Sean - Ketone Bodies Flashcards
List the phases of metabolism during fasting as time progresses
Gastrointestinal (0-1)
Glycogenolysis (1-2)
Gluconeogenesis (2-7)
Ketosis (7+)
List in order the preferred energy sources as fasting progresses
Glucose
Glycogen
Fatty acids -> produce ketones
Proteins/amino acids
When are ketones produced
Ketone bodies are produced from fatty acids when liver glycogen is depleted
What type of fuel is preffered by the heart
Long chain fatty acids
How do fatty acids circulate in blood
Bound to albumin
What are fatty acids broken down into
Oxidised to CO2 and H2O
The use of fatty acids by the liver provides energy for what two processes?
Gluconeogenesis
Ureagenesis
Why is synthesis of ketones important?
Ketone synthesis further reduces the need for glucose utilisation (brain needs this)
Name three ketone bodies
(DRAW THESE)
Acetone
Acetoacetate
D-B-hydroxybutyrate
What happens to the ketone acetone?
Its exhaled from the body
What happens to the ketone acetoacetate?
Energy source for tissues such as skeletal and heart muscle and the renal cortex
What happens to D-B-Hydroxybutyrate?
Energy source for skeletal muscle, heart muscle, renal cortex
AND
Used as fuel by brain under starvation conditions (last resort)
How much of your daily energy intake is used by the brain?
20%
Can the brain use fatty acids as a fuel source?
NO
Only glucose or B-hydroxybutyrate ketone
Describe how much of energy for the brain is produced by ketone bodies after 3 days and 40 days
After 3 days of fasting = 25% of energy is from ketone
After 40 days of fasting = 70% is from ketones
What is ketosis
The overproduction of ketone bodies
What two things can cause ketosis
Diabetes mellitus
Low carb diets
How does diabetes cause ketosis
This is because the hepatocytes cannot take up glucose as a fuel
Acetyl-CoA accumulates in the hepatocytes and are converted into ketone bodies
Concentrations of ketones acetoacetate and D-B-hydroxybutyrate lower blood pH (acidosis)
What can acidosis lead to?
Coma
Death
Comment on the ketone levels in untreated diabetics
Can be 60x the normal concentrations
List some side effects of ketosis
Diarrhea
Constipation
Headaches
Thirst
Dizziness
Nausea
Lack of energy
How does the body deal with ketosis
(3)
Body tries to remove ketones via urine
Causes further removal of eater and electrolytes
Results in potentially fatal dehydration, tachycardia, hypotension
What is ketogenesis
The formation of ketone bodies in the liver mitchondria
What are ketones formed from?
Formed from acetyl CoA produced by B oxidation of fatty acids
When can fatty acids be metabolised in the liver
When the TCA cycle is not functioning
i.e. when components of TCA have been cannibalised to generate amino acids/nucleotides (starvation -> no glucose for TCA)
List the events that occur during starvation
Gluconeogenesis kicks in -> steals oxaloacetate from citric acid cycle to generate glucose
Acetyl-CoA accumulates as fatty acids undergo b oxidation
Citric acid cycle slows -> acetyl CoA is directed to ketone body formation instead of citric acid cycle
Ketone bodies are generated in the liver
Ketone bodies transported to regions in need of energy
Ketones reconverted into acetyl CoA to produce energy
What is the first step of ketogenesis?
Two molecules of acetyl CoA react together to form acetoacetyl CoA
Thiolase enzyme catalyses the reaction
What catalyses the formation of acetoacetyl CoA
Thiolase
What is the second step of ketogenesis?
Acetoacetyl CoA undergoes condensation in the presence of Acetyl CoA + H2O
Forms HMG CoA (and CoA-SH)
Catalysed by HMG CoA synthase
What is HMG CoA?
B-Hydroxy-B-methylglutaryl-CoA
What catalyses the formation of B-Hydroxy-B-methylglutaryl-CoA?
HMG CoA synthase
What is the third step of ketogenesis?
HMG-CoA is cleaved by HMG CoA lyase
Forms acetoacetate (ketone) and acetyl CoA
What enzyme cleaves HMG CoA?
HMG CoA lyase
What is the fourth step of ketogenesis?
(2)
Acetoacetate is dehydrogenated to B-hydroxybutyrate
Catalysed by B-hydroxybutyrate dehydrogenase in the presence of NADH + H+
What catalyses the formation of B-hydroxybutyrate?
B-hydroxybutyrate dehydrogenase
What is the fifth step in ketogenesis?
Acetoacetate and B-hydroxybutyrate are transported across the mitochondrial membrane and the plasma membrane of the liver cells
They can now enter the blood stream to be used as a fuel by other cells of the body
Where is acetoacetate and B-hydroxybutyrate transported across?
Mitochondrial membrane
Plasma membrane
What is the sixth step of ketogenesis?
Small amounts of acetoacetate are decarboxylated to acetone in the blood stream
Catalysed by acetoacetate decarboxylase
What catalyses the formation of acetone?
Acetoacetate decarboxylase
Other than via ketogenesis, how can acetone be formed?
The spontaneous decarboxylation of acetoacetate
List the molecules of ketogenesis
2 Acetyl-CoA
Acetoacetyl-CoA
HMG-CoA
Acetoacetate
B-hydroxybutyrate
Acetoacetate
Acetone
List the enzymes of ketogenesis
Thiolase
HMG-CoA synthase
HMG-CoA lyase
D-B-hydroxybutyrate dehydrogenase
Acetoacetate decarboxylase
What is acetone at standard pressure/temp?
A gas
How is acetone treated by the body?
Treated as a waste product
It dissolves in blood stream and is exhaled
If someone has high ketone bodies then acetone can be smelt in breath or urine
What is the regulatory enzyme of ketogenesis?
HMG CoA synthase
What activates HMG CoA synthase
Increased fatty acids in the blood
What inactivates HMG CoA synthase
Inhibited by high levels of CoASH
How does high levels of CoASH activates/inhibit HMG CoA synthase?
When fatty acids are taken to liver, CoASH is used to activate them
Therefore, low CoASH indicate high fatty acids and therefore HMG CoA is activated
High CoASH indicates low fatty acids and therefore HMG CoA synthase is inhibited
What is ketolysis?
The complete oxidation of ketone bodies to CO2 and water
The use of ketones by the body
Where does ketolysis occur?
The mitochondria of extrahepatic tissues
Why does ketolysis occur in the mitochondria of extrahepatic tissues?
Due to the high activity of the enzyme B-ketoacyl-coA transferase
Why does ketolysis not occur in the liver
Due to a deficiency of B-ketoacyl-CoA transferase
What ketone produced by fatty acids can not be broken down in ketolysis?
Acetone
What is the fuel produced by ketolysis?
Acetyl CoA
What enzymes are used in ketolysis?
Thiolase
B-hydroxybutyrate dehydrogenase
Enzyme-B-ketoacyl-CoA transferase
What energy carrier is used in ketolysis (and produced in ketogenesis)?
NAD+
What is the first step in ketolysis?
B-hydroxybutyrate is dehydrogenated
This forms acetoacetate
Catalysed by B-hydroxybutyrate dehydrogenase
What catalyses the formation of acetoacetate in ketolysis?
B-hydroxybutyrate dehydrogenase
What is the second step of ketolysis?
Acetoacetate is activated, forming acetoacetyl CoA
Catalysed by B-ketoacyl Co A transferase/ Succinyl CoA acetoacetate CoA transferase
Requires the conversion of succinyl CoA to succinate
What catalyses the formation of acetoacetyl CoA?
Succinyl CoA acetoacetate CoA transferase
ALSO CALLED
B-ketoacyl-CoA transferase
What is the second method of forming acetoacetyl CoA (without succinyl CoA)?
(4)
Acetoacetate is converted to acetoacetyl CoA
Requires ATP
Must be in the presence of CoA SH
Catalysed by thiokinase/ acetoacetyl CoA synthetase
What is the third reaction in ketolysis?
Acetoacetyl CoA is converted to 2 Acetyl CoA
Catalysed by thiolase
What happens to the 2 acetyl-CoA produced by ketolysis?
They enter the citric acid cycle
How much ATP is produced by the 2 acetyl-CoA produced in ketolysis
20 ATP
Other than acetyl-CoA, what product of ketolysis can be used to make energy?
B-hydroxybutyrate can be converted back into acetoacetate
This generates 1 NADH
This provides an additional 2.5 ATP after entering electron transport chain
What is the total ATP production by ketolysis?
22.5 ATP
What effect can ketones have on epilepsy?
Elevated ketone bodies in blood can lead to a reduction in the frequency of epileptic seizures
