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Additional Pathways in Carbohydrate Metabolism

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Additional Pathways in Carbohydrate Metabolism Hormonal Regulation of Glycogen Metabolism Insulin Secreted by pancreas under high blood [glucose] Stimulates Glycogen ... – PowerPoint PPT presentation

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Title: Additional Pathways in Carbohydrate Metabolism


1
  • Additional Pathways in Carbohydrate Metabolism

2
Following the carbons through the TCA cycle
3
The Glyoxylate Cycle
  • A variant of TCA for plants and bacteria
  • Acetate-based growth - net synthesis of
    carbohydrates and other intermediates from
    acetate - is not possible with TCA
  • Glyoxylate cycle offers a solution for plants and
    some bacteria and algae
  • The CO2-evolving steps are bypassed and an extra
    acetate is utilized
  • Isocitrate lyase and malate synthase are the
    short-circuiting enzymes

4
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5
Glyoxylate Cycle
  • Rxns occur in specialized organelles
    (glycoxysomes)
  • Plants store carbon in seeds as oil
  • The glyoxylate cycle allows plants to use
    acetyl-CoA derived from B-oxidation of fatty
    acids for carbohydrate synthesis
  • Animals can not do this! Acetyl-CoA is totally
    oxidized to CO2
  • Malate used in gluconeogenesis

6
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7
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

8
  • 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

9
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.

10
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11
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

12
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

13
Hormonal Regulation of Glycogen Metabolism
14
Effect of glucagon and epinephrine on glycogen
phosphorylase glycogen synthase activities
15
Effect of insulin on glycogen phosphorylase
glycogen synthase activities
16
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

17
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!

18
  • 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

19
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

20
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

21
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

22
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

23
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.

24
  • 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 -gt OAA -gt
    gluconeogenesis

25
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!

26
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27
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.

28
Oxidative Stage
Non-oxidative Stage
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