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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


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


  • 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


Glycogen Synthase to generate glucose-1-phosphate

  • 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.


Control of Glycogen Metabolism to generate glucose-1-phosphate

  • 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 to generate glucose-1-phosphate

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


Hormonal regulation of glycogen metabolism1
Hormonal Regulation of Glycogen Metabolism to generate glucose-1-phosphate




Gluconeogenesis
Gluconeogenesis synthase activities

  • 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


Gluconeogenesis synthase activities

  • 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!


  • Seven steps of glycolysis are retained synthase activities

  • 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


Pyruvate Carboxylase synthase activities

  • 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


PEP Carboxykinase synthase activities

  • 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 synthase activities

  • 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


Fructose-1,6-bisphosphatase synthase activities

  • Thermodynamically favorable - G in liver is -8.6 kJ/mol

  • Allosteric regulation:

    • citrate stimulates

    • fructose-2,6--bisphosphate inhibits

    • AMP inhibits


Glucose-6-Phosphatase synthase activities

  • 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.


  • Metabolites other than pyruvate can enter gluconeogenesis synthase activities

  • 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


Regulation of Gluconeogenesis synthase activities

  • 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!


Pentose Phosphate Pathway synthase activities

  • 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.


Oxidative Stage synthase activities

Non-oxidative

Stage


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