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Systems biology of GAL regulon in Saccharomyces cerevisiae

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Abstract Evolutionary success of an organism depends on its ability to express or adapt to constantly changing environmental conditions. Saccharomyces cerevisiae has evolved an elaborate genetic circuit to regulate the expression of galactose‐metabolizing enzymes in the presence of galactose but in the absence of glucose. The circuit possesses molecular mechanisms such as multiple binding sites, cooperativity, autoregulation, nucleocytoplasmic shuttling, and substrate sensing mechanism. Furthermore, the GAL system consists of two positive (activating) feedback and one negative (repressing) feedback loops. These individual mechanisms, elucidated through experimental approach, can be integrated to obtain a system‐wide behavior. Mathematical models in conjunction with guided experiments have demonstrated system‐level properties such as ultrasensitivity, memory, noise attenuation, rapid response, and sensitive response arising out of the molecular interactions. These system‐level properties allow S. cerevisiae to adapt and grow in a galactose medium under noisy and changing environments. This review focuses on system‐level models and properties of the GAL regulon Copyright © 2009 John Wiley & Sons, Inc. This article is categorized under: Models of Systems Properties and Processes > Cellular Models

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A schematic diagram of Saccharomyces cerevisiae GAL genetic system. The induction of GAL system takes place as galactose enters the cell facilitated by the action of permease, Gal2p. Gal3p activation by the allosteric interactions of galactose and adenosine triphosphate (ATP) will cause the activated Gal3p to interact with Gal80p in the cytoplasm making it to shuttle from nucleus to the cytoplasm of the cells. Decreased amounts of nuclear Gal80p may hamper its dimerization and ability to interact with Gal4p‐bound DNA. Gal4p bound to UASG is then relieved from repression and transcriptional process proceeds. D1 and D2 represent GAL genes with one and two binding sites, respectively.

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Illustration of effect of various molecular mechanisms on the system‐level properties in the GAL system obtained from dynamic analysis. (a) Effect of Gal3p feedback. Curve (i) shows the wild‐type response when precultured on galactose, curve (ii) shows the wild‐type response when precultured on raffinose, and curve (iii) shows the response for a Gal3p feedback deleted strain when precultured on raffinose. (b) Effect of Gal80p feedback. Curve (i) shows the number density of Gal80p in a wild‐type strain and curve (ii) shows the number density in a mutant strain lacking Gal80p. (c) Long‐term adaptation because of removal of gal3. Curve (i) shows the dynamic profile of fractional protein expression in a wild‐type strain. Curve (ii) shows the long‐term adaptation of GAL genes in gal3‐mutated strain.

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Illustration of effect of various molecular mechanisms on the system‐level properties in the GAL system obtained from steady‐state analysis. (a) Cooperative binding of activator Gal4p to the multiple binding sites. Dashed line represents a response with a Hill coefficient of value 1 and solid line represent Hill coefficient value of 3 showing ultrasensitivity as seen in the GAL system. A typical Michealis–Menten response requires 81‐fold change in the stimulus to bring about a change from 10% to 90% in the response. An ultrasensitive response requires less than 81‐fold change for a similar stimulus–response relationship. This steepness in the response is typically characterized by fitting a Hills equation and the Hills coefficient (ηH) provides a measure of steepness of the response curve. A value of (ηH = 1) indicates Michealis–Menten response, whereas (ηH > 1) implies ultrasensitivity. (b) Effect of Gal2p feedback. Curve (i) shows the wild‐type response and curve (ii) shows the response of Ga2p feedback deletion strain. (c) Effect of overexpression of Gal3p. Curve (i) shows the wild‐type steady‐state response to varying galactose concentration and curve (ii) shows the constitutive synthesis of GAL enzymes because of overexpression of Gal3p.

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Schematic diagram showing feedback effects in GAL system of Saccharomyces cerevisiae. Gal80p represses the induction mechanism and forms a negative feedback loop, whereas Gal3p relieves the Gal80p inhibition on Gal4p, and thus forms a positive feedback loop. In parallel, Gal2p provides a positive feedback loop in the GAL system through facilitated transport of galactose from extracellular medium. The dotted line represents plasma membranes. The red blunt‐ended arrows represent repression and green arrows represent activation.

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