Aulanni

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Carbohydrate MetabolismCont.

• Aulanniam
• Biochemistry Laboratory
• Chemistry Departement
• Brawijaya University

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Gluconeogenesis

• Some tissues, such as
• brain, RBCs, kidney medulla, testes, embrionic
  tissues and exercising muscle require a
  continuing supply of glucose as a metabolic
  energy.
• The human brain requires over 120 gm of glucose
  per day. Mammalian cells make glucose from
  simpler precursors. Liver glycogen can meet these
  needs only for 10 to 18 hours without dietary
  carbohydrate.

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Glycolysis and Gluconeogenesis in the liver
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Gluconeogenesis
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Pyruvate precursors

• The direct Glc reserves are sufficient to meet
  Glc needs for about a day!
• Gluconeogenic pathway makes Glc from pyruvate
  precursors.
• Triacyl glycerol-------gt Glycerol Fatty acids
• Glycerol is a precursor of glc, glycerol enters
  glycolytic pathway as dihydroxyacetone phosphate.

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Gluconeogenesis is NOT a reversal of glycolysis

• Several reactions MUST differ because of the
  irreversible steps.
• HK (hexokinase)
• PFK (phosphofructokinase)
• PK (pyruvate kinase)

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• The stoichiometry of gluconeogenesis is
• 2pruvate 4ATP 2GTP 2NADH 6H2O--------gtGlc
  4ADP 2GDP 6Pi 2NAD 2H
• In contrast, the stoichiometry of reversal of
  glycolysis is
• 2 pyruvate 2ATP 2NADH 2H2O-------gt
• Glc 2ADP 2Pi 2NAD
• The difference is 4ATP, this is needed to turn
  energetically unfavorable process to a favorable
  one!

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Gluconeogenesis and glycolysis are reciprocally
regulated

• Both glycolysis and gluconeogenesis are highly
  exorgonic under cellular conditions so there is
  no thermodynamic barrier.
• But, amounts and activities of the distinctive
  enzymes of each pathway are controlled so that
  both pathways are not highly active at the same
  time.

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Substrate cycles

• F-6-P -------gt F 1,6BisP
• lt---------
• A pair of reactions such as the above one is
  called substrate cycle
• There is also some cycling in irreversible
  reactions.
• Imperfection in metabolism?
• They are sometimes referred as futile cycles
• Futile cycles amplify metabolic signals!
• The other potential biological role of substrate
  cycles is the generation of heat produced by the
  hydrolysis of ATP.

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Lactate and alanine formed by contracting muscle
are used by other organs

• Lactate is a dead end in metabolism.
• Lactate should be converted to pyruvate.
• The plasma membranes of most cells are highly
  permeable to lactate and pyruvate, therefore they
  easily diffuse to go to liver!
• Excess lactate enters the liver and is converted
  pyruvate first then glucose.
• Thus, the liver restores the level of glucose
  necessary for active muscle cells, which derive
  ATP from the glycolytic conversion of glucose
  into lactate. Contracting skeletal muscle
  supplies lactate to the liver, which uses it to
  make glucose.
• These reactions constitute CORI CYCLE.

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LDH enzyme

• Lactate-------gt Pyruvate by LDH (lactate
  dehydrogenase).
• The interconversion of pyruvate and lactate are
  done by different subunits of LDH. LDH is a
  tetramer.

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The Cori Cycle
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Cooperation between glycolysis and gluconeogenesis
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Two alternative fates of pyruvate
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2nd control point
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Hormonal Control

• The special role of liver to maintain constant
  blood glucose level requires additional control
  mechanisms.
• When blood glucose decreases, glycogen increases
  and glucose is released.
• This hormonal regulation in liver is mediated by
  fructose-2,6-bisphosphate, which is a allosteric
  effector for PFK-1, and F-1,6-bisphosphate

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Role of F2,6BP in regulation of Glycolysis and
Gluconeogenesis
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What is F-2,6-BP?

• It is structurally related to F-1,6-BP.
• It is not an intermediate.
• It is a regulator
• F-2,6-BP activates PFK-1 and glycolysis.
• FBPase and PFK-2 are part of the same enzyme!
• An increase in glucagon (during starvation) leads
  to a decrease in F-2,6-BP overall which goes to a
  decrease in glycolysis, an increase in glucone
  ogenesis
• A decrease in glucagon (after carbohydrate rich
  diet) leads to an increase in F-2,6-BP and an
  increase in glycolysis.
• Therefore, F-2,6-BP acts as an intracellular
  signal indicating glucose abundant.

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thank you