Flashcards in Protein and Amino Acid Metabolism Deck (172):
Give 8 nitrogen containing compounds in the body?
Amino acids, Proteins, Purines, Pyrimidines, Porphyrins (haem), Creatine, Neurotransmitters (e.g. dopamines, Some hormones (e.g. adrenaline)
What is creatinine?
Breakdown product of creatine and creatine phosphate
What can creatinine be used as?
A useful clinical marker
Where is creatinine produced?
What can creatine phosphate be used as?
A very short term energy supply of ATP in skeletal muscle
At what rate is creatinine usually produced?
Constant rate depending on muscle mass
How is creatinine excreted?
Filtered via kidneys into urine
What is creatinine excretion over a 24 hour period proportional to?
What is the result of creatinine excretion over 24hrs being proportional to muscle mass?
It can provide an estimate for muscle mass
What is creatinine commonly used as an indicator for?
What do raised creatinine levels indicate regarding kidney function?
Why can’t we use a urine volume to determine nephron damage?
Because would vary depending on urine dilution
When is the body said to be in N equilibrium?
When intake = output
What is happening to body protein in N equilibrium?
No change in total body protein
When is N equilibrium normal?
What is happening in positive N balance?
Intake > output
What happens to body protein in positive N balance?
Increase in total body protein
When is positive N balance the normal state?
In pregnancy, growth or an adult recovering from malnutrition
What is negative N balance?
What happens to body protein in negative N balance?
Net loss of body protein
When is negative N balance normal?
Give 3 causes of negative N balance
Describe the nitrogen balance in a 70kg male
- 16g N in from dietary nitrogen
- 16g N in amino acid pool
- 2g N lost in skin, hair and nails
- 14g N lost in N-waste products
Where does the N in the amino acid pool go?
N-containing compounds, and cycled round to and from body protein
How much is there of N-containing compounds in the body of a 70kg male?
How much of body protein is there in the body of a 70kg male?
What are the N-waste products?
What is given when dietary protein is digested?
Free amino acids
Other than dietary protein digestion, how can free amino acids be produced?
By de novo amino acid synthesis
What are free amino acids in cycle with?
Cellular proteins in muscle
What happens in the cycle between free amino acids and cellular proteins in muscle?
Free amino acids are made into cellular proteins in synthesis, and cellular proteins are made into free amino acids in proteolysis
What happens to free amino acids in emergency situations?
They are split into their carbon skeleton and amino group in the liver
What happens to the amino group produced when free amino acids are split in emergency situations?
It is converted into urea, and excreted in urine
What happens to the carbon skeleton produced when free amino acids are split in emergency situations?
- Glucogenic amino acids undergo gluconeogenesis
- Ketogenic amino acids are converted to ketone bodies
What is a glucogenic amino acid?
One that can be converted to glucose by gluconeogenesis
Give 2 glucogenic amino acids
What is a ketogenic amino acid?
One that can be converted into ketone bodies
Give 2 ketogenic amino acids
Give 2 amino acids that are both glucogenic and ketogenic
What does wether an amino acid is glucogenic or ketogenic depend on?
The side chain
What can protein be mobilised to produce?
Why is protein mobilised to produce glucose?
To meet the need for glucose of some tissues
When does mobilisation of protein reserves occur?
During extreme stress, including starvation
How is mobilisation of protein reserves controlled?
Which hormones control the mobilisation of protein reserves?
- Growth hormone
- Glucocorticoids (e.g. cortisol)
What is the effect of insulin and growth hormone on protein?
What effect do glucocorticoids have on protein?
- Decrease protein synthesis
- Increase protein degradation
When can excessive breakdown of protein occur?
What is Cushing’s syndrome caused by?
What is the result of the excessive breakdown of protein in Cushing’s syndrome?
It weakens the skin structure, leading to striae formation
How many different types of R groups are there in amino acids?
What does an amino acids R group determine?
What type of amino acid it is
How do amino acids link together?
Through the formation of peptide bonds
How can amino acids be obtained other than dietary intake?
The body can synthesise some amino acids that it requires
Where do the carbon atoms for non-essential amino acids come from?
- Intermediates of glycolysis (C3)
- Pentose phosphate pathway (C4 & C5)
- Krebs cycle (C4 & C5)
Where does the amino group for non-essential amino acids come from?
What are amino acids required for?
Synthesis of other important compounds
Give 3 things tyrosine is important for the synthesis of
- Thyroid hormones
What is histidine important for the synthesis of?
What is arginine important in the synthesis of?
What is nitric oxide important for?
Give 2 things cysteine is important for the synthesis of?
- Hydrogen sulphide
What is hydrogen sulphide important for?
What is serine important in the synthesis of?
Give 3 things tryptophan is important in the synthesis of?
Give 4 things glycine is important in the synthesis of
Why is the ability to remove nitrogen from amino acids essential?
To allow the carbon skeleton of amino acids to be utilised in oxidative metabolism
What can happen to nitrogen from amino acids once removed?
It can be incorporated into other components or excreted from the body as urea
What are the two main pathways that facilitate the removal of nitrogen from amino acids?
What enzyme is required for transamination?
What does aminotransferase do?
Transfers the amino group from amino acid to the keto acid α-ketoglutarate
What is the result of the action of aminotransferase?
The amino acid is converted to a keto acid, and the keto acid α-ketoglutarate is converted to glutamate
What is the alternative to using the keto acid α-ketogluatarate for transamination?
Using the keto acid oxaloacetate
What enzyme is required when using the keto acid oxaloacetate for transamination?
What does aspartate aminotransferase do?
Converts the amino acid to a keto acid, and oxaloacetate to aspartate
What do all amino transferases require?
The coenzyme pyridoxal phosphate
What is pyridoxal phosphate a derivative of?
What are the key aminotransferase enzymes?
- Alanine aminotransferase (ALT)
- Aspartate aminotransferase (AST)
What amino acid conversion does alanine aminotransferase catalyse?
Alanine to glutamate
What amino acid conversion does aspartate aminotransferase catalyse?
Glutamate to aspartate
What is routinely measured as part of a liver function test?
Plasma ALT and AST levels
What do the results of the plasma ALT and AST levels mean?
Aren’t normally present in plasma, so if found, bad
Where will plasma ALT and AST increase?
In conditions causing extensive cellular necrosis
Give 3 conditions that may cause extreme cellular necrosis
- Viral hepatitis
- Autoimmune liver disease
- Toxic injury
What does deamination do?
Liberates amin group as free ammonia
Where does deamination mainly occur?
In the liver and kidney
What is deamination important for?
- Utilisation of keto acids for energy
- Deamination of dietary D-amino acids
Where are dietary D-amino acids found?
What is the problem with ammonia?
It’s very toxic
What must be done to ammonia in the body?
Must be removed
How is ammonia removed?
What happens to ammonia at physiological pH?
It is rapidly converted to ammonium ion
Give 3 enzymes that can deaminate amino acids
- Amino acid oxidases
- Glutamate dehydrogenase
Does urea have a high or low nitrogen content?
Is urea toxic?
Is urea hydrophilic or hydrophobic?
What is the advantage of urea being very hydrophilic?
It is very water soluble, so can easily excrete in urine
Is urea chemically reactive or inert?
How can urea be broken down?
What is released when bacteria break down urea?
How is most urea excreted?
In urine via kidneys
What important role does urea perform in kidney tubules?
Where does the urea cycle occur?
In the liver
How many enzymes does the urea cycle involve?
What is the amount of urea normally related to?
Need to dispose of urea
Is amount of urea under direct control?
No, just governed by amount of substrate
What induces high urea cycle enzyme levels?
A high protein diet
What represses urea cycle protein levels?
- Low protein diet
Is the urea cycle regulated?
No, but can be induced
When can re-feeding syndrome occur?
When nutritional support is given to severely malnourished patients
What causes re-feeding syndrome?
Why does ammonia toxicity occur when re-feeding malnourished patients?
Because the urea cycle has been down regulated, so the body can’t cope with the amount of ammonia being produced
How is re-feeding syndrome prevented?
By re-feeding at 5 to 10 kcal per kg per day, raising gradually to full needs within a week
What are the risk factors for re-feeding syndrome?
- BMI 15% in 3-6 months
- ~17 days with little/no nutritional intake
What causes defects in the urea cycle?
Autosomal recessive genetic disorders
What defects occur in the urea cycle?
Deficiency in one of the enzymes in the urea cycle
How often to defects in the urea cycle occur?
~1 in 30,000 live births
What do mutations in enzymes involved in the urea cycle cause?
Partial loss of enzyme function
Why are defects in the urea cycle only partial losses of enzyme function?
Complete loss would be incompatible with life, and the foetus would die
What do defects in the urea cycle lead to?
- Accumulation/excretion of urea cycle intermediates
What is hyperammonemia?
Too much ammonia in the blood
What does the severity of defects in the urea cycle depend on?
- Nature of defect
- Amount of protein eaten
How quickly do severe urea cycle disorders show symptoms?
Within 1 day of birth
What happens if severe urea cycle defects are left untreated?
The patient will die
What can be the case with mild urea cycle deficiencies?
Symptoms don’t show until early childhood
What are the symptoms of urea cycle deficiencies
- Mental retardation
How are urea cycle disorders managed?
- Low protein diet
- Replace amino acids in diet with keto acids
What is the biochemical basic of ammonia toxicity?
It is readily diffusible, so can easily access through the blood brain barrier, and is highly toxic to the brain
At what levels must blood levels of ammonia be kept?
Very low- 25-50µmol/L
What are the potential effects of too much ammonia?
- Interfere with amino acid transport and protein synthesis
- Disruption of cerebral blood flow
- Alkalisation of blood
- Interfere with metabolism of excitatory amino acid neurotransmitters
- Alteration of blood-brain barrier
- Interfere with TCA cycle
Why can excess ammonia interfere with the TCA cycle?
It can react with α-ketoglutarate to form glutamate
What are the two mechanisms for the safe transport of ammonia from tissues for disposal?
How does the glutamine mechanism of safe ammonia transport work?
- Ammonia combined with glutamate to form glutamine
- Glutamine transported in blood to liver or kidneys, where it is cleaved by glutaminase to reform glutamate and ammonia
- In the liver, ammonia is fed into the urea cycle.
- In the kidney, ammonia is excreted directly into urine
How does the alanine mechanism of safe ammonia transport work?
- Alanine formed in peripheral tissues by transamination of pyruvate- essentially, pyruvate is combined with ammonia to form alanine
- Alanine is transported in blood to the liver
- In the liver, it is converted back to pyruvate by transamination
- Amino group is fed via glutamate into urea cycle for disposal as urea, and pyruvate is used to synthesise glucose
How many inherited diseases involving defects in amino acid metabolism are there?
What causes defects in amino acid metabolism?
Either total, or more commonly partial, loss of enzyme activity
What can happen is problems in amino acid metabolism are left untreated?
They frequently lead to intellectual impairment
What does treatment of defects in amino acid metabolism involve?
Restricting specific amino acids in the diet
What is the heel prick test?
A test that every child in western countries receives to systematically screen for diseases
What diseases are tested for with the heel prick test?
- Sickle cell disease
- Cystic fibrosis
- Congenital hyperthyroidism
- Inborn errors in metabolism
What inborn errors in metabolism are tested for using the heel prick test?
- Maple syrup urine disease
- Isovaleric acidaemia
- Glutaric aciduria
Why are the diseases in the heel prick test tested for?
Because something, often dietary modification, can be done about them, but if not done as soon as possible, can lead to the development of things such as mental retardation
What is the most common inborn error of amino acid metabolism?
What causes PKU?
Deficiency in phenylalanine hydroxylase
What is the inheritance pattern of PKU?
Where is the affected gene in PKU?
What is the result of the lack of phenylalanine hydroxylase?
Accumulation of phenylalanine in tissue, plasma and urine
How can PKU be detected?
Phenyl ketones in urine and musty smell
What is the treatment for PKU?
What high protein foods should be avoided in PKU
What are the symptoms of PKU?
- Severe intellectual disability
- Developmental delay
- Microcephaly (small head)
How can the symptoms of PKU be avoided?
What causes the symptoms of PKU?
Not producing enough tyrosine
Why is not enough tyrosine produced in PKU?
No phenylalanine hydroxylase, so phenylalanine not converted to tyrosine
What pathways are affected by lack of tyrosine?
What builds up in the blood in PKU?
Where does the phenylalanine come from?
Dietary protein and endogenous protein
What does the build up of phenylalanine in the blood lead to?
Accumulation of phenylketones
Why does build up of phenylalanine in the blood lead to accumulation of phenylketones?
Because phenylalanine is converted to phenylpyruvate by transamination, which is then converted into phenylacetate and phenyllactate
What causes homocystinurias?
Problems breaking down methionine
What is the result of problems breaking down methionine?
Excess homocystine excreted in urine
What is homocystine?
2 homocysteines linked together by a disulphide bond- the oxidised fomr of homocysteine
What is the inheritance pattern of homocystinurias?
What defect causes homocystinurias?
What cystathionine defect is most common?
What do homocystinurias affect?
What is the treatment for homocystinurias?
- Low methionine diet
- Avoid meat, milk, fish, cheese, nuts and eggs
- Cysteine, Vit B 6 , betaine, B 12 , and folate supplements
What accumulates in homocystinurias?
Methionine and homocysteine
Why does methionine and homocysteine accumulate in homocystinurias?
No cystathionine ß-synthase, so homocysteine not converted to cystathionine. Because homocysteine not removed, methionine also accumulates because they interconvert into each other
What is the result of the lack of conversion into cystathionine in homocystinurias?
There is a consequent lack of cysteine, which comes from cystathionine
What is the homocysteine to methionine conversion promoted by?
- B 12