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Chapter 9 : Regulation of Sugar Metabolism, 1920 to 2004
Category: Fungi and Fungal Pathogenesis; History of Science
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This chapter includes an account of the investigation of certain well-known, general regulatory mechanisms that control sugar metabolism, which involves enzyme induction, repression, and inactivation. Some of the mechanisms which regulate sugar metabolism have been named after those who first described the respective phenomena: the Pasteur, Kluyver, Custers, and Crabtree effects. Other general regulatory phenomena are glucose or catabolite repression and glucose or catabolite inactivation. However, what has been called the Crabtree effect in yeasts should be called ‘’glucose repression’’. All these effects involve regulatory changes in the amounts of enzyme synthesis or of enzyme activity, or both. The author along with Tony Sims extended the notion of the Kluyver effect to the utilization of D-galactose. The chapter provides the basis for understanding the roles of the Snf kinase and Mig1p in glucose repression through a series of observations. The Pasteur, Kluyver, and Custers effects are responses by yeasts to changes in the amount or character of the sugars available to them. Enzymic regulation, induction, repression, and inactivation bring about these effects and make possible other adaptations to alterations in the supplies of nutrients. The first major analysis of a microbial adaptation, carried out during the 1960s to 1980s, was that of the induction and repression of enzymes of the galactose pathway in Saccharomyces cerevisiae. Research on the molecular biology of cellular regulation is very active today and will undoubtedly bring to light even greater complexities.
Walter Bartley (1916–1994). Courtesy of Joan Brown.
Albert Jan Kluyver (1888–1956). Courtesy of C. T. Kluyver.
Custers effect: reduction of NAD(P)+ by formation of acetate from acetaldehyde lowers the concentration of NAD+ which is necessary for oxidizing glyceraldehyde 3-phosphate in glycolysis.
External hydrolysis of sucrose by invertase and internal hydrolysis by α-glucosidase.
Structure of raffinose.
Diagram of aspects of metabolism of d-glucose and ethanol by Saccharomyces cerevisiae in derepressed (A) and glucose-repressed (B) cells. Modified from reference 1850.
Tricarboxylic acid and glyoxylate cycles. Reproduced from reference 1101. Courtesy of Hans Kornberg.
Regulation of glycolysis by activators and deactivators.
Pabitra Maitra (1932–2007) and his wife, Zita Lobo (1945–2000). Photograph courtesy of Pratima Sinha.
Diagram of the two-hybrid system of Fields and Song, based on their Fig. 1 in reference 615. The Gal4 protein is a transcriptional activator, which expresses genes encoding enzymes of the galactose pathway. (1) The Gal4 protein consists of two separable domains, which do not function when separated: (a) Gal4-BD, a domain which binds specific DNA sequences (UASG), and (b) Gal4-AD, a domain which activates gene transcription. (2 and 3) Fields and Song separated these two domains as two genes (2) and fused Gal4-BD to protein X and Gal4-AD to protein Y (3). (4) If X and Y interact to form a dimer, the two domains are brought together and transcription is activated.
Diagram of protein interactions involved in regulating glucose repression in Saccharomyces cerevisiae. Events in low glucose concentration: (i) scaffold proteins bring Snf1p kinase and Snf4p protein together; (ii) Snf4p protein activates Snf1p kinase; (iii) Snf1p kinase permits transcription of glucose-repressed genes. Modified from reference 272.
Regulation of class II glucose-repressible genes, such as the structural genes for gluconeogenesis and the glyoxylate cycle. If glucose is exhausted in the medium, the Snf kinase is activated and has a dual function. (i) Snf/Cat kinase phosphorylates the Mig1 repressor. Consequently, the phosphorylated Mig1 repressor is exported to the cytoplasm. (ii) Snf kinase phosphorylates the Cat8 gene activator.
Simplified diagram of the regulation of glucose repression. The Snf kinase is inactive if glucose is available in the medium. Hence, the Snf complex has a dual function in regulating glucose repression. If activated when no glucose is available, the Snf kinase (i) inactivates the transcriptional repressor and (ii) activates the transcriptional activator, so that finally the transcriptional repressor dissociates from the glucose-repressible structural genes and the activator binds to the structural gene.
Regulation of class I glucose-repressible genes, such as the structural genes for SUC2 and CAT8. (i) If glucose is present in the medium, the Mig1 repressor binds to the respective URS sites (upstream repressing sequences) of class I genes and prevents their transcription; under these conditions, Snf kinase is inactive. (ii) If glucose is exhausted in the medium, the Snf kinase is activated and phosphorylates the Mig1 repressor; consequently, the phosphorylated Mig1 repressor is exported to the cytoplasm.
Helmut Holzer (1921–2007). Courtesy of Karl Decker.
The concept of fructose bisphosphatase (FBPase) inactivation in the vacuole, by means of Vid vesicles. When starved cells of Saccharomyces cerevisiae are given d-glucose, FBPase is taken into Vid vesicles and then degraded in the vacuole. The first step involves at least two cytosolic proteins, Ssa2p and Cpr1p, the level of the latter being regulated by the plasma membrane protein Vid22p. Formation of Vid vesicles is thought to be regulated by the ubiquitin conjunction enzyme Ubc1p. Delivery of FBPase by Vid vesicles to the vacuole depends on Vid24p. Vacuolar proteinase degrades the FBPase. Adapted from reference 206.
Major regulatory mechanisms in carbohydrate metabolism
The Pasteur effect: chronology of some findings
Abilities of Candida utilis and Saccharomyces cerevisiae to utilize d-glucose and maltose
Location of hydrolysis of oligosaccharides in most yeasts studied a
Genetic and biochemical characterization of genes involved in glucose repression a
Pleiotropic effects of mutations of the genes CYC8 and TUP1