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Semester 2 - MEH > 2. Protein and amino acid metabolism > Flashcards

2. Protein and amino acid metabolism Flashcards

1
Q

Give the major nitrogen containing compounds

A
  • Amino acids
  • Proteins
  • Purines + Pyrimidines (DNA / RNA)
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2
Q

where are smaller amounts of nitrogen found?

A 
Smaller amounts of others - e.g.
• Porphyrins (haem)
• Creatine phosphate
• Neurotransmitters (e.g. dopamine)
• Some hormones (e.g. adrenaline
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3
Q

what is creatinine?

A

Breakdown product of creatine & creatine phosphate in muscle

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4
Q

what is the Rate of production of creatinine adn what does it depend on?

A

Usually produced at constant rate depending on muscle mass (unless muscle is wasting)

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5
Q

How is creatinine removed from the body?

A

It’s filtered via kidneys into urine

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6
Q

How can creatinine be used as a clinical marker?

A
  • Creatinine urine excretion over 24h proportional to muscle mass
  • Provides estimate of muscle mass
  • Also commonly used as indicator of renal function (raised plasma level and low urine level on damage to nephrons)
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7
Q

What is the creatinine Reference range for both men and women?

A

Excreted in urine per day
• Men 14-26 mg/kg
• Women 11-20 mg/kg

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8
Q

what is N (nitrogen) equilibrium?

A

Intake = output
No change in total body protein.
Normal state in adult

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9
Q

what is Positive N balance?

A

Intake > output
Increase in total body protein.
Normal state in growth & pregnancy, tissue repair and convalescence or in adult recovering from malnutrition

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10
Q

what is Negative N balance?

A

Intake < output
Net loss of body protein.
Never normal.
Causes include trauma, infection, or malnutrition

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11
Q

how does nitrogen usually enter and leave the body?

A

Most nitrogen (N) enters the body as protein (>90%). and most N leaves the body as urea (~85%), creatinine (5%), ammonia (3%) and uric acid in the urine (some in sweat and faeces). In addition, there is some direct loss of protein (skin, hair, nails etc.) from the body.

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12
Q

Give a brief description of protein turnover

A
  • dietary protein is broken down into free amino acids.
  • the de novo amino acid synthesis also provides to the free amino acid pool.
  • the free amino acids are used to synthesise cellular proteins.
  • the cellular proteins can also feed free amino acids into the AA pool by proteolysis.
  • The excess free amino acids are taken to the liver where they are broken down and the amino group(NH2) is converted to urea and excreted as urine, to ensure that it does not become ammonia and build up which is very toxic.
  • The carbon skeleton is either used to generate glucose or to generate ketone bodies, depending on the amino acid. Carbon skeleton of Glucogenic amino acids are used in gluconeogenesis to generate glucose and carbon skeleton from ketogenic amino acids are used to generate ketone bodies. both glucose and ketone bodies are used to generate energy.
  • some amino acids are bothe glucogenic and ketogenic
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13
Q

give an example of a glucogenic amino acid and where in metabolism does it feed in?

A

alanine - feeds glucose into pyruvate

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14
Q

giove an example of a ketogenic amino acid and where in metabolism does it feed in?

A

lycine - feeds into acetyl-CoA

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15
Q

give an example of a glytogenic and ketogenic amino acid and where in metabolism does it feed in?

A

tyrosine - feeds into acetyl-CoA

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16
Q

when does protein mobilisation occur?

A

Occurs during extreme stress (starvation)

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17
Q

what controls Mobilisation of protein reserves?

A

Under hormonal control - Insulin & Growth hormone, Glucocorticoids (e.g. Cortisol)

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18
Q

what is the effect of Insulin & Growth hormone on protein synthesis and protein degradation?

A

synthesis increases

degradation decreases

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19
Q

what is the effect of Glucocorticoids (e.g. Cortisol) on protein synthesis and protein degradation?

A

synthesis decreases

degradation increases

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20
Q

what causes Cushing’s syndrome and what is its effect?

A

Excessive breakdown of protein can occur in Cushing’s syndrome (excess cortisol). Weakens skin structure leading to striae formation.

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21
Q

List the 9 essential dietary amino acids

A 
If                        Isoleucine                   
Learned            Lysine
This                   Threonine
Huge                Histidine
List                    Leucine
May                  Methionine
Prove               Phenylalanine
Truly                Tryptophan
Valuable          Valine
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22
Q

which are the conditionally essential amino acids and when are they needed in the diet?

A

Children & Pregnant women = high rate of protein synthesis. Also require some arginine, tyrosine & cysteine in diet

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23
Q

proteins of which origin are high quality?

A

Protein of animal origin considered “High quality” (Contain all essential amino acids)

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24
Q

proteins of which origin are low quality?

A

• Proteins of plant origin generally considered
“lower quality” since most are deficient in one
or more essential amino acids.
• Therefore essential that vegetarian diet
obtains protein from a wide variety of plant
sources

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25
Q

in non-essential amino acid, where is the carbon atoms and amino group from?

A

Carbon atoms for non-essential amino acid synthesis
come from:
• Intermediates of glycolysis (C3)
• Pentose phosphate pathway (C4 & C5)
• Krebs cycle (C4 & C5)

Amino group provided by other amino acids by the
process of transamination or from ammonia

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26
Q

Other than proteins, what compounds can tyrosine form?

A
  • Catecholamines
  • Melanin
  • Thyroid hormones
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27
Q

Other than proteins, what compounds can cysteine form?

A

• Hydrogen sulphide
(signalling molecule)
• Glutathione

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28
Q

Other than proteins, what compounds can trytophan form?

A
  • Nicotinamide
  • Serotonin (5HT)
  • Melatonin
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29
Q

Other than proteins, what compounds can Histidine form?

A

• Histamine

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30
Q

Other than proteins, what compounds can Glutamate

form?

A

• GABA

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31
Q

Other than proteins, what compounds can Glycine form?

A
  • Purines
  • Glutathione
  • Haem
  • Creatine
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32
Q

Other than proteins, what compounds can Arginine form?

A

• Nitric oxide

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33
Q

Other than proteins, what compounds can Serine form?

A

• Sphingosine

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34
Q

why is the amino group removed from amino acids and what happens to it?

A

• Removal of amino group is 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

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35
Q

what are the Two main pathways facilitate removal of nitrogen from amino acids?

A
  • Transamination

* Deamination

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36
Q

what is transamination?

A

Transamination is a chemical reaction that causes the transfer of an amine group from an amino acid to a keto acid (amino acid without an amine group), thus creating a new amino acid and keto acid.

37
Q

what is the enzyme used for transamination?

A

Aminotransferase enzymes are used for this reaction

38
Q

what is the function of alpha-ketoglutarate in transamination?

A

α-ketoglutarate acts as the predominant amino-group acceptor (keto acid) and produces glutamate as the new amino acid.
Amino acid + α-ketoglutarate ↔ α-keto acid + Glutamate

39
Q

what is the function of oxaloacetate in transamination?

A

sometimes acts as the amino-group acceptor (keto acid) and produces aspartate as the new amino acid.

40
Q

what does All aminotransferases require?

A

All aminotransferases require the coenzyme pyridoxal phosphate which is a derivative of vitamin B6

41
Q

what are the Key aminotransferase enzymes and their function?

A 
Alanine aminotransferase (ALT)
- Converts alanine to glutamate
Aspartate aminotransferase (AST)
- Converts glutamate to aspartate
42
Q

why is ALT and AST clinically important?

A

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 Liver Diseases
• Toxic injury

43
Q

how does transamination help to get rid of the amine group?

A

Glutatamate and aspartate more readily feed into the urea cycle so help to get rid of the amine group

44
Q

How can “death cap” mushrooms affect plasma ALT levels?

A

Death cap mushrooms can cause acute liver failure if ingested. It results in plasma ALT levels up to 20x normal.

45
Q

what is deamination?

A

In deamination an amine group is removed from a molecule.

46
Q

what is the function of deamination?

A

The function of this process is to remove be the amino group from an amino acid, this amino group can then be converted to ammonia.
The keto acids remaining can then be metabolised and used for energy.
Also important in deamination of dietary D-amino acids (found in plants and microorganisms)

47
Q

where does deamination occur?

A

Mainly occurs in liver & kidney

48
Q

what happens to the ammonia produced from deamination?

A

• Ammonia (and ammonium ions) very toxic and
must be removed. Ultimately converted to urea or
excreted directly in urine

49
Q

what are the enzymes involved in deamination?

A

Several enzymes can deaminate amino acids
• Amino acid oxidases
• Glutaminase
• Glutamate dehydrogenase

50
Q

what is urea?

A 
• High nitrogen content
• Non-toxic
• Extremely water soluble
• Chemically inert in humans (bacteria
can break it down to release NH3)
• Most urea is excreted in urine via the
kidneys
• Also performs useful osmotic role in
kidney tubules
51
Q

where does the urea cycle occur and what are the components it involves?

A

This process occurs in the liver and involves 5 enzymes

52
Q

Compare the levels of urea cycle enzymes to the level of ammonia

A

The amount of urea cycle enzymes present will relate to the need to dispose of ammonia

53
Q

what is the Function of the urea cycle?

A

The urea cycle is used to convert highly toxic ammonia to urea for excretion. Urea produced by the liver is then released into the bloodstream where it travels to the kidneys and is ultimately excreted in urine.

54
Q

what is the Effect of low/ high protein diet on urea cycle enzyme levels?

A

A high protein diet induces enzyme levels however a low protein diet or starvation represses urea cycle enzyme levels

55
Q

Is the urea cycle regulated?

A

This cycle is inducible but not regulated

56
Q

What is refeeding syndrome

A

• BMI less than 16, weight losses of 15% of body in 3-6 months
• 10 days or more without nutritional intake
• Occurs when nutritional support given to severely malnourished patients
• The urea cycle enzymes have been down regulated due to insignificant protein consumption
• If you feed them protein high foods, ammonia conc will build - ammonia toxicity - lead to hyperammonaemia as the excess amino acids are degraded
• It is therefore important to re-feed starving or
malnourished patients by gradual re-introduction of protein and energy.
• rapidly increasing blood sugar and insulin result in glycogen, fat and protein synthesis. These processes will utilise phosphate, magnesium and potassium from body stores that are already depleted and therefore result in electrolyte abnormalities such as hypophosphataemia resulting in a condition known as re-feeding syndrome.

57
Q

Explain defects in the urea cycle and what it can lead to

A

Autosomal recessive genetic disorders can be caused by a
deficiency of one of enzymes in the urea cycle. It occurs ~1 in 30,000 live births.
These mutations can cause a partial loss of enzyme function.

This can then lead to:
• hyperammonaemia
• An accumulation /excretion of urea cycle intermediates

58
Q

why is ammonia toxic especially in the CNS?

A

The central nervous system is very sensitive to ammonia and high levels of ammonia in the blood (hyperammonaemia) are associated with blurred vision, tremors, slurred speech, coma and eventually death. The molecular basis of the toxic effect of ammonia may involve its reaction with α-ketoglutarate to form glutamate in mitochondria via glutamate dehydrogenase. This effectively removes α-ketoglutarate from the TCA cycle which slows, disrupting the energy supply to brain cells. In addition, it may affect the pH inside cells of the CNS and interfere with neurotransmitter synthesis and release.

59
Q

what does the severity of the defect in the urea cycle depend on?

A

Severity depends on:
• nature of defect
• amount of protein eaten

60
Q

what are the symptoms of defects in urea cycle?

A
  • Vomiting
  • Lethargy
  • Irritability
  • Mental retardation
  • Seizures
  • Coma
61
Q

when does symptoms of urea cycle disorders show?

A

• Severe urea cycle disorders show symptoms within 1 day after birth. If untreated, child will die.
• Mild urea cycle enzyme deficiencies may not show
symptoms until early childhood

62
Q

how are urea cycle disorders managed?

A
  • Low protein diet

* Replace amino acids in diet with keto acids

63
Q

why does ammonia need to be removed from the body?

A
  • Readily diffusible and extremely toxic to brain

* Blood level needs to be kept low (25-40 µmol/L)

64
Q

what are the potential toxic effects of ammonia?

A

• 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
• Interference with TCA cycle (reacts with α-ketoglutarate to
form glutamate)

65
Q

how are amino groups safely transported from tissues to liver for disposal without forming ammonia?

A

2 mechanism:
as glutamine
as alanine

66
Q

describe transport of amine groups as glutamine

A

• 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 liver ammonia fed into urea cycle. In kidney excreted directly in urine

67
Q

describe transport of amine groups as alanine

A
  • Amine groups transferred to glutamate by transamination
  • Pyruvate then transaminated by glutamate to form alanine
  • Alanine transported in blood to liver where it is converted back to pyruvate by transamination.
  • Amino group fed via glutamate into urea cycle for disposal as urea whereas pyruvate is used to synthesise glucose which can be fed back to tissues
68
Q

describe the glucose alanine cycle

A
  • Amine groups transferred to glutamate by transamination
  • Pyruvate then transaminated by glutamate to form alanine
  • the alanine transported in the blood to the liver where it is converted to pyruvate and then to glucose.
  • the glucose then transported back to muscle where it can produce pyruvate which can then be transaminated by glutamate to alanine.
69
Q

what is the function of the glucose alanine cycle?

A

alanine can be used to transport excess amine groups to the liver to get pyruvate back

70
Q

What are the clinical problems of amino acid metabolism?

A

There are over 50 inherited diseases involving defects in amino acid metabolism.
It causes either total, or more commonly partial loss of enzyme activity.
However whilst the diseases individually are rare these metabolism defects collectively constitute a significant portion of paediatric genetic disease.

71
Q

why do problems of amino acid metabolism have to be detected early?

A

It has to be detected at an early age as if left untreated frequently it can lead to intellectual impairment.
Treatment involves restricting specific amino acids in diet.

72
Q

what does the heel prick test test 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
73
Q

when is the heel prick test performed

A

ideally 5 days after babies are born

74
Q

What is phenylketonuria?

A

• Most common inborn error of amino acid
metabolism (~1 in 15,000 births)
• Deficiency in phenylalanine hydroxylase

75
Q

what is the inheritance pattern of phenylketonuria?

A

Autosomal recessive. Affected gene is on

chromosome 12

76
Q

what is the effect of phenylalanine hydroxylase deficiency?

A

This deficiency means that phenylalanine can’t be converted to tyrosine, this causes an accumulation of phenylalanine in tissue, plasma & urine.
The phenylalanine will enter another pathway where it is transaminated to phenylpyruvatewhich is converted to phenylketones. Thus, there is an accumulation of phenylketones in urine resulting in a musty smell

77
Q

what is the effect of phenylalanine hydroxylase deficiency on brain development?

A

• Phenylalanine is a large neutral amino acid (LNAA)
• Competes for transport across the blood brain barrier via Large Neutral Amino Acid Transporter (LNAAT)
• Excess phenylalanine can saturate this transporter
• Levels of other LNAA in the brain decreased
• Protein/neurotransmitter synthesis inhibited
• Brain development affected
• Causes mental retardation
also:
• phenylpyruvate inhibits pyruvate uptake into mitochondria and interferes with energy metabolism in the brain

78
Q

what are the symptoms of phenylketonuria?

A
  • Severe intellectual disability
  • Developmental delay
  • Microcephaly (small head)
  • Seizures
  • Hypopigmentation
79
Q

what is tyrosine needed for?

A 
precursor for:
• Noradrenaline
• Adrenaline
• Dopamine
• Melanin
• Thyroid hormone
• Protein synthesis
80
Q

what is the treatment for phenylketonuria?

A 
• Strictly controlled low
phenylalanine diet
enriched with tyrosine
• Avoid artificial sweeteners
(contain phenylalanine)
• Avoid high protein foods such
as meat, milk, and eggs
81
Q

how is phenylketonuria diagnosed?

A

The condition is diagnosed by the detection of phenylketones in the urine or by the measurement of the blood phenylalanine concentration.

82
Q

what causes Homocystinuria?

A

Homocystinuria is a rare inherited autosomal recessive defect in methionine metabolism, in which Type 1 is caused by a deficiency in the cystathionine β-synthase (CBS) enzyme

83
Q

what process does Homocystinuria affect?

A

The CBS enzyme normally converts homocysteine to cystathionine, which is further converted to cysteine. If CBS is deficient then the levels of homocysteine increase in the blood and some of the homocysteine can be converted to methionine.

84
Q

how is Homocystinuria diagnosed?

A

The condition is usually detected by elevated levels of

homocysteine and methionine in plasma and the presence of homocystine (the oxidised form of homocysteine) in the urine

85
Q

what problems does homocystinuria result in?

A

Chronic elevated plasma levels of homocysteine cause disorders of connective tissue, muscle, CNS and the cardiovascular system, although the mechanisms are not fully understood

86
Q

what promotes the conversion of homocysteine to methionine?

A

methionine from dietary protein and endogenous proteins is usuallu converted to homocysteine. When homocysteine accumulates, it is converted to methionine instead. This is promoted by Betaine,
Vit B12, and Folate

87
Q

what does cystathionine β-synthase require as a co-factor

A

Requires active form of vit B6 as a co-factor

88
Q

what is the treatment for homocystinuria ?

A
  • Low-methionine diet
  • Avoid milk, meat, fish, cheese, eggs
  • Nuts, and peanut butter also contain methionine
  • Cysteine, Vit B6, Betaine, B12 & Folate supplement

Semester 2 - MEH (23 decks)

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