Metabolism S4 - Energy Storage Flashcards
Describe the three major energy stores in the body of a 70kg man.
Include approximate weight and approximate energy content for each store.
Triacylglycerols (TAGs) - 15kg - 600,000kJ
Glycogen - 0.4kg - 4,000kJ
Muscle Protein - 6kg - 100,000kJ
How many reactions are involved in glycogen synthesis? (glycogenesis)
4
What’s the equation of the first reaction in glycogenesis?
Which enzyme catalyses the reaction?
Glucose + ATP —> G-6-P + ADP
Hexokinase
What’s the equation for the second reaction in glycogenesis?
What enzyme catalyses this reaction?
G-6-P —> Glucose-1-Phosphate
Phosphoglucomutase
What’s the equation for the third reaction in glycogenesis?
Glucose-1-Phosphate + UTP + H2O —> UDP-Glucose + 2Pi
What is the final reaction of glycogenesis?
What two enzymes are involved and what is the difference in their action?
Glycogen (n residues) + UDP-Glucose —> Glycogen (n+1 residues) + UDP
Glycogen synthase forms 1-4 glycosidic bonds
Branching enzyme forms 1-6 glycosidic bonds
how often is a branch produces during glycogen synthesis?
about every 10 subunits
Where is glycogen stored and what is it broken down in response to at each respective location?
Liver - In response to fasting
Skeletal muscle - In response to exercise
What is the equation for the complete degradation of glycogen?
Glycogen (n residues) + nPi —> 0.9n G-6-P + 0.1n Glucose
Is glycogen ever fully degraded?
No, small sections of primer always preserved
How many reactions are involved in the degradation of glycogen?
3
Give the equation for the first step of glycogen degradation
What enzymes catalyse this reaction and what varies between their action?
Glycogen (n residues) + Pi —> Glucose-1-Phosphate + Glycogen (n-1 residues)
Glycogen phosphorylase (1-4 glycosidic cleavage)
De-branching enzyme (1-6 glycosidic cleavage)
Give the equation for the second step of glycogen degradation
What enzyme catalyses this reaction?
Glucose-1-Phosphate —> G-6-P
Phosphoglucomutase
How is glucose liberated from glycogen used in the skeletal muscle as compared to the liver?
In skeletal muscle G-6-P produced by step 2 of glycogen breakdown is fed directly into glycolysis for utilisation.
The liver requires another reaction (step 3 of glycogen degradation) to use the liberated glucose
Give the equation for step 3 of glycogen degradation
What enzyme catalyses this reaction?
G-6-P + H2O —> Glucose + Pi
Glucose-6-phosphatase
Compare the functions of liver and skeletal muscle glycogen
Liver - Glucose store for all tissues
Muscle - G-6-P store, useful only to muscle cells
How do glycogen metabolic disorders arise?
Abnormality in one or more of the enzymes of glycogen metabolism
What are the three enzymes that may be defective in a patient with a glycogen metabolism disorder?
Glycogen phosphorylase
Phosphoglucomutase
Glucose-6-phosphatase
What 3 effects are seen in glycogen metabolic disorders?
Increased/Decreased amount of glycogen
Glycogen structure may be abnormal
Usually liver or muscle effects
What are the clinical consequences of increased or decreased levels of glycogen?
Decreased exercise tolerance
Fasting hypoglycaemia
Tissue damage if excessive storage
What is the process of producing glucose from non-carbohydrate sources called?
Gluconeogenesis
Why is gluconeogenesis necessary?
To maintain constant glucose level in blood after glycogen been used
Some tissue are glucose dependent (eg. CNS)
Where is the main site of gluconeogenesis?
Liver
How long do glycogen stores last after eating?
8-10 hours
What are the possible substrates for gluconeogenesis?
Pyruvate, Lactate, Glycerol
Essential and non-essential amino acids whose metabolism involves pyruvate or intermediates of the TCA cycle
Is Acetyl-CoA a suitable substrate for gluconeogenesis? Explain.
No
Pyruvate dehydrogenase reaction is irreversible
What is the overall equation for gluconeogenesis from pyruvate?
2 Pyruvate + 4 ATP + 2 GTP + 2 NADH —> Glucose + 4 ADP + 2 GDP + 2 NAD+ + 6 Pi + 2H+
How are the reversible steps of glycolysis bypassed in gluconeogenesis from pyruvate?
With irreversible reactions
How are the irreversible reactions of glycolysis bypassed in gluconeogenesis of pyruvate?
Steps 1 and 3 are bypassed by thermodynamically spontaneous reactions catalysed by phosphatases
Step 10 is bypassed by two reactions driven by ATP/GTP hydrolysis
What are the equations for the bypass reactions of steps 1 and 3 in gluconeogenesis?
What enzymes catalyse these reactions?
STEP 1
G-6-P + H20 —> Glucose + Pi
Glucose-6-phosphatase
STEP 2
Fructose-1,6-phosphate + H20 —> Fructose-6-Phosphate + Pi
Fructose-1,6-biphosphatase
What are the two equations for the bypass of step 10 of glycolysis in gluconeogenesis?
What enzymes catalyse these reactions?
1.
Pyruvate + CO2 + ATP + H2O —> Oxaloacetate + ADP + Pi + 2H+
Pyruvate carboxylase
2.
Oxaloacetate + GTP + 2H+ —> Phosphoenolpyruvate + GDP + CO2
Phosphoenolpyruvate carboxykinase (PEPCK)
How are products of amino acids that are also intermediates of the TCA cycle utilised by gluconeogenesis?
Oxaloacetate is featured in the TCA cycle and in gluconeogenesis, so the intermediates are converted to oxaloacetate so they can be utilised.
How is gluconeogenesis regulated and what are the major targets of control?
Hormonal control
PEPCK and Fructose-1,6-biphosphatase
How is PEPCK activity controlled?
Increased - Glucagon, Cortisol
Decreased - Insulin
How is Fructose-1,6-biphosphatase activity controlled?
Increased - Glucagon
Decreased Insulin
In diabetics what is the significance of gluconeogenesis control?
Inadequate levels of insulin allow excess gluconeogenesis to occur which contributes heavily to hyperglycaemia
How are TAGs stored and what controls storage?
Note: what promotes and depletes stores?
Anhydrous form in adipocytes
Controlled hormonally
Storage promoted by insulin
Storage depletion activated by glucagon, cortisol, adrenaline, growth hormone and thyroxine
How are TAGs produced in the gut delivered to adipose tissue?
In the blood stream transported in chylomicrons
Describe the process of Beta-Oxidation of fatty acids.
Hint: What happens to the fatty acids? What’s required?
Cycled sequence of reactions oxidises and removes C2 units (acetate) from FAs continuously until only 2 remain
Requires NAD+ and FAD
Cannot occur without oxygen (needed to oxidise NADH and FAD2H formed)
No direct ATP synthesis
All C2 units linked to CoA to form AcetylCoA
Where does Lipogenesis occur?
The cytoplasm
Give the equation for the formation of a 16 carbon fatty acid
8 AcetylCoA + 7 ATP + 14 NADPH + 6 H+ —> Fatty acid (C16) + 14 NADP+ + 8CoA + 7 ADP + 7 Pi + 6 H2O
How are most steps of lipogenesis catalysed?
Multi enzyme complex known as fatty acid synthase complex
Describe how Fatty acids are built up during lipogenesis
Built up from C2 units donated from AcetylCoA
Is lipogenesis a reverse of fatty acid degradation? Explain
Nope, units added in the form of MalonylCoA (C3) with subsequent loss of CO2
How is malonylCoA produced?
Give an equation and the enzyme that catalyses the reaction
Produced from AcetylCoA
AcetylCoA + CO2 + ATP —> MalonylCoA + ADP + Pi
AcetlyCoA carboxylase
Explain the importance of AcetylCoA carboxylase and explain how it is regulated
Plays important role in controlling rate of lipogenesis
Allosterically controlled (AMP inhibits / citrate activates)
Covalent modification (reversible phosphorylation)
Insulin activates by promoting dephosphorylation
Glucagon and adrenaline inhibit by promoting phosphorylation
In what stage of catabolism are amino acids first broken down?
Stage 2
Why is amino acid catabolism such a diverse process?
All amino acids have their own unique catabolic pathway
What factor is common to all amino acid catabolic pathways?
Initial deamination (-NH2 released and converted to urea)
What are some common products of amino acid deamination (C-skeleton products)
Pyruvate
Oxaloacetate
Succinate
Fumarate
Acetyl-CoA
Alpha-ketoglutarate
What are ketogenic amino acids?
Amino acids (eg. leucine, lysine) that produce AcetlyCoA when catabolised that can be used in the synthesis of ketone bodies
What are glucogenic amino acids?
Amino acids that don’t produce AcetylCoA when metabolised and the products are used in gluconeogenesis
What amino acids are ketogenic and glucogenic?
isoleucine, threonine, phenylalanine
What is transamination?
Transfer of an amino acids NH2 group to a keto acid
What is the most common keto acid and what is it converted to during transamination?
alpha-ketoglutarate converted to glutamate
What is the enzyme responsible for transamination of alanine?
Give a reaction equation for this process
Hint: The enzyme has two names
Alanine transaminase (ALT)
aka glutamate-pyruvate transaminase
Alanine + alpha-ketoglutarate —-> pyruvate + glutarate
What is the enzyme responsible for transamination of Aspartate?
Give a reaction equation for this process
Hint: The enzyme has two names
Aspartate transaminase (AST)
aka glutamate-oxaloacetate transaminase
Aspartate + alpha-ketoglutarate —> glutamate + oxaloacetate
What apart from alpha-ketoglutarate can be used as a keto acid and what is it converted into?
oxaloacetate converted to aspartate
What stimulates transaminase synthesis and where are they synthesised?
Cortisol
Liver
What is deamination?
Removal of NH2 group from amino acids to form ammonia (which is converted to ammonium)
What enzymes are responsible for deamination?
What can be said about their specificity?
L and D amino acid oxidases
Low specificity
Why are D amino acid oxidases important and where are they found in high concentration?
Important to convert D-amino acids to keto acids (not optically active)
This is important as D-amino acids (found in plant and bacterial cells) must not be used in protein synthesis as the proteins would be structurally abnormal and non functional
What is the enzyme that deaminates glutamine and what is the product of the reaction?
Glutaminase
Glutamate + NH3
Give the equation for the breakdown of glutamate into a keto acid.
Give the enzyme that catalyses this reaction
Glutamate + H2O + NAD+ —-> alpha-ketoglutarate + NH4+ + NADH + H+
Glutamate dehydrogenase
What is Phenylketonuria?
Inherited disorder resulting in large amounts of phenylketones in the urine
What is the metabolic basis for Phenylketonuria?
Phenylalanine is normally oxidised to tyrosine by phenylalanine hydroxylase, In PKU cases this enzyme is defective, causing buildup of phenylalanine.
Phenylalanine is metabolised via other pathways to form phenylpyruvate which is excreted in urine
How is Phenylketonuria diagnosed?
Detection of phenylketones in urine or high phenylalanine blood concentration (>0.1mM)
How is Phenylketonuria treated and what are the consequences of not treating it?
Treated with diet low in phenylalanine
Left untreated it can inhibit brain development
What is the cause of homocystinuria?
Rare autosomal recessive defect in methionine metabolism
What is the metabolic basis of homocystinuria?
Cystathionine beta-synthase deficiency
This enzyme normally metabolises homocysteine into cystathionine (which is further converted to cysteine).
Deficiency causes elevated levels of homocyteine and methionine in plasma and homocysteine in the urine
What are the physiological effects of Homocystinuria?
Chronic elevated levels of homocyteine cause disorders of connective tissue, muscle, CNS and cardiovasular system
Why is homocystinuria easily misdiagnosed in childhood?
Symptoms are similar to Marfan’s syndrome’s symptoms
What is the clinical relevance of measuring creatinine concentration in the blood and urine?
Amount of creatinine excretion in 24hr in the urine is proportional to muscle mass
How and when is creatinine produced?
Spontaneous reaction in muscles all the time at constant rate, increases during muscle wasting and high protein diet
In what form is ammonia normally present in the body and where does the ammonia come from?
98.5% of ammonia in ammonium ion form
Produced by many tissues and absorbed from the gut
What is hyperammonaemia associated with and what tissues are particularly sensitive to it? Explain
Hyperammonaemia seen in liver disease
Associated with blurred vision, tremors, slurred speech coma and eventually death.
Also affects pH in cells of CNS and interferes with neurotransmitter synthesis/release
CNS sensitive to hyperammonaemia due to disruption of TCA cycle which CNS relies on more heavily than other cells
Why is ammonia toxic to the body?
Reacts with alpha-ketoglutarate to form glutamate in mitochondria which removes alpha-ketoglutarate from the TCA cycle and disrupts energy supply
How is ammonia detoxified?
Conversion to N-compounds such as glutamine or conversion to urea
Can ammonia be excreted in urine?
Yup
Give an equation for glutamine synthesis from ammonium and the enzyme required
NH4+ + glutamate + ATP ——> Glutamine + ADP + Pi
Glutamine synthetase
What happens to glutamine in the liver an kidneys? Why?
Give an equation and any enzymes required
Glutamine —> Glutamate + NH4+
Glutaminase
Ammonium then excreted in kidneys
Converted to urea in liver
Why is urea a good way of disposing of nitrogen?
Non-toxic
metabolically inert
water soluble
high nitrogen content (47%)
Where does urea synthesis occur and what is the name of the enzyme pathway responsible?
After urea synthesis, what happens to it?
Synthesis in liver via the urea cycle
Transported to kidneys for excretion
Give the full equation for conversion of NH4+ into urea
NH4+ + HCO3- + Aspartate + 3 ATP —> Urea + Fumarate + 2ADP + AMP + 4Pi
How is the Urea cycle regulated?
Enzymes are inducible Induced by high protein diet
Suppressed by low protein/starvation
When treating starvation/low protein diet why is it important to reintroduce food gradually?
Starvation has suppressed enzymes of the urea cycle and so lots of protein in the diet all of a sudden will result in hyperammonaemia as ammonia is not metabolised fast enough
With inherited disorders of the urea cycle what are the two effects all disorders have?
Hyperammonaemia
Accumulation or excretion of urea cycle intermediates
What are the symptoms of defects in the urea cycle and what does their severity depend on?
Depends on severity of defect and how much protein eaten
Vomiting, lethargy, irritability and generally includes mental retardation
Severe cases may include seizures, coma and eventual death.
How are defects in the urea cycle managed?
Low protein diet
Replacing essential amino acids in diet with keto acids that use up NH4+ when converted to amino acids
How does hyperammonaemia arise as a consequence of liver disease such as cirrhosis?
Livers ability to remove ammonia from portal blood is impaired
During excretion of urea from the kidneys how is urea lost from the blood stream if not from filtration in the kidney?
How is this reabsorbed?
Diffuses across the intestinal wall and is broken down by gut bacteria into ammonia to be reabsorbed
How does kidney failure affect ammonia concentration in the blood?
Gut bacteria produce ammonia which is absorbed into the blood stream and cannot be metabolised, contributing to hyperammonaemia
