Carbohydrate Metabolism Flashcards
The body aims to maintain body glucose (critical level is about 2.5 mM). What are the conditions when we have too much or too little blood glucose, and what are their symptoms?
Hypoglycaemia (too little glucose): • muscle weakness • loss of coordination • mental confusion • sweating • hypoglycaemic coma and death
Hyperglycaemia (too much glucose):
• non-enzymatic modifications of proteins (cataracts, lipoproteins important in atherosclerosis, etc.).
• hyperosmolar coma.
How does the body deal with excess and the lack of glucose in the body?
It deals with excess glucose by:
1. glycogen synthesis (in liver and muscle – short term)
2. pentose phosphate pathway
3. fatty acid synthesis (stored as fat in adipose tissues)
It deals with the lack of glucose by:
1. glycogen breakdown
2. gluconeogenesis
What happens to the body’s blood glucose after food?
Increases a lot after 100g of glucose (food).
The body brings this back to the normal level.
What happens to the body’s blood glucose during exercise?
Blood glucose stays normal as glycogen is converted to glucose.
What happens to glucose in the liver?
Glucose from the bloodstream gets transported into the liver. It then, using glucokinase, (with the help of ATP, changing it to ADP) gets phosphorylated to Glucose-6-Phosphate.
This could then take three different routes:
1. It could get converted to Glycogen (and be converted back). – This helps maintain glucose levels.
2. It could be converted to Ribose-5-Phosphate (and back?) (in the pentose phosphate pathway).
3. It could be converted to Pyruvate (and back). – This is for aerobic/anaerobic respiration.
What is Glycogen?
A storage of glucose.
• In the liver, this is the main storage of glucose – its available to other tissues in the body.
• In muscle, this is also the storage of glucose. – but for its own use (not for circulating).
Describe glycogen synthesis.
1) Glucose-6-phosphate in converted to glucose-1-phosphate (inactive form) by Phosphoglucomutase.
2) Glucose-1-Phosphate is then converted to UDP-Glucose via UDP-glucose-pyrophosphorylase (using UTP – Uridine triosphospahte).
• UDP – Glucose is active
3) The UDP-Glucose then combined with Glycogenin to initiate glycogen synthesis, as it acts as a primer required by Glycogen Synthase (GS) to attach additional glucose molecules.
4) As preluded, Glycogen Synthase facilitates the addition of additional glucose monomers via 1-4 glycosidic bonds) until it reaches 11 residues.
5) When 11th residue is reached, Branching enzyme is activated and splits the 11 residue molecule and forms 1-6 glycosidic bond. – Branch and increase until 11th residue and branches and continues and so forms highly branched glycogen molecule
What enzymes required to break down glycogen?
1) Phosphorylase: - breaks the α 1-4 links
2) Translocase: - transports G-6-P to ER for further modification
3) Debranching enzymes: - … debranches (acts on 1-6 links)
4) Phosphoglucomutase: - converts G1P to G6P
These enzymes are also involved in glucose formation.
What enzymes are needed to form glucose?
1) Phosphorylase: - breaks the α 1-4 links
2) Translocase: - transports G-6-P to ER for further modification
3) Debranching enzymes: - … debranches (acts on 1-6 links)
4) Phosphoglucomutase: - converts G1P to G6P
5) Glucose-6-Phosphatase: - converts G6P to glucose (it’s present in the liver and kidney, but not muscle)
The first four are also involved in glycogen breakdown
What activities are associated with debranching enzymes?
- Transferase activity moves the last glucose residue to the non-reducing end of an existing chain.
- The glucosidase that removes the 1-6 link releasing glucose.
Describe glycogen breakdown.
The way glycogen is broken down is, in essence, the reverse of synthesis. The enzyme important for breaking down glycogen will remove individual units until it eventually removes the whole branch.
1) The α 1-4 links are broken to remove the units individually, done by the enzyme Phosphorylase. This will give G1P, which are then converted to G6P by Phosphoglucomutase.
• The fate of this G6P will vary depending on the tissue.
• In muscle, it can be used for ATP Synthesis for its own use. The muscle, however, cannot use it to control blood glucose as it doesn’t have the enzyme to convert G6P to glucose (Glucose-6-Phosphatase).
• In the liver, it does contain the enzyme needed to convert G6P to glucose (Glucose-6-Phosphatase), and so can control blood glucose levels.
2) The residues are removed till you get to a certain length (an end portion of a particular branch). This portion left is then broken off and moved to the non-reducing end of an existing chain. This is done by the first kind of debranching enzyme, Transferase.
3) Glucosidase is the second kind of debranching enzyme which removes the final residue left on the branch, releasing a glucose molecule (that could be converted to G6P in the muscle and so used in glycolysis).
Describe Glycogen Phosphorylase.
- It’s a key enzyme in glycogenolysis and its activity forms G1P.
- It’s a large, multisubunit enzyme.
- Many Phosphorylase molecules are bound to each glycogen particle.
- The G6P ultimately formed provides fuel for working muscles.
- In the liver, the G6P is dephosphorylated (by G-6-Phosphatase) and secreted into the blood, maintaining the 5mM blood sugar concentration.
How is Glycogen Phosphorylase controlled?
- It has interchangeable active and inactive forms.
- The inactive form is Phosphorylase B, and the active form is Phosphorylase A.
- Phosphorylase b kinase transfers a phosphate from ATP to one serine residue of each phosphorylase subunit.
- Phosphorylase is an example of an “allosteric” enzyme; it is activated by phosphorylation, but modulated by other factors (e.g. Ca2+).
- In the liver, glycogen breakdown by Phosphorylase is inhibited by the presence of glucose, even after the enzyme has been activated to the a form by being phosphorylated.
- In muscle, Glycogen Phosphorylase b can also be activated (by 5’-AMP) without being phosphorylated. 5´-AMP (which forms when ATP is depleted) binds to another allosteric site, the nucleotide-binding site. ATP will bind to the same site, blocking the activation. Glucose-6-phosphate also blocks 5´-AMP activation.
Describe the hormonal regulation of glycogenolysis.
Different hormones stimulate it in different places.
- in the liver, it is stimulated by Glucagon, glucose inhibits phosphorylase
- in the muscle, it is stimulated by Adrenaline
(Cortisol is a weak stimulus of glycogenolysis, and Insulin inhibits it.)
What happens after the Beta-adrenergic receptors are acitivated?
- Adenylate Cyclase is stimulated to make more Cyclic AMP.
- This activates Protein Kinase A.
- This, in turn, activates Phosphorylase Kinase
- This, in turn, activates Phosphorylase, turning it from Phosphorylase B to Phosphorylase A (active form).
- This, in turn, removes glucose molecules from Glycogen as G1P.
(Side Note: Activated Protein Kinase inhibits the activity of Glycogen Synthase, converting the active Glycogen Synthase A to the inactive form Glycogen Synthase B)
How is Phosphorylase b Kinase activated by Ca2+?
• In muscle, mediating glycogenolysis during muscle contraction (needs energy for contraction).
Only get maximum activity with Ca2+ and phosphorylation.
• In liver, alpha-adrenergic activation stimulates Ca2+ release.
How is Phosphorylase b Kinase regulated?
Phosphorylase b Kinase is under dual regulation via two different receptor types:
1. The most important is through the elevation of cAMP and the activation of PKA.
The other is calcium-mediated through the alpha adrenergic/IP3 pathway
Give a summary of what Glycogen Synthase and Glycogen Phosphorylase are activated and inhibited by.
GLYCOGEN SYNTHASE:
• activated by ATP and G6P
• inactivated by phosphorylation (by Protein Kinase A)
• activated by dephosphorylation (by Protein Phosphatase-1)
GLYCOGEN PHOSPHORYLASE:
• inactivated by ATP and G6P
• activated by phosphorylation (by Phosphorylase B Kinase)
• inactivated by dephosphorylation (by Protein Phosphatase-1)
Describe the Pentose Phosphate Pathway.
- G-6-P is oxidised by NADP+, to release NADPH
- The product is then oxidised by NADP+ to release NADPH, and is also decarboxylated to release CO2.
• The NADPH is converted back to NADP+ by being used to convert precursors into fatty acids, sterols. Etc.
• (and by converting GSH to GSSH). - This forms Ribose-5-phosphate.
- The ribose-5-phosphate is used for nucleotides, coenzymes, DNA, RNA. OR it can be converted back into G-6-P.
What is the significance of the Pentose Phosphate Pathway?
• The pentose phosphate pathway is a metabolic pathway parallel to glycolysis.
• It is activated when there is plenty of glucose.
• The two most important products from this process are:
1. The ribose-5-phosphate sugar used to make DNA and RNA.
2. The NADPH molecules which help with building other molecules.
• This pathway is special because no energy in the form of ATP is produced or used up in this pathway.
Define Gluconeogenesis and what process is it usually accompanied by?
- Formation of glucose from non-carbohydrates, e.g. amino acids and glycerols.
- Ketogenesis.
What is the significance of Gluconeogenesis?
• The body maintains the blood glucose because it’s the preferred fuel for the brain (and the only fuel for RBC).
• Total body reserves is not enough for long term, so we need to constantly make more glucose.
• Gluconeogenesis converts pyruvate to glucose.
• It takes place mostly in the liver, and a little in the kidney (during starvation, kidney gluconeogenesis rises up to 40%). (glucose for kidney medulla, not for bloodstream?)
• The 3 important substrates for Gluconeogenesis are:
1. amino acid Alanine
2. Lactate
3. Glycerol.
Describe Gluconeogenesis.
- Pyruvate (3C) is converted to Oxaloacetic Acid by Pyruvate Carboxylase.
- Oxaloacetic Acid is then converted to Phosphoenol Pyruvate by Phosphoenol Pyruvate Carboxykinase.
- Phosphoenol Pyruvate is then converted to the C3 molecule (GAP)
- GAP is then converted to Fructose-1,6-bisphosphate
- Fructose-1,6-bisphosphate is then converted to Fructose-6-phosphate by Fructose Bisphosphatase.
- Fructose-6-phosphate is converted to G6P.
- Glucose-6-Phosphate is then converted to Glucose by Glucose-6-Phosphatase.
Some amino acids can also be converted back to glucose. These are called the Gluconeogenic amino acids. They can be fed in at different parts of the process.
(Note: Glucagon inhibits Phosphofructokinase and Pyruvate Kinase, ensuring that the two pathways don’t happen simultaneously)
How does Pyruvate get converted to Oxaloacetate in the liver?
- Pyruvate is brought into the mitochondria (in the liver) via a Pyruvate carrier.
- Pyruvate is converted to Oxaloacetate by Pyruvate Carboxylase.
- To leave the liver, the Oxaloacetate is converted to Malate.
- The Malate is then brought out of the mitochondria.
- Now outside, it is converted back to Oxaloacetate and then the process continues.
