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MEH > Session 1 > Flashcards

Session 1 Flashcards

1
Q

Where is most alcohol metabolised and what happens to the rest?

A

Most alcohol is metabolised in the liver (>90%), the rest is excreted passively in urine or in breath.

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2
Q

Can alcohol be metabolised in the brain?

A

Smaller amounts of alcohol can be metabolised by cytochrome P450 enzyme 2E1 (CYP2E1) or catalase in the brain.

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3
Q

Can alcohol be used for energy?

A

Alcohol can be converted to Acetate and Acetate can be converted to acetyl-CoA which can be used in the TCA (Krebs) cycle and in fatty acid synthesis.

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4
Q

What is the maximum recommended alcohol intake in the UK?

A

14 units per week max recommended for both men and women over a minimum of 3 days.

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5
Q

How much is one unit of alcohol?

A

One unit of alcohol is 10ml / 8g of pure ethanol

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6
Q

How fast can the body metabolise alcohol

A

Body metabolises 7g of ethanol per hour

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7
Q

How is alcohol metabolised?

A

Ethanol is converted to acetaldehyde by alcohol dehydrogenase. This converts an NAD+ to NADH.
Acetaldehyde is then converted to acetate by aldehydedehydrogenase. This also converts an NAD+ to NADH.

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8
Q

Accumulation of what molecule causes hangovers?

A

Acetaldehyde

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9
Q

What keeps acetaldehyde concentration low?

A

Acetaldeyde concentration kept low by aldehyde dehydrogenase. It has a high affinity and low Kd.

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10
Q

What can prolonged and excessive alcohol consumption cause?

A

Prolonged and excessive alcohol consumption can cause sufficient acetaldehyde accumulation to cause liver scarring (cirrhosis). Other conditions can include alcoholic cirrhosis, alcoholic hepatitis and fatty liver.

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11
Q

What drug can be given to people with alcoholism and how does it work?

A

Disulfiram acts as an inhibitor to aldehyde dehydrogenase preventing the breakdown of acetaldehyde causing it to accumulate and cause a hangover. It is used as a chronic alcohol dependence treatment.

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12
Q

Increased alcohol oxidation causes what changes in the body?

A
  • Lactic acidosis
  • Urate crystals accumulate in tissues causing gout
  • Hypoglycaemia
  • Fatty Liver
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13
Q

How does excessive alcohol oxidation cause lactic acidosis?

A
  1. Decrease in NAD+/NADH ratio
  2. Inadequate NAD+ for conversion of lactate to pyruvate
  3. Lactate accumulates in the blood causing lactate acidosis.
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14
Q

How does excessive alcohol oxidation cause gout?

A
  1. Decrease in NAD+/NADH ratio
  2. Inadequate NAD+ for conversion of lactate to pyruvate.
  3. Lactate accumulates in blood
  4. Kidneys’ ability to excrete Uris acid reduced
  5. Urate crystals accumulate in tissues producing gout
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15
Q

How does excessive alcohol oxidation cause hypoglycaemia?

A
  1. Decrease in NAD+/NADH ratio.
  2. Inadequate NAD+ for glycerol metabolism and conversion of lactate to pyruvate.
  3. This causes a deficit in gluconeogenesis.
  4. This results in hypoglycaemia
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16
Q

How does excessive alcohol oxidation cause fatty liver?

A

Three ways:
First:
1. Decrease in NAD+/NADH ratio
2. Inadequate NAD+ for fatty acid oxidation.
3. Increased synthesis of triacylglycerol
4. This leads to fatty liver.
Second:
1. Increased. Acetyl-CoA
2. Increased synthesis of fatty acids and ketone bodies
3. Increased synthesis of triacylglycerol
4. This results in fatty liver.
Third:
1. Excessive/prolonged alcohol consumption results in lower lipoprotein synthesis
2. This results in a fatty liver

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17
Q

Why is oxidative stress such an important topic to understand?

A

Cellular damage caused by ROS and RNS is a significant component in a wide range of disease states.

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18
Q

What is oxidative stress?

A

A state where cell damage caused by ROS and RNS is more tan the cell defences can handle

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19
Q

What are free radicals?

Give some information also

A

A free radical is an atom or molecule that contains one or more
unpaired electrons and is capable of independent
existence.
Free radicals are usually very reactive and tend to acquire electrons from other atoms, molecules or ions.
Reaction of a radical with a molecule typically generates a second radical thereby propagating damage.

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20
Q

What is an ROS?

A

Reactive oxygen species

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21
Q

What is an RNS?

A

Reactive nitrogen species

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22
Q

What are the two RNS that you need to know?

A

Nitric oxide (NO*)and peroxynitrite (ONOO^-)

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23
Q

How is peroxynitrite made? and is it a free radical?

A 
Superoxide can react
with nitric oxide to
produce peroxynitrite 
O2*^- + NO* -> ONOO^- 
Peroxynitrite is not
itself a free radical, but
is a powerful oxidant
that can damage cells
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24
Q

What are the three ROS that you need to know?

A 
Superoxide (O2*^-)
Hydrogen peroxide (H2O2)
Hydroxyl radical (OH*)
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25
Q

How is superoxide produced?

A

Produced by adding
Superoxide electron to molecular oxygen. Also Important
source of other ROS

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26
Q

Is hydrogen peroxide a free radical?

A

Not a free radical but can

react e.g. with Fe2+ to produce free radicals. Readily diffusible.

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27
Q

Why is the hydroxyl radical so dangerous?

A

It’s the most reactive and so reacts with anything.

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28
Q

How are the ROS made?

A

Oxygen molecule gains an electron to become superoxide.
Superoxide gains two H+ and an electron to become hydrogen peroxide.
Hydrogen peroxide gains an electron and a H+ and the. Splits to form a water molecule and a hydroxyl radical.

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29
Q

What are the two main types of damage ROS can do to DNA?

A

Two main types of damage:
• ROS reacts with base
Modified base can lead to mispairing and mutation
• ROS reacts with sugar (ribose or deoxyribose)
Can cause strand break and mutation on repair

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30
Q

How can ROS damage lead to cancer?

A
  1. ROS reacts with DNA
  2. DNA damage
  3. Failure in repair can lead to mutation
  4. Mutation can lead to cancer
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31
Q

What can be used as a measurement of oxidative damage?

A

The amount of 8-oxo-dG present in cells can be used as measurement of oxidative damage.
When damaged by ROS deoxyguanosine becomes 8-oxo-dG.

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32
Q

How can ROS cause damage to proteins?

A

Two ways:
By damaging backbone:
1. ROS reacts with protein.
2. If it reacts with backbone it can cause fragmentation.
3. This leads to protein degradation
By damaging side chain:
1. ROS reacts with protein
2. If it reacts with a side chain it could result in a modified amino acid e.g making a ring opened species or carbonyl.
3. This causes change in the protein’s structure.
This can result in protein degradation, loss of function or gain of function.

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33
Q

What role do disulphide bonds play in proteins and what may be the consequences of inappropriate disulphide bond formation?

A
  • Play important role in folding and stability of some proteins (usually secreted proteins or in extracellular domains of membrane proteins)
  • Formed between thiol groups of cysteine residues
  • Inappropriate disulphide bond formation can occur if ROS takes electrons from cysteines causing misfolding, crosslinking and disruption of function (e.g. enzyme)
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34
Q

How can ROS damage lipids?

A

• Free radical (e.g. *OH)
extracts hydrogen atom from a polyunsaturated fatty acid in membrane lipid.
• Lipid radical formed which
can react with oxygen to form a lipid peroxyl radical.
• Chain reaction formed as lipid peroxyl radical extracts hydrogen form nearby fatty acid
• Hydrophobic environment of bilayer disrupted and membrane integrity fails

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35
Q

What are the main sources of biological oxidants?

A 
Endogenous:
• Electron transport chain 
• Nitric oxide synthases 
• NADPH oxidases 
Exogenous:
• Radiation
Cosmic rays
UV light
X-rays 
• Pollutants 
• Drugs
Primaquine (anti-malarial) 
• Toxins
Paraquat (herbicide)
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36
Q

How can the electron transport chain be a source of ROS?

A
  • NADH and FADH2 supply electrons (e−) from metabolic substrates
  • electrons pass through ETC and reduce oxygen to form H2O at Complex IV
  • Occasionally electrons can accidently escape chain and react with dissolved O2 to form superoxide.
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37
Q

What are the three types of nitric oxide synthase (NOS)?

A
  • iNOS: Inducible nitric oxide synthase. Produces high NO concentrations in phagocytes for direct toxic effect.
  • eNOS: Endothelial nitric oxide synthase (Signalling)
  • nNOS: Neuronal nitric oxide synthase (Signalling)
38
Q

What does nitric oxide synthase do?

A

It’s an enzyme that produces nitric oxide. It converts arginine to citrulline and nitric oxide.

39
Q

What does nitric oxide do in the body?

A

Signalling molecule
• Vasodilation
• Neurotransmission
• S-Nitrosylation

Use in phagocytes for direct toxic effect.

40
Q

What is the downside of using nitric oxide?

A

It has toxic effects at high levels

41
Q

How are free radicals made in phagocytes?

A

NADPH Oxidase converts NADPH to NADP+ to convert an oxygen molecule into superoxide.
Superoxide can combine with nitric oxide to make peroxynitrite or be made into hydrogen peroxide which can be converted into hypochlorite; both of which can be used to kill bacteria.

42
Q

What is chronic granulomatous disease?

A

Genetic defect in NADPH oxidase complex causes
enhanced susceptibility to bacterial infections
• Atypical infections
• Pneumonia
• Abscesses
• Impetigo
• Cellulitis

43
Q

How do superoxide dismutase and catalase work together to defend against oxidative stress?

A

Superoxide dismutase (SOD)
• Converts superoxide to H2O2 and oxygen
• Primary defence because superoxide is strong initiator of chain reactions
Catalase
• Converts H2O2 to water and oxygen
• Widespread enzyme. Important in immune cells to protect against oxidative burst.

44
Q

What is glutathione and how does it work to defend cells against oxidative stress?

A

• Tripeptide (glycine, cysteine and glutamate) synthesised by body to protect against oxidative damage
• Thiol group of Cys donates e− to ROS. GSH (reduced form)then reacts with another GSH to form disulphide (GSSG).
• Glutathione peroxidase requires Selenium
• GSSG reduced back to GSH by
glutathione reductase which
catalyses the transfer of electrons
from NADPH to disulphide bond
phosphate pathway
• NADPH from pentose phosphate
pathway is therefore essential for
protection against free radical

45
Q

How is the reduced from of glutathione restored.

A

Glutathione reductase converts NADPH, from the pentose phosphate pathway, to NADP+ in order to convert one GSSG to two GSH(reduced form).

46
Q

What do you need to know about thee pentose phosphate pathway?

A
  • Starts from Glucose-6-phosphate
  • It’s an important source of NADPH required for:
    Reducing power of biosynthesis
    Maintenance of GSH levels
    Detoxification reactions
  • Produces ribose-5-phosphate required for synthesis of nucleotides, RNA and DNA.
  • No ATP synthesised. CO2 produced.
  • The rate limiting enzyme is glucose-6-phosphate dehydrogenase.
47
Q

What are free radical scavengers?

Give examples.

A

Free radical scavengers reduce free radical damage by donating hydrogen atom (and its electron) to free radicals in a nonenzymatic reaction.

Vitamin E
• Lipid soluble antioxidant Vitamin E
• Important for protection against lipid peroxidation.

Vitamin C
• Water soluble antioxidant
• Important role in regenerating reduced form of Vitamin E

Others:
Carotenoids.
Uric acid.
Flavonoids.
Melatonin.
48
Q

What causes galactosaemia?

What are the symptoms?

A 
When there is a defect in one of three enzymes involved in the metabolism of galactose (galactokinase, uridyl transferase or UDP - galactose epimerase) so galactose builds up. This results in galactose concentration being higher than normal in the blood.
Symptoms:
Hepatomegaly + Cirrhosis
Renal failure 
Vomiting 
Seizure + Brain damage
Cataracts 
Hypoglycaemia
49
Q

How does galactosaemia compromise bodily defences against ROS damage?

A

Aldose reductase converts galactose to galactitiol using NADPH. This consumes excess NADPH which could be used to reform GSH but without it this cant happen reducing the body’s defence against ROS damage.

50
Q

Why do people with galactosaemia get cataracts?

A

High concentration of galactitol causes osmotic pressure combined with ROS damage resulting in crystalline protein in the lens of the eye being denatured

51
Q

Why would glucose-6-phosphate dehydrogenase deficiency result in ROS damage?

A

Glucose-6-phosphate dehydrogenase converts glucose 6 phosphate to 6-phosphogluconate and when it does this is reduces NADP to NADPH. NADPH is required for reduction of oxidised glutathione (GSSG) back to reduced glutathione (GSH). If there is a lack of G6PDH then there is less NADPH and so less GSH resulting in oxidative stress.

52
Q

What are Heinz bodies?

A 
Protein damage due to ROS causes aggregates of cross linked haemoglobin in RBCs. Dark staining within RBC resulting from precipitated haemoglobin. 
• Bind to cell membrane altering
rigidity 
• Increased mechanical stress
when cells squeeze through
small capillaries 
• Spleen removes bound Heinz
bodies resulting in “blister cells” 
• Clinical sign of G6PDH
deficiency.
This results in haemolysis of the RBCs.
53
Q

Explain the normal metabolism of paracetamol and what happens during an overdose?

A

Paracetamol at prescribed dosage is safely converted into glucuronide and sulphate. When there is too much paracetamol this pathway becomes saturated and the paracetamol is instead converted into NAPQI which is toxic. Glutathione then deals with the the NAPQI but is used up, depleting the cells store of glutathione. Acetylcysteine works as an antidote by replenishing glutathione levels.

54
Q

What are the major nitrogen containing compounds?

A 
Amino acids
Proteins
Purine and pyrimidines (DNA and RNA)
Smaller amounts of others:
• Porphyrins (haem) 
• Creatine phosphate 
• Neurotransmitters (e.g. dopamine) 
• Some hormones (e.g. adrenaline)
55
Q

What is creatinine and why is it useful?

A 
• Breakdown product of creatine & creatine phosphate in muscle
• Usually produced at constant rate
depending on muscle mass (unless muscle is wasting)
• Filtered via kidneys into urine
• Creatinine urine excretion over 24h
proportional to muscle mass.
• Provides estimate of muscle mass 
• Also commonly used as indicator of
renal function (raised level on damage
to nephrons)
56
Q

Explain how nitrogen is lost gained and held in the body?

A

In 70kg male:
2kg nitrogen stored as body proteins
16g nitrogen in an amino acid pool which can be used to make body proteins or other N-containing compounds.
These their N-containing compounds make up about 60g of nitrogen.
Nitrogen can be lost through waste products such as faeces and urine which we lose about 14g nitrogen and through loss of skin hair and nails about 2g of nitrogen.
We gain nitrogen through dietary proteins which is roughly 16g a day.

57
Q

What is nitrogen equilibrium?

A

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

58
Q

What is positive nitrogen balance?

A

Positive N balance
Increase in total body protein.
Normal state in growth & pregnancy or in adult recovering from malnutrition.

59
Q

What is negative nitrogen balance?

A 
Negative N balance 
Intake < output 
Net loss of body protein. 
Never normal. 
Causes include trauma, infection, or malnutrition.
60
Q

Explain protein turnover

A

In your body there’s is a pool of free amino acids. These can come from new amino acid synthesis, dietary protein digestion or proteolysis of cellular proteins. These can be used to synthesise more proteins or sent to the liver. At the liver they are broken down and the amino group is converted to urea to be excreted in urine as we don’t want it to form ammonia which is very toxic to cells. Depending on the carbon skeleton left over the amino acid can be divided into glucogenic and ketogenic amino acids. The glucogenic amino acids can be used for gluconeogenesis and the ketogenic amino acids can be used for ketone bodies. Both of which are used for energy.

61
Q

Give an example of a glucogenic amino acid, a ketogenic amino acid, and an amino acid that is both ketogenic and glucogenic.

A

Glucogenic: Alanine
Ketogenic: Lysine
Both: Tyrosine

62
Q

When does mobilisation of proteins occur?

A

Occurs during extreme stress (starvation)
Occurs under hormonal control
Insulin and growth hormone increase protein synthesis and decrease protein degradation whereas glucocorticoids (e.g cholesterol) decrease protein synthesis and increases protein degradation.

63
Q

Why might someone with high cortisol have striae (stretch marks)?

A

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

64
Q

How many amino acids are there and how many are dietary essentials?

A

20 amino acids

9 essential amino acids

65
Q

What are the 9 essential amino acids?

A 
If                        Isoleucine 
Learned            Lysine
This                  Threonine
Huge                 Histidine 
List.                   Leucine
May.                  Methionine
Prove                Phenylalanine
Truly                 Tryptophan
Valuable           Valine
66
Q

What are conditonally essential amino acids?

A

Children and pregnant women have a high rate of Presteigne synthesis so also require dietary arginine, tyrosine and cysteine

67
Q

What determine if something is high quality in terms of its protein content?

A

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

68
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)
69
Q

Name 8 compounds and the specific amino acids that they require

A 
Thyroid hormone - Tyrosine
Hydrogen sulphide - Cysteine 
Serotonin - Tryptophan
Histamine - Histidine
GABA - Glutamate
Nitric Oxide - Arginine
Sphingosine - Serine
Creatine - Gycine
70
Q

What are the two methods used in the body to remove nitrogen from amino acids?

A

Transamination

Deamination

71
Q

What is transamination?

A

An aminotransferase enzyme is used to move the amine group from the amino acid to a keto acid. The new amino acid formed is more easily able to enter the urea cycle.
• Most aminotransferase enzymes use α-ketoglutarate to funnel the amino group to glutamate.
• Exception to rule is aspartate aminotransferase which uses oxaloacetate to funnel amino group to aspartate
• All aminotransferases require the coenzyme pyridoxal phosphate which is a derivative of vitamin B6

72
Q

Name the two enzymes involved in transamination

A 
Alanine aminotransferase (ALT)
Converts alanine to glutamate
Aspartate aminotransferase (AST)
Converts glutamate to aspartate
73
Q

When would you measure plasma ALT and AST?

A 
As part of a over function test.
Levels particularly high in conditions that cause extensive cellular necrosis such as:
• Viral hepatitis
• Autoimmune Liver Diseases
• Toxic injury
74
Q

What is deamination?

A

• Liberates amino group as free ammonia
• Mainly occurs in liver & kidney
• Keto acids can be utilised for energy
• Also important in deamination of dietary D-amino
acids (found in plants and microorganisms)

75
Q

What enzymes can deamination amino acids?

A

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

76
Q

What are the properties of urea?

A
  • High nitrogen content
  • Non-toxic
  • Extremely water soluble
  • Chemically inert in humans (bacteria can break it down to release NH 3)
  • Most urea is excreted in urine via the kidneys
  • Also performs useful osmotic role in kidney tubules
77
Q

Give information on the urea cycle

A
  • Occurs in liver and involves 5 enzymes
  • Amount of urea cycle enzymes normally related to need to dispose of ammonia
  • High protein diet induces enzyme levels
  • Low protein diet or starvation represses levels
  • Cycle is inducible but not regulated
78
Q

What is reseeding syndrome?

A

Urea cycle down regulated due to malnutrition. So when when lots of protein is digested the urea cycle doesn’t have enough enzymes working the urea cycle so toxic ammonia builds up.

79
Q

Where might a defect in the urea cycle come from?

A

Autosomal recessive genetic orders caused by deficiency in one of the enzymes in the urea cycle.
Mutations cause a partial loss of enzyme function.
Leads to:
• hyperammonaemia
• accumulation/excretion of urea cycle intermediates

80
Q

What are the symptoms of defects in the urea cycle?

A 
Symptoms
• Vomiting 
• Lethargy 
• Irritability 
• Mental retardation 
• Seizures 
• Coma
81
Q

What does the severity of a defect in thee urea cycle depend on?

A
  • nature of defect

* amount of protein eaten

82
Q

When do symptoms of a defect in the urea cycle 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

83
Q

How is a defect in the urea cycle managed?

A
  • Low protein diet

* Replace amino acids in diet with keto acids

84
Q

Why is ammonia so toxic?

A

• Readily diffusible and extremely toxic to brain
• Blood level needs to be kept low (25-40 µmol/L)
Several potential toxic effects:
• 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)

85
Q

What are the two mechanisms for safe transport of amino acid nitrogen from tissues to the liver?

A

Glutamine
• 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

Alanine
• 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

86
Q

What does the heel prick test, test for?

A

Heel prick test
• Sickle cell disease
• Cystic fibrosis
• Congenital hypothyroidism

Inborn errors of metabolism
• Phenylketonuria (PKU)
• Maple syrup urine disease
• Isovaleric acidaemia (IVA)
• Glutaric aciduria
• Homocystinuria
87
Q

What is phenylketonuria? And how is it treated?

A 
Most common inborn error of amino acid metabolism 
Deficiency in phenylalanine hydroxylase 
Autosomal recessive. Affected gene is on chromosome 12
Accumulation of phenylalanine in tissue, plasma &amp; urine 
Phenylketones in urine 
Musty smell
Symptoms:
• Severe intellectual disability 
• Developmental delay 
• Microcephaly (small head) 
• Seizures 
• Hypopigmentation

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

88
Q

What are the affected pathways in phenylketonuria and why?

A
  • Noradrenaline
  • Adrenaline
  • Dopamine
  • Melanin
  • Thyroid hormone
  • Protein synthesis

This is due to a lack of tyrosine, as the phenylalanine’s hydroxylase cant convert phenylalanine to tyrosine. Instead it’s converted to phenylpyruvate which is made into phenylacetate and phenyllactate (these are phenylketones which accumulate in blood and urine)

89
Q

What is Homocystinurias and how is it treated?

A 
• Problem breaking down methionine 
• Excess homocystine (oxidised form of
homocysteine) excreted in urine 
• Autosomal recessive disorders. 
• Incidence ~1 in 344,000 Treatment
• Defect in cystathionine β-synthase
• Affects connective tissue, muscles, CNS, CVS
Treatment:
• Low-methionine diet 
• Avoid milk, meat, fish, cheese,
eggs 
• Nuts, and peanut butter also contain methionine 
• Cysteine, Vit B6, Betaine, B12 &amp; Folate supplement
90
Q

Describe the pathway change with Homocystinuria

A

Normally methionine is converted to homocysteine and then that is converted to cystathionine by cystathionine β-synthase, which will go on to become cysteine. Homocysteine can go back to methionine and this is promoted by beating, vit B12 and folate. cystathionine β-synthase requires an active for of VitB6 as a co-factor.

In homocystinuria there’s a defect in the cystathionine β-synthase so homocysteine is not sufficiently converted to cystathionine causing methionine and homocysteine to accumulate which is what causes disease symptoms.

MEH (11 decks)

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