Session 4 : Alcohol metabolism, oxidative stress & protein, amino acid metabolism Flashcards
(72 cards)
1
Q
Where is alcohol metabolised?
A
in the liver
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
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
4
Q
What is acetyl CoA derived from alcohol metabolism used for?
A
TCA cycle & fatty acid synthesis
5
Q
How does excessive alcohol consumption cause liver damage?
A
- aldehyde dehydrogenase => keeps acetaldehyde toxicity low
- acetaldehyde accumulation from prolonged & excessive alcohol consumption
6
Q
How is aldehyde dehydrogenase able to keep acetaldehyde toxicity levels low?
A
it has a low Km for acetaldehyde = high affinity
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
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
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
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
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
12
Q
What other consequences can occur due to increased availability of acetyl CoA (alcohol)?
A
Production of ketone bodies can cause ketoacidosis
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.
14
Q
How are superoxide formed? (O2*-)
A
formed by adding electron to molecular O2
15
Q
What is OH* (hydroxyl radical)?
A
most damaging free radical, reacts with anything
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
17
Q
What is formed from the reaction between superoxide (O2-) & nitric oxide (NO)?
A
peroxynitrite (ONOO-)
18
Q
What is peroxynitrite (ONOO-)?
A
not a free radical but a powerful oxidant that damages cells
19
Q
Name the different cellular defences against oxidative stress.
A
- Superoxide dismutase (SOD) & catalase
- Glutathione (GSH)
- Free radical scavengers
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
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
22
Q
What are the different free radical scavengers?
A
- Vitamin E
- Vitamin C
- Uric acid
- Melatonin
- Carotenoid
- Flavonoids
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
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
25
How do cataracts form in galactosaemia?
- 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
26
How does oxidative stress such as lipid peroxidation & protein occur in G6PDH deficiency?
- 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
27
What happens in paracetamol overdose?
- 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
28
How does the antidote acetylcysteine treat paracetamol overdose?
Replenishes glutathione (GSH) levels
29
What is creatinine?
Breakdown product of creatine & creatinine phosphate in muscle
30
How can creatinine be used in terms of energy?
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
Explain the clinical relevance of measuring creatinine in blood and urine.
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
What are the uses of creatinine?
- Provides an estimate of muscle mass
- It can be used as an indicator of renal function
33
What is nitrogen balance?
- 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
When might there be a positive N balance?
growth, pregnancy & recovering from malnutrition
35
When might there be a negative N balance?
trauma, infection or malnutrition
36
What is protein turnover?
Proteins undergo continuous breakdown & resynthesis (turnover)
37
How does protein turnover work?
- 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
How is the mobilisation of protein reserves controlled?
under hormonal control using insulin & growth hormone and glucocorticoids eg cortisol
39
Which hormones increase protein synthesis and decrease protein degradation?
insulin & growth hormone
40
Which hormones decrease protein synthesis and increase protein degradation?
glucocorticoids eg cortisol
41
What is transamination? Where does it occur and which enzymes are involved?
- Removal of NH2 group from AA
- Occurs in the liver
- Involves aminotransferases (transaminases)
42
Aminotransferases require __?__. Where do they come from?
the coenzyme pyridoxal phosphate which is a derivative of vitamin B6
43
What do aminotransferases do?
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
How is liver function assessed?
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
What is alanine aminotransferase (ALT) and what does it do?
it is a transaminase
catalyses conversion of alanine & α-ketoglutarate to pyruvate & glutamate
46
What is aspartate aminotransferase (AST) and what does it do?
it is a transaminase
catalyses conversion of aspartate & α-ketoglutarate to oxaloacetate & glutamate
47
What is deamination?
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
At what pH is ammonia converted to ammonium ion?
pH 7.4 (physiological pH)
49
What enzymes are involved in deamination?
- Amino acid oxidases
- Glutaminase
- Glutamate dehydrogenase
50
How are dietary D-amino acids used for energy?
converted to keto acids
51
Where are dietary D-amino acids found?
in plants & microrganisms
52
What are glucogenic amino acids? Give 2 examples.
AAs that can be converted to glucose through gluconeogenesis eg alanine & serine
53
What are ketogenic amino acids? Give 2 examples.
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
What is the enzyme involved in phenylketonuria (PKU) called?
phenylalanine hydroxylase
55
What is phenylketonuria (PKU)?
an inherited metabolic disorder in which urine contains large amounts of phenyl ketones produced from phenylamine
56
What causes phenylketonuria (PKU)?
deficiency in phenylalanine hydroxylase causing phenylamine to accumulate in blood, tissues & urine
57
What are the symptoms of phenylketonuria (PKU)? (5)
- Severe intellectual disability
- Development delay
- Seizures
- Microcephaly (small head)
- Hypopigmentation
58
How is phenylketonuria (PKU) diagnosed?
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
How can symptoms of phenylketonuria be avoided?
by early intervention
60
Where is ammonia absorbed?
GI tract
61
Which part of the body is especially sensitive to hyperammonaemia? What are the symptoms of this? (5)
the CNS
blurred vision, tremors, slurred speech, coma & eventually death.
62
Where is ammonia metabolised?
in the liver
63
What are the key features of the urea cycle? (6)
- 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
What happens to enzymes when there is a high-protein diet? Why?
enzymes are activated as there is more ammonia to dispose of
65
What happens to enzymes when there is a low-protein diet/starvation? Why?
enzymes are inhibited as there is less ammonia to dispose of
66
What are the 2 ways in which glutamate can be used to join the urea cycle?
1. Be deaminated by glutamate dehydrogenase -> releasing NH2 which feeds straight into cycle
2. Can be converted to aspartate & join cycle
67
Why are amino acids converted to glutamate?
it is MORE readily able to feed into urea cycle
68
What makes urea a good way to excrete ammonia?
- High nitrogen content
- Non-toxic
- Very water soluble
- Chemically inert
- Excreted in urine via kidneys
- Performs useful osmotic role in kidney tubules
69
What is refeeding syndrome?
Occurs when high amount of nutrition given to severely malnourished patients
70
How does hypophosphataemia develop from refeeding syndrome?
Influx of nutrition drains phosphate stocks that are already low
71
How does ammonia toxicity develop from refeeding syndrome?
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
How is refeeding syndrome treated?
Gradual nourishment eg 5-10/kcal/kg/day
