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Glucose metabolism

Glucose metabolism. Processes Glycolysis Glycogenolysis Gluconeogenesis Substrate level regulation Hormone level regulation. Carbohydrate metabolism. Glycolysis Breakdown of glucose to pyruvate Provides substrate for TCA cycle Gluco-/glyco-neogenesis Synthesis of glucose or glycogen

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Glucose metabolism

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  1. Glucose metabolism • Processes • Glycolysis • Glycogenolysis • Gluconeogenesis • Substrate level regulation • Hormone level regulation

  2. Carbohydrate metabolism • Glycolysis • Breakdown of glucose to pyruvate • Provides substrate for TCA cycle • Gluco-/glyco-neogenesis • Synthesis of glucose or glycogen • Storage of excess substrate • Regulatory mechanisms • Allosteric • Phosphorylation

  3. Glycolysis • Convert Glucose to Pyruvate • Yield 2 ATP + 2 NADH per glucose • Consume 2 ATP to form 2x glyceraldehyde phosphate • Produce 2 ATP + 1 NADH per GAP • Carefully controlled • 12 different enzyme-catalyzed steps • Limited by phosphofructokinase • Limited by substrate availability

  4. Glycolysis/Gluconeogenesis Starch/glycogen breakdown Glyceraldehyde-3P Hexose import GAPDH a-D-Glucose-1P Glycerate-1,3P2 phosphoglucomutase phosphoglycerate kinase a-D-Glucose-6P Glycerate-3P glucose-6-phosphate isomerase phosphoglycerate mutase b-D-Fructose-6P Glycerate-2P fructose-1,6-bisphosphatase 6-phosphofructokinase enolase b-D-Fructose-1,6,P2 Phosphoenolpyruvate fructose-bisphosphate aldolase pyruvate kinase Except for these steps, glycolysis happily runs backward. Backwards glycolysis is gluconeogenesis Pyruvate

  5. Glycolysis: phosphorylation • ATP consuming • Glucose phosphorylation by hexokinase • Fructose phosphorylation by phosphofructokinase • Triose phosphate isomerase

  6. Glycolysis: oxidation • Pyruvate kinase • Transfer Pi to ADP • Driven by oxidative potential of 2’ O • Summary • Start C6H12O6 • End 2xC3H3O3 • Added 0xO • Lost 6xH • Gained 2xNADH, 2xATP GAPDH phosphoglycerate kinase NADH ATP pyruvate kinase

  7. Pyruvate • Lactic Acid • Regenerates NAD+ • Redox neutral • Ethanol • Regenerates NAD+ • Redox neutral • Acetyl-CoA • Pyruvate import to mitocondria • ~15 more ATP per pyruvate S-acetyldihydro-lipoyllysine 2-Hydroxyethyl-Thiamine diphosphate pyruvate Acetyl-CoA

  8. Carbohydrate Transport • H+, pyruvate cotransporter Major Facilitator Superfamily Monocarboxylate transporter Competition between H+ driven transport to mitochondria and NADH/H+ driven conversion to lactate Cytoplasmic NADH is also used to generate mitochondrial FADH2, coupling transport to ETC saturation “glycerol-3P shuttle” Halestrap & Price 1999

  9. Gluconeogenesis • Regenerate glucose from metabolites • Mostly liver • Many glycolytic enzymes are reversible • Special enzymes • Pyruvate carboxylase • Generate 4-C oxaloacetate from 3-C pyruvate • Phosphoenyl pyruvate carboxykinase • Swap carboxyl group for phosphate • Generates 3-C phosphoenolpyruvate from OA • Fructose-1,6-bisphosphatase • Generates fructose-6-phosphate Mitochondrial

  10. Glycogen • Glucose polysaccharide • Intracellular carbohydrate store • Easily converted to glucose • Glycogenolysis • Phosphorylase generates glucose-1-P from glycogen • Glycogenesis • Glycogen synthase adds UDP-glucose-1-P to glycogen

  11. Substrate control of CHO metabolism • Kinetic flux balance • Competition for energy-related molecules • Oxaloacetate: endpoint of TCA • Pyruvate • Allosteric regulation by energy-related molecules • ATP/AMP: PFK/PFP • F-1,6-BP: pyruvate kinase • Fatty acids

  12. Substrate competition • Oxaloacetate • Oxa + AcCoA  citrate • Oxa + GTP  GDP + PEP • Acetyl-CoA • Oxa + AcCoA  citrate • AcCoA + HCO3  MalonylCoA fatty acids • Amino acid synthesis Oxaloacetate Citrate = Phosphoenylpyruvate

  13. Adenine nucleotides balance glucose breakdown • PFK activity depends on ATP/AMP • Competitive binding to regulatory domain • PFP activity depends on AMP/citrate ATP AMP PFK PFP AMP Glycolysis PFK Glycolysis ATP PFP Glycolysis AMP

  14. Pyruvate kinase • Substrate cooperativity • Fructose 1,6-bisphosphate +cAMP Mansour & Ahlfors, 1968

  15. Hormonal control of CHO metabolism • Liver/periphery (liver/muscle) • Glucagon – glucose release • Insulin – glucose uptake • System wide response • Distribution of receptors • Tissue specialization • Effector systems • Glucose uptake • PFK/PFP balance

  16. Systemic Regulation of Blood Sugar • Pancreas • b-cells:GlucoseATP--|KATP--| depolarizationCainsulin+GABA release • a-cells:GABACl- --|glucagon • Peripheral tissues • Insulin  IRPI3KGLUT4 translocation glucose uptake • PI3KPKB--|GSK--|GS • Liver • GlucagonGRGsACPKA--|GS Glucose uptake, glycogenesis (muscle) Blood glucose Glycogenolysis (Liver) Insulin Glucagon

  17. Glucagon • Endocrine factor, Gs coupled receptor • PLC, AC enhance glycogenolysis • Rapid secretion of glucose from liver AC PLC Hepatic cAMP Insulin/Glucagon ratio Jiang, G. et al. Am J Physiol Endocrinol Metab 284: E671-E678 2003; doi:10.1152/ajpendo.00492.2002 Tiedgen & Seitz, 1980

  18. Glucagon Liver only GPCR PLC Adenylate cyclase Activates GP Inhibits GS Stimulates gluconeogenesis Insulin Most tissues RTK PI-3K PP1 Activates GS Inhibits GP GLUT-4 translocation Glucagon:Insulin Glucose distribution (liver) Glucose storage (muscle)

  19. PKA +GP via phosphorylase kinase -GS -PP1 via G-subunit PKB +GS via GSK +PP1 via G-subunit Phospho-regulation of glycogenThe straight activity version • PP1 • +GS • -GP Activates Inhibits PK GP GP Glycogen Synthesis PKA PKB PP1-G PP1 PP1 PP1-G GS GS GSK3

  20. PKA +GP via phosphorylase kinase -GS -PP1 via G-subunit PKB +GS via GSK +PP1 via G-subunit Phospho-regulation of glycogenThe phosphorylation story • PP1 • +GS • -GP Phos/Increase Dephos/Decr Active Inactive PK GP GP Glycogen Synthesis PKA PKB PP1-G PP1 PP1 PP1-G GS GS GSK3

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