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MEH > Protein and amino acid metabolism > Flashcards

Protein and amino acid metabolism Flashcards

1
Q

stage 1 catabolism of protein

A
  • proteases and peptidases hydrolyse peptide bonds to release free amino acids in GI tract
  • amino acids absorbed into circulation and used for synthesis of proteins and various nitrogen-containing compounds (purines, pyrimidines, haem, creatine)
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2
Q

stage 2 catabolism of amino acids

A
  • removal of amino group -NH2
  • converted to urea and excreted from body in urine
  • remaining C-skeletons converted to one or more of following: pyruvate, oxaloacetate, fumarate, α-ketoglutarate, succinate, acetyl Co-A
  • acetyl Co-A enters stage 3 of catabolism - TCA cycle
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3
Q

products at the end of stage 2 catabolism

A
  • glucose, galactose, fructose > pyruvate > acetyl Co-A
  • glycerol > pyruvate > acetyl Co-A
  • fatty acids and ketone bodies > acetyl Co-A
  • amino acids > acetyl Co-A
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4
Q

N compounds in the body

A

total amount of N in 70kg male ~2kg
- 90% major N compounds: amino acids, proteins, purines+pyrimidines (DNA + RNA)
- smaller amounts of porphyrins, creatine phosphate, neurotransmitters, hormones, carnitine

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5
Q

Nitrogen balance (N-balance)

A

amount of N taken into body equals amount of N lost from body

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6
Q

positive N balance

A

intake > output
- increase in total body protein
- normal state in periods of active growth, pregnancy, tissue repair, convalescence

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7
Q

negative N balance

A

intake < output
- net loss of body protein
- never normal
- causes include trauma, infection, starvation, malnutrition

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8
Q

how does nitrogen leave the body

A
  • 85% as urea
  • 5% as creatinine
  • 3% as ammonia
  • uric acid in urine, sweat and faeces
  • direct loss of protein (skin, hair, nails)
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9
Q

mobilisation of protein reserves

A

insulin and growth hormone
- stimulate uptake of amino acids into tissues such as skeletal muscle, adipose tissue and liver and their incorporation into proteins
- decrease protein degradation
glucocorticoids e.g.cortisol
- promoting breakdown of muscle proteins (proteolysis) and release of amino acids
- decrease protein synthesis

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10
Q

protein turnover

A

continuous breakdown and resynthesis of body proteins
- rate depends on protein and varies during growth and ageing
- average half-life of body protein ~80 days
- total protein turnover ~300-400g a day
- rate of protein breakdown normally equals rate of protein resynthesis

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11
Q

what are ketogenic amino acids

A

amino acids that produce acetyl Co-A as they can produce ketone bodies e.g.leucine, lysine

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12
Q

what are glucogenic amino acids

A

amino acids that give rise to products other than acetyl Co-A as they can be used for gluconeogenesis e.g. glycine, alanine

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13
Q

examples of both ketogenic and glucogenic amino acids

A

isoleucine, threonine, phenylalanine, tyrosine, tryptophan

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14
Q

what are conditionally essential amino acids

A
  • need dietary input when demand exceeds ability to synthesise them
  • children and pregnant women need arginine, tyrosine and cysteine in diet
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15
Q

what are essential amino acids

A
  • cannot be synthesised in body so taken in through diet
  • isoleucine, lysine, threonine, histidine, leucine, methionine, phenylalanine, tryptophan, valine
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16
Q

what is the amino acid pool

A
  • total amount of free amino acids in the body (intracellular and extracellular)
  • ~100g in 70kg male
  • normal fasting concentration ~3mmol/L
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17
Q

amino acid reutilisation

A
  • 75% of amino acids released during protein breakdown are reused for synthesis
  • 25% oxidised to release energy or used in synthesis of other N-containing compounds
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17
Q

amino acid reutilisation

A
  • 75% of amino acids released during protein breakdown are reused for synthesis
  • 25% oxidised to release energy or used in synthesis of other N-containing compounds
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18
Q

where do carbon atoms for non-essential amino acid synthesis come from

A
  • intermediates of glycolysis (C3)
  • pentose phosphate pathway (C4 & C5)
  • Krebs cycle (C4 & C5)
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19
Q

where do amino groups for non-essential amino acid synthesis come from

A
  • other amino acids by transamination
  • ammonia
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20
Q

main functions of amino acids

A
  • protein synthesis (all 20)
  • synthesis of other N-compounds (specific amino acids)
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21
Q

2 signalling molecules synthesised from amino acids

A
  • nitric oxide from L-argining
  • hydrogen sulphide from L-cysteine
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22
Q

synthesis of N-compounds

A
  • tryptophan: 5HT, nicotinamide, melatonin
  • histidine: histamine (local mediator)
  • glycine: purines, glutathione, porphyrins, creatine
  • tyrosine: melanin, thyroid hormones, catecholamines
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23
Q

amino acid breakdown

A

liver is major site of breakdown
- C-atoms converted to intermediates of carbohydrate and lipid metabolism
- removal of -NH2 group (transamination or deamination)
- N-atoms converted to urea

24
Q

fate of the C-atoms of amino acids

A
  • glucogenic converted to pyruvate, oxaloacetate, fumarate, α-ketoglutarate or succinyl Co-A
  • ketogenic converted to acetyl Co-A or acetoacetyl Co-A
  • normally products oxidised to CO2 and H2O and energy released
  • in starvation and diabetes products can be used to produce glucose and ketone bodies
25
Q

removal of nitrogen from amino acids

A
  • removing amino group essential to allow carbon skeleton to be utilised in oxidative metabolism
  • nitrogen incorporated into compounds or excreted in urea
  • amino groups transferred to other molecules (transamination) or removed (deamination)
26
Q

transamination

A
  • aminotransferases (transaminases) specific for individual/groups of amino acids
  • use α-ketoglutarate to funnel amino group to glutamate
  • aminotransferases require coenzyme pyridoxal phosphate which is a derivative of vitamin B6
  • cortisol stimulates transaminase synthesis in liver
27
Q

clinically important aminotransferases

A

alanine aminotransferase (ALT)
alanine + α-ketoglutarate to pyruvate + glutamate
aspartate aminotransferase (AST)
aspartate + α-ketoglutarate to oxaloacetate + glutamate

28
Q

plasma ALT and AST levels

A
  • measured routinely as part of liver function test
  • high levels in conditions causing extensive cellular necrosis (viral hepatitis, autoimmune liver diseases, toxic injury)
29
Q

deamination

A

enzymes in liver and kidney react with amino acids to remove the -NH2 group as free NH3

30
Q

what are D-amino acids

A
  • found in plants and microorganisms so enter through diet
  • not used for protein synthesis as proteins would be structurally abnormal and non-functional
  • D-amino acid oxidase converts them to keto acids that aren’t optically active
31
Q

enzymes involved in deamination

A

amino acid oxidases
- low specificity enzymes that convert amino acids to keto acids and ammonia

glutaminase
- high specificity enzyme that converts glutamine to glutamate and ammonia

glutamate dehydrogenase
- high specificity enzyme that catalyses interconversion of glutamate and α-ketoglutarate
- involved in disposal of amino acids and synthesis of non-essential amino acids

32
Q

disorders of amino acid metabolism

A
  • over 50 inherited disorders due to specific enzyme defects in amino acid metabolism
  • either total or partial loss of enzyme activity
  • amino acid/products of breakdown accumulate which may be toxic or metabolised to toxic products
  • significant portion of paediatric genetic disease
  • mental retardation and developmental abnormalities
  • treatment involves restricting specific amino acids in diet
33
Q

what diseases can heel prick test screen for

A
  • sickle cell disease
  • cystic fibrosis
  • congenital hypothyroidism

inborn errors of metabolism
- phenylketonuria (PKU)
- maple syrup urine disease
- isovaleric acidaemia (IVA)
- glutaric aciduria
- homocystinuria

34
Q

what is phenylketonuria (PKU)

A
  • most common inborn error of amino acid metabolism (~1 in 15000)
  • large amounts of phenylketones in urine
  • deficiency in phenylalanine hydroxylase
  • autosomal recessive (gene on Chr12)
35
Q

how does PKU occur

A
  • deficiency in phenylalanine hydroxylase so phenylalanine can’t be oxidised to tyrosine
  • phenylalanine accumulates in tissues and blood so metabolised by other pathways
  • converted to phenylpyruvate by transamination and phenylketones which are excreted in urine
36
Q

how can PKU be diagnosed

A
  • detection of phenylketones in urine
  • measurement of blood phenylalanine concentration (normally <0.1mmol/L)
  • heel prick test
37
Q

what is the treatment for PKU

A
  • strictly controlled low phenylalanine diet enriched with tyrosine
  • avoid artificial sweeteners
  • avoid high protein foods like meat, milk and eggs
38
Q

symptoms of PKU

A
  • severe intellectual disability
  • developmental delay
  • microcephaly
  • seizures
  • hypopigmentation

can be avoided with early intervention

39
Q

what is homocystinuria

A
  • autosomal recessive disorder
  • problem breaking down methionine
  • ~1 in 344000
  • excess homocystine (oxidised form of homocysteine) in urine
  • defect in cystathione β-synthase (CBS) most common
40
Q

how does homocystinuria occur

A
  • methionine converted to homocysteine
  • CBS enzyme deficient so can’t convert homocysteine to cystathione which would be converted to cysteine
  • levels of homocysteine increase in blood and some converted to methionine (promoted by betaine, Vit B12 + folate)
  • accumulation of homocysteine and metabolites causes disease symptoms
41
Q

how is homocystinuria diagnosed

A
  • elevated levels of homocysteine and methionine in plasma
  • presence of homocystine in urine
42
Q

symptoms of homocystinuria

A
  • elevated plasma homocysteine cause disorders of connective tissue, muscle, CNS and cardiovascular system
  • in children, symptoms similar to Marfan’s (Marfan’s = lack of expression of fibrillin-1 protein whereas homocystinuria is disrupted protein)
43
Q

what is the treatment for homocystinuria

A
  • low methionine diet
  • avoid milk, meat, fish, eggs, cheese, nuts
  • cysteine, Vit B6 (cofactor for CBS enzyme), betaine, B12 + folate supplement
44
Q

what is the peripheral blood concentration of ammonia

A

25-40 µmol/L

45
Q

toxic effects of ammonia

A

readily diffusable and extremely toxic to brain
- interference with amino acid transport and protein synthesis
- disruption of cerebral blood flow
- pH effects (alkaline)
- interference with metabolism of excitatory amino acid neurotransmitters
- alteration of blood-brain barrier
- interference with TCA cycle - reacts with α-ketoglutarate to form glutamate)

46
Q

ammonia detoxification using glutamine

A
  • in tissues ammonia combined with glutamate to form glutamine
  • glutamine transported in blood to liver or kidneys
  • cleaved by glutaminase to reform glutamate and ammonia
  • ammonia fed into urea cycle in liver and excreted directly in urine in kidney
47
Q

how are amino acid nitrogen transported using alanine

A
  • amine groups transferred to glutamate by transamination
  • pyruvate transaminated by glutamate to form alanine
  • alanine transported in blood to liver
  • converted back to pyruvate by transamination (alanine aminotransferase)
  • amino group fed via glutamate into urea cycle for disposal as urea
  • pyruvate used to synthesise glucose which is fed back to tissues (glucose-alanine cycle)
48
Q

glutamine synthesis

A
  • normal blood concentration is 0.5mmol/L
  • synthesised from ammonia and glutamate via glutamine synthetase
  • used by cells to reduce ammonia toxicity as hydrolysed in liver and kidneys by glutaminase to release ammonia to be disposed of in urine (kidney) or converted to urea (liver)
49
Q

what is urea

A
  • extremely water soluble so excreted in urine
  • non-toxic, metabolically inert and high nitrogen content so effective way of disposing of nitrogen
  • synthesised in liver by urea cycle
  • transported via blood to kidneys for excretion in urine
  • useful osmotic role in kidney tubules
50
Q

urea synthesis (urea cycle)

A

NH2 groups come from ammonia and aspartate
- ammonia comes from enzymes in liver that deaminate amino acids releasing NH3 and from NH3 produced by gut bacteria that enters liver via portal circulation
- aspartate formed from oxaloacetate by transmaination

51
Q

what happens if urea diffuses across intestinal wall and enters intestine

A
  • gut bacteria break down urea, releasing ammonia that can be reabsorbed
  • contributes to hyperammonaemia in kidney failure when concentration of urea in blood is high
52
Q

regulation of urea synthesis

A
  • urea cycle involves 5 enzymes which are not subjected to feedback inhibition by end product of cycle as function is to dispose of ammonia as urea

enzymes of the cycle are inducible but not regulated
- high protein diet induces enzyme levels
- low protein diet or starvation represses enzyme levels

53
Q

defects in the urea cycle

A
  • autosomal recessive genetic disorders caused by deficiency in each one of the five enzymes discovered
  • complete loss of enzyme is fatal but partial loss occurs ~1 in 30000
  • leads to hyperammonaemia and accumulation/excretion of urea cycle intermediates
54
Q

symptos of diseases of urea cycle

A
  • vomiting
  • lethargy
  • irritability
  • mental retardation
  • seizures
  • coma
  • eventually death
55
Q

treatment of diseases of urea cycle

A
  • low protein diet
  • replace amino acids in diet with keto acids
56
Q

severity of diseases of urea cycle

A
  • severity depends on nature of defect and amount of protein eaten
  • severe urea cycle disorders show symptoms within 1 day after birth
  • mild urea cycle enzyme deficiencie may not show symptoms until early childhood
57
Q

what is hyperammonaemia

A
  • high levels of ammonia in blood
  • blurred vision, tremors, slurred speech, coma, eventually death
  • secondary consequence of liver disease (cirrhosis) where ability to remove NH3 from portal blood impaired
58
Q

overview of protein metabolism

A
  • free amino acids from digestion, de novo amino acid synthesis and proteolysis of cellular proteins
  • synthesis of cellular proteins from free amino acids
  • breakdown of free amino acids in liver
  • carbon skeleton used for energy (glucogenic for gluconeogenesis and ketogenic for ketone bodies)
  • amino group converted to urea and excreted in urine

MEH (26 decks)

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