L3: Energy Storage Glycogen and Fat Flashcards
What is the normal plasma level of glucose?
5mM elevates after meal
What tissues have an absolute requirement for glucose?
RBC (few mitochondrial ↑SA for heamoglobin and O2)
Neutrophils (mitochondrial burst> metabolism)
Lens of the eye (poor blood supply- no OP)
Innermost cells of the kidney medulla
What is special about the brain and glucose?
Can use ketone bodies–> time to adapt + only 50% energy requirement
GLUT1 transport Km=0.6mM, plasma < doesn’t use glucose
What happens to excess glucose?
Stored as glycogen
Where does glycogen get stored?
Stored as granules in:
Skeletal muscle–> inter- between cells, intra- within cells
Liver–> hepatocytes
What is the structure of glycogen?
Polymer
Branched every 8-10 residues–> originates from dimer glycogenin
alpha 1-4 glycosidic bonds in chain
alpha 1-6 glycosidic bond to branches
Why is it stored as a branched molecule?
Branches–> more sites for synthesis or degradation
Easier to release glucose
Reduced osmotic effect –> less water
Name the process of glycogen synthesis?
Glycogenesis
Name the main enzymes involved in glycogenesis?
- Hexokinase (glucokinase in liver)
- Phosphoglucomutase
- G1P uridyltransferase
- Glycogen synthase or branching enzyme
What is each step of glycogenesis?
Step 1. Glucose + ATP –> Glucose-6-phosphate and ADP (requires hexokinase)
Step 2. Glucose-6-phosphate < –>Glucose-1-phosphate (phosphoglucomutase)
Step 3. Glucose-1-phosphate + UTP + H20 –> UDP-glucose + PPi (G1P Uridyltransferase) UTP=ATP
Step 4. Glycogen(n) + UDP-glucose –> Glycogen (n+1) + UDP (glycogen synthase alpha1-4 glycosidic bond or branching enzyme alpha1-6 glycosidic bond)
How many ATPs are required for glycogenesis?
2 ATP (1ATP and 1UTP)
What is glycogen breakdown called?
Glycogenolysis
What are the enzymes involved in glycogenolysis?
Glycogen phosphorylase or de-branching enzyme
Phosphoglutamutase
What is the common process of glycogenolysis in muscle and liver?
Glycogen(n) + Pi–> Glucose-1-phosphate + Glycogen(n-1) (glycogen phosphorylase or de-branching enzyme)
Glucose-1-phosphate –> glucose-6-phosphate (phosphoglucomutase)
What happens to glucose-6-phosphate in muscle? What happens to glucose-6-phosphate in liver?
Muslce –> lacks glucose-6-phosphatase–> GP6 enter glycolysis
Liver–> converted to glucose by glucose-6-phosphatase–> released into blood –> buffer of blood glucose
How is glycogen metabolism regulated in liver?
Hormonal control
Rate limiting enzymes= glycogen synthase and glycogen phosphorylase
Insulin and glucagon/adrenaline
How is glycogen metabolism regulated in the muscles? What is another allosteric activator?
Hormonal control
Rate limiting enzymes- glycogen synthase and glycogen phosphorylase
Insulin and adrenline –> no glucagon receptor
AMP allosteric activator of Glycogen phosphorylase
How does insulin and glucagon/adrenaline affect the rate limiting enzymes?
↑ Insulin and ↓ glucagon/adrenaline = ↑ glycogen synthase
↓ Insulin and ↑ glucagon/adrenaline = ↓glycogen phosphorylase
What are glycogen storage diseases?
Inherited
Dysfunctional or deficiency of enzymes of metabolism
12 distinct types
Severity–> varies–> depends on enzyme/tissue affected
What are the results of glycogen storage disease?
Liver +/or muscle affected
Excess –> tissue damage
Diminished –> hypoglycemia + poor exercise tolerance
Give two examples of disease caused by excess storage and name the dysfunctional enzyme involved?
Von Gierke’s disease –> glucose-6-phosphase deficiency
McArdles disease –> glycogen phosphorylase deficiency (muscle)
What is the production of new glucose called?
Gluconeogenesis
Why do we need gluconeogenesis?
> 8hrs fasting –> ↓ glycogen stores –> alternative source
Where does gluconeogenesis occur?
Majority –> liver
Minor –> kidney cortext
What are the precursors for gluconeogenesis?
Lactate–> anaerobic glycolysis (muscle and RBC)- Cori cycle
Glycerol –> released from adipose tissue from TAG
Amino acids –> mainly alanine
What is the Cori cycle?
Muscle –> glucose converted to 2x lactate –> blood–> liver (gluconeogenesis) –> glucose –> muscle
cyclic process
Why can acetyl CoA not be used as a substrate for glucose synthesis?
Acetyl CoA (2C) --> not converted to pyruvate--> pyruvate dehydrogenase reaction irreversible No net synthesis of glucose from Acetyl CoA as 2 xCO2 lost
What are the key enzymes involved in gluconeogenesis?
- Phosphoenolpyruvate carboxykinase (PEPCK): pyruvate–> oxaloacetate –> phosphoenolpyruvate (PEPCK converts occeloacetate)
- Fructose 1,6- bisphosphatase: fructose 1,6-bisphophate –> fructose 6-phosphate
- Glucose 6-phosphatase: glucose 6-phosphate –> glucose
not simply the reversal of glycolysis as irreversible steps in glycolysis
How is gluconeogenesis regulated?
Hormonal control; Insulin and glucagon/cortisol
key enzymes: PEPCK (phosphoryenolpyruvate carboxykinase) + Fructose 1,6-bisphosphate
What affect does insulin and glucagon/cortisol have on gluconeogenesis?
Insulin –> inhibits–> ↓ PEPCK + fructose 1,6-bisphosphate
Glucagon/cortisol–> stimulates–> ↑ PEPCK + fructose 1,6-bisphosphate
How long after eating does glycogenolysis and gluconeogenesis occur?
Glucose- 2 hours
Glycogenolysis >2 hours <8 hours
Gluconeogenesis >8 hours
How is excess energy stored?
Converted to triacylglycerol for storage
Where are triacylglycerides stored and how?
Adipose tissue
Hydrophobic –> stored anhydrous form
Highly efficient energy store
Energy content x2 of carbs/protein
When are TAG utilised?
Prolonged exercise, stress, starvation and during pregnancy
What controls the storage and utilisation of TAG?
Hormones
What are the adipocytes? What are some of the characterisitcs?
Fat storage cells Large lipid droplet Organelle at edge 0.1mm diameter 30 billion--> 15kg
How do adipocytes increase in number?
Expand –> Fourfold –>Divide
How do fats get from your food into the adipocytes?
SI–> pancreatic lipase –> fatty acids and glycerol
Intestinal epithelial cell–> TAG reformed –>chylomicrons
Lymphatic system –> thoracic duct–> left subclavian vein –> blood
Stroage –> Adipose tissue
How do we mobilise TAG for use?
Hormone sensitive lipase –> mobilise TAG
Regulated by insulin and glucagon/adrenaline
Broken down into FA and glycerol
Transported FA-albumin to tissue
Tissue –> fatty acid oxidation
Glycerol –> gluconeogenesis
Which cells cannot use FA for energy?
Cells without mitochondria
Brain –> cannot pass BBB
Where does fatty acid synthesis occur?
Liver
What is lipogenesis?
Synthesis of fatty acids from acteyl CoA
What is the process of lipogeneis?
Pyruvate (glycolysis of glucose)–> Acetyl CoA by pyruvate dehydrogenase (in mitochondria)
Combines with oxaloacetate –> citrate (in mitochondria)
In cytoplasm cleaved release Acetyl CoA and oxaloacetate
Acetyl CoA –> malonyl CoA by acetyl CoA carboxylase
Oxaloacetate –> malate –> pyruvate + NADPH (malic enzyme)
Malonyl CoA and NADPH –> fatty acid synthesis complex–> FA
Why does pyruvate get converted to Acetyl Co-A to citrate and then broken back down again?
Pyruvate conversion to Acetyl CoA can only occur in the mitochondria
No transporters for Acetyl CoA–> converted to Citrate–> into cytoplasm–> broken down
What are the key regulators of lipogenesis?
Acetyl CoA carboxylase (produces malonyl CoA from Acetyl CoA which is need for the fatty acid synthase complex)
Hormonal control
Insulin (dephosphorylates) and citrate (allosteric) –> ↑activity
Glucagon/ adrenaline (phosphorylation) and AMP (allosteric) –> ↓activity
How does the fatty acid synthase complex work?
Addition of 2C provided by malonyl-CoA (produce CO2)
NADPH is required
What happens to fatty acids once they have been synthesised?
Esterification to TAG with glycerol 3-phosphate
Transported by VLDL to tissue
Compare and contrast fatty acid synthesis and oxidation (beta oxidation)?
Synthesis followed by oxidation
- -> add 2C from malonyl CoA / removes 2C as acetyl CoA
- -> Consumes acetyl CoA/ produces acetyl CoA
- -> cytoplasm / mitochondria
- -> multienzyme complex / separate enzymes
- -> reductive (NADPH required) / oxidative (NADH and FADH2 produced)
- -> Require ATP / Small amount ATP required
- -> intermediate linked to FA synthase by carrier protein / intermediates linked to CoA
- -> Regulated directly –> acetyl CoA carboxylase / Indirectly via avaliability of FA
- -> Glucagon and adrenaline inhibit/ Stimulate
- -> insulin stimulates / Inhibits
What is the benefit of synthesis and oxidation occurring by different pathways?
Greater flexibility –> substrates and intermediates different
Better control –> independently or coordinately
Themodynamically irreversible steps bypassed
