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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 – Storage of excess substrate • Regulatory mechanisms – Allosteric – Phosphorylation 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 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 fructose-1,6bisphosphatase Glycerate-2P 6-phosphofructokinase b-D-Fructose-1,6,P2 fructose-bisphosphate aldolase Except for these steps, glycolysis happily runs backward. Backwards glycolysis is gluconeogenesis enolase Phosphoenolpyruvate pyruvate kinase Pyruvate Glycolysis: phosphorylation • ATP consuming – Glucose phosphorylation by hexokinase – Fructose phosphorylation by phosphofructokinase • Triose phosphate isomerase Glycolysis: oxidation • Pyruvate kinase – Transfer Pi to ADP – Driven by oxidative potential of 2’ O • Summary GAPDH NADH ATP – Start C6H12O6 – End 2xC3H3O3 – Added 0xO – Lost 6xH – Gained 2xNADH, 2xATP phosphoglycerate kinase pyruvate kinase Pyruvate • Lactic Acid – Regenerates NAD+ – Redox neutral • Ethanol – Regenerates NAD+ – Redox neutral • Acetyl-CoA – Pyruvate import to mitocondria – ~15 more ATP per pyruvate pyruvate 2-HydroxyethylThiamine diphosphate S-acetyldihydrolipoyllysine Acetyl-CoA 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 Gluconeogenesis • Regenerate glucose from metabolites – Mostly liver – Many glycolytic enzymes are reversible • Special enzymes • 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 – Pyruvate carboxylase 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 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 Substrate competition • Oxaloacetate – Oxa + AcCoA citrate – Oxa + GTP GDP + PEP • Acetyl-CoA Oxaloacetate Citrate = Phosphoenylpyruvate – Oxa + AcCoA citrate – AcCoA + HCO3 MalonylCoA fatty acids – Amino acid synthesis Adenine nucleotides balance glucose breakdown • PFK activity depends on ATP/AMP – Competitive binding to regulatory domain • PFP activity depends on AMP/citrate ATP PFK PFP AMP AMP Glycolysis PFK Glycolysis ATP PFP Glycolysis AMP Pyruvate kinase • Substrate cooperativity • Fructose 1,6-bisphosphate +cAMP Mansour & Ahlfors, 1968 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 Systemic Regulation of Blood Sugar • Pancreas – b-cells:GlucoseATP--|KATP--| depolarizationCainsulin+GABA release – a-cells:GABACl- --|glucagon • Peripheral tissues – Insulin IRPI3KGLUT4 translocation glucose uptake – PI3KPKB--|GSK--|GS • Liver – GlucagonGRGsACPKA--|GS Glucose uptake, glycogenesis (muscle) Insulin Blood glucose Glucagon Glycogenolysis (Liver) Glucagon • Endocrine factor, Gs coupled receptor • PLC, AC enhance glycogenolysis – Rapid secretion of glucose from liver AC Hepatic cAMP PLC Jiang, G. et al. Am J Physiol Endocrinol Metab 284: E671-E678 2003; doi:10.1152/ajpendo.00492.2002 Insulin/Glucagon ratio Tiedgen & Seitz, 1980 Glucagon:Insulin • Glucagon – Liver only – GPCR • PLC • Adenylate cyclase – Activates GP – Inhibits GS – Stimulates gluconeogenesis Glucose distribution (liver) • Insulin – Most tissues – RTK • PI-3K • PP1 – Activates GS – Inhibits GP – GLUT-4 translocation Glucose storage (muscle) Phospho-regulation of glycogen The straight activity version • PKA • PKB +GP via phosphorylase kinase -GS -PP1 via G-subunit +GS via GSK +PP1 via G-subunit •PP1 +GS -GP PK PKA GP PP1-G GS PP1 Activates Inhibits GP Glycogen Synthesis PP1 PP1-G GS GSK3 PKB Phospho-regulation of glycogen The phosphorylation story • PKA • PKB +GP via phosphorylase kinase -GS -PP1 via G-subunit +GS via GSK +PP1 via G-subunit •PP1 +GS -GP Phos/Increase Dephos/Decr Active PK PKA GP PP1-G GS PP1 Inactive GP Glycogen Synthesis PP1 PP1-G GS GSK3 PKB