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DENTAL BIOCHEMISTRY 2015
LECTURE 10
GLUCONEOGENESIS
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: Lippincott’s 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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ADPATPX
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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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ATPADPX 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