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MEH - SEM1 > Session 4 : Alcohol metabolism, oxidative stress & protein, amino acid metabolism > Flashcards

Session 4 : Alcohol metabolism, oxidative stress & protein, amino acid metabolism Flashcards

1
Q

Where is alcohol metabolised?

A

in the liver

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2
Q

What are the enzymes involved in alcohol metabolism? What does each of them do?

A

alcohol dehydrogenase oxidises alcohol to acetaldehyde
and aldehyde dehydrogenase oxidises acetaldehyde to acetate

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3
Q

Explain how alcohol metabolism produces energy.

A
  • alcohol is oxidised to acetaldehyde and then further oxidised to acetate by aldehyde dehydrogenase
  • acetate is converted to acetyl CoA used in TCA cycle => produces ATP
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4
Q

What is acetyl CoA derived from alcohol metabolism used for?

A

TCA cycle & fatty acid synthesis

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5
Q

How does excessive alcohol consumption cause liver damage?

A
  • aldehyde dehydrogenase => keeps acetaldehyde toxicity low
  • acetaldehyde accumulation from prolonged & excessive alcohol consumption
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6
Q

How is aldehyde dehydrogenase able to keep acetaldehyde toxicity levels low?

A

it has a low Km for acetaldehyde = high affinity

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7
Q

How does a decrease in NAD+/NADH ratio cause lactic acidosis?

A
  • An increase in NADH means that there are inadequate (low) levels of NAD+ needed for lactate to be converted to pyruvate.
  • decreased use of lactate by liver cells causes an accumulation of lactate in cells
  • leads to lactic acidosis
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8
Q

How does a decrease in NAD+/NADH ratio cause gout?

A
  • An increase in NADH means that there are inadequate (low) levels of NAD+ needed for lactate to be converted to pyruvate.
  • Increased lactate reduces the kidney’s ability to excrete uric acid
  • Urate crystals accumulate in tissues causing gout
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9
Q

How does a decrease in NAD+/NADH ratio cause hypoglycaemia?

A
  • Low NAD+ and inability of liver cells to use lactate & glycerol means that glucogenesis cannot be activated
  • cannot produce glucose => hypoglycaemia
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10
Q

How does an increased availability of acetyl CoA cause fatty liver?

A
  • Increased acetyl CoA = cannot be oxidised due to low NAD+/NADH ratio
  • Leads to increased synthesis of FA & ketone bodies => FA converted to triacylglycerol
  • Triacylglycerol cannot be transported from liver cells due to lack of lipoprotein synthesis
    = triacylglycerol remain in liver => contribute to fatty liver
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11
Q

Why can FAs not travel in the blood without being carried by lipoprotein molecules?

A

FAs are insoluble & cannot be transported in the blood as blood is aqueous

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12
Q

What other consequences can occur due to increased availability of acetyl CoA (alcohol)?

A

Production of ketone bodies can cause ketoacidosis

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13
Q

What is the name of the medication used to treat alcohol dependence? How does it work?

A

Disulfiram
It is an inhibitor for aldehyde dehydrogenase
Every time patient drinks alcohol, acetaldehyde will build up causing symptoms of a ‘hangover’ eg nausea.

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14
Q

How are superoxide formed? (O2*-)

A

formed by adding electron to molecular O2

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15
Q

What is OH* (hydroxyl radical)?

A

most damaging free radical, reacts with anything

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16
Q

How is H2O2 (hydrogen peroxide ) damaging if it isn’t a radical?

A

reacts eg with Fe2+ to form free radicals, readily diffusible

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17
Q

What is formed from the reaction between superoxide (O2-) & nitric oxide (NO)?

A

peroxynitrite (ONOO-)

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18
Q

What is peroxynitrite (ONOO-)?

A

not a free radical but a powerful oxidant that damages cells

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19
Q

Name the different cellular defences against oxidative stress.

A
  • Superoxide dismutase (SOD) & catalase
  • Glutathione (GSH)
  • Free radical scavengers
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20
Q

How does superoxide dismutase (SOD) & catalase protect cells from oxidative stress?

A
  • Enzyme that counters damaging effects of superoxide by converting superoxide to hydrogen peroxide (H2O2) & oxygen
  • Catalase breaks down H2O2 to oxygen & water.
  • H2O2 = powerful oxidising agent so damaging => rapidly broken down to oxygen & water by catalase
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21
Q

How does glutathione (GSH) protect cells from oxidative stress?

A
  • Tripeptide (Gly-Cys-Glu) => central Cys can donate electron to a ROS
  • GSH reacts with another GSH to form a disulphide bond (GSSG)
  • Reaction catalysed by glutathione reductase (requires trace element selenium)
  • Glutathione reductase reduces GSSG back to GSH which catalyses the transfer of electrons from NADPH to disulphide bond
  • NADPH essential for regeneration of GSH, w/o = susceptible to oxidative stress
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22
Q

What are the different free radical scavengers?

A
  • Vitamin E
  • Vitamin C
  • Uric acid
  • Melatonin
  • Carotenoid
  • Flavonoids
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23
Q

How do free radical scavengers work?

A

They reduce ROS damage by donating a hydrogen atom & its electron to free radicals from a non-enzymatic reaction

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24
Q

How do Vitamin E & C work in protecting cells from oxidative damage?

A
  • Vitamin E (alpha-tocopherol) => lipid-soluble antioxidant important for protection against lipid peroxidation by donating an electron
  • Vitamin C (ascorbic acid) => water-soluble antioxidant important role in regenerating the reduced form of Vitamin E
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25
Q

How do cataracts form in galactosaemia?

A
  • The increased activity of aldose reductase consumes excess NADPH.
  • GSH unable to be regenerated due to low levels of NADPH
  • Compromised defences against ROS damage
  • Crystallin protein in the lens of eye = denatured
    => CATARACTS
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26
Q

How does oxidative stress such as lipid peroxidation & protein occur in G6PDH deficiency?

A
  • Decreased G6PDH activity limits amount of NADPH in the pentose phosphate pathway
  • NADPH required for reduction of GSSG back to GSH
  • Less GSH regenerated = less protection against damage from oxidative stress
  • Oxidative stress: infection, drugs (eg anti-malarial)
    o Lipid peroxidation => cell membrane damage, lack of deformability => mechanical stress
    o Protein damage => aggregates of cross-linked haemoglobin form (Heinz bodies)
    => LEAD TO HAEMOLYSIS
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27
Q

What happens in paracetamol overdose?

A
  • Overload of paracetamol means that excess paracetamol cannot be metabolised safely => forms toxic intermediate NAPQI
  • Too much paracetamol converted to NAPQI causes glutathione to deplete = reduced protection against oxidative damage to liver cells
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28
Q

How does the antidote acetylcysteine treat paracetamol overdose?

A

Replenishes glutathione (GSH) levels

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29
Q

What is creatinine?

A

Breakdown product of creatine & creatinine phosphate in muscle

30
Q

How can creatinine be used in terms of energy?

A

Readily available source of ATP in muscles eg fuels muscle contraction in first few seconds of rigorous activity when there isn’t enough time to get energy from glycolysis

31
Q

Explain the clinical relevance of measuring creatinine in blood and urine.

A

It can be used as an indicator of renal function
=> high plasma creatinine & low creatinine urine level = suggest damage to nephrons = kidneys not filtering creatinine properly

32
Q

What are the uses of creatinine?

A
  • Provides an estimate of muscle mass
  • It can be used as an indicator of renal function
33
Q

What is nitrogen balance?

A
  • N equilibrium => intake = output (no change in total body protein)
  • Positive N balance => intake > output (increase in total body protein)
  • Negative N balance => Intake < output (net loss of body protein)
34
Q

When might there be a positive N balance?

A

growth, pregnancy & recovering from malnutrition

35
Q

When might there be a negative N balance?

A

trauma, infection or malnutrition

36
Q

What is protein turnover?

A

Proteins undergo continuous breakdown & resynthesis (turnover)

37
Q

How does protein turnover work?

A
  • Free amino acids used to synthesise and recycle proteins
  • Dietary proteins & recycling of proteins sources free amino acid pool
  • Carbon skeleton of amino acid can be used to generate energy through glucogenesis & ketone bodies
  • Amino acids may release ammonia = very toxic to cells
  • Amine groups of AA converted to urea which is excreted in urine
38
Q

How is the mobilisation of protein reserves controlled?

A

under hormonal control using insulin & growth hormone and glucocorticoids eg cortisol

39
Q

Which hormones increase protein synthesis and decrease protein degradation?

A

insulin & growth hormone

40
Q

Which hormones decrease protein synthesis and increase protein degradation?

A

glucocorticoids eg cortisol

41
Q

What is transamination? Where does it occur and which enzymes are involved?

A
  • Removal of NH2 group from AA
  • Occurs in the liver
  • Involves aminotransferases (transaminases)
42
Q

Aminotransferases require __?__. Where do they come from?

A

the coenzyme pyridoxal phosphate which is a derivative of vitamin B6

43
Q

What do aminotransferases do?

A

Aminotransferase use α-ketoglutarate to convert AA group to glutamate which is MORE readily able to feed into the urea cycle and safely produce urea rather than ammonium.

44
Q

How is liver function assessed?

A

Assessing the presence of Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST)
- Plasma ALT & AST = part of liver function test
- High levels in conditions that cause severe necrosis eg viral hepatitis, autoimmune liver diseases & toxic injury.

45
Q

What is alanine aminotransferase (ALT) and what does it do?

A

it is a transaminase
catalyses conversion of alanine & α-ketoglutarate to pyruvate & glutamate

46
Q

What is aspartate aminotransferase (AST) and what does it do?

A

it is a transaminase
catalyses conversion of aspartate & α-ketoglutarate to oxaloacetate & glutamate

47
Q

What is deamination?

A

a way of metabolising amino acids
involves enzymes reacting with AA to liberate NH2 group as free ammonia (NH3/NH4+) so that it can be dealt with quickly by the urea cycle

48
Q

At what pH is ammonia converted to ammonium ion?

A

pH 7.4 (physiological pH)

49
Q

What enzymes are involved in deamination?

A
  • Amino acid oxidases
  • Glutaminase
  • Glutamate dehydrogenase
50
Q

How are dietary D-amino acids used for energy?

A

converted to keto acids

51
Q

Where are dietary D-amino acids found?

A

in plants & microrganisms

52
Q

What are glucogenic amino acids? Give 2 examples.

A

AAs that can be converted to glucose through gluconeogenesis eg alanine & serine

53
Q

What are ketogenic amino acids? Give 2 examples.

A

AAs that can be converted to ketone bodies to be converted to acetyl CoA which enters citric acid cycle (Krebs) & oxidised to produce energy eg lysine & leucine

54
Q

What is the enzyme involved in phenylketonuria (PKU) called?

A

phenylalanine hydroxylase

55
Q

What is phenylketonuria (PKU)?

A

an inherited metabolic disorder in which urine contains large amounts of phenyl ketones produced from phenylamine

56
Q

What causes phenylketonuria (PKU)?

A

deficiency in phenylalanine hydroxylase causing phenylamine to accumulate in blood, tissues & urine

57
Q

What are the symptoms of phenylketonuria (PKU)? (5)

A
  • Severe intellectual disability
  • Development delay
  • Seizures
  • Microcephaly (small head)
  • Hypopigmentation
58
Q

How is phenylketonuria (PKU) diagnosed?

A

diagnosed by the detection of phenyl ketones in urine or measurement of blood phenylalanine concentration
- normally < 0.1mmol/L, in PKU can exceed 1.0mmol/L

59
Q

How can symptoms of phenylketonuria be avoided?

A

by early intervention

60
Q

Where is ammonia absorbed?

A

GI tract

61
Q

Which part of the body is especially sensitive to hyperammonaemia? What are the symptoms of this? (5)

A

the CNS
blurred vision, tremors, slurred speech, coma & eventually death.

62
Q

Where is ammonia metabolised?

A

in the liver

63
Q

What are the key features of the urea cycle? (6)

A
  • Involves 5 enzymes
  • Ammonia converted to urea = safely excreted in urine
  • Occurs in mitochondria of liver cells
  • Amount of enzymes related to the need to dispose of ammonia
  • High protein diet activates enzyme levels (more ammonia to dispose of)
  • Low protein diet/starvation inhibits levels (less ammonia to dispose of)
64
Q

What happens to enzymes when there is a high-protein diet? Why?

A

enzymes are activated as there is more ammonia to dispose of

65
Q

What happens to enzymes when there is a low-protein diet/starvation? Why?

A

enzymes are inhibited as there is less ammonia to dispose of

66
Q

What are the 2 ways in which glutamate can be used to join the urea cycle?

A
  1. Be deaminated by glutamate dehydrogenase -> releasing NH2 which feeds straight into cycle
  2. Can be converted to aspartate & join cycle
67
Q

Why are amino acids converted to glutamate?

A

it is MORE readily able to feed into urea cycle

68
Q

What makes urea a good way to excrete ammonia?

A
  • High nitrogen content
  • Non-toxic
  • Very water soluble
  • Chemically inert
  • Excreted in urine via kidneys
  • Performs useful osmotic role in kidney tubules
69
Q

What is refeeding syndrome?

A

Occurs when high amount of nutrition given to severely malnourished patients

70
Q

How does hypophosphataemia develop from refeeding syndrome?

A

Influx of nutrition drains phosphate stocks that are already low

71
Q

How does ammonia toxicity develop from refeeding syndrome?

A

the urea cycle is downgraded due to malnourishment so when given a high protein diet it cannot metabolise ammonia as effectively so a high concentration of ammonia remains in the body = toxic

72
Q

How is refeeding syndrome treated?

A

Gradual nourishment eg 5-10/kcal/kg/day

MEH - SEM1 (6 decks)

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