DENTAL BIOCHEMISTRY 2015 LECTURE 10 GLUCONEOGENESIS

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DENTAL BIOCHEMISTRY 2015LECTURE
10GLUCONEOGENESIS

• Michael Lea

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Lecture Outline

• Function of gluconeogenesis and tissue
  distribution
• Reaction sequence
• Rate-limiting steps
• Energy requirement
• Substrates and regulation of gluconeogenesis
• Suggested reading Lippincotts Biochemistry, 6th
  edition, pages 117-123

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Function of gluconeogenesis and tissue
distribution

• Gluconeogenesis is the synthesis of glucose from
  three carbon precursors including lactate,
  pyruvate and glycerol
• Gluconeogenesis occurs in the liver and kidney

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Reaction sequence

• The conversion of pyruvate to glucose occurs in a
  series of eleven reactions.
• Seven of the reactions are catalyzed by enzymes
  that are also used in glycolysis.
• The conversion of pyruvate to phosphenolpyruvate
  occurs in two steps catalyzed by pyruvate
  carboxylase and phosphoenolpyruvate
  carboxykinase.
• Two specific phosphatases catalyze the hydrolysis
  of fructose 1,6-bisphosphate and glucose
  6-phosphate.

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Rate-limiting Steps in Gluconeogenesis

• Hormonal and dietary regulation is exerted on the
  enzymes whose function is restricted to
  gluconeogenesis pyruvate carboxylase,
  phosphoenolpyruvate carboxykinase, fructose
  1,6-bisphosphatase and glucose 6-phosphatase.
• Activation of pyruvate carboxylase by acetyl
  coenzyme A is an important regulatory mechanism.

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Energy Requirement

• The conversion of two moles of pyruvate to one
  mole of glucose requires the equivalent of 6
  moles of ATP and two moles of NADH.

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ADP ATP
X
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Substrates for Gluconeogenesis

• Major substrates include lactate, pyruvate and
  glycerol.
• Most amino acids can be metabolized to form
  precursors for gluconeogenesis.

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Reciprocal Control of Glycolysis and
Gluconeogenesis

• Insulin increases glycolysis and decreases
  gluconeogenesis
• Glucocorticoids and glucagon increase
  gluconeogenesis and decrease glycolysis.

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Reciprocal Control of Glycolysis and
Gluconeogenesis by Fructose 2,6-bisphosphate

• Fructose 2,6-bisphosphate (F26BP) is a switch
  molecule that increases glycolysis by activating
  phosphofructokinase 1 and inhibiting fructose
  1,6-bisphosphatase.
• F26BP levels are controlled by an enzyme with 2
  active sites. The un-phosphorylated enzyme has
  phosphofructokinase 2 activity and yields F26BP.
  The phosphorylated enzyme has fructose
  2,6-bisphosphatase activity and lowers the
  concentration of F26BP.

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ATP
ADP
X
X
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Gluconeogenesis and Diabetes

• In diabetes mellitus there is impaired uptake of
  glucose, particularly in muscle and adipose
  tissue.
• The body responds as in starvation with an
  increase in gluconeogenesis. This results in a
  further elevation of blood glucose levels that
  may exceed the renal glucose threshold resulting
  in significant glucose in urine.

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Lecture Objectives

• After studying this lecture material you should
  be able to
• Describe the function of gluconeogenesis
• Identify where gluconeogenesis occurs
• Distinguish the enzyme catalyzed reactions common
  to glycolysis and gluconeogenesis and those
  unique to gluconeogenesis
• Identify the energy requirement for
  gluconeogenesis
• Describe the substrates and regulation of
  gluconeogenesis