3. Energy Storage Flashcards
What should the plasma glucose level be?
5mmol/L
Which tissues have an absolute requirement for glucose as an energy store and why?
- Red blood cells - do not have mitochondria so need glucose for glycolysis to continue to produce ATP as they do not have oxidative phosphorylation
- Neutrophils - mitochondria adapted to produce ROS to destroy bacteria by respiratory burst
- Innermost cells of kidney medulla - blood supply limited so not enough oxygen for oxidative phosphorylation
- Lens of the eye -blood supply limited so not enough oxygen for oxidative phosphorylation
- Stable blood glucose level absolutely essential for normal brain function.
What can cause hypoglycaemia?
Acute alcohol poisoning
Diabetic taking insulin and not eating
Athlete pushing beyond limit
What are the consequences of hypoglycaemia at the different blood glucose levels of 2.8, 1.7, 1.1, 0.6 mmol /L?
- 8 - confusion
- 7 - weakness and nausea
- 1 - muscle cramps
- 6 - brain damage, death
What is glucose mainly stored as ?
Glycogen
Where is glycogen stored and in what form?
Glycogen is stored as granules
Mainly In muscle and liver
Distinguish between intramyofibrillar and intermyofibrillar glycogen in muscle
intra - granules within muscle fibres
inter - granules in spaces between muscle fibres
Describe the structure of glycogen
• Glycogen is a polymer consisting of chains of
glucose residues
• Chains are organized like the branches of a tree originating from a dimer of the protein glycogenin
(acts as a primer at core of glycogen structure).
• Glucose residues linked by α-1-4 glycosidic bonds with α-1-6 glycosidic bonds forming branch points every 8-10 residues
what is the advantage of storing glucose in a branched format?
- The highly branched structure provides many sites to which glucose residues can be added or removed allowing rapid synthesis or degradation of glycogen
- allows more compact structure so less osmotic effect so is a good storage molecule
describe glycogenesis
The pathway of glycogen synthesis from glucose involves a number of steps:
Step 1. Glucose + ATP → glucose 6-P + ADP
catalysed by hexokinase (glucokinase in liver)
Step 2. Glucose 6-P ↔ Glucose 1-P
catalysed by phosphoglucomutase
Step 3. Glucose 1-P + UTP + H2O → UDP-glucose + 2Pi
catalysed by G1P uridylyltransferase
Step 4. Glycogen (n residues) + UDP-glucose → glycogen (n + 1 residues) + UDP
This irreversible reaction is catalysed by two enzymes:
• Glycogen synthase
• Branching enzyme
whats the difference between glycogen synthase and branching enzyme?
Glycogen synthase links glucose residues in series to a glycogen primer by α1-4 glycosidic bonds.
At appropriate points (after every ~10 units)
branching enzyme links a glucose residue by an α1-6 glycosidic bond introducing a branch point
what does synthesis of glycogen require?
Synthesis of glycogen requires ENERGY
what is UTP and UDP?
UTP is structurally similar and energetically equivalent to ATP. UDP glucose can be considered as a highly activated form of glucose. It is an important intermediate in the synthesis of a number of sugar containing molecules (e.g. lactose and glycogen) and in the interconversion of glucose and galactose.
describe step 1 of glycogenolysis
Step 1.
Glycogen (n residues) + Pi → glucose 1-phosphate + glycogen (n-1)
This reaction is catalysed by the enzyme GLYCOGEN PHOSPHORYLASE that attacks the α1-4 bonds. The bonds are subjected to phosphorolysis rather than hydrolysis with the result that glucose residues are released as glucose 1-phosphate rather than free glucose.
Glycogen phosphorylase does not attack the α1-6 branch points and this requires the activity of a DE-BRANCHING ENZYME. De-branching enzyme produces free glucose.
describe step 2 of glycogenolysis
Glucose 1-phosphate ↔ glucose 6-phosphate
This reaction is catalysed by the enzyme PHOSPHOGLUCOMUTASE. In muscle, the glucose 6-phosphate enters glycolysis and is used to provide energy for the exercising muscle. Thus, muscle glycogen represents a store of glucose 6-phosphate that can only be used by the muscle cells. In liver during fasting or during stress the glucose 6-phosphate is converted to glucose by the enzyme glucose 6-phosphatase (this enzyme is absent from muscle)
describe step 3 of glycogenolysis
(In Liver but not muscle)
Glucose 6-phosphate + H2O → glucose + Pi
This reaction is catalysed by GLUCOSE-6-PHOSPHATASE. The glucose is released into the blood stream and transported to other tissues. Thus
liver glycogen represents a store of glucose that can be made available to all tissues of the body.
When is glycogen degraded?
Glycogen is degraded in skeletal muscle in response to exercise and in the liver in response to fasting or as part of the stress response (“fright, fight or flight response”).
Compare the functions of glycogen stores in the liver and muscle respectively
Glycogen stores serve different functions in liver and muscle.
In liver, G6P converted to glucose and exported to blood. Liver glycogen is a buffer of blood glucose levels.
Muscle lacks the enzyme Glucose-6-phosphatase. G6P enters glycolysis for energy production in muscle cells
What is the rate limiting enzyme that is changed to regulate glycogen synthesis?
glycogen synthase
What is the rate limiting enzyme that is changed to regulate glycogen degradation?
glycogen phosphorylase
what are the 3 hormones that are involved in regulating liver glycogen metabolism?
glucagon
adrenaline
insulin
Outline the regulation of Liver glycogen synthesis
glucagon and adrenaline causes phosphorylation of glycogen synthase which decreases enzyme activity.
Insulin causes de-phosphorylation of glycogen synthase which increases enzyme activity.
outline the regulation of Liver glycogen degradation
glucagon and adrenaline causes phosphorylation of glycogen phosphorylase which increases enzyme activity.
Insulin causes de-phosphorylation of glycogen phosphorylase which decreases enzyme activity.
what is the difference in regulation of liver and muscle glycogen?
Muscle glycogen stores differ in that Glucagon has no effect because muscle does not have glucagon receptors.
Also AMP is an allosteric activator of muscle glycogen phosphorylase but not of the liver form of enzyme
how are the glycogen metabolism regulatory enzymes controlled?
Regulation occurs in a reciprocal fashion when one is
activated the other is inhibited
What are glycogen storage diseases?
This refers to condition involving abnormal (excessive or inadequate) storage of glycogen.
• Inborn errors of metabolism (inherited diseases)
• Arise from deficiency or dysfunction of enzymes of glycogen
metabolism
• 12 distinct types. Incidence varies ~1 in 20,000 – ~1 in 100,000.
• Severity depends on enzyme/tissue affected
what do glycogen storage diseases result in?
- Liver and /or muscle can be affected
- Excess glycogen storage can lead to tissue damage
- Diminished glycogen stores can lead to hypoglycaemia & poor exercise tolerance
give two examples of Glycogen Storage Diseases
- von Gierke’s disease - glucose 6-phosphatase deficiency
* McArdle disease - muscle glycogen phosphorylase deficiency
what is gluconeogenesis?
It’s the production of of glucose from non-carbohydrate substrates.
when does gluconeogenesis occur?
Beyond ~ 8 hours of fasting, liver glycogen stores start
to deplete and an alternative source of glucose is
required
where does gluconeogenesis occur?
Occurs in Liver and to lesser extent in Kidney cortex
what are the 3 major precursors for gluconeogenesis?
Lactate - From anaerobic glycolysis in exercising muscle and red blood cells (Cori cycle)
Glycerol - Released from adipose tissue breakdown of triglycerides.
Amino acids - Mainly alanine.
what is the Cori cycle?
This refers to the cycle of lactate to glucose between the muscle and liver.
Can Acetyl CoA be used as a precursor for gluconeogenesis, explain your answer?
Acetyl-CoA cannot be converted into pyruvate
(pyruvate dehydrogenase reaction is irreversible) so there is no net synthesis of glucose from acetyl-CoA
give the 3 steps of gluconeogenesis where a key enzyme is needed
Seven of the ten reactions of glycolysis are reversible and can be used in the synthesis of glucose. The three irreversible steps (steps 1, 3 & 10) are by-passed.
Step 1
Lactate is converted to pyruvate
Pyruvate is converted to oxaloacetate
oxaloacetate is converted to phoshoenolpyruavte in the presence of Phosphoenolpyruvate carboxykinase (PEPCK).
Step 3
Fructose 1,6 bisP is converted to Fructose 6-P
[Fructose 1,6 bisphosphatase]
Step 10
Glucose-6P is converted to glucose.
[Enzyme- Glucose-6-Phosphatase]
which are the key enzymes regulated in gluconeogenesis?
- Fructose 1,6-bisphosphatase
- Phosphoenolpyruvate carboxykinase
(PEPCK)
what regulates gluconeogenesis and when is it regulated?
2 key enzymes regulated by hormones, insulin, glucagon, cortisol in response to:
• Starvation/fasting
• Prolonged exercise
• Stress
describe gluconeogenesis regulation
glucagon and cortisol increase the amount of PEPCK and increase the amount and activity of Fructose 1,6-bisphosphatase which results in stimulation of gluconeogenesis.
insulin decreases the amount of PEPCK and deacreases the amount and activity of Fructose 1,6-bisphosphatase which inhibits gluconeogenesis.
describe the Time Course of Glucose Utilisation
Glucose from food~2 Hours
Glycogenolysis - Up to 8-10 hours
Gluconeogenesis - 8-10 hours onwards
How are lipids stored?
Lipids are stored as triacylglycerol molecules (1 glycerol and 3 FA carbon chains)
How are TAGs stored?
As TAGs are hydrophobic they’re stored in their anhydrous form in adipose tissue
How efficient is TAG storage?
Highly efficient energy store. Energy content per gram twice that of carbohydrate or protein
When are lipid stores utilised?
Utilised in prolonged exercise, stress, starvation, during pregnancy
what controls The storage & mobilisation of TAGs?
The storage & mobilisation of TAGs is under hormonal control
What are adipocytes?
They’re fat cells used to store TAGs
what is the Structure of adipocytes?
White adipocytes are made up of a large lipid droplet (mainly TAG and cholesterol ester) with the cytoplasm
and organelles pushed to edge.
what is the Size of a typical adipocyte?
A typical adipocyte Is around ~0.1mm in diameter but the cells expand as more fat is added and can shrink
what is the Effect on adipocytes as a result of weight gain and then weight loss?
These cells can increase in size about fourfold due to weight gain before dividing and increasing the total number of fat cells. when weight is lost, the number of fat cells remain meaning that it is easier to gain weight afterwards because there are empty adipocytes already present.
Give the total number of fat cells and the weight of this in an average adult
An average adult has roughly 30 billion fat cells weighing ~15 kg.
what is the advantage of glycogen being a large molecule?
minimal osmotic effect
The fact that degradative (catabolic) and biosynthetic (anabolic) pathways occur by partially different routes (glycolysis/gluconeogenesis) or totally-different routes (fatty acid oxidation/synthesis) allows what?
- Greater flexibility (substrates and intermediates can be different).
- Better control (can be controlled independently or co-ordinately).
- Thermodynamically irreversible steps can be by-passed.
Give an Overview of dietary triacylglycerol metabolism
- dietary fat is acted on by pancreatic lipase in the small intestines which breaks it down to glycerol and fatty acids
- the fatty acids and glycerol enter the epithelial cells lining the small intestines where they are reconstituted to form triacylglycerols
- the triacylglycerol is incorporated into a lipoprotein particle called chylomicron
- chylomicrons drain into the lacteals and then to the lymphatic system and then to the circulatory system (left subclavian vein)
- the chylomicrons can travel to the adipose tissues where the fat is stored as triacylglycerols. the stored triacylglycerols can be mobilised by the enzyme hormone sensitive lipase(regulated by insulin, glucagon and adrenaline)
- the chylomicrons can also travel to other tissues where fatty acid oxidation releases energy
what is lipogenesis?
This refers to the formation of fatty acids from Acetyl-CoA
Site of occurrence of lipogenesis?
It mainly takes place in the liver
describe the process of liver lipogenesis
• Glucose –> pyruvate in cytoplasm (glycolysis).
• Pyruvate enters mitochondria and forms acetyl-CoA &
OAA which then condense to form citrate
• Citrate–>cytoplasm and cleaved back to Acetyl-CoA &
OAA.
• the oxaloacetate is converted to malate and then back to pyruvate which reduces NAD to NADH
• the NADH is important because the fatty acid synthase complex needs the reducing power to build fatty acids. NADHP is also obtained from the pentose phosphate pathway
• Acetyl-CoA carboxylase (key regulator) produces
malonyl-CoA from Acetyl-CoA which requires ATP hydrolysis
• Fatty acid synthase complex builds fatty acids by
sequential addition of 2 carbon units provided by malonylCoA. CO2 is lost from malonylCoA
• the fatty acids are combined with glycerol-3P by esterification to form triacylglycerols which will be transported from the liver by VLDLs
Process requires both ATP and NADPH
what is the key regulatory enzyme in lipogenesis?
Acetyl-CoA carboxylase = Key regulatory enzyme
describe regulation of Acetyl-CoA carboxylase
INCREASE ACTIVITY
Insulin (covalent de-phosphorylation)
Citrate (allosteric regulation)
DECREASE ACTIVITY
Glucagon / adrenaline (covalent phosphorylation)
AMP (allosteric regulation)
Compare fatty acid synthesis and β oxidation
fatty acid synthesis:
• Cycle of reactions that remove C2 as acetyl~CoA
• Produces acetyl~CoA
• Occurs in mitochondria
• Separate enzymes (mitochondrial matrix)
• Oxidative - produces NADH and FAD2H
• Requires small amount of ATP to activate
the fatty acid
• Intermediates are linked to CoA
• Regulated indirectly by availability of fatty
acids in mitochondria.
• Glucagon and adrenaline stimulate
• Insulin inhibits
β oxidation: • Cycle of reactions that add C2 as malonyl CoA • Consumes acetyl~CoA • Occurs in cytoplasm • Multi-enzyme complex (cytoplasm) • Reductive - requires NADPH • Requires large amount of ATP to drive the process • Intermediates are linked to fatty acid synthase by carrier protein • Regulated directly by activity of acetyl~CoA carboxylase • Glucagon and adrenaline inhibit • Insulin stimulates
describe Fat mobilisation (lipolysis)
- hormone sensitive lipase breaks down triacylglycerol into glycerol and fatty acids.
- glycerol transported to liver and utilised as carbon source for gluconeogenesis
- fatty acid Travels complexed with albumin to muscle and other tissues where it is used to release energy via β oxidation
describe regulation of hormone sensitive lipase
Glucagon & Adrenaline leads to phosphorylation and ACTIVATION of HSL
Insulin leads to dephosphorylation and INHIBITION of HSL
Give the fuel stores found in a human
- Triacylglycerol
Stopes lipids as glycerol and fatty acids - Liver glycogen
Stores glucose in the liver and acts as a buffer for plasma glucose levels - Muscle glycogen
Stores glycogen in the muscle for metabolism - Muscle protein
