2.6 - Integration of metabolism Flashcards
1
Q
Metabolic features of tissues - brain
A
- brain (2% of total body weight) uses 20% of resting metabolic rate as it has a continuous high ATP requirement
- requires a continuous supply of glucose
- cannot metabolise fatty acids
- ketone bodies (e.g. B-hydroxybutyrate) can partially substitute for glucose
- hypoglycaemia causes faintness and coma
- hyperglycaemia can cause irreversible damage
2
Q
Metabolic features of tissues - skeletal muscle
A
- muscle (40% of total body weight) - can have periods of very high ATP requirement (vigorous contraction) and relies on carbohydrate and fatty acid oxidation
- ATP requirements vary depending on exercise undertaken
- light contraction - requirements met by oxidative phosphorylation
- vigorous contraction - ATP requirement > ATP supply, O2 becomes limiting factor, glycogen breakdown occurs, lactate is formed (enters liver via bloodstream)
3
Q
Metabolic features of tissues - heart
A
- heart (1% of total body weight) - 10% of resting metabolic rate and can oxidise fatty acids and carbohydrate
- heart must beat constantly
- designed for completely aerobic metabolism and is rich in mitochondria
- utilises TCA cycle substrates e.g. free fatty acids, ketone bodies
- loss of O2 supply to the heart leads to cell death and myocardial infarction (energy demand > energy supply)
4
Q
Metabolic features of tissues - liver
A
- liver (2.5% of total body weight) - 20% of resting metabolic rate; body’s main carbohydrate store (glycogen) and a source of blood glucose
- undertakes a wide repertoire of metabolic processes and is highly metabolically active
- can interconvert nutrient types
- plays a central role in maintaining blood glucose concentrations
- glucose storage organ (glycogen)
- key role in lipoprotein metabolism (transport of triglycerides and cholesterol)
5
Q
An overview of carbohydrate metabolism
A
- during extreme exercise, the ATP demands of the muscle outstrip the oxygen supply needed for aerobic respiration and lactate is produced
- during fasting fat breakdown > fat biosynthesis, so much of the acetyl CoA produced results in ketone body production (rather than entering the TCA cycle)
6
Q
Avoiding hypoglycaemia
A
- breakdown of liver glycogen stores = maintain BGC in plasma
- release FFA from adipose tissue
- convert acetyl CoA –> ketone bodies via the liver
- FFA and ketone bodies used by the muscle to produce ATP, so less glucose is metabolised and there are increased plasma glucose levels available to the brain
7
Q
Gluconeogenesis
A
- generates glucose from pyruvate (like reverse of glycolysis)
- non-carbohydrate precursors enter the pathway
- lactate is utilised to regenerate pyruvate by lactate dehydrogenase (LDH)
- AA can be derived from the diet or the breakdown of skeletal muscle
- the glycerol backbone from triglyceride hydrolysis is used to generate DHAP
- delta G value for straight reversal of glycolysis is +90 kJ/mol, which is energetically unfavourable –> must find a way to bypass the irreversible kinase-driven reactions
- six phosphoanhydride bonds are required to turn an energetically unfavourable process into an energetically favourable one
- delta G for gluconeogenesis is -38 kJ/mol
8
Q
What are the bypass reactions of gluconeogenesis?
A
- must find way to reverse three irreversible kinase-driven reactions - glucose–>G6P, F6P–>F1,6BP, phosphoenolpyruvate–>pyruvate
- we need 4 additional enzymes:
- pyruvate –> OAA by pyruvate carboxylase (mitochondria, -2ATP)
- OAA –> phosphoenolpyruvate by phosphoenolpyruvate carboxykinase (cytoplasm, -2ATP)
- phosphoenolpyruvate –> fructose-1,6-bisP = -2ATP
- fructose-1,6-bisP –> fructose-6-P by fructose 1,6-bisphosphatase
- fructose-6-P –> glucose-6-P
- glucose-6-P –> glucose by glucose-6-phosphatase
- net loss 6 ATP
9
Q
Protein as a fuel source
A
- glucogenic AA used to generate glucose via gluconeogenesis (using carbon skeletons)
- ketogenic AA used to synthesise fatty acids and ketone bodies
10
Q
Fats as a fuel source
A
- triglycerides are broken down into fatty acids and glycerol
- glycerol –> DHAP and enter gluconeogenic pathway
- fatty acids can be converted into ketone bodies (used as energy source when glucose is unavailable)
11
Q
Energy stores and energy consumption - aerobic respiration
A
- with adequate oxygen, ATP demands of muscle can be met by oxidative phosphorylation using glucose and other substrates
- contracting muscle requires more ATP and glucose transporters
- adrenalin helps increase the rate of glycolysis in muscle by increasing gluconeogenesis in the liver, and releasing fatty acids from adipocytes
- glucose in blood –> muscle cells –> metabolism by glycolysis and TCA –> ATP produced by OxPhos
12
Q
Energy stores and energy consumption - anaerobic respiration
A
- ATP demands > oxygen supply
- glycogen is broken down to meet the glucose demands of the muscle
- lactate synthesis replenishes NAD+ levels so glycolysis can continue
- lactate used in gluconeogenesis to synthesise more glucose
13
Q
Control of metabolic pathways
A
Several levels of control e.g:
- product inhibition of enzymes
- signalling molecules e.g. hormones
- metabolic pathways are centred around irreversible reactions
- increasing enzyme activity increases rate of the downstream steps, more control if this occurs early on
- the Michaelis constant (Km) is the concentration of substrate at which an enzyme functions at a half maximal rate (Vmax)
14
Q
How is glucose metabolism in the liver and muscles controlled?
A
- BGC maintained around 4 mM
- hexokinase catalyses the first irreversible step in glycolysis and muscle and liver contain isoforms of the enzyme (different forms) which catalyse the same reaction but are maximally active at different glucose concs
- hexokinase I in muscle is active at low glucose conc (Km 0.1 mM - operates at max velocity at all the time) due to high glucose affinity (low Km), and is highly sensitive to G6P inhibition - under anaerobic conditions when TCA cycle and glycolysis drops, Hk I inhibited by accumulating G6P
- hexokinase IV in liver is active at high glucose conc (Km 4 mM) due to low glucose affinity (high Km), and is less sensitive to G6P inhibition - less sensitive to BGCs, more active in fed state when liver-glucose levels are high
- glucose 6-phosphatase is found in the liver and not muscle, and catalyses the reverse reaction of Hk, generating glucose from G6P
15
Q
Hormonal control of blood glucose concentration
A
- insulin is secreted when BGC rises - stimulates uptake and use of glucose and storage as glycogen and fat
- glucagon is secreted when BGC falls - stimulates gluconeogenesis and breakdown of glycogen and fat
- adrenalin (epinephrine) - strong and fast metabolic effects to mobilise glucose for ‘fight or flight’
- glucocorticoids - steroid hormones which increase synthesis of metabolic enzymes concerned with glucose availability
