MICROBIOLOGY AND MOLECULAR BIOLOGY REVIEWS June 1998 p 334 361 1092 2172 98 04 0010 Copyright 1998 American Society for Microbiology Vol 62 No 2 Yeast Carbon Catabolite Repression JUANA M GANCEDO Instituto de Investigaciones Biome dicas Unidad de Bioqu mica y Gene tica de Levaduras CSIC 28029 Madrid Spain INTRODUCTION 334 LEVELS OF CONTROL 334 ELEMENTS OF THE SYSTEM 336 Activators 336 The Hap2 3 4 5 complex 336 Gal4 337 Mal63 337 Adr1 338 Other activators 338 Repressors 339 The Mig1 complex 339 Other repressors 340 Intermediary Elements 341 The Snf1 complex 341 The Glc7 complex 342 Elements Involved in Glucose Signaling 343 Elements Which Play an Indirect Role 345 The Snf Swi complex and the Spt proteins 345 The mediator 346 The Ada Gcn5 complex 347 Other elements 347 REGULATION OF SPECIFIC GENES 347 The GAL Genes 347 SUC2 348 FBP1 349 ADH2 350 CYC1 350 Other Genes 350 CONCLUSIONS AND PERSPECTIVES 352 ACKNOWLEDGMENTS 353 REFERENCES 353 95 96a 96b 124 163 289 and 346 Although the solution of the puzzle has progressed important pieces are still missing and it has been found that other pieces originally thought to belong do not really pertain to the basic frame The last few years have seen important advances which are reviewed and discussed in this article I also propose some models for catabolite repression of different genes and discuss some perspectives for future research Although the review deals mainly with S cerevisiae reference to other yeast species is made as far as information is available For easy reference Table 2 provides an overview of the alternative names given to genes related to catabolite repression since these genes have been repeatedly isolated by different groups and given different names INTRODUCTION Saccharomyces cerevisiae and many other yeasts may thrive on a variety of carbon sources but glucose and fructose are the preferred ones When one of these sugars is present the enzymes required for the utilization of alternative carbon sources are synthesized at low rates or not at all This phenomenon is known as carbon catabolite repression or simply catabolite repression and since no catabolite derived from glucose and involved in the repression has been yet identified the term glucose repression has also been proposed In this review I still use the term catabolite repression as well as glucose repression to stress that other sugars such as galactose or maltose are able to affect the synthesis of enzymes repressed by glucose Table 1 A comprehensive picture of the mechanism s of catabolite repression is not yet available in spite of the accumulation of information on the subject for earlier reviews see references LEVELS OF CONTROL Glucose may affect enzyme levels by causing a decrease in the concentration of the corresponding mRNAs a decrease in their translation rate or an increase in the degradation rate of the protein In turn mRNA levels would depend both on the rate of transcription of the corresponding gene and on the stability of the mRNA The main effect of glucose takes place at the transcriptional level accordingly this review deals Mailing address Instituto de Investigaciones Biome dicas C S I C Arturo Duperier 4 28029 Madrid Spain Phone 34 91 585 4622 Fax 34 91 585 4587 E mail jmgancedo iib uam es Dedicated to the memory of Helmut Holzer who greatly contributed to the knowledge of yeast metabolism 334 VOL 62 1998 YEAST CARBON CATABOLITE REPRESSION 335 TABLE 1 Catabolite repression caused by different sugars Yeast species Carbon source Saccharomyces cerevisiaea Glucose Galactose Pyruvate Schizosaccharomyces pombeb Glucose Maltose Ethanol a b c Enzyme activity mU mg of protein Malate synthase Fructose bisphosphatase Isocitrate lyase Cytochrome oxidase Malate dehydrogenase Glutamate dehydrogenasec 1 1 180 1 1 40 1 1 80 6 19 38 450 700 11 000 1 8 53 9 20 90 100 250 3 400 15 45 48 1 1 80 Data from references 120 and 274 Data from reference 100 NAD dependent isoenzyme mainly with this mechanism of regulation Nevertheless alternative mechanisms which are operative in certain cases are briefly discussed in this section Control of the mRNA translation rate is not common in yeast however in the case of the transcriptional activator Adr1 glucose appears to act at this step While the concentration of Adr1 is at least 10 fold higher in ethanol grown yeast than in glucose grown yeast there is only a 2 fold difference in the levels of the corresponding mRNAs 354 Since the halflife of Adr1 itself is not longer in ethanol grown cells than in glucose grown cells it has been concluded that the observed decrease in the level of Adr1 is due mainly to a reduction in the rate of Adr1 synthesis brought about by glucose The molecular mechanism by which glucose acts remains unclear but it has been shown that the translational control does not depend on the long untranslated 59 leader sequence of ADR1 mRNA 354 Removal of the gene sequence corresponding to the 681 C terminal residues of Adr1 more than half the length of the protein did not disrupt the translational control but the ADR1 coding sequence between amino acids 262 and 642 is required for the control of ADR1 translation by glucose While translational control by glucose is rare glucose triggers inactivation and or proteolysis of a number of proteins By analogy to catabolite repression this phenomenon has been called catabolite inactivation 151 it affects a variety of proteins from gluconeogenic enzymes to transport molecules but it is not yet known whether the same mechanism underlies the inactivation in the different cases 125a Inactivation of fructose 1 6 bisphosphatase FbPase by glucose 121 has been most extensively studied and it has been shown that glucose causes a very rapid phosphorylation of FbPase and a proteolytic degradation of the enzyme 119 224 225 236 Two alternative mechanisms for the proteolysis have been described i transfer of FbPase to the vacuole and degradation by vacuolar proteases 56 and ii ubiquitination of FbPase 310 followed by degradation by the proteasome 309 The relative contribution of each pathway could depend on the physiological state of the yeast 306 Proteolysis of FbPase triggered by glucose can occur even in the absence of phosphorylation 291 but it has not been established whether phosphorylation may be a requirement or a facilitator of at least one of the degradation systems The mechanism by which glucose triggers the proteolysis is not known but glucose appears to induce the
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