboxylase (ODC). AzI is highly homologous to ODC but is not enzymatically active. In order to understand these specific characteristics of AzI and its differences from ODC, we determined the 3D structure of mouse AzI to 2.05 Å resolution. Both AzI and ODC crystallize as a dimer. However, fewer interactions at the dimer interface, a smaller buried surface area, and lack of symmetry of the interactions between residues from the two monomers in the AzI structure suggest that this dimeric structure is nonphysiological. In addition, the absence of residues and interactions required for pyridoxal 59-phosphate (PLP) binding suggests that AzI does not bind PLP. Biochemical studies confirmed the lack of PLP binding and revealed that AzI exists as a monomer in solution while ODC is dimeric. Our findings that AzI exists as a monomer and is unable to bind PLP provide two independent explanations for its lack of enzymatic activity and suggest the basis for its enhanced affinity toward Az.Keywords: structure/function studies; protein crystallization; protein structures-new; antizyme inhibitor; antizyme; ornithine decarboxylase Polyamines are small organic polycations that are essential for cell proliferation and play an important role in regulating other fundamental cellular processes. Elevated polyamine levels are observed in rapidly growing cells including transformed cells; thus, polyamine metabolism has been suggested as a potential target for cancer therapy (Pegg 1988;Marton and Pegg 1995;Wallace and Fraser 2004). The range of intracellular polyamines is determined at the lower limit by their absolute requirement for cellular proliferation and at the upper limit by their cytotoxicity (Poulin et al. 1993;Tobias and Kahana 1995), indicating a need for strict regulation of their intracellular concentration. Multiple pathways such as synthesis, uptake, degradation, and efflux regulate cellular polyamine levels. Ornithine decarboxylase (ODC) is the first and rate-limiting enzyme in the polyamine biosynthesis pathway (Pegg 2006). It is a pyridoxal 59-phosphate (PLP)-dependent enzyme that provides the only route for converting ornithine to putrescine. ODC, which is characterized by a short intracellular half-life, is part of an autoregulatory circuit mediated by a polyamine-induced protein, termed Antizyme (Az). An increased intracellular polyamine concentration increases the synthesis of Az by stimulating ribosomal frameshifting (Rom and Kahana 1994;Matsufuji et al. 1995). Az, in turn, binds to transient ODC monomer subunits with high affinity, preventing their re-association into active homodimers and targeting them for rapid degradation by the 26S proteasome (Murakami et al. 1992). Az also regulates polyamine transport across the plasma membrane via an unknown mechanism Mitchell et al. 1994;Suzuki et al. 1994;Sakata et al. 2000). 3 These authors contri...

show abstract

Conformational changes in ornithine decarboxylase enable recognition by antizyme

Cited by 51 publications

References 22 publications

Rapid and regulated degradation of ornithine decarboxylase

Rapid and regulated degradation of ornithine decarboxylase

Feedback repression of polyamine transport is mediated by antizyme in mammalian tissue-culture cells

Crystallographic and biochemical studies revealing the structural basis for antizyme inhibitor function

Contact Info

Product

Resources

About