How metabolites modulate metabolic flux.

Adaptation to metabolic needs and changing environments is a basic requirement of every living system. These adaptations can be very quick and mild or slower but more drastic. In any case, cells have to constantly monitor their metabolic state and requirements. In this article we review general concepts as well as recent advances on how metabolites can regulate metabolic fluxes. We discuss how cells sense metabolite levels and how changing metabolite levels regulate metabolic enzymes on different levels, from specific allosteric regulation to global transcriptional regulation. We thereby focus on local metabolite sensing in mammalian cells and show that several major discoveries have only very recently been made.

[1]  E. Gottlieb,et al.  Rocking cell metabolism: revised functions of the key glycolytic regulator PKM2 in cancer. , 2012, Trends in biochemical sciences.

[2]  Jesse M. Platt,et al.  Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability , 2011, Proceedings of the National Academy of Sciences.

[3]  R. Sun,et al.  Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth. , 2014, Cell metabolism.

[4]  F. Massi,et al.  Allosteric inhibition of a stem cell RNA-binding protein by an intermediary metabolite , 2012, eLife.

[5]  G. Semenza HIF-1 and mechanisms of hypoxia sensing. , 2001, Current opinion in cell biology.

[6]  S. Gygi,et al.  Chemical genetic screen for AMPKα2 substrates uncovers a network of proteins involved in mitosis. , 2011, Molecular cell.

[7]  R. Verhaak,et al.  Transformation by the R Enantiomer of 2-Hydroxyglutarate Linked to EglN Activation , 2012, Nature.

[8]  Eric Verdin,et al.  The nexus of chromatin regulation and intermediary metabolism , 2013, Nature.

[9]  R. Deberardinis,et al.  Oxidation of alpha-ketoglutarate is required for reductive carboxylation in cancer cells with mitochondrial defects. , 2014, Cell reports.

[10]  Thomas M. Wasylenko,et al.  Reductive glutamine metabolism is a function of the α-ketoglutarate to citrate ratio in cells , 2013, Nature Communications.

[11]  A metabolic network described in absolute terms. , 2009, Nature chemical biology.

[12]  David G. Watson,et al.  Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. , 2005, Cancer cell.

[13]  Yuen-Li Chung,et al.  HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. , 2005, Cancer cell.

[14]  M. Magnuson,et al.  Hepatic Glucokinase Is Required for the Synergistic Action of ChREBP and SREBP-1c on Glycolytic and Lipogenic Gene Expression* , 2004, Journal of Biological Chemistry.

[15]  Fabian V. Filipp,et al.  Reverse TCA cycle flux through isocitrate dehydrogenases 1 and 2 is required for lipogenesis in hypoxic melanoma cells , 2012, Pigment cell & melanoma research.

[16]  D. Hardie,et al.  AMP Is a True Physiological Regulator of AMP-Activated Protein Kinase by Both Allosteric Activation and Enhancing Net Phosphorylation , 2013, Cell metabolism.

[17]  Christian M. Metallo,et al.  Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia , 2011, Nature.

[18]  B. Kemp,et al.  AMPK Is a Direct Adenylate Charge-Regulated Protein Kinase , 2011, Science.

[19]  Christian M. Metallo,et al.  Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis , 2012, Nature chemical biology.

[20]  W. Winder,et al.  Phosphorylation-activity relationships of AMPK and acetyl-CoA carboxylase in muscle. , 2002, Journal of applied physiology.

[21]  Liang Zheng,et al.  Succinate is an inflammatory signal that induces IL-1β through HIF-1α , 2013, Nature.

[22]  Chunaram Choudhary,et al.  The growing landscape of lysine acetylation links metabolism and cell signalling , 2014, Nature Reviews Molecular Cell Biology.

[23]  Christian M. Metallo,et al.  Understanding metabolic regulation and its influence on cell physiology. , 2013, Molecular cell.

[24]  Bin Wang,et al.  Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. , 2011, Cancer cell.

[25]  H. Towle,et al.  Direct Role of ChREBP·Mlx in Regulating Hepatic Glucose-responsive Genes* , 2005, Journal of Biological Chemistry.

[26]  K. Wellen,et al.  A two-way street: reciprocal regulation of metabolism and signalling , 2012, Nature Reviews Molecular Cell Biology.

[27]  T. Mak,et al.  Regulation of cancer cell metabolism , 2011, Nature Reviews Cancer.

[28]  W. Marston Linehan,et al.  Reductive carboxylation supports growth in tumor cells with defective mitochondria , 2011, Nature.

[29]  Alessandro Vespignani,et al.  ATP-Citrate Lyase Links Cellular Metabolism to Histone Acetylation , 2009 .

[30]  J. Licht,et al.  Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. , 2010, Cancer cell.

[31]  Ronald R. Breaker,et al.  Eukaryotic TPP riboswitch regulation of alternative splicing involving long-distance base pairing , 2013, Nucleic acids research.

[32]  J. Girard,et al.  Novel insights into ChREBP regulation and function , 2013, Trends in Endocrinology & Metabolism.

[33]  Katsumi Iizuka,et al.  Carbohydrate response element binding protein directly promotes lipogenic enzyme gene transcription. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[34]  D. Hardie,et al.  AMPK: a nutrient and energy sensor that maintains energy homeostasis , 2012, Nature Reviews Molecular Cell Biology.

[35]  K. Storey Functional metabolism : regulation and adaptation , 2005 .

[36]  E. Eigenbrodt,et al.  Structural and kinetic differences between the M2 type pyruvate kinases from lung and various tumors. , 1983, Biomedica biochimica acta.

[37]  Eyal Gottlieb,et al.  Serine is a natural ligand and allosteric activator of pyruvate kinase M2 , 2012, Nature.

[38]  W. Atchley,et al.  A Novel N-Terminal Domain May Dictate the Glucose Response of Mondo Proteins , 2012, PloS one.

[39]  David Carling,et al.  Structure of Mammalian AMPK and its regulation by ADP , 2011, Nature.