Lecture 5.1: Amino Acid/ Protein Metabolism Flashcards
The 9 Essential Amino Acids
If : Isoleucine
Learned: Lysine
This: Threonine
Huge: Histidine
List: Leucine
May: Methionine
Prove: Phenylalanine
Truly: Tryptophan
Valuable: Valine
Where do amino acids come from?
Essential AAs come from diet
In addition to this, non-essential AAs can be synthesised by the body
Where do carbon atoms for amino acid synthesis come from? (3)
• Intermediates of glycolysis (C3)
• Pentose phosphate pathway (C4 and C5)
• Krebs cycle (C4 and C5)
What is transamination?
Amino group provided by other amino acids by the process of transamination or from ammonia
What compounds require Tyrosine for synthesis?
• Catecholamines
• Melanin
• Thyroid hormones
What compounds require Cysteine for synthesis?
• Hydrogen sulphide (signalling molecule)
• Glutathione
What compounds require Tryptophan for synthesis?
• Nicotinamide
• Serotonin (5HT)
• Melatonin
What compounds require Histidine for synthesis?
• Histamine
What compounds require Glutamate for synthesis?
• GABA
What compounds require Glycine for synthesis?
• Purines
• Glutathione
• Haem
• Creatine
What compounds require Arginine for synthesis?
• Nitric oxide
What compounds require Serine for synthesis?
• Sphingosine
Nitrogen Containing Compounds: Major
• Proteins
• Amino acids
• Purines + Pyrimidines (DNA /RNA)
Nitrogen Containing Compounds: Minor
• Porphyrins (haem)
• Creatine
• Neurotransmitters (e.g. dopamine)
• Some hormones (e.g. adrenaline)
Nitrogen Balance: Zero N balance
(N equilibrium)
Intake = output
No change in total body protein
Normal state in adult
Nitrogen Balance: Positive N balance
Intake > output
Increase in total body protein
Normal state during growth and pregnancy
Or in adult recovering from malnutrition.
Nitrogen Balance: Negative N balance
Intake < output
Net loss of body protein
Never normal
Causes include trauma, illness, burns or malnutrition
Creatinine
• A useful clinical marker
• Breakdown product of creatine and creatine phosphate in muscle
• Produced at constant rate depending on muscle mass
• Creatinine urine excretion over 24h proportional to muscle mass
• Also commonly used as indicator of renal function (↑ in blood → damage to nephrons)
Creatinine: Excreted in urine per day (M/F)
• Men 14-26 mg/kg
• Women 11-20 mg/kg
When does mobilisation of protein reserves occur?
Occurs during extreme stress (starvation)
Under hormonal control
Mobilisation of Protein Reserves: Insulin and Growth Hormone
Effect on protein synthesis: Increases
Effect on protein degradation: Decreases
Mobilisation of Protein Reserves: Glucocorticoids (e.g. cortisol)
Effect on protein synthesis: Decreases
Effect on protein degradation: Increases
Cushing’s Syndrome
Excessive breakdown of protein
Excess cortisol
Weakens skin structure leading to striae formation
Why is removal of Nitrogen from Amino Acids important?
Removal of NH2 is essential →allows carbon skeleton of amino acids to be used in oxidative metabolism
Removed N can be incorporated into other compounds or excreted from body as urea
Pathways of Removal of Nitrogen from Amino Acids (2)
Two main pathways facilitate removal of N from amino acids:
• Transamination: switches NH2 from an amino acid to a ketoacid creating a
new amino acid
• Deamination: removes ammonia (NH3)
Transamination (4)
The NH2 group from one amino acid is transferred to α-ketoglutarate, which becomes glutamate
Most aminotransferases use α-ketoglutarate to funnel the amino group to glutamate
Keto acid is produced from the initial amino acid
Aminotransferases require the coenzyme pyridoxal phosphate, a derivative of vitamin B6
Aminotransferases
They are Important Diagnostic Markers
Plasma ALT and AST levels measured routinely as part of liver function test
Levels particularly high in conditions that cause extensive cellular necrosis
such as:
• Viral hepatitis
• Autoimmune LiverDiseases
• Toxic injury
Aminotransferases: Alanine aminotransferase (ALT)
Converts alanine to glutamate
Aminotransferases: Aspartate aminotransferase (AST)
Converts aspartate to glutamate
Deamination
Releases NH2 as free ammonia
Also important in deamination of dietary D-amino acids
Converted to urea or excreted directly in urine
Keto acids can be utilised for energy
At physiological pH, ammonia (NH3) is rapidly converted to ammonium 4 ion (NH +)
Which enzymes can deaminate amino acids?
• Amino acid oxidases
• Glutaminase
• Glutamate dehydrogenase
Where does Deamination occur? Why is it important?
Mainly occurs in liver and kidney
Ammonia (and ammonium ions*) is very toxic and must be removed
Biochemical Basis of Ammonia Toxicity
Readily diffusible and extremely toxic to brain
Blood level needs to kept low (25 – 40 μmol/l)
Several potential toxic effects
Several potential toxic effects of Ammonia Toxicity
• Interference with amino acid transport and proteinsynthesis
• pH effects(alkaline)
• Interference with TCA cycle (reacts with α-ketoglutarate toform glutamate)
• Alteration of the blood–brainbarrier
• Disruption of cerebral blood flow
• Interference with metabolism of excitatory amino acid neurotransmitters (e.g.
glutamate andaspartate)
Urea
• High N content
• Non-toxic
• Extremely water soluble
• Chemically inert in humans (bacteria can break it down to release NH3)
Urea: where made? where removed? function?
• Synthesised in liver by the urea cycle
• Most urea is excreted in urine via the kidneys
• Also performs useful osmotic role in kidney tubules
Urea Cycle: where + overview
Occurs in liver and involves 5 enzymes
Amount of urea cycle enzymes normally related to need to dispose of ammonia as urea
Urea Cycle: Regulation
Cycle is inducible but not regulated:
• High protein diet induces enzymes
• Low protein diet or starvation represses enzymes
Re-feeding Syndrome
Can occur when nutritional support given to severely malnourished patients
Ammonia toxicity significant factor (urea cycle down regulated)
Re-feed at 5 to 10 kcal/kg/day
Raise gradually to full needs within a week
Defects in the Urea Cycle
Autosomal recessive disorders caused by deficiency of one of enzymes in the urea cycle
Mutations cause a partial loss of enzyme function
Defects in the Urea Cycle: Effects
Leads to:
• hyperammonaemia
• accumulation/excretion of urea cycle intermediates
Ornithine Transcarbamylase (OCT) Deficiency
Severity depends on:
• nature of defect
• amount of protein eaten
Severe urea cycle disorders symptoms within 1 day of birth, if untreated child will die
Mild urea cycle enzyme deficiencies may not show symptoms until early childhood
Ornithine Transcarbamylase (OCT) Deficiency: Symptoms
• Vomiting
• Lethargy
• Irritability
• Mental retardation
• Seizures
• Coma
Ornithine Transcarbamylase (OCT) Deficiency: Management
• Low protein diet
• Replace amino acids in diet with keto acids
Amino Acid Metabolism Disorders
• Either total or more commonly partial loss of enzyme activity
• If untreated, frequently lead to intellectual impairment
• Treatment involves restricting the amount of specific amino acids in diet
Phenylketonuria (PKU): What is it?
• Most common inborn error of amino acid metabolism
• Deficiency in phenylalanine hydroxylase (PAH)
• Autosomal recessive (chromosome 12)
• Accumulation of phenylalanine in tissue, plasma and urine
• Phenylketones in urine
• Phenylketones oxidised to phenylacetate give musty smell
Phenylketonuria (PKU): Treatments
• Strictly controlled low phenylalanine diet plus supplementation with tyrosine
• Avoid artificial sweeteners (contain phenylalanine)
• Avoid high protein foods such as meat, milk, and eggs
Phenylketonuria (PKU): Symptoms
• Severe intellectual disability
• Developmental delay
• Microcephaly (small head)
• Seizures
• Hypopigmentation
Homocystinurias: What is it?
• Defect in cystathionine β-synthase (CBS) is the most common (defect in methionine synthase also possible)
• Autosomal recessive disorders
• Excess homocystine (oxidised form of homocysteine) excreted in urine
• Accumulation of homocysteine and methionine causes disease symptoms
Homocystinurias: Treatments
• Low-methionine diet
• Avoid milk, meat, fish, cheese, eggs
• Nuts, and peanut butter also contain methionine
• Cysteine, vit B6, Betaine, B12 and folate supplements
Homocystinurias: Symptoms
• Disclocation of the lens
• Long limbs and fingers
• Intellectual disability
