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Chapter 13 (part 1). Additional Pathways in Carbohydrate Metabolism. Metabolism of Tissue Glycogen. But tissue glycogen is an important energy reservoir - its breakdown is carefully controlled Glycogen consists of "granules" of high MW

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chapter 13 part 1

Chapter 13 (part 1)

Additional Pathways in Carbohydrate Metabolism

slide2
Metabolism of Tissue Glycogen
  • But tissue glycogen is an important energy reservoir - its breakdown is carefully controlled
  • Glycogen consists of "granules" of high MW
  • Glycogen phosphorylase cleaves glucose from the nonreducing ends of glycogen molecules
  • This is a phosphorolysis, not a hydrolysis
  • Metabolic advantage: product is a sugar-P - a "sort-of" glycolysis substrate
slide3
Glycogen phosphorylase cleaves glycogen at non-reducing end to generate glucose-1-phosphate
  • Debranching of limit dextran occurs in two steps.
  • 1st, 3 X 1,4 linked glucose residues are transferred to non-reducing end of glycogen
  • 2nd, amylo-1,6-glucosidase cleaves 1,6 linked glucose residue.
  • Glucose-1-phosphate is converted to glucose-6-phosphate by phosphoglucomutase
slide4
Glycogen Synthase
  • Forms -(1 4) glycosidic bonds in glycogen
  • Glycogen synthesis depends on sugar nucleotides UDP-Glucose
  • Glycogenin (a protein!) protein scaffold on which glycogen molecule is built.
  • Glycogen Synthase requires 4 to 8 glucose primer on Glycogenin (glycogenein catalyzes primer formation)
  • First glucose is linked to a tyrosine -OH
  • Glycogen synthase transfers glucosyl units from UDP-glucose to C-4 hydroxyl at a nonreducing end of a glycogen strand.
slide6
Control of Glycogen Metabolism
  • A highly regulated process, involving reciprocal control of glycogen phosphorylase (GP) and glycogen synthase (GS)
  • GP allosterically activated by AMP and inhibited by ATP, glucose-6-P and caffeine
  • GS is stimulated by glucose-6-P
  • Both enzymes are regulated by covalent modification - phosphorylation
hormonal regulation of glycogen metabolism
Hormonal Regulation of Glycogen Metabolism

Insulin

  • Secreted by pancreas under high blood [glucose]
  • Stimulates Glycogen synthesis in liver
  • Increases glucose transport into muscles and adipose tissues

Glucagon

  • Secreted by pancreas in response to low blood [glucose]
  • Stimulates glycogen breakdown
  • Acts primarily in liver

Ephinephrine

  • Secrete by adrenal gland (“fight or flight” response)
  • Stimulates glycogen breakdown.
  • Increases rates of glycolysis in muscles and release of glucose from the liver
effect of glucagon and epinephrine on glycogen phosphorylase glycogen synthase activities
Effect of glucagon and epinephrine on glycogen phosphorylase glycogen synthase activities
gluconeogenesis
Gluconeogenesis
  • Synthesis of "new glucose" from common metabolites
  • Humans consume 160 g of glucose per day
  • 75% of that is in the brain
  • Body fluids contain only 20 g of glucose
  • Glycogen stores yield 180-200 g of glucose
  • The body must still be able to make its own glucose
slide12
Gluconeogenesis
  • Occurs mainly in liver and kidneys
  • Not the mere reversal of glycolysis for 2 reasons:
    • Energetics must change to make gluconeogenesis favorable (delta G of glycolysis = -74 kJ/mol
    • Reciprocal regulation must turn one on and the other off - this requires something new!
slide13
Seven steps of glycolysis are retained
  • Three steps are replaced
  • The new reactions provide for a spontaneous pathway (G negative in the direction of sugar synthesis), and they provide new mechanisms of regulation
slide14
Pyruvate Carboxylase
  • The reaction requires ATP and bicarbonate as substrates
  • Biotin cofactor
  • Acetyl-CoA is an allosteric activator
  • Regulation: when ATP or acetyl-CoA are high, pyruvate enters gluconeogenesis
slide15
PEP Carboxykinase
  • Lots of energy needed to drive this reaction!
  • Energy is provided in 2 ways:
    • Decarboxylation is a favorable reaction
    • GTP is hydrolyzed
  • GTP used here is equivalent to an ATP
pep carboxykinase
PEP Carboxykinase
  • Not an allosteric enzyme
  • Rxn reversible in vitro but irreversible in vivo
  • Activity is mainly regulated by control of enzyme levels by modulation of gene expression
  • Glucagon induces increased PEP carboxykinase gene expression
slide17
Fructose-1,6-bisphosphatase
  • Thermodynamically favorable - G in liver is -8.6 kJ/mol
  • Allosteric regulation:
    • citrate stimulates
    • fructose-2,6--bisphosphate inhibits
    • AMP inhibits
slide18
Glucose-6-Phosphatase
  • Presence of G-6-Pase in ER of liver and kidney cells makes gluconeogenesis possible
  • Muscle and brain do not do gluconeogenesis
  • G-6-P is hydrolyzed as it passes into the ER
  • ER vesicles filled with glucose diffuse to the plasma membrane, fuse with it and open, releasing glucose into the bloodstream.
slide19
Metabolites other than pyruvate can enter gluconeogenesis
  • Lactate (Cori Cycle) transported to liver for gluconeogenesis
  • Glycerol from Triacylglycerol catabolism
  • Pyruvate and OAA from amino acids (transamination rxns)
  • Malate from glycoxylate cycle -> OAA -> gluconeogenesis
slide20
Regulation of Gluconeogenesis
  • Reciprocal control with glycolysis
  • When glycolysis is turned on, gluconeogenesis should be turned off
  • When energy status of cell is high, glycolysis should be off and pyruvate, etc., should be used for synthesis and storage of glucose
  • When energy status is low, glucose should be rapidly degraded to provide energy
  • The regulated steps of glycolysis are the very steps that are regulated in the reverse direction!
slide22
Pentose Phosphate Pathway
  • Provides NADPH for biosynthesis
  • Produces ribose-5-P for RNA and DNA
  • oxidative steps (formation of NADPH) followed by non-oxidative steps
  • Cytosolic pathway
  • Active in tissues that synthesis fatty acids and sterols (liver, mammary glands, adrenal glands, adipose tissue)
  • Active in red blood cells to maintain heme in reduced form.
slide23
Oxidative Stage

Non-oxidative

Stage

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