Integration of Metabolism Flashcards
What does the brain require for metabolism?
requires a continuous supply of glucose
- ketone bodies (e.g. β-hydroxybutyrate) can partially substitute for glucose
- cannot metabolise fatty acids
What is hypoglycemia?
- too little glucose in the brain
- causes faintness and coma
What is hyperglycaemia?
- can cause irreversible damage
- too much glucose
What is required for light contraction of skeletal muscle?
requirements met by OxPhos
What is required for vigorous contraction of skeletal muscle?
O2 becomes a limiting factor
- glygogen breakdown (muscles)
- lactate formation
What is needed for the heart to contract?
- completely aerobic metabolism
- utilises TCA cycle substrates, e.g. free fatty acids, ketone bodies
- Loss of O2supply Leads to cell death and myocardial infarction (energy demand»_space;> energy supply)
Role of the liver?
- Can interconvert nutrient types
- highly metabolically active
- plays a central role in maintaining blood [glucose] at 4.0-5.5 mM
- is a glucose storage organ (glycogen)
- plays a key role in lipoprotein metabolism
- (transport of triglycerides & cholesterol)
What do muscles rely on for metabolism?
carbohydrate and fatty acid oxidation
What does the brain rely on for metabolism?
uses 20 % of resting metabolic rate as it has a continuous high ATP requirement; cannot utilise fatty acids as a fuel source
What is adipose tissue?
long term storage site for fatty acids in the form of triglycerides
What does the heart rely on for metabolism?
can oxidise fatty acids and carbohydrate
-10 % of resting metabolic rate
What does the liver rely on for metabolism?
20 % of resting metabolic rate
the body’s main carbohydrate store (glycogen) and a source of blood glucose
What can excess glucose-6-phosphate be used for?
generate glycogen in liver and muscle
What can excess Acetyl CoA be used for?
generate fatty acids
which are stored as triglycerides in adipose tissue
What happens during fasting?
rather than enter the TCA, much of the acetyl CoA produced results in ketone body production
What can be a source of aa?
Pyruvate and other TCA cycle intermediates
The backbone of these molecules can be used to used to make nucleotides.
What else can glucose-6-phosphate be used for?
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 can the body do to avoid hypoglycemia?
short term
- breakdown of liver glycogen stores occurs to maintain plasma glucose levels.
- releases free fatty acids from adipose tissue.
- convert Acetyl CoA into ketone bodies via the liver.
How is more glucose available for the brain?
Both fatty acids and ketone bodies can be used by muscle
What is gluconeogenesis?
another pathway to generate glucose
What is the pathway of gluconeogenesis?
(lactate, some aa) pyruvate (3C) --> (some aa) oxaloacetate (4C) --> phosphoenol pyruvate (C3) --> (glycerol) --> (DHAP (3C) G3P (3C) --> fructose-1,6-bisphosphate (6C) --> fructose-6-phosphate (6C) --> glucose-6-phosphate (6C) --> glucose (6C) OR glycogen
What are the non-carbohydrate precursors that enter the gluconeogenesis pathway ?
lactate, amino acids and glycerol
How is lactate generated?
by skeletal muscle during strenuous exercise, when the rate of glycolysis exceeds the rate of the TCA cycle and the electron transport chain
How is lactate utilised?
taken up by the liver and utilised to regenerate pyruvate by lactate dehydrogenase (LDH), also known as the Cori cycle
How can aa be derived?
from the diet or during times of starvation, e.g. from the breakdown of skeletal muscle
What is the glycerol backbone used for?
to generate dihydroxyyacetone phosphate (DHAP)
What enzymes catalysed the 3 irriversible reactions in glycolysis?
kinases hexokinase, phosphofructokinase and pyruvate kinase
What are the 4 enzymes needed for gluconeogenesis?
pyruvate carboxylase
phosphoenolpyruvate carboxykinase
fructose-1,6-bisphosphate
glucose-6-phosphate
How many additional bonds are there in the pathway?
The four “additional” high energy bonds are required to turn an energetically unfavourable process into an energetically favourable one
What is the ΔG for the straight reversal of glycolysis?
+90 kJ/mol which is energetically unfavourable
What is ΔG for gluconeogenesis?
-38 kJ/mol
What is the sequence of bypass reactions of gluconeogenesis?
pyruvate --> PYRUVATE CARBOXYLASE oxaloacetate--> PHOSPHOENOLPYRUVATE CARBOXYKINASE phosphoenolpyruvate --> fructose-1,6-BisP --> FRUCTOSE 1,6-BISPHOSPHATE fructose 6-P --> glucose 6-P -> GLUCOSE-6-PHOSPHATASE glucose
What does the deamination of all 20 amino acids give rise to?
-pyruvate
-acetyl CoA
-acetoacetyl CoA
-α-ketoglutarate
-succinyl CoA
-fumerate
-oxaloacetate
(Urea is lost as a waste product)
Why are some called glucogenic aa?
because their skeletons can give rise to glucose via gluconeogenesis
Why are some called ketogenic aa?
give rise to skeletons which cannot enter gluconeogenesis but can be used to synthesis fatty acids and ketone bodies
Can fatty acids be converted into glucose?
no
What happens to glycerol?
can be converted to DHAP and enter the gluconeogenic pathway upstream
What can fatty acids be converted into?
ketone bodies and used by tissues such as muscle and brain
What happens as muscle contracts?
the demand for ATP increases e.g. requirements of muscle actomyosin ATPase and cation balance
What happens when glucose demand is increased?
it is met by an increase in the number of glucose transporters on the membranes of muscle cells
What effect does adrenaline have on metabolism?
- increasing the rate of glycolysis in muscle
- increasing the rate of gluconeogensis by the liver
- increasing the release of fatty acids from adipocytes
What happens during anaerobic conditions in the muscle?
glycogen is broken down
What happens in the liver during anaerobic conditions in muscles?
To replenish NAD+ levels and maintain glycolysis, pyruvate is taken up by the liver and converted into lactate by lactate dehydrogenase
Lactate can then be used by the liver to generate glucose by gluconeogenesis
What levels can control of metabolism be at?
-product inhibition
-under the influence of signalling molecules such as hormones
What is the typical blood [glucose] ?
maintained at around 4mM
What does hexokinase catalyse?
first irreversible step in the glycolysis pathway
Where is hexokinase found?
Muscle and liver contain suitably different forms (isoforms) of this enzyme
What is the difference between the isoforms of hexokinase?
they are maximally active at different concentrations of glucose
What is the Michaelis constant?
the concentration of substrate at which an enzyme functions at a half-maximal rate (Vmax)
What is the Michaelis constant used for?
compare the relative activities of enzymes
What is the Km of hexokinase I in the muscle?
0.1mM
- active at low concentrations of glucose
- essentially operating at maximal velocity at all times
What inhibits hexokinase I ?
glucose-6-phosphate
under anaerobic conditions when the rate of the TCA cycle drops, and glycolysis therefore slows, Hexokinase I is inhibited by accumulating levels of glucose-6-phosphate
What is the Km of hexokinase IV in the liver?
4mM
- much less sensitive to blood glucose concentrations
- less sensitive to the inhibitory effects of glucose-6-phosphate
when is insulin secreted?
when glucose levels rise: it stimulates uptake and use of glucose and storage as glycogen and fat
when is glucagon secreted?
when glucose levels fall: it stimulates production of glucose by gluconeogenesis and breakdown of glycogen and fat
What organ secretes insulin and glucagon?
islets of the pancreas
What is adrenaline?
strong and fast metabolic effects to mobilise glucose for “flight or fight”
What are glucocorticoids?
steroid hormones which increase synthesis of metabolic enzymes concerned with glucose availability
What are the effects of secretion of insulin?
- increased glucose uptake by liver – used for glycogen synthesis and glycolysis (acetyl-CoA produced is used for fatty acid synthesis)
- increased glucose uptake and glycogen synthesis in muscle.
- increased triglyceride synthesis in adipose tissue.
- increased usage of metabolic intermediates due to a general stimulatory effect on the body’s synthesis and growth.
How are falling glucose levels controlled?
- increased glucagon secretion (and reduced insulin) from islets.
- glucose production in liver resulting from glycogen breakdown and gluconeogenesis.
- utilisation of fatty acid breakdown as alternative substrate for ATP production (important for preserving glucose for brain).
What does NB adrenalin stimulate?
stimulates skeletal muscle towards glycogen breakdown and glycolysis, and adipose tissue towards fat lipolysis to provide other tissues with alternative substrate to glucose
What happens after prolonged fasting?
i.e. longer than can be covered by glycogen reserves
- glucagon/insulin ratio increases further
- adipose tissue begins to hydrolyse triglyceride to provide fatty acids for metabolism
- TCA cycle intermediates are reduced in amount to provide substrate for gluconeogenesis
- protein breakdown provides amino acid substrates for gluconeogenesis
- ketone bodies are produced from fatty acids and amino acids in liver to substitute partially the brain’s requirement for glucose
What is diabetes mellitus?
a disorder of insulin release and signalling, resulting in an impaired ability to regulate blood glucose concentrations
What is the 1st type of diabetes mellitus?
Type I diabetes in which individuals fail to secrete enough insulin (β-cell dysfunction)
What is the 2nd type of diabetes mellitus?
Type II diabetes in which individuals fail to respond appropriately to insulin levels (insulin resistance)
what are the complications of diabetes?
- hyperglycaemia with progressive tissue damage (e.g. retina, kidney, peripheral nerves)
- increase in plasma fatty acids and lipoprotein levels with possible cardiovascular complications
- hypoglycaemia with consequent coma
- ketoacidosis
What protects against hypoglycaemia?
Glucagon
What is hypoglycaemia?
Insulin deficiency and relative excess of glucagon leads to increased hepatic output of glucose and, thus, hyperglycaemia
In the fed state, insulin acts to increase the synthesis of which molecules?
Proteins
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