Flashcards in Carbohydrate Metabolism Deck (18):
The body aims to maintain body glucose (at 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
- 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:
- glycogen synthesis
- pentose phosphate pathway
- fatty acid synthesis
It deals with the lack of glucose by:
- glycogen breakdown
Describe 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:
- It could get converted to Glycogen (and be converted back). This helps maintain glucose levels.
- It could be converted to Ribose-5-Phosphate (in the Pentose Phosphate Pathway)
- It could be converted to Pyruvate (and back). This is for aerobic/anaerobic respiration.
Describe glycogen synthesis.
1) Glucose-6-Phosphate is converted to Glucose-1-Phosphate by Phosphoglucomutase.
2) Glucose-1-Phosphate is then converted to UDP-Glucose via UDP-glucose-pyrophosphorylase (using UTP).
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)
How are branches made?
For every 11 glucose monomers that are added, some are transferred (by branching enzymes) to be in a branch via a 1-6 glycosidic bond.
Why do we utilise glycogen?
- we can't store glucose (as it is osmotically active)
- 400 mM glucose is stored as 0.01 μm glycogen (so 10 mM)
- fat can't be mobilised as readily
- fat can't be used as an energy source in the absence of oxygen
- fat can't be converted in to glucose
What are the four enzymes required to break down glycogen, and the five that are needed to form glucose?
PHOSPHORYLASE: breaks the α 1-4 links
TRANSLOCASE: transports G-6-P to ER for further modification
DEBRANCHING ENZYME: ... debranches (acts on 1-6 links)
PHOSPHOGLUCOMUTASE: converts G1P to G6P
To form: the four above and
GLUCOSE 6 PHOSPHATASE: converts G6P to glucose (it’s present in the liver and kidney, but not muscle)
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.
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. In the liver, it does contain the enzyme needed to convert G6P to glucose (Glucose-6-Phosphatase), and so can control blood glucose levels.
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 onto the end of the main chain. This is done by the first kind of debranching enzyme, Transferase.
Glucosidase is the second kind of debranching enzyme which removes the final residue left on the branch, releasing it as G6P (that could be converted to glucose in the liver)
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 is an example of an "allosteric" enzyme; it is activated by phosphorylation, but modulated by other factors.
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 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
- in the muscle, it is stimulated by Adrenaline
(Cortisol is a weak stimulus of glycogenolysis, and Insulin inhibits it.)
1) Adenylate Cyclase is stimulated to make more Cyclic AMP.
2) This activates Protein Kinase A.
3) This, in turn, activates Phosphorylase Kinase
4) This, in turn, activates Phosphorylase, turning it from Phosphorylase B to Phosphorylase A.
5) 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 Gluycogen Synthase B)
How is Phosphorylase Kinase regulated?
Phosphorylase Kinase is under dual regulation via two different receptor types.
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.
How do we reciprocally regulate Glycogen Synthesis and Degradation?
We do it via Glycogen Synthase and Glycogen Phosphorylase.
Glycogen Synthase is activated in times of plenty glucose.
Glycogen Phosphorylase is activated when glucose is in short supply.
Give a summary of what Glycogen Synthase and Glycogen Phosphorylase are activated and inhibited by.
- activated by ATP and G6P
- inactivated by phosphorylation (by Protein Kinase A)
- activated by dephosphorylation (by Protein Phosphatase-1)
- inactivated by ATP and G6P
- activated by phosphorylation (by Phosphorylase B Kinase)
- inactivated by dephosphorylation (by Protein Phosphatase-1)
What is the significance of the Pentose Phosphate Pathway?
The pentose phosphate pathway is a metabolic pathway parallel to glycolysis. The two most important products from this process are the ribose-5-phosphate sugar used to make DNA and RNA, and 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.
What is the significance of Gluconeogenesis?
The body maintains the blood glucose because it's the preferred fuel for the brain. We use up more than our total body reserves can hold, so we constantly need to be making more.
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%).
The most important substrates for Gluconeogenesis are the amino acid Alanine, Lactate and Glycerol.
1) Pyruvate (3C) is converted to Oxaloacetic Acid by Pyruvate Carboxylase.
2) Oxaloacetic Acid is then converted to Phosphoenol Pyruvate by Phosphoenol Pyruvate Carboxykinase.
3) Phosphoenol Pyruvate is then converted to the C3 molecule (GAP)
4) GAP is then converted to Fructose-1,6-bisphosphate
5) Fructose-1,6-bisphosphate is then converted to Glucose-6-Phosphate by Fructose Bisphosphatase.
6) 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)