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Translational recoding as a feedback controller: systems approaches reveal polyamine-specific effects on the antizyme ribosomal frameshift.

Rato C, Amirova SR, Bates DG, Stansfield I, Wallace HM - Nucleic Acids Res. (2011)

Bottom Line: Combinatorial polyamine treatments showed polyamines compete for binding to common ribosome sites.Using concepts from enzyme kinetics and control engineering, a mathematical model of the translational controller was developed to describe these complex ribosomal responses to combinatorial polyamine effects.Each one of a range of model predictions was successfully validated against experimental frameshift frequencies measured in S-adenosylmethionine-decarboxylase and antizyme mutants, as well as in the wild-type genetic background.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Sciences, School of Medical Sciences, University of Aberdeen, UK.

ABSTRACT
The antizyme protein, Oaz1, regulates synthesis of the polyamines putrescine, spermidine and spermine by controlling stability of the polyamine biosynthetic enzyme, ornithine decarboxylase. Antizyme mRNA translation depends upon a polyamine-stimulated +1 ribosomal frameshift, forming a complex negative feedback system in which the translational frameshifting event may be viewed in engineering terms as a feedback controller for intracellular polyamine concentrations. In this article, we present the first systems level study of the characteristics of this feedback controller, using an integrated experimental and modeling approach. Quantitative analysis of mutant yeast strains in which polyamine synthesis and interconversion were blocked revealed marked variations in frameshift responses to the different polyamines. Putrescine and spermine, but not spermidine, showed evidence of co-operative stimulation of frameshifting and the existence of multiple ribosome binding sites. Combinatorial polyamine treatments showed polyamines compete for binding to common ribosome sites. Using concepts from enzyme kinetics and control engineering, a mathematical model of the translational controller was developed to describe these complex ribosomal responses to combinatorial polyamine effects. Each one of a range of model predictions was successfully validated against experimental frameshift frequencies measured in S-adenosylmethionine-decarboxylase and antizyme mutants, as well as in the wild-type genetic background.

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The polyamine biosynthetic pathway in S. cerevisiae. (A) Antizyme (Oaz1), the main regulator is indicated; it targets ODC (Spe1) for degradation by the 26S proteasome. Metabolites are shown in italics and proteins in Roman type. Asterisks denote genes deleted in the spe1 spe2 paa1 fms1 deletant strain. See text for further details. (B) Block diagram representing the regulation of polyamine biosynthesis by antizyme as a modular feedback control system.
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Figure 1: The polyamine biosynthetic pathway in S. cerevisiae. (A) Antizyme (Oaz1), the main regulator is indicated; it targets ODC (Spe1) for degradation by the 26S proteasome. Metabolites are shown in italics and proteins in Roman type. Asterisks denote genes deleted in the spe1 spe2 paa1 fms1 deletant strain. See text for further details. (B) Block diagram representing the regulation of polyamine biosynthesis by antizyme as a modular feedback control system.

Mentions: Ornithine decarboxylase (ODC) is the first and rate limiting enzyme in the biosynthesis of the polyamines (Saccharomyces cerevisiae pathway shown in Figure 1). The key regulator of ODC in a wide range of eukaryotes is the protein antizyme (5). There is a single antizyme isoform in S. cerevisiae, Oaz1 (6). Antizyme binds to and inhibits ODC, and targets it for ubiquitin-independent proteolysis by the 26S proteasome (7,8). Antizyme synthesis is in turn dependent upon a polyamine-stimulated +1 ribosomal frameshift event during translation of its mRNA. Antizyme degradation by the ubiquitin pathway is inhibited by polyamines (6). Polyamines thus regulate their homeostasis via a negative feedback system, by controlling Oaz1 synthesis and inhibiting its proteolysis.Figure 1.


Translational recoding as a feedback controller: systems approaches reveal polyamine-specific effects on the antizyme ribosomal frameshift.

Rato C, Amirova SR, Bates DG, Stansfield I, Wallace HM - Nucleic Acids Res. (2011)

The polyamine biosynthetic pathway in S. cerevisiae. (A) Antizyme (Oaz1), the main regulator is indicated; it targets ODC (Spe1) for degradation by the 26S proteasome. Metabolites are shown in italics and proteins in Roman type. Asterisks denote genes deleted in the spe1 spe2 paa1 fms1 deletant strain. See text for further details. (B) Block diagram representing the regulation of polyamine biosynthesis by antizyme as a modular feedback control system.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3113565&req=5

Figure 1: The polyamine biosynthetic pathway in S. cerevisiae. (A) Antizyme (Oaz1), the main regulator is indicated; it targets ODC (Spe1) for degradation by the 26S proteasome. Metabolites are shown in italics and proteins in Roman type. Asterisks denote genes deleted in the spe1 spe2 paa1 fms1 deletant strain. See text for further details. (B) Block diagram representing the regulation of polyamine biosynthesis by antizyme as a modular feedback control system.
Mentions: Ornithine decarboxylase (ODC) is the first and rate limiting enzyme in the biosynthesis of the polyamines (Saccharomyces cerevisiae pathway shown in Figure 1). The key regulator of ODC in a wide range of eukaryotes is the protein antizyme (5). There is a single antizyme isoform in S. cerevisiae, Oaz1 (6). Antizyme binds to and inhibits ODC, and targets it for ubiquitin-independent proteolysis by the 26S proteasome (7,8). Antizyme synthesis is in turn dependent upon a polyamine-stimulated +1 ribosomal frameshift event during translation of its mRNA. Antizyme degradation by the ubiquitin pathway is inhibited by polyamines (6). Polyamines thus regulate their homeostasis via a negative feedback system, by controlling Oaz1 synthesis and inhibiting its proteolysis.Figure 1.

Bottom Line: Combinatorial polyamine treatments showed polyamines compete for binding to common ribosome sites.Using concepts from enzyme kinetics and control engineering, a mathematical model of the translational controller was developed to describe these complex ribosomal responses to combinatorial polyamine effects.Each one of a range of model predictions was successfully validated against experimental frameshift frequencies measured in S-adenosylmethionine-decarboxylase and antizyme mutants, as well as in the wild-type genetic background.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Sciences, School of Medical Sciences, University of Aberdeen, UK.

ABSTRACT
The antizyme protein, Oaz1, regulates synthesis of the polyamines putrescine, spermidine and spermine by controlling stability of the polyamine biosynthetic enzyme, ornithine decarboxylase. Antizyme mRNA translation depends upon a polyamine-stimulated +1 ribosomal frameshift, forming a complex negative feedback system in which the translational frameshifting event may be viewed in engineering terms as a feedback controller for intracellular polyamine concentrations. In this article, we present the first systems level study of the characteristics of this feedback controller, using an integrated experimental and modeling approach. Quantitative analysis of mutant yeast strains in which polyamine synthesis and interconversion were blocked revealed marked variations in frameshift responses to the different polyamines. Putrescine and spermine, but not spermidine, showed evidence of co-operative stimulation of frameshifting and the existence of multiple ribosome binding sites. Combinatorial polyamine treatments showed polyamines compete for binding to common ribosome sites. Using concepts from enzyme kinetics and control engineering, a mathematical model of the translational controller was developed to describe these complex ribosomal responses to combinatorial polyamine effects. Each one of a range of model predictions was successfully validated against experimental frameshift frequencies measured in S-adenosylmethionine-decarboxylase and antizyme mutants, as well as in the wild-type genetic background.

Show MeSH
Related in: MedlinePlus