Lecture 07 (Slides Only)

lwky gave up on making flashcards directly from the notes

What products can be formed from Glucose in cells?

• Ribose

• Pyruvate

• Glycogen

How many pyruvate can be made per glucose?

2

Glycolysis

Glucose becomes 2 pyruvates

Glucose Uses

• Excess glucose is stored as glycogen

• Glucose is oxidized through the pentose phosphate pathway into ribose

Gluconeogenesis

• Glycogen breakdown back into usuable glucose

• Helps maintain blood glucose during fasting, primarily in the liver

• Reverse reaction of Glycolysis

How did our brain get glucose while we are asleep?

Overnight blood glucose is maintained mainly by the liver. First by liver glycogen breakdown, then increasingly by gluconeogenesis as glycogen becomes limited

Glucose is ______ to become pyruvate

oxidized via glycolysis

Glucose is ______ to become Ribose-5-phosphate

Oxidized via pentose phosphate pathway

Glucose is ______ to become extracellular matrix and cell wall polysaccharides (ie starch or cellulose)

Synthesis of structural polyme

Glucose, if unused can be stored in the cells as ______to be converted back into glucose later

G6PD deficiency

Glucose-6-phosphate dehydrogenase deficiency

• Affects

Glycogen structure

• Core protein of glycogenin

• Surrounded by branches of glucose units

How does fasting affect glucose and how does the body maintain blood glucose levels?

• ↓ glucose levels due to lack of food

• Liver glycogen breakdown increases to maintain blood glucose levels

What differentiates muscle glycogen and liver glycogen breakdown?

• Liver glycogen breakdown delivers new glucose to the bloodstream

• Muscle glycogen breakdown uses the glucose for the working muscle,

Glycogen Synthesis

1. Glucose

   1. by Glucokinase (hexokinase 4)

2. Glucose-6-phosphate

   1. Phosphoglucomutase

3. Gluco-1-phosphate

   1. UDP-glucose pyrophosphorylase

4. Uracil-disphosphate glucose

   1. Glycogenin

   2. Glycogen synthase

   3. Glycogen branching enzyme

5. G

What does Glycogen phosphorylase do to branches of glucose of glycogen?

Glycogen phosphorylase catalyzes phosphorolytic cleavage at the nonreducing ends of glycogen chains

• Makes a Glucose-1-phosphate

• Glycogen shortened by one residue

What do Debranching enzymes do?

Debranching enzymes transfer brahcnes onto main chains and releases the residue at the (alpha 1 —> 6) branch as

Nonreducing end of glycogen

The outermost glucose at the end of a glucose chain

Alpha 1 —> 6 linkage

Where glucose chains branch off of other glucose

After glycogen phosphorylase cuts off nonreducing ends of glycogen, what is the next step of debranching?

Transferase activity relocates the branched glucose (off the alpha-1 —> 6 linkage) to the parent branch

What happens to the remaining lone glucose with the alpha-1 —> 6 linkage?

(alpha1 —> 6) glucosidase activity of the branching enzyme unbranches the final glucose

Which enzyme in the liver is responsible for the releasing of free glucose into the bloodstream?

The liver has glucose-6-phosphatase (G6Pase), enabling conversion of glucose-6-phosphate (G6P) to free glucose for release into the bloodstream

Why can’t skeletal muscle export glucose derived from glycogen?

Skeletal muscles lack G6Pase

How can a liver full of stored glucose (via glycogen) fail to maintain blood glucose?

Issues with enzyme activity

• eg Von Gierke disease

Von Gierke disease

glucose-6-phosphatase deficiency

• The liver can make G6P and stored glycogen but can not convert G6P to free glucose

How does ATP affect Glucose regulation?

Inhibits Gluconeogenesis

How does ADP affect Glucose regulation?

Activates Gluconeogenesis

How does AMP affect Glucose regulation?

• Activates Gluconeogenesis

• Inhibits Glycolysis

How does Citrate affect Glucose regulation?

Inhibits Gluconeogenesis

Effects of insulin release in the liver when fed

• ↑ Glycogen synthesis

• ↑ Glycolysis

• ↓ Gluconeogenesis

Effects of glucagon release in the liver when fed

• ↑ Glycogen breakdown

• ↓ Glycolysis

• ↑ Gluconeogenesis

Why does the liver slow glycolysis during fasting?

It relies more on fatty acid oxidation for its own energy while pereserving and producing glucose for the rest of the body

How does epinephrine differ from glucagon?

• Both are used to stimulate glycogen breakdown in the liver

• Glucagon can not stimulate glycogen breakdown in

What are the products of the Pentose Phosphate Pathway?

• NADP+ becomes NADPH

  • NADPH regeneration

• Ribose-5-phosphate is produced

What are teh effects of G6PD deficiency?

G6PD deficiency > Low NADPH > Oxidant hemolysis

Insulin favors glucose ______ while glucagon favors hepatic glucose ______.

• Storage/Use

• Production and release

How does the liver respond to high blood glucose?

• ↑ insulin levels

• release of GLUT2

What occurs in response to high insulin?

• ↑ insulin-sensitive protein kinase

• ↑ in Protein Kinase B (PKB)

• Synthesis of hexokinase-2, PFK-1, pyruvate kinase

What occurs as a response of released GLUT2?

• ↑ Liver glucose

  • ↑ Glycogen synthesis

  • ↑ Glycolysis

What does an increase in insulin-sensitive protein kinase lead to?

• ↑ Protein phosphatase (PP1)

How does PKB influence levels of Glycogen synthase kinase 3 (GSK-3)?

• ↓ GSK-3

  • ↑ Glycogen synthase

    • ↑ Glycogen synthesis

Which glucose pathway is a result of the synthesis of hexokinase-2, PFK-1, and/or pyruvate kinase?

• ↑ Glycolysis

How does an increase in Protein Phosphatase (PP1) affect Enzyme concentration and activity in the liver?

• ↓ Phosphorylase kinase

  • ↓ Glycogen phosphorylase

• ↓ glycogen phosphorylase

• ↑ Glycogen synthase

What is Glucose synthase kinase-3 (GSK-3) responsible for?

• It is a regulatory kinase that inhibits the production and activity of Glycogen synthase

  • ↓ GSK-3 leads to ↑ Glycogen synthase

    • ↑ Glycogen synthesis

Which process in the liver is affected by a decrease in Glycogen phosphorylase?

• ↓ Glycogen breakdown

Which process in the liver is affected by an increase in Glycogen synthase?

• ↑ Glycogen synthesis

Summary: How does High blood glucose lead to increased Glycolysis?

• High blood glucose

  • GLUT2

    • ↑ Glucose

      • ↑ in Glycolysis

• High blood glucose

  • ↑ insulin

    • Synthesis of HK-2, PFK-1, pyruvate kinase

      • ↑ in Glycolysis

Summary: How does High blood glucose lead to increased Glycogen synthesis?

• High blood glucose

  • GLUT2

    • ↑ Glucose

      • ↑ Glycogen synthesis

• High blood glucose

  • ↑ insulin

    • ↑ PKB

      • decreased GSK-3

        • ↑ Glycagon synthase

          • ↑ Glycogen synthesis

• High blood glucose

  • ↑ insulin

    • ↑ insulin-sensitive protein kinase

      • ↑ PP1

        • ↑ Glycagon synthase

          • ↑ Glycogen synthesis

Summary: How does High blood glucose lead to decreased Glycogen breakdown?

• High blood glucose

  • ↑ insulin

    • ↑ insulin-sensitive protein kinase

      • ↑ PP1

        • ↓ Phosphorylase kinase

          • ↓ Glycogen phosphorylase

            • decreased Glycogen breakdown

• High blood glucose

  • ↑ insulin

    • ↑ insulin-sensitive protein kinase

      • ↑ PP1

        • decreased Glycogen phosphorylase

          • decreased Glycogen breakdown

How does the liver respond to low blood glucose?

• ↑ Glucagon

  • ↑ cAMP concentraion

    • ↑ Protein Kinase A (PKA)

      • ↑ Phosphorylase kinase

      • ↓ Glycogen synthase

      • ↑ FBPase-2 and ↓ PFK-2

      • ↓ Pyruvate kinase L

How does an increase in phosphorylase kinase influence Blood glucose levels?

• ↑ Glycogen phosphorylase

  • ↑ Glycogen breakdown

How does a decrease in Glycogen synthase influence Blood glucose levels?

• ↓ Glycogen synthesis

How does an increase in FBPase-2 and decrease in PFK-2 influence Blood glucose levels?

• ↓ [F268P

How does a decrease in Pyruvate kinase L influence Blood glucose levels?

• ↓ Glycolysis

Summary: How does Low blood glucose lead to increased Glycogen breakdown?

• ↑ Glucagon

  • cAMP

    • PKA

      • Phosphorylase kinase

        • Glycogen phosphorylase

          • Glycogen breakdown

Summary: How does Low blood glucose lead to increased Glycogen synthesis?

• ↑ Glucagon

  • ↑ cAMP

    • ↑ PKA

      • ↑ FBPase-2 and ↓ PFK-2

        • ↓ [F268P]

          • ↓ PFK-1

            • ↑ Glycolysis

      • ↓ Pyruvate kinase L

        • ↑ Glycolysis

What is metformin?

• Lowers blood glucose by suppressing gluconeogenesis

  • ↓ Lactate utilization

  • ↓ Mitochondrial metabolism

What is the role of Fructose 2,6 Bisphosphate in Glucose regulation?

• Activates glycolysis

• Inhibits Gluconeogenesis

What ways is glucose stored in the body

• Glycogen

• Lactate

• Alanine

  • Glucose becomes pyruvate becomes alanine

Which three glucose reactions strongly favor the forward direction?

• Glucose —> G6P

• Fructose-6-phosphate —> fructose-1,6-bisphosphate

• PEP —> pyruvate

What is the difference between odd-chain fatty acids and even-chain fatty acids?

• Odd-chain fatty acids can be broken down into glucose

• Even-chain fatty acid can be broken down into acetyl-CoA but can not give net glucose

How can triglyceride break down into glucose?

• Triglyceride breaks down into glycerol

  • Glycerol kinase phosphorylates glycerol into G3P

    • G3P oxidizes into DHAP

      • DHAP enters gluconeogenesis as an intermediate and finally becomes glucose

What are the three bypasses and why do they exist?

There are three irreversible, highly exergonic steps of glycolysis. Reversing these steps require immense energy and specific enzymes, hence these three work arounds.

• Pyruvate kinase bypass

• PFK-1-bypass

• Hexokinase / glucokinase bypass

Pyruvate kinase bypass

Pyruvate is converted to oxaloacetate by pyruvate carboxylase in mitocondria. This reaction uses ATP and requires biotin. PEP carboxykinase (PEPCK) then converts oxaloacetate to PEP using GTP

PFK-1-bypass

Fructose-1,6-bisphosphatase (FBPase-1) removes a phosphate from fructose-1,6-bisphosphate, producing fructose-6-phosphate and inorganic phosphate (P_i)

Hexokinase / glucokinase bypass

G6Pase, found in the endoplasmic reticulum of liver and kidney cells, converts G6P to free glucose and P_i. Free glucose can then leave the cell and enter the blood

How much energy does Gluconeogenesis require?

2 pyruvate + 4ATP + 2GTP + 2NADH + 2H⁺ + 4H₂O —>

glucose + 4ADP + 2GDP + 6P_i + 2NAD⁺

• 4 ATP

• 2 GTP

• 2 NADH