S3) Protein & Amino Acid Metabolism Flashcards
Identify three major nitrogen containing compounds
- Amino acids
- Proteins
- Purines + Pyrimidines (DNA / RNA)
Identify three minor nitrogen containing compounds
- Creatine
- Neurotransmitters e.g. dopamine
- Some hormones e.g. adrenaline
What is creatinine?
Creatinine is a breakdown product of creatine & creatine phosphate in muscle
Explain how creatinine can be used a clinical marker for renal function
- Produced at constant rate and filtered via kidneys into urine
- Creatinine urine excretion over 24h is proportional to muscle mass
- Provides estimate of muscle mass
What is nitrogen balance?
Nitrogen balance is the measure of nitrogen input minus nitrogen output i.e. nitrogen input — nitrogen loss
Which three concepts revolve around nitrogen balance?
- Nitrogen equilibrium
- Positive nitrogen balance
- Negative nitrogen balance
What are the clinical features of nitrogen equilibrium?
- Intake = output
- No change in total body protein
- Normal state in adult
What are the clinical features of a positive nitrogen balance?
- Intake > output
- Increase in total body protein
- Normal state in growth, pregnancy or adult recovering from malnutrition
What are the clinical features of a negative nitrogen balance?
- Intake < output
- Net loss of body protein
- Never normal (trauma, infection, malnutrition)
What is protein turnover?
Protein turnover is the balance between protein synthesis and protein degradation
Illustrate the pathways involved in protein turnover
Provide an example of the following:
- Glucogenic amino acid
- Ketogenic amino acid
- Both ketogenic and glucogenic amino acid
- Glucogenic amino acid: alanine
- Ketogenic amino acid: leucine
- Both ketogenic and glucogenic amino acid: isoleucine
When are protein stores mobilised?
Occurs under extreme stress (starvation)
Describe the hormonal control over the mobilisation of protein reserves
In de novo amino acid synthesis, where do the carbon atoms come from?
- Intermediates of glycolysis (C3)
- Pentose phosphate pathway (C4 & C5)
- Krebs cycle (C4 & C5)
In the de novo amino acid synthesis, where does the amino group come from?
Amino group provided by other amino acids by the process of transamination or from ammonia
Which compounds are synthesised from tyrosine?
- Catecholamines
- Melanin
- Thyroid hormones
Which compound is synthesised from histidine?
Histamine
Which compound is synthesised from arginine?
Nitric oxide
Which compound is synthesised from cysteine?
Glutathione
Which compounds are synthesised from tryptophan?
- Serotonin (5HT)
- Melatonin
Which molecules are synthesised from glycine?
- Purines
- Glutathione
- Haem
- Creatine
Why does nitrogen have to be removed from amino acids in protein metabolism?
- Essential to allow carbon skeleton of amino acids to be utilised in oxidative metabolism
- Once removed nitrogen can be incorporated into other compounds or excreted from body as urea
What are the two main pathways that facilitate removal of nitrogen from amino acids?
- Transamination
- Deamination
Explain the process of transamination
- Most aminotransferase enzymes use a-ketoglutarate to funnel the amino group to glutamate
- Exception to rule is aspartate aminotransferase which uses oxaloacetate to funnel amino group to aspartate
Which aminotransferase enzymes are measured routinely as part of liver function test?
- Alanine aminotransferase (ALT) which converts alanine to glutamate
- Aspartate aminotransferase (AST) which converts glutamate to aspartate
High plasma AST and ALT levels are associated with which conditions?
- Viral hepatitis
- Autoimmune liver diseases
- Toxic injury
Explain the process of deamination
- Liberates amino group as free ammonia
- Mainly occurs in liver & kidney
- Keto acids can be utilised for energy
Several enzymes can deaminate amino acids.
Identify three
- Amino acid oxidases
- Glutaminase
- Glutamate dehydrogenase
What happens to ammonia at physiological pH?
At physiological pH, ammonia (NH3) is rapidly converted to ammonium ion (NH4+)
Ammonia (and ammonium ions) are very toxic and must be removed.
How does this occur?
Ultimately converted to urea or excreted directly in urine
Describe four properties of urea
- High nitrogen content
- Non-toxic
- Extremely water soluble
- Chemically inert in humans
What is the urea cycle?
- The urea cycle is a process occurring in liver and involves 5 enzymes
- It is used to dispose of ammonia
Explain how the amount of urea cycle enzymes normally related to need to dispose of ammonia
- High protein diet induces enzyme levels (up-regulation)
- Low protein diet or starvation represses enzyme levels (down-regulation)
What is refeeding syndrome?
- Refeeding syndrome is a condition which can occur when nutritional support given to severely malnourished patients
- Ammonia toxicity significant factor (urea cycle down regulated)
What are the risk factors for refeeding syndrome?
- BMI < 16
- Unintentional weight loss > 15% in 3-6 months
- 10/more days with little or no nutritional intake
What are the effects of autosomal recessive genetic disorders caused by deficiency of one of enzymes in the urea cycle?
- Hyperammonaemia
- Accumulation/excretion of urea cycle intermediates
What does the severity of defects in the urea cycle depend on?
- Nature of defect
- Amount of protein eaten
What are the symptoms of genetic disorders due to defects in the urea cycle?
- Vomiting
- Lethargy
- Irritability
- Mental retardation
- Seizures
What is the management for autosomal recessive disorders due to defects in the urea cycle?
- Low protein diet
- Replace amino acids in diet with keto acids
What is the biochemical basis for ammonia toxicity?
- Ammonia is readily diffusible and extremely toxic to brain
- Blood level needs to be kept low (25-40 µmol/L)
Identify 5 toxic effects of ammonia
- Interference with amino acid transport and protein synthesis
- Disruption of cerebral blood flow
- pH effects (alkaline)
- Interference with metabolism of excitatory amino acid neurotransmitters e.g. glutamate and aspartate
- Alteration of the blood–brain barrier
Two mechanisms are utilised for the safe removal of ammonia from tissues for disposal.
In 4 steps, outline the use of glutamine
⇒ Ammonia combines with glutamate to form glutamine
⇒ Glutamine transported in blood to liver /kidneys
⇒ Cleavage by glutaminase to reform glutamate and ammonia
⇒ Ammonia fed into urea cycle (liver) / excreted directly in urine (kidneys)
Two mechanisms are utilised for the safe removal of ammonia from tissues for disposal.
In 5 steps, outline the use of alanine
⇒ Ammonia combines with pyruvate to form alanine
⇒ Alanine transported in blood to liver
⇒ Conversion to pyruvate by transamination
⇒ Amino group fed via glutamate into urea cycle for disposal as urea
⇒ Pyruvate is used to synthesise glucose
Identify 5 clinical conditions which can utilise the heel prick test
- Sickle cell disease
- Cystic fibrosis
- Congenital hypothyroidism
- Phenylketonuria (PKU)
- Homocystinuria
What is phenylketonuria?
- PKU is the common inborn error of amino acid metabolism due to an autosomal recessive deficiency in phenylalanine hydroxylase
- Phenylalanine accumulates in the tissue, plasma & urine, hence presenting with phenylketones in urine (musty smell)
Outline the treatment of phenylketonuria
- Strictly controlled low phenylalanine diet
- Avoid artificial sweeteners (contain phenylalanine)
- Avoid high protein foods such as meat, milk, and eggs
Identify 5 symptoms of PKU
- Severe intellectual disability
- Developmental delay
- Microcephaly (small head)
- Seizures
- Hypopigmentation
Illustrate the affected pathways in PKU
What is homocystinuria?
- Homocystinuria is an autosomal recessive disorder, commonly due to a defect in cystathionine β-synthase, leading to an inability in breaking down methionine
- Excess homocystine (oxidised form of homocysteine) is excreted in urine
Which tissues/systems are affected in homocystinuria?
- Connective tissue
- Muscles
- CNS
- CVS
Outline the treatment of homocystinuria
- Low-methionine diet
- Avoid: milk, meat, fish, cheese, eggs and nuts
- Supplements: cysteine, Vit B6, Betaine, B12 & Folate
Illustrate the affected pathways in homocystinuria
