Additional Pathways in Carbohydrate Metabolism

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• Additional Pathways in Carbohydrate Metabolism

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Following the carbons through the TCA cycle
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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

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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

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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

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• 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

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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.

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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

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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

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Hormonal Regulation of Glycogen Metabolism
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Effect of glucagon and epinephrine on glycogen
phosphorylase glycogen synthase activities
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Effect of insulin on glycogen phosphorylase
glycogen synthase activities
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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

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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!

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• 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

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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

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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

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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

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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

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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.

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• 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

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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!

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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.

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Oxidative Stage
Non-oxidative Stage