Integration Of Metabolism Flashcards
What are the metabolic features of muscle?
(40% of total body weight) can have periods of very high ATP requirement (vigorous contraction) and relies upon carbohydrate and fatty acid oxidation
What are the metabolic features of brain and nervous tisse?
(2% of total body weight) uses 20% of resting metabolic rate as it has a continuous high ATP requirement; cannot utilise fatty acids as a fuel source
Requires a continuous supply of glucose
What are the metabolic features of adipose tissue?
(15% of total body weight) and a long term storage site for triglycerides
What are the metabolic features of the heart?
(1% of total body weight) 10% of resting metabolic rate and can oxidise fatty acids and carbohydrates
What are the metabolic features of the liver?
(2.5% of total body weight) 20% of resting metabolic rate; the body’s main carbohydrate store (glycogen) and a source of blood glucose
During light contraction of skeletal muscle, how is ATP consumption met?
through oxidative phosphorylation
During vigorous contraction, how is ATP consumption met?
O2 becomes a limiting factor
- glycogen breakdown (muscles)
- lactate formation
Under anaerobic conditions, what is pyruvate converted into?
Lactate
What is the only substrate that the brain can use as a source of energy?
Glucose / carbohydrates
Which energy source can the brain not use?
The brain cannot metabolise fatty acids
What can partially substitute for glucose in the brain?
Ketone bodies like 3-Beta-Hydroxy-butyrate in extreme situtations
What can too little glucose in the brain cause?
Hypoglycaemia - faintness and coma
What can too much glucose in the brain cause?
Hyperglycaemia - irreversible damage to multiple organ systems like retinas
What does the heart utilise for energy substrates?
TCA cycle substrates like free fatty acids and ketone bodies
What happens to the heart when energy demand > energy supply?
Myocardial infarction (heart attack)
When can energy demand> energy supply?
Loss of O2 supply to the heart, leading to cell death then myocardial infarction
Name four fuel sources for the heart
Ketone bodies, glucose, fatty acids and lactate
Why does the heart have a lot of mitochondria?
Because the heart is designed for aerobic conditions - high energy supply
How does the liver store glucose?
As glycogen
What does the liver do?
undertakes a wide repertoire of metabolic processes and is highly metabolically active and can interconvert nutrient types and plays a key role in lipoprotein metabolism (transport of triglycerides and cholesterol)
What range does the liver try keep the blood glucose levels between?
4.0-5.5 mmol/L
Excess of what can be used to generate glycogen in the liver and muscle?
Excess glucose-6-phosphate
How are fatty acids stored in adipose tissue?
They are stores as triglycerides in the adipose tissue
During fasting, what happens to the Acetyl CoA which is produced?
Much of the Acetyl CoA is used to generate ketone bodies
What happens to lactate production during periods of intense exercise?
It increases - produced from pyruvate
As the ATP demands of the muscle outstrip the oxygen supply needed for aerobic respiration
What four things can the body initially do when the blood glucose concentration drops below 3mM?
- Breakdown liver glycogen stores to maintain levels
- Release free fatty acids from adipose tissue
- Convert Acetyl CoA into ketone bodies in the liver
- gluconeogenesis
How does the brain get more glucose when the body is in a hypoglycaemic coma?
The skeletal muscle can use ketone bodies and fatty acids, to increase the blood glucose concentration, making more plasma glucose available for the brain which cannot metabolise fatty acids
What is the order of gluconeogenesis?
red arrow in pathway shows key steps that need to be bypassed by non-glycolytic enzymes
How is lactate used during gluconeogenesis?
It is utilised to regenerate pyruvate by lactate dehydrogenase (LDH)
How are AA used during gluconeogenesis and where are the AA derived from?
AA can be derived from the diet or breakdown of skeletal muscle
AA can be used to form oxaloacetate or pyruvate
How is glycerol used in gluconeogenesis?
The glycerol backbone is used to generate dihydroxyacetone (DHAP)
After how many hours are the bodies glycogen stores depelated?
12-18 hours
After the body has depleted its glycogen stores, what is used to generate glucose?
Gluconeogenesis
Which reaction in gluconeogenesis occurs in the mitochondria?
The convertion of pyruvate to oxaloacetate
What enzyme is used to convert pyruvate into oxaloacetate?
Pyruvate carboxylase
Why is gluconeogenesis a bypass reaction?
delta G value for a straight reversal of glycolysis would be +90kJ/mol (energetically unfavourable)
Six phosphoanhydride bonds are required to turn an energetically unfavourable process into an energetically favourable one:
delta G for gluconeogenesis is -38kJ/mol (energetically favourable)
How does oxaloacetate move out the mitochondria once it has been produced from pyruvate?
It moves via the malate shuttle, where it is then converted into phosphophenolpyruvate
How do glucogenic amino acids give rise to glucose?
They undergo transamination reactions which results in the production of pyruvate, which yields glucose through gluconeogenesis
where do the reactions of gluconeogenesis occur?
First reaction occurs in mitochondria
the rest occurs in the cytosol
What do ketogenic amino acids give rise to?
Skeletons that can be used to synthesise FAs and ketone bodies.
How does adrenaline help increase the rate of glycolysis in muscles?
Increased gluconeogenesis by the liver
Increased released of fatty acids from adipocytes
What do contracting muscles require?
increased ATP
increased glucose transporters
What happens to pyruvate during anaerobic respiration and where does this occur and by what and why?
It is taken up by the liver and converted into lactate by LD to replenish NAD+ levels and maintain glycolysis
What happens to glycogen during anaerobic respiration?
glycogen is broken down to meet the glucose demands of the muscle
In the fasting state, what is the main metabolic fuel for the heart?
fatty acids
In the fasting state, what is the main metabolic fuel for the brain?
Glucose
In the fed state, why does insulin stimulate an increase in the number of glucose transporters on the adipocyte surface?
To facilitate glucose uptake to make triglycerides.
Why do plasma levels of ketone bodies increase as the fed state progresses into fasting and then starvation ?
Ketone bodies produced by the liver
The products of which reactions can enter the pathway to increase oxaloacetate production for gluconeogenesis?
Transamination reactions
In the fasting state, glucagon acts to increase the synthesis of glucose from which molecules?
Glycogen, Glycerol and Amino acids.
What generates the bulk of the NADPH needed for anabolic pathways?
Glucose-6-phosphate via the pentose phosphate pathway can also be used as a source for nucleotide production in a pathway that generates the bulk of the NADPH needed for anabolic pathways e.g. cholesterol synthesis.
What are three non-carbohydrate precursoers which enter into the gluconeogenic cycle?
Lactate, Amino acid and glycerol
What is the cori cycle?
The generation of pyruvate from lactate
How does glycerol act as a non-carbohydrate substrate of gluconeogenesis?
It is used to produced DHAP
Which are the three reactions of gluconeogenesis which need to be bypassed through using kinase enzymes?
Oxaloacetate to Phosphoenolpyruvate
Fructose - 1,6 - Bisphosphate to Fructose - 6 - Phosphate
Glucose - 6 - Phosphate to Glucose
What enzyme is used to convert Glucose - 6 - Phosphate into Glucose?
Glucose - 6 - Phosphatase
What organs is Glucose - 6 - Phosphatase found in?
Liver and kidneys
What to things are triglycerides broken down into?
fatty acids and glycerol
What are the seven molecules which deamination of all 20 amino acids gives rise to?
Pyruvate Oxaloacetate Succinyl CoA Fumerate Acetyl CoA Acetoacetyl CoA Alpha-ketoglutarate
What happens to the rest of the amino acid once it has been broken down by deamination?
Remaining compounds are excreted in the urea
which tissues can use ketone bodies as an energy source?
Muscle and brain
What happens to the glucose transporters on the membranes of muscle cells as the muscle contracts?
The number present on the membranes of the muscle cells increases
What three effects does adrenaline have on helping the cell meet the adequate demands for ATP?
Increases the rate of glycolysis in muscle
increases the rate of gluconeogenesis in liver
Increases the release of fatty acids from adipocytes
what causes an increase in muscle glycolysis, gluconeogenesis and fatty acid breakdown during exercise?
The release of adrenaline
During anaerobic conditions what happens to the glycogen in the muscle?
It is broken down
What is the name of the pathway given to the breakdown of glycogen into glucose?
Glycogenolysis
What triggers glycogenolysis?
Glucagon
How is the Cori cycle used in anaerobic conditions?
Pyruvate is taken up by the liver and converted into lactate, using lactate dehydrogenase - replenished NAD+ levels allows glycolysis to continually occur
What does insulin do?
Stimulates the uptake and use of glucose, and storage of glycogen and fat
it is secreted when glucose levels rise
What enzymes catalyses the first, irreversible step of glycolysis?
Hexokinase
What are the two different isoforms of hexokinase found in the muscle and the liver?
Hexokinase I is found in the muscle
hexokinase IV is found in the liver
What is the Michaelis Constant (Km)?
The concentration of substrate at which an enzyme functions at half-maximal rate (Vmax)
What is the KM of Hexokinase 1 and what does it mean?
0.1 - this means it is active at very low concentrations of glucose and therefore is functioning at max velocity at almost all times
- high glucose affinity
Which hexokinase is sensitive to inhibition by product glucose - 6 - phosphate?
Hexokinase 1
When is hexokinase IV active?
active at high glucose
- low glucose affinity
- less sensitive to G-6-P
What are the four changes which occur during aerobic exercise?
- Increase in number of glucose transporters in muscle
- Increase glycolysis in muscle
- Increase gluconeogenesis in Liver
- Increased bet oxidation to make Acetyl CoA which is the used to generate ATP
Where does the convertion of lactate into pyruvate occur?
In the liver
During the fasted state, the transamination reactions of amino acid are an important substrate for what process?
Gluconeogenesis
During anaerobic conditions, why is Hexokinase 1 Inhibited?
During anaerobic conditions, glycolysis slows, and the concentration of glucose drops
This means that hexokinase is readily active
Therefore a lot of glucose is converted into glucoe-6-phosphate
Hence glucose - 6 - phosphate accumulates which inhibits hexokinase 1
Where is Hexokinase IV found?
In the liver
what does Hexokinase IV do?
Converts glucose into glucose-6-phosphate in the liver
What is the KM of Hexokinase IV?
4
What does the KM value of Hexoinase IV indicate?
4 - active at very high concentrations of glucose
Which hexokinase enzyme is more sensitive to G-6-P inhibition?
hexokinase 1
What is the role of glucagon in the hormonal control of blood glucose?
It is secreted when glucose levels fall: it stimulates production of glucose by gluconeogenesis and breakdown of glycogen and fat
What is the role of adrenaline in the hormonal control of blood glucose?
strong and fast metabolic effects to mobilise glucose for fight or flight
What is the role of glucocorticoids in the hormonal control of blood glucose?
steroid hormones which increase the synthesis of metabolic enzymes concerned with glucose availability
What occurs straight after a meal has been consumed?
- Insulin is secreted, causes glucose to be stored as glycogen
- Increase in glycolysis
- Acetyl CoA is used to generate fatty acids through Lipogenesis, meaning they can stored for future use
Overall stimulation of synthetic (anabolic) pathways
What happens after a period of fasting following a meal?
Glucose has been all stored as glycogen so blood glucose levels start to drop
- This triggers glucagon secretion
- Glucagon triggers glycogenolysis, and gluconeogenesis
- Fatty acid Beta Oxidation occurs so that Acetyl CoA is produced (used as an AP substrate)
- adrenaline stimulates glycogen breakdown and glycolysis (skeletal muscle) and lipolysis (adipose)
What happens after prolonged fasting?
Glucagon/ insulin ratio increases further
Adipose tissue hydrolyses triglycerides to provide fatty acids for metabolism
TCA cycle intermediates are reduced in amount to provide substrates for gluconeogenesis
Protein breakdown provides AA substrates for gluconeogenesis
Ketone bodies are produced from fatty acids and AA in liver to partially substitute the brain’s requirement for glucose
Why does triglyceride hydrolysis increase during periods of prolonged fasting?
The triglycerides are broken down into glycogen and fatty acids
fatty acids used in beta-oxidation to make ATP substrates (Acetyl CoA)
Glycogen can assist with gluconeogenesis, enters as DHAP
Why does ketone body synthesis occur during periods of prolonged fasting?
During fasting, gluconeogenesis ic occuring
This means all oxaloacetate is being used up
Therefore, there may be an excess of Acetyl CoA
The excess Acetyl CoA is used to produce Ketone bodies through ketogenesis
How does diabetic ketoacidosis occur?
The body does not produce enough insulin, therefore glucose cannot be stored in cells, body relies on fats for energy
fatty acids are broken down into ketone bodies
What happens to the insulin:glucagon ration after periods of prolonged fasting?
Increases further
Which cells of the ISLETs is glucagon released from?
Alpha cells
What two processes does glucagon stimulate in the liver?
Glycogenolysis and gluconeogenesis
What are glucocorticoids?
Steroid hormones which increase synthesis of metabolic enzymes concerned with glucose availability
Why are ketone bodies produced after periods of prolonged fasting?
Ketone bodies are produced from fatty acids and amino acids in liver to substitute partially the brain’s requirement for glucose
What is type I diabetes?
failure to secrete enough insulin (beta cell dysfunction)
What is type II diabetes?
failure to respond appropriately to insulin levels (insulin resistance)
What are some complications of diabetes?
hyperglycaemia
cardiovascular complications
ketoacidosis
hypoglycaemia
