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      Nutrient sensing and signaling in the yeast Saccharomyces cerevisiae

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          Abstract

          The yeast Saccharomyces cerevisiae has been a favorite organism for pioneering studies on nutrient-sensing and signaling mechanisms. Many specific nutrient responses have been elucidated in great detail. This has led to important new concepts and insight into nutrient-controlled cellular regulation. Major highlights include the central role of the Snf1 protein kinase in the glucose repression pathway, galactose induction, the discovery of a G-protein-coupled receptor system, and role of Ras in glucose-induced cAMP signaling, the role of the protein synthesis initiation machinery in general control of nitrogen metabolism, the cyclin-controlled protein kinase Pho85 in phosphate regulation, nitrogen catabolite repression and the nitrogen-sensing target of rapamycin pathway, and the discovery of transporter-like proteins acting as nutrient sensors. In addition, a number of cellular targets, like carbohydrate stores, stress tolerance, and ribosomal gene expression, are controlled by the presence of multiple nutrients. The protein kinase A signaling pathway plays a major role in this general nutrient response. It has led to the discovery of nutrient transceptors (transporter receptors) as nutrient sensors. Major shortcomings in our knowledge are the relationship between rapid and steady-state nutrient signaling, the role of metabolic intermediates in intracellular nutrient sensing, and the identity of the nutrient sensors controlling cellular growth.

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          Most cited references374

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          Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function.

          The first step in metabolism of glucose (Glc) is usually phosphorylation, catalyzed by hexokinase. However, the Glc-6-P produced can then enter one or more of several alternative pathways. Selective expression of isozymic forms of hexokinase, differing in catalytic and regulatory properties as well as subcellular localization, is likely to be an important factor in determining the pattern of Glc metabolism in mammalian tissues/cells. Despite their overall structural similarity, the Type I, Type II and Type III isozymes differ in important respects. All three isozymes are inhibited by the product, Glc-6-P, but with the Type I isozyme, this inhibition is antagonized by P(I), whereas with the Type II and Type III isozymes, P(i) actually causes additional inhibition. Reciprocal changes in intracellular levels of Glc-6-P and P(i) are closely associated with cellular energy status, and it is proposed that the response of the Type I isozyme to these effectors adapts it for catabolic function, introducing Glc into glycolytic metabolism for energy production. In contrast, the Type II, and probably the Type III, isozymes are suggested to serve primarily anabolic functions, e.g. to provide Glc-6-P for glycogen synthesis or metabolism via the pentose phosphate pathway for lipid synthesis. Type I hexokinase binds to mitochondria through interaction with porin, the protein that forms channels through which metabolites traverse the outer mitochondrial membrane. Several experimental approaches have led to the conclusion that the Type I isozyme, bound to actively phosphorylating mitochondria, selectively uses intramitochondrial ATP as substrate. Such interactions are thought to facilitate coordination of the introduction of Glc into glycolysis, via the hexokinase reaction, with the terminal oxidative stages of Glc metabolism occurring in the mitochondria, thus ensuring an overall rate of Glc metabolism commensurate with cellular energy demands and avoiding excessive production of lactate. The Type II isozyme also binds to mitochondria. Whether such coupling occurs with mitochondrially bound Type II hexokinase in normal tissues, and how it might be related to the proposed anabolic role of this isozyme, remain to be determined. The Type III isozyme lacks the hydrophobic N-terminal sequence known to be critical for binding of the Type I and Type II isozymes to mitochondria. Immunolocalization studies have indicated that, in many cell types, the Type III has a perinuclear localization, the possible metabolic consequences of which remain unclear.
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            TOR, a Central Controller of Cell Growth

            Cell, 103(2), 253-262
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              Systematic identification of pathways that couple cell growth and division in yeast.

              Size homeostasis in budding yeast requires that cells grow to a critical size before commitment to division in the late prereplicative growth phase of the cell cycle, an event termed Start. We determined cell size distributions for the complete set of approximately 6000 Saccharomyces cerevisiae gene deletion strains and identified approximately 500 abnormally small (whi) or large (lge) mutants. Genetic analysis revealed a complex network of newly found factors that govern critical cell size at Start, the most potent of which were Sfp1, Sch9, Cdh1, Prs3, and Whi5. Ribosome biogenesis is intimately linked to cell size through Sfp1, a transcription factor that controls the expression of at least 60 genes implicated in ribosome assembly. Cell growth and division appear to be coupled by multiple conserved mechanisms.

                Author and article information

                Journal
                FEMS Microbiol Rev
                FEMS Microbiol. Rev
                fmr
                Fems Microbiology Reviews
                BlackWell Publishing Ltd (Oxford, UK )
                0168-6445
                1574-6976
                March 2014
                03 March 2014
                : 38
                : 2
                : 254-299
                Affiliations
                [1 ]Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven Leuven-Heverlee, Flanders, Belgium
                [2 ]Department of Molecular Microbiology, VIB Leuven-Heverlee, Flanders, Belgium
                Author notes
                Correspondence: Johan M. Thevelein, Department of Molecular Microbiology, VIB, Kasteelpark Arenberg 31, B-3001 Leuven-Heverlee, Flanders, Belgium. Tel.: +32 16 321507; fax: +32 16 321979; e-mail: johan.thevelein@ 123456mmbio.vib-kuleuven.be
                Article
                10.1111/1574-6976.12065
                4238866
                24483210
                b9e9515f-fc44-4977-a496-7faac28c3375
                Copyright © 2014 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 19 August 2013
                : 23 December 2013
                : 22 January 2014
                Categories
                Review Articles

                Microbiology & Virology
                snf1 protein kinase,g-protein-coupled receptor,ras,pho85 protein kinase,target of rapamycin,transceptor

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