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Metabolism > Session 4 > Flashcards

Session 4 Flashcards

0
Q

Describe the major energy stores is a 70kg man

A
  • Triacylglyerides: 15kg (600,000kJ)
  • Glycogen: 0.4kg (4000kJ)
  • Muscle protein: 6kg (100,000)
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1
Q

What tissues have an absolute requirement for glucose?

A
  • Erythrocytes
  • Leukocytes
  • Kidney medulla
  • Lens of eye
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2
Q

How is the need for a continuous supply of glucose to some tissues met?

A
  • Initially breakdown of glycogen stores

- After 8-12hrs glucose must be synthesised by gluconeogenesis (as glycogen stores have been depleted)

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3
Q

Where is glycogen stored?

A
  • In granules in the liver and skeletal muscle
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4
Q

Why is glycogen a good storage molecules?

A
  • Has little osmotic effect
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5
Q

Why is glycogen a bad storage molecule?

A
  • Is polar so can attract a lot of water, so there is a limit to the amount that can be stored in tissues
  • No specialised storage tissue, so must be stored in tissues that have other important functions
  • There are glycogen storage diseases in which the storage of glycogen is abnormal (either excessive or inadequate)
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6
Q

What are the stages of glycogenesis?

A
  • Glucose + ATP -> glucose 6-phosphate + ADP
    Enzymes: hexokinase; glucokinase in liver
  • Glucose 6-phosphate glucose 1-phosphate
    Enzyme: phosphoglucomutase
  • Glucose 1-phosphate + UTP + H2O -> UDP-glucose + 2Pi
  • Glycogen(nresidues) + UDP-glucose -> glycogen(n+1residues) + UDP
    Enzymes: glycogen synthase (links glucose residues to glycogen with a-1,4-glycosidic bonds); branching enzyme (links glucose residues with a-1,6-glycosidic bonds introducing a branch point)
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7
Q

What is the importance of UTP?

A
  • Structurally similar and energetically equivalent to ATP
  • UDP-glucose is a highly activated form of glucose
  • UDP-glucose is an important intermediate in: the synthesis of sugar containing molecules (eg lactose and glycogen); and in the interconversion of glucose and galactose
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8
Q

Why is glycogen degraded?

A
  • Skeletal muscle: exercise

- Liver: fasting; stress response (fight/flight/fright response)

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9
Q

How many stages are in glycogenolysis?

A
  • 3
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10
Q

What is the first stage of glycogenolysis and what enzymes are used?

A
  • Glycogen (n residues) + Pi -> glycogen (n-1) + glucose 1-phosphate
    Enzymes: glycogen phosphorylase (attack a-1,4-glycosidic bonds
    which undergo phosphorylis so glucose 1-phosphate is produced
    not free glucose); de-branching enzyme (attach a-1,6-glycosidic
    bonds which undergo hydrolysis and produces free glucose)
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11
Q

What is the second stage of glycogenolysis and what enzymes are used?

A
  • Glucose 1-phosphate glucose 6-phosphate
    Enzymes: phosphoglucomutase
    ~ Muscle: glucose 6-phosphate enters glycolysis to provide energy
    for muscle (glucose 6-phosphate is a store that can only be used
    by muscle cells) muscle lacks enzyme glucose 6-phosphatase so
    cannot carry out last stage of glycogenolysis
    ~ Liver: takes part in stage 3 of glycogenolysis
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12
Q

What is stage 3 of glycogenolysis and what enzyme is used?

A
  • Glucose 6-phosphate + H2O -> glucose + Pi
    Enzyme: glucose 6-phosphatase
    ~ Liver: stage 3 occurs here, so therefore liver glycogen is a store
    that can be used by all tissues, glucose is released into blood
    stream and is transported to other tissues
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13
Q

How is glycogen metabolism controlled?

A
  • Control of enzymes catalysing irreversible reactions in biosynthetic and degradative pathways: glycogen synthase; glycogen phosphorylase
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14
Q

What activates and inhibits glycogen phosphorylase?

A
  • Allosteric control: AMP activates
  • Covalent modification: phosphorylation activates; dephosphorylation inhibits
  • Hormonal control: glucagon and adrenaline activate (as they increase phosphorylation); insulin inhibits (as increases dephosphorylation)
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15
Q

What activates and inhibits glycogen synthase?

A
  • Covalent modification: dephosphorylation activates; phosphorylation inhibits
  • Hormonal control: insulin activates (as increases dephosphorylation); glucagon and adrenaline inhibits (as increases phosphorylation)
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16
Q

What are glycogen metabolism disorders?

A
  • A number of inherited disorders
  • Result from an abnormality in one or more enzymes as glucose metabolism
  • Clinical picture and severity depends on which enzyme or tissue is affected
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17
Q

What are the main features of glycogen metabolism disorders?

A
  • Increased or decreased amount of glycogen which may cause:
    ~ tissue damage if excess storage
    ~ fasting hypoglycaemia
    ~ poor exercise tolerance
  • Glycogen structure may be abnormal
  • Usually liver and/or muscle are affected
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18
Q

Where does glucose come from when carbohydrates are absent from the diet? (Eg during fasting and starvation)

A
  • Initially from breakdown of glycogen in the liver (only sufficient for 8-10 hours)
  • After this time, glucose must be produced by gluconeogenesis in the liver (kidney also in starvation)
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19
Q

What intermediates can be used as substrates for gluconeogenesis?

A
  • Pyruvate, lactate and glycerol can be converted to glucose
  • Essential and non-essential amino acids whose metabolism involves pyruvate or the intermediates of the TCA cycle can be converted to glucose
    (Acetyl CoA cannot be converted to glucose as pyruvate dehydrogenase reaction is irreversible-loss of CO2)
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20
Q

What is the overall reaction of gluconeogenesis from pyruvate?

A
  • 2pyruvate + 4ATP + 2GTP + 2NADH ->

glucose + 2NAD+ + 4ADP + 2GDP + 6Pi + 2H+

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21
Q

What reactions does gluconeogenesis share with what process?

A
  • Shares 7 of the 10 reactions of glycolysis

- Irreversible steps 1,3 and 7 are bypassed

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22
Q

How are the steps 1, 3 and 7 of glycolysis bypassed?

A
  • Steps 1 and 3: thermodynamically spontaneous reactions catalysed by phosphatases (glucose 6-phosphatase and fructose 1,6-bisphosphatase)
    1: Glucose 6-phosphate + H2O -> glucose + Pi (G6P) Go = -ve
    3: Fructose 1,6-bisphosphate + H2O -> fructose 6-phosphate + Pi
    (F1,6BP) Go = -ve
  • Step 10: two reactions driven by ATP and GTP catalysed by pyruvate carboxylate and phosphoenolpyruvate carboxykinase (PEPCK)
    (Provides the link between TCA cycle and gluconeogenesis-enables products of amino acid catabolism that are intermediates of the TCA cycle to be used in the synthesis of glucose)
    Pyruvate + CO2 + ATP + H2O ->oxaloacetate + ADP + Pi + 2H+ (PC)
    Oxaloacetate + GTP + 2H+ -> phosphoenolpyruvate + GDP + CO2
    (PEPCK)
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23
Q

When does gluconeogenesis occur?

A
  • As part of the stress response eg during fasting, starvation or prolonged exercise
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24
Q

How is gluconeogenesis regulated?

A
  • Major control sites are PEPCK and fructose 1,6-bisphosphatase
  • Largely under hormonal control ie insulin:glucagon ratio
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25
Q

What happens to gluconeogenesis with the lack of insulin and why?

A
  • Insulin:glucagon ratio is very important in controlling the rate of gluconeogenesis
  • Eg during diabetes, low insulin:high glucagon causes increased rates of gluconeogenesis which contributes significantly to hyperglycaemia
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26
Q

How is PEPCK regulated?

A
  • Activated by glucagon and cortisol
  • Inhibited by insulin
    (Hormones change amount of enzyme)
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27
Q

How is fructose 1,6-bisphosphatase regulated?

A
  • Activated by glucagon
  • Inhibited by insulin
    (Hormones affect the amount and activity of enzyme)
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28
Q

Why are triacylglyerols an efficient way of storing energy?

A
  • Can be stored in bulk in anhydrous form in adipose tissue
  • Are highly calorific
  • Are a store of fuel molecules: fatty acids and glycerol
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29
Q

When are the triacylglycerol stores used?

A
  • Prolonged aerobic exercise
  • Stress situations eg starvation
  • Pregnancy
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30
Q

How is triaclyglycerol storage controlled?

A
  • Hormonal control
  • Activated by: insulin
  • Inhibited by: glucagon; adrenaline; cortisol; growth hormone; thyroxine
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31
Q

How are fatty acids synthesised by lipogenesis?

A
  • Synthesised from acetyl CoA using ATP and NADPH
  • Occurs in the cytoplasm
  • Uses multi-enzyme complex fatty acid synthase complex
  • Built up from acetyl CoA in a cycle of reactions that adds C2 every turn (however is not the reverse of B-oxidation pathway)
  • Malonyl CoA (C3) is added and then CO2 is removed to add the C2
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32
Q

How is Malonyl CoA produced?

A
  • Acetyl CoA + CO2 + ATP -> Malonyl CoA + ADP + Pi

Enzyme: acetyl CoA reductase (requires biotin) (is not a component of the fatty acid synthase complex)

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33
Q

How is acetyl CoA regulated?

A
  • Allosteric regulation: activated by citrate; inhibited by AMP
  • Covalent modification: activated by dephosphorylation; inhibited by phosphorylation
  • Hormonal control: activated by insulin (promotes dephosphorylation); inhibited by glucagon and adrenaline (promotes phosphorylation)
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34
Q

What happens to most excess dietary carbohydrates and protein?
Why is this important clinically?
What hormones activate/inhibit the process?

A
  • Converted to fatty acids then esterification to triacylglycerols for storage in adipose tissue
  • Excess lipid synthesis and storage causes obesity and associated problems eg type 2 diabetes and atherosclerosis
  • Process is activated by insulin and inhibited by glucagon and adrenaline
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35
Q

What does the difference in catabolic and anabolic pathways allow?

A
  • Greater flexibility: substrates and intermediates can be different
  • Better control: can be controlled independently or co-ordinately
  • Thermodynamically irreversible steps can be bypassed
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36
Q

Compare and contrast fatty acid oxidation (B oxidation) and fatty acid synthesis

A
  • Fatty acid oxidation: - Fatty acid synthesis:
    ~ cycle of reactions remove C2 ~ cycle of reactions add C2
    ~ C2 atoms removed as acetyl ~ C2 atoms added as malonyl
    CoA CoA
    ~ produces acetyl CoA ~ consumes acetyl CoA
    ~ occurs in mitochondria ~ occurs in cytoplasm
    ~ enzymes separate in ~ multi-enzyme complex in
    mitochondrial matrix cytoplasm
    ~ oxidative: produces NADH ~ Reductive: requires NADH
    and FAD2H
    ~ requires small amount of ATP ~ requires large amount of ATP
    to activate fatty acid to drive the process
    ~ intermediates linked to CoA ~ intermediates linked to fatty
    acid synthase by carrier
    protein
    ~ regulated indirectly by ~ regulated directly by activity of
    availability of fatty acids in acetyl CoA carboxylase
    mitochondria
    ~ glucagon/adrenaline activate ~ insulin activates
    ~ insulin inhibits ~ glucagon/adrenaline inhibits
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37
Q

Why is protein essential in the diet?

A
  • Supplies body with amino acids (essential amino acids cannot be synthesised in the body)
  • Lack of adequate protein is a major cause of illness in developing countries
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38
Q

Where does stage 1 of protein catabolism occur?

A
  • Gastrointestinal tract
  • Variety of enzymes eg proteases and peptidases hydrolyse peptide bonds to release free amino acids
  • Amino acids are them absorbed into the circulation
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39
Q

What are amino acids used for?

A
  • Protein synthesis

- Synthesis of various nitrogen-containing compounds eg purines, creatine haem

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40
Q

What does insulin and growth hormone stimulate in regards to protein and amino acids?

A
  • Uptake of amino acids into tissues (eg skeletal muscle, adipose tissue, liver) and protein synthesis
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41
Q

What does cortisol stimulate in regards to protein and amino acids?

A
  • Proteolysis (breakdown of muscle protein) in skeletal muscle and release of amino acids
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42
Q

What happens to excess dietary protein?

A
  • Excess amino acids are not stored

- Broken down in stage 2 of catabolism instead

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43
Q

How many stage 2 amino acid catabolism pathways are there?

A
  • One for each amino acid (therefore over 20)
  • Many share common features
  • All end up converting the amino acid into important precursor molecules
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44
Q

What happens during stage 2 of amino acid catabolism?

A
  • Amino group (-NH2) is removed from the amino acid
  • Amino group is converted to urea (CO(NH2)2) and is excreted from the body in urine
  • Remaining carbon skeleton of the amino acid is converted into: pyruvate; oxaloacetate; fumarate; a-ketoglutarate; succinate or acetyl CoA
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45
Q

What are ketogenic amino acids?

A
  • Produce acetyl CoA (eg leucine, lysine) as the acetyl CoA can be used to produce ketone bodies
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46
Q

What are glucogenic amino acids?

A
  • Produce the other products as they can be used for glucose synthesis by gluconeogenesis
47
Q

Which amino acids are both ketogenic and glucogenic?

A
  • Isoleucine
  • Threonine
  • Phenylalanine
  • Tyrosine
  • Tryptophan
48
Q

What are the products of stage 2 catabolism of sugars (glucose, galactose, fructose) glycerol, fatty acids and ketone bodies, and amino acids?

A
  • Glucose, galactose, fructose: pyruvate -> acetyl CoA
  • Glycerol: pyruvate -> acetyl CoA
  • Fatty acids, ketone bodies: acetyl CoA
  • Amino acids: pyruvate -> acetyl CoA; acetyl CoA; oxaloacetate; a-ketoglutarate; fumarate; succinate
49
Q

What happens to the products of all the stage 2 catabolism?

A
  • Enter stage 3 catabolism the TCA cycle in the mitochondria
50
Q

What does the term ‘nitrogen metabolism’ mean?

A
  • Covers all the metabolic processes of all the nitrogen containing compounds in the body
  • Metabolism of individual N-compounds alters in various diseases
  • Measurement of N-compounds in the blood and urine can be useful in the diagnosis of specific diseases
51
Q

What is the total amount of nitrogen in a 70kg male?

A
  • ~2kg
52
Q

Where is nitrogen found in the body?

A
  • Mainly in: proteins; DNA; RNA

- Smaller amounts in: amino acids; purines; pyrimidines; hormones; neurotransmitters; porphyrins; creatine; carnitine

53
Q

Why are proteins synthesised?

A
  • For specific functions

- Not for a store of amino acids

54
Q

What is protein turnover?

A
  • All body proteins are continually being broken down and resynthesised eg muscle proteins; digestive enzymes
  • Rate of turnover depends on protein and varies during growth and ageing
  • Normally is equal
  • Not a random process, mechanisms exist for identifying proteins to be degraded
55
Q

How does most nitrogen enter the body and how does most leave?

A
  • Enters as: protein

- Leaves as: urea; creatinine; ammonia; uric acid in urine, protein from skin, hair and nails

56
Q

What is N-balance?

A
  • In healthy adults amount of nitrogen taken in equals the amount that leaves the body
57
Q

What is positive N-balance and when does it occur?

A
  • Intake of nitrogen is larger than the loss of nitrogen

- Occurs during periods of active growth; pregnancy; tissues repair and convalescence

58
Q

What is negative N-balance and when does it occur?

A
  • Intake of nitrogen is less than the loss of nitrogen

- Eg starvation; malnutrition; trauma

59
Q

What are the essential amino acids?

A
  • Lysine
  • Leucine
  • Isoleucine
  • Tryptophan
  • Threonine
  • Methionine
  • Phenylalanine
  • Valine
60
Q

What amino acids can become essential amino acids and in what circumstances?

A
  • Histidine and Arginine: small quantities can be synthesised in the body; needed in the diet during periods of active growth eg pregnancy
  • Tyrosine: can be synthesised from phenylalanine; needed in diet if phenylalanine intake is low
  • Cysteine: can be synthesised from methionine; needed in the diet if methionine intake is low
61
Q

What is the amino acid pool?

A
  • Total amount of free amino acids in the body (intracellular and extracellular)
  • ~100g in a 70kg male
  • Four non-essential amino acids make up ~50% of the pool: glutamine; alanine; proline and glycine
62
Q

What is the normal fasting concentration of amino acids in the blood?

A
  • ~3mmol/L
63
Q

What happens to the amino acids released from protein breakdown?

A
  • 75% reutilised for protein synthesis

- 25% are oxidised to release energy or used in the synthesis of other N-compounds

64
Q

Where do the carbon atoms for the synthesis of non-essential amino acids come from? Where does the amino group come from?

A
  • Intermediates of glycolysis (C3)
  • Pentose phosphate pathway (C4 and C5)
  • Amino group comes from other amino acids by transamination or from ammonia
65
Q

What are the main functions of amino acids?

A
  • Proteins synthesis (requires all 20 amino acids)

- Synthesis of other N-compounds (requires specific amino acids)

66
Q

What happens to excess amino acids?

A
  • Are not stored
  • Converted to intermediates of carbohydrate and lipid metabolism
  • Oxidised to provide energy
67
Q

What important signalling molecules are synthesised from amino acids?

A
  • Nitric oxide from L-arginine

- Hydrogen sulphide from L-cysteine

68
Q

What N-compounds are synthesised from which amino acids?

A
  • Tryptophan: 5-hydroxytryptamine (5-HT) a neurotransmitter
  • Histidine: Histimine a local mediator
  • Tyrosine: melanin; thyroid hormones; catecholamines
  • Glycine: purines; glutathione; porphyrins; creatine
    (Tyrosine and glycine are unusual as more than one N-compound can be produced from each of them)
69
Q

Where is the major site of amino acid breakdown?

A
  • Liver
70
Q

What features do the pathways of amino acid breakdown share?

A
  • C-atoms are converted to intermediates of carbohydrate and lipid metabolism
  • Usually start with the removal of the -NH2 group by deamination or transamination
  • N-atoms are usually converted to urea
71
Q

What are the C-atoms of amino acids converted into?

Which amino acids are converted to which group?

A
  • (i) Pyruvate; oxaloacetate; fumarate; a-ketoglutarate; succinate
  • (II) Acetyl CoA; acetoacetyl CoA
  • 14 amino acids are converted one or more products in (i) - they are glucogenic as they can be used to synthesise glucose or glycogen
  • Lysine and leucine are converted to intermediates in (ii) - they are ketogenic as they can be used to synthesise fatty acids or ketone bodies
  • Isoleucine, tyrosine, phenylalanine and tryptophan are glucogenic and ketogenic
72
Q

What normally happens to products of amino acid degradation?

A
  • Oxidised to H2O and CO2

- Energy is used by the cell

73
Q

What happens to products of amino acid degradation during starvation and diabetes?

A
  • Produce glucose and ketone bodies
74
Q

What happens to N-atoms of amino acids?

A
  • Transamination or deamination
75
Q

What is transamination?

A
  • Major mechanism for removal of -NH2 group from amino acids
  • Uses enzymes aminotransferases (transaminases) which are specific to individual amino acids or groups of structurally similar amino acids
  • Amino acid 1 + keto acid 2 -> amino acid 2 + keto acid 1
76
Q

What hormone stimulates transaminase synthesis and where?

A
  • Cortisol

- Liver

77
Q

What molcules are used as keto acid 2 and what are they converted into (keto acid 1)?

A
  • Most transaminases use a-ketoglutarate as keto acid 2, which is converted to glutamate (keto acid 1)
  • Oxaloacetate (keto acid 2) -> aspartate (keto acid 1) - is an important intermediate in urea synthesis
78
Q

Which transaminases are clinically important and why?

A
  • Alanine aminotransferase (glutamate-pyruvate transaminase):
    ~ alanine + a-ketoglutarate pyruvate + glutamate
  • Aspartate aminotransferase (glutamate-oxaloacetate transaminase):
    ~ aspartate + a-ketoglutarate oxaloacetate + glutamate
  • Enzymes are measured in serum of patients to asses liver function
79
Q

What is deamination?

A
  • Removal of -NH2 group as free NH3 (NH4+) by several enzymes of varying specificity in the liver and kidneys
80
Q

What enzymes are used in deamination?

A
  • L and D-amino acid oxidises
  • Glutaminase
  • Glutamate dehydrogenase
81
Q

What does L and D-amino acid oxidases do?

A
  • Low specificity enzymes
  • Convert amino acids to keto acids and NH3
  • Human liver cells have a high activity of D-amino acid oxidase (D-amino acids are found in plant and bacterial cells-enter though the diet; cannot be used in proteins synthesis as the proteins would be structurally abnormal and non-functional; enzyme converts them to keto acids that are not optically active)
82
Q

What does glutaminase do?

A
  • High specificity enzyme

- Converts glutamine to glutamate and NH3

83
Q

What does glutamate dehydrogenase do?

A
  • High specificity enzyme
  • Catalyses:
    ~ glutamate + NAD+ + H2O -> a-ketoglutarate + NH4+ + NADH +H+
  • Important in amino acid metabolism in the liver as it is involved in the disposal of amino acids (glutamate -> a-ketoglutarate + NH4+) and the synthesis of non-essential amino acids (a-ketoglutarate -> glutamate) Reaction direction is determined by the relative concentration of substrates and products
84
Q

What do disorders of amino acid metabolism result from?

A
  • Inherited causing a specific enzyme defect

- Partial or total loss of enzyme activity

85
Q

When do disorders of amino acid metabolism have clinical consequences?

A
  • When the affected enzyme is involved in amino acid breakdown
  • Amino acid or breakdown product accumulate and are toxic or metabolised to toxic products
  • May cause mental retardation or physical abnormalities
86
Q

Why do defects in enzymes in synthesis of amino acids not normally have clinical consequences?

A
  • Sufficient amino acids are supplied in the diet to overcome a defect in amino acid synthesis
87
Q

How are disorders of amino acid metabolism treated?

A
  • Restricting amount of a particular amino acid in the diet by using a special diet early in life
88
Q

What is phenylketonuria?

A
  • Inherited metabolic disorder
  • Urine contains large amounts of phenylketones produced from phenylalanine
  • Causes inhibition of brain development: phenylpyruvate inhibits pyruvate uptake into mitochondria and interferes with energy metabolism in the brain
89
Q

Which enzyme is missing in phenylketonuria?

A
  • Phenylalanine hydroxylase
  • Converts phenylalanine to tyrosine
  • Lack causes build up of phenylalanine in tissues and blood in PKU
90
Q

What happens to phenylalanine in PKU?

A
  • Metabolised via other pathways to produce other products eg phenylpyruvate which is excreted in the urine
91
Q

How is phenylketonuria diagnosed?

A
  • Presence of phenylketones in the urine

- Measurement of blood phenylalanine (normally less than 0.01 mmol/L; PKU <1.0 mmol/L

92
Q

How is phenylketonuria treated?

A
  • Diet low in phenylalanine
93
Q

What is homocystinuria?

A
  • Inherited autosomal recessive fault in methionine metabolism
  • Chronic elevated plasma levels of homocysteine causes disorders of connective tissue, muscle, CNS and the cardiovascular system (also is a risk factor for cardiovascular disease)
94
Q

What enzyme is there a deficiency in in type 1 homocystinuria?

A
  • Cystathionine B-synthase (CBS) enzyme
  • Normally converts homocysteine to cystathionine, which is then converted to cysteine
  • Also can metabolise cysteine to produce hydrogen sulphide, a signalling molecule (not involved in homocystinuria)
95
Q

What happens to homocysteine in homocystinuria?

A
  • Levels of homocysteine increase in the blood

- Some is converted to methionine

96
Q

How is homocystinuria diagnosed?

A
  • Elevated levels of homocysteine and methionine in the plasma
  • Presence of homocystine (oxidised form of homocysteine) in the urine
97
Q

What can homocystinuria be misdiagnosed as?

A
  • In childhood symptoms are similar to Marfan’s syndrome
  • Marfan’s syndrome is caused by a lack of expression of the protein fibrillin-1 in connective tissue
  • In homocystinuria the protein’s structure is disrupted
98
Q

In what form is most ammonia in the body?

A
  • Ammonium ion: NH4+

- NH3 + H2O NH4+ + OH-

99
Q

Where does ammonia in the body come from?

A
  • Produced by many tissues

- Absorbed from the gut

100
Q

What symptoms are caused by hyperammonaemia?

A
  • Blurred vision
  • Tremors
  • Slurred speech
  • Coma
  • Eventually death
101
Q

Why is ammonia toxic?

A
  • CNS is very sensitive to ammonia
  • Ammonia reacts with a-ketoglutarate to form glutamate in mitochondria with the glutamate dehydrogenase
  • Removes a-ketoglutarate from the TCA cycle, which slows and disrupts energy supply to brain cells
  • Also affects pH inside cells of the CNS
  • Also interferes with neurotransmitter synthesis and release
102
Q

What organ is involved with ammonia detoxification?

A
  • Liver

- Hyperammonaemia is seen in liver disease

103
Q

How can ammonia be detoxified?

A
  • Used in the synthesis of other N-compounds eg glutamine
  • Conversion to urea which is excreted
  • Can be excreted directly from the body in urine
104
Q

Describe glutamine

A
  • Normal blood concentration is higher than any other amino acid and increases more after a protein rich meal
  • Is non-toxic
105
Q

What is the reaction of glutamine synthesise?

A

NH4+ + Glutamate + ATP -> Glutamate + ADP + Pi

Enzyme: glutamate synthase

106
Q

What happens to glutamine after it has been synthesised?

A
  • Released from the cell that synthesised it
  • Transported to liver and kidney
  • Hydrolysed which releases ammonia
  • Ammonia is disposed of in the urine (kidney) or converted to urea (liver)
    Glutamine -> NH4+ + Glutamate
    Enzyme: glutaminase
107
Q

Why is urea an effective way of disposing of unwanted nitrogen?

A
  • Very soluble in water (therefore can be excreted in urine)
  • Non-toxic
  • Metabolically inert
  • High nitrogen content
108
Q

Where is urea synthesised and how?

A
  • In the liver
  • Urea cycle: has 5 enzymes
  • Overall reaction:
    ~ HCO3- + NH4+ + aspartate + 3ATP ->
    CO(NH2)2 + fumarate + 2ADP + AMP + Pi
  • NH4+ in the form of NH3 comes from deamination of amino acids and gut bacteria that enters the liver by portal circulation
  • Aspartate is formed from oxaloacetate in transamination
109
Q

How is urea synthesis (urea cycle) regulated?

A
  • Not regulated by feedback inhibition by the end product (as the function is to produce ammonia)
  • Instead enzymes are inducible (change in regards to the stimulus eg low protein diets represses enzymes -> refeeding syndrome (hyperammonaemia) as excess amino acids are degraded)
110
Q

What are inherited diseases of the urea cycle caused by?

A
  • Defects in one of the 5 urea cycle enzyme causing a partial loss
  • Complete loss of an enzyme is fatal
  • Defects cause:
    ~ hyperammonaemia
    ~ accumulation and/or excretion of urea cycle intermediate(s)
111
Q

What is the clinical presentation of defects of urea cycle enzymes?

A
  • Depends on extent of defect and amount of protein eaten

- Symptoms/signs: vomiting; lethargy; irritability; mental retardation; seizures; coma; death

112
Q

What is the treatment for symptoms of inherited urea cycle disorders?

A
  • Low protein diet
  • Diets where keto acids of the essential amino acids are used to replace the amino acids
    ~ keto acids are converted to amino acids using some NH4+ which lowers the concentration in the tissues
113
Q

What is a secondary consequence of liver disease eg cirrhosis?

A
  • Hyperammonaemia

- Liver’s ability to remove NH3 from the portal blood is impaired

114
Q

What happens to the urea after it has been synthesised?

A
  • Diffuese from liver cells into the blood
  • Transported to the kidney
  • Filtered and excreted in urine
  • Small amount can diffuse across intestinal wall and enter intestine
  • Bacteria break it down
  • Releases ammonia which can be reabsorbed
115
Q

What happens in kidney failure when urea blood concentration is high?

A
  • Hyperammonaemia

- Contributed to by the production of ammonia from urea by gut bacteria

Metabolism (11 decks)

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