Gluconeogenesis

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Gluconeogenesis
Dr. Sooad Al-Daihan Biochemistry department
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Introduction

• Some tissues, such as the brain, and red blood
  cells require a continuous supply of glucose as a
  metabolic fuel.
• During a prolonged fast, hepatic glycogen stores
  are depleted, and glucose is formed from
  precursors such as lactate, pyruvate, glycerol,
  and a-ketoacids by a special pathway,
  gluconeogenesis, that requires both mitochondrial
  and cytosolic enzymes.

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• Gluconeogenesis occurs mainly in liver.
• It also occurs to a more limited extent in
  kidney small intestine under some conditions. 
• Synthesis of glucose from pyruvate utilizes many
  of the same enzymes as Glycolysis.
• Almost reverse of glycolysis except for 3
  reactions ,which are essentially irreversible.
• Hexokinase (or Glucokinase)
• Phosphofructokinase
• Pyruvate Kinase.
• These steps must be bypassed in Gluconeogenesis.

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• Four enzymes are needed to reverse the 3
  irreversible steps of glycolysis
• Mitochondrial - Pyruvate Carboxylase (liver,
  kidney but not in muscle)
• Cytoplasmic - Phosphoenolpyruvate (PEP)
  Carboxykinase
• Cytoplasmic -Fructose-1,6,-Bisphosphatase
• Cytoplasmic -Glucose 6-Phosphatase

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1-Bypass of Pyruvate Kinase

• In gluconeogenesis PK is bypassed by 2 enzyme
  catalyzed reactions
• 1- Pyruvate Carboxylase
• Pyruvate is carboxylated to oxaloacetate in the
  mitochondria .
• pyruvate HCO3- ATP ? oxaloacetate ADP
  Pi
• 2- PEP Carboxykinase
• Oxaloacetate is decarboxylated and phosphorylated
  to yield PEP in the cytosol .
• oxaloacetate GTP ? PEP GDP CO2

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Transport of oxaloacetate to the cytosol
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• 2- Bypass of Phosphofructokinase
• In gluconeogenesis PFK bypassed by Fructose 1,6 -
  bisphosphatase reaction (Removes phosphate group)
  
• fructose-1,6-bisP H2O ?fructose-6-P Pi
• 3- Bypass of Hexokinase (or Glucokinase)
• In gluconeogenesis this reaction bypassed by
  glucose 6-phosphatase reaction (Removes phosphate
  group)
• Glucose-6-P H2O ?Glucose Pi
• Free glucose is formed by the action of
  glucose-6- phosphatase in liver and kidney while
  it is absent in muscles and adipose tissues
• ?Glucose can not be formed by these organs

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Total Energy Cost

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Precursors for Gluconeogenesis

• i- Cori Cycle
• Lactate released by active skeletal muscle or red
  blood cells is carried to the liver where it is
  converted to glucose by gluconeogenic pathway
  (Cori cycle) and released for reuptake by
  skeletal muscle
• ii- Glucose-Alanine Cycle
• Protein broken down in skeletal muscle during
  exercise
• Amino acids converted to alanine and released by
  skeletal muscle
• Taken up by liver and converted to glucose and
  released for reuptake by skeletal muscle

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• iii- Glycerol
• Glycerol released from adipocytes and skeletal
  muscle during lipolysis.
•  Glycerol enters gluconeogenic pathway as
  dihydroxyacetone phosphate active form of
  glycerol.
•  2 glycerol required to make one glucose in liver
  and kidney in fasting or low CHO diet .
• Glycerol cannot be utilized in adipose tissue due
  to the lack of glycerol kinase in the adipose
  tissue.

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• iv- Propionate
• Propionyl-CoA is converted to the TCA
  intermediate, succinylCoA.
• This conversion is carried out by the
  ATP-requiring enzyme, propionyl-CoA carboxylase
  then methylmalonyl-CoA epimerase and finally the
  vitamin B12 requiring enzyme, methylmalonyl-CoA
  mutase
• The utilization of propionate in gluconeogenesis
  only has quantitative significance in ruminants.

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Regulation of Gluconeogenesis

• Control of glycolysis and gluconeogenesis is
  reciprocal
• Gluconeogenesis and Glycolysis are regulated by
  similar effector molecules but in the opposite
  direction
• When one pathway is activated , the other is
  inhibited
• Gluconeogenesis is subject to both
• - Hormonal control by Glucagon, Cortisol,
  Adrenaline and Insulin
• - Allosteric regulation of gluconeogenic enzymes
  

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Hormonal Regulation

• Glucagon, Cortisol, Adrenaline
• Are secreted during fasting, stress and sever
  muscular exercise
• Induce gluconeogenic enzymes
• Repress glycolytic enzymes
• Insulin
• Secreted after CHO meal
• Induce glycolytic enzymes
• Repress gluconeogenic enzymes

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Allosteric regulation
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Uronic Acid Pathway
Dr. Sooad Al-Daihan Biochemistry department
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Overview

• It is an alternative oxidative pathway for
  glucose that doesnt lead to ATP generation.
• It includes oxidation of glucose to
• Glucuronic acid
• Ascorbic acid
• It occurs mainly in the liver cytoplasm.

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Metabolic reactions

• Glucose 6-phosphate is isomerized to glucose
  1-phosphate
• Glucose 1-phosphate reacts with uridine
  triphosphate (UTP) to form uridine diphosphate
  glucose (UDPGlc) in a reaction catalyzed by
  UDPGlc pyrophosphorylase
• UDPGlc is oxidized at carbon 6 by NAD-dependent
  UDPGlc dehydrogenase in a two-step reaction to
  yield UDP-glucuronate

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UDP Glucuronic acid (active form) is needed in

• Conjugation to less polar compounds as bilirubin,
  steroids and some drugs making them more water
  soluble (detoxicated) .
• Synthesis of glycosaminoglycans
  (mucopolysaccharide) as heparin, hyaluronic acid.
• In plants and some animals (not Human) glucuronic
  acid serves as a precursor of L-ascorbic acid.
• The uronic acid pathway also provides a mechanism
  by which dietary D-xylulose enter the central
  pathway.