S1 Flashcards
(86 cards)
1
Q
Describe the metabolism of alcohol
A
Oxidised by alcohol dehydrogenase to acetaldehyde then oxidised to acetate by aldehyde dehydrogenase
2
Q
What can acetate be used for?
A
Converted to acetyl-CoA – TCA cycle or for FA synthesis
3
Q
where is the major site of alcohol metabolism and where can smaller amounts be oxidised?
A
Liver
Smaller amounts can be oxidised in live by cytochrome P450 2E1 enzyme (CYP2E1) or by catalase in brain
4
Q
What is the recommended limit of alcohol consumption for men and women?
A
14 units/week spread over at least 3 days
5
Q
How much is one unit of alcohol in grams?
A
8g
6
Q
What is the rate of alcohol elimination?
A
~7g per hour
7
Q
How is acetaldehyde toxicity normally kept to a minimum?
A
By aldehyde dehydrogenase- low Km for acetaldehyde
8
Q
What does prolonged and excessive alcohol consumption cause?
A
Acetaldehyde accumulation = liver damage
Excess NADH and acetyl-CoA leads to changes in liver metabolism
9
Q
How does chronic alcohol consumption cause lactic acidosis?
A
Decreased NAD+/NADH ratio
Inadequate NAD+ for conversion of lactate to pyruvate
Lactate accumulates in blood causing lactic acidosis
10
Q
How does chronic alcohol consumption cause gout?
A
Decreased NAD+/NADH ratio
Inadequate NAD+ for conversion of lactate to pyruvate
Lactate accumulates in blood
Kidney’s ability to excrete uric acid reduced
Urate crystals accumulate in tissues producing gout
11
Q
How does chronic alcohol consumption cause hypoglycaemia?
A
Decreased NAD+/NADH ratio
Inadequate NAD+ for glycerol metabolism
Deficit in gluconeogenesis
12
Q
How does chronic alcohol consumption cause fatty liver?
A
Increased acetyl-CoA
Increased synthesis of fatty acids and ketone bodies
Increased synthesis of triacylglycerol
13
Q
What can be used to treat chronic alcohol dependence?
A
Disulfiram
14
Q
What does disulfiram do?
A
Inhibitor of aldehyde dehydrogenase
If patient drinks alcohol acetaldehyde will accumulate causing symptoms of a hangover
15
Q
What diseases do oxidative stress contribute to?
A
Alzheimer’s disease Rheumatoid arthritis Crohn’s disease COPD Ischaemia/reperfusion injury Cancer Pancreatitis Parkinson’s disease Multiple sclerosis
16
Q
What is oxidative stress?
A
Imbalance between cell damage (ROS and RNS) and cell defences (antioxidants)
17
Q
What is a free radical?
A
An atom of molecule that contains one or more unpaired electrons and is capable of independent existence
18
Q
What is nitric oxide?
A
Nitric oxide (NO•) is an example of both a free radical and a ROS. It is useful in the body as it signals vasodilation, angiogenesis, oxidative bursts and neurotransmission. It is toxic at high levels because it is a ROS, so levels need to be controlled.
19
Q
What is a reactive oxygen species?
A
a molecule that contains oxygen and a free radical (an unpaired electron in the outer shell).
20
Q
What is NO formed?
A
a reaction between arginine (an amino acid) and oxygen catalysed by the enzyme nitric oxide synthase (NOS) to produce nitric oxide, water and citrulline (a different amino acid).
21
Q
What happens with superoxide reacts with NO?
A
Produces peroxynitrite
Peroxynitrite not a free radical but is a powerful oxidant that can damage cells and kill bacteria
22
Q
What is the most reactive and damaging free radical?
A
Hydroxyl radical
23
Q
What are the two types of ROS damage to DNA?
A
ROS reacts with base- modified base can lead to mispairing and mutation
ROS reacts with sugar- can cause strand break and mutation on repair
24
Q
What can be used as a measurement of oxidative damage in a cell?
A
Amount of 8-oxo-dG (8-Oxo-2’ deoxyguanosine)
25
What happens when ROS reacts with protein?
Backbone fragments causing protein degradation
Sidechain= modifies amino acid e.g. carbonyls, hydroxylated adducts, ring opened species, dimers, disulphide bonds= change in protein structure causing protein degradation, gain of function or loss of function
26
What does inappropriate disulphide bond formation cause?
Misfolding, crosslinking and disruption of function
27
How does ROS damage lipids?
Free radicals extracts hydrogen atom from a polyunsaturated fatty acid in membrane lipid
Lipid radical formed reacts with oxygen to form lipid peroxyl radical= chain reaction forms
Results in hydrophobic environment of bilayer disrupted and membrane integrity fails
28
Name some endogenous biological oxidants
Electron transport chain
Nitric oxide synthases
NADPH oxidases
29
Name some exogenous biological oxidants
Radiation: cosmic rays, UV light x-rays
Pollutants
Drugs: primaquine (anti-malarial)
Toxins: paraquat (herbicide)
30
What are the three types of nitric oxide synthase?
iNOS: inducible nitric oxide synthase. Produces high [NO] in phagocytes for direct toxic effect
eNOS: endothelial nitric oxide synthase (signalling)
nNOS: neuronal nitric oxide synthase (signalling)
31
What is respiratory burst?
The respiratory burst is an emission from a phagocytic cell designed to kill bacteria. It contains H2O2 (hydrogen peroxide) or O2-• (superoxide) which is used to make HOCl• (hypochlorite/bleach). HOCl• and ONOO- are used to kill the bacteria
Part of antimicrobial defence system
32
What is chronic granulomatous disease (CGD)?
form of immunodeficiency- genetic defect in NADPH oxidase complex causes enhanced susceptibility to bacterial infections.
In CGD, cells fail to produce this respiratory burst
Granulomas that form in organs to try to contain the infection. The formation of these granulomas damages the organs.
33
What does superoxide dismutase (SOD) do?
superoxide dismutase (SOD), which catalyses the reaction between superoxide (O2-•) and 2 hydrogen ions (H+) to produce hydrogen peroxide (H2O2). This is key because it stops the radical chain reaction from propagating.
Primary defence because superoxide is a strong initiator of chain reactions
Has three izoenzymes: Cu-Zn cytosolic, Cu-Zn extracellular, Mn mitochondria
34
What does catalase do?
Converts H2O2 to water and oxygen
Widespread enzyme- important in immune cells to protect against oxidative burst
Declining levels in hair follicles with age may explain grey hair
35
What is glutathione (GSH) and what does it do?
Tripeptide synthesised by body to protect against oxidative damage
Thiol group of Cys donates electron to ROS. GSH then reacts with another GSH to form disulphide (GSSG)
GSSG is reduced by to GSH by glutathione reductase which catalyses the transfer of electrons from NADPH to disulphide bond
36
What is NADPH used for?
Reducing power for biosynthesis
Maintenance of GSH levels
Detoxification reactions
Produces C5 sugar ribose
37
What happens in G6PDH deficiency?
NADPH levels are too low to regenerate GSH in cells without mitochondria
cells not being able to neutralise ROS and = inappropriate disulphide bond formation in these cells
This causes Heinz bodies to form
This can cause haemolysis
38
What are the free radical scavengers and what do they do?
vitamins A, C and E.
Vitamin E donates a H+ ion to the radical to neutralise it in a nonenzymatic reaction. Important for protection against lipid peroxidation
Vitamin C regenerates reduced form of vitamin E so it can perform its function.
39
What happens to Heinz bodies?
Bind to cell membrane altering rigidity
Increased mechanical stress caused when cells squeeze through small capillaries
Spleen removes bound Heinz bodies resulting in blister cells
40
What happens to paracetamol at therapeutic doses?
paracetamol can be safely metabolised into glucuronide and sulphates which can be excreted in the urine
41
What happens when there are high levels of paracetamol in the body?
the safe pathway is saturated
alternate pathway produces NAPQI as a product. As NAPQI depletes glutathione (the active GSH is oxidised to inactive GSSG) and there is not enough NADPH to regenerate GSH from GSSG, NAPQI builds up and can cause oxidative damage to cells of the liver.
42
What is the treatment for paracetamol overdose?
The treatment for a paracetamol overdose is acetylcysteine, which replenishes glutathione, so that it can prevent some of the damage to liver cells.
43
How is nitrogen used in the body?
```
DNA/RNA
Neurotransmitters e.g. dopamine
Some Hormones
Proteins
Amino acids
```
44
What is creatinine?
Breakdown product of creatine and creatine phosphate in muscles
Creatinine urine excretion over 24h proportional to muscle mass- provides estimate for muscle mass
Used as indicator of renal function
45
What are the three types of nitrogen balance?
In equilibrium, intake = loss. This is a normal nitrogen balance.
In a positive nitrogen balance: intake > loss. This occurs in growth and pregnancy as more protein is required for growth.
In a negative nitrogen balance: intake < loss. This occurs with trauma, malnutrition, or infection, and is never physiological.
46
What are glucogenic amino acids?
can be converted to glucose through gluconeogenesis, e.g. Alanine, Aspartate
47
What are ketogenic amino acids?
can be converted into Acetyl CoA (a precursor of ketone bodies that can be used in respiration), e.g. Lysine, Leucine.
48
Which amino acids can be both ketogenic and glucogenic?
Threonine, Tyrosine, Tryptophan
49
How does insulin control mobilisation of protein reserves?
Insulin ("the hormone of plenty") increases protein synthesis and decreases amino acid release. This is because high concentrations of insulin indicate that there is lots of glucose available in the blood, so no gluconeogenesis is needed. Growth hormone also exhibits similar effects to insulin
50
How does glucocorticoids control mobilisation of protein reserves?
increase amino acid release for gluconeogenesis and decrease protein synthesis. High levels of cortisol indicate that more glucose is needed in the blood.
51
What happens in Cushing’s Syndrome?
excess cortisol causes excessive protein breakdown, causing characteristic thin skin and purple abdominal striae
52
Where do carbon atoms for non-essential amino acid synthesis come from?
Intermediates of glycolysis (C3)
Pentose phosphate pathway (C4 & C5)
Krebs cycle (C4 & C5)
53
Name compounds that require tyrosine for its synthesis
Catecholamines
Melanin
Thyroid hormones
54
Name compounds that require cysteine for its synthesis
```
Hydrogen sulphide (signalling molecule)
Glutathione
```
55
Name compounds that require tryptophan for its synthesis
Nicotinamide
Serotonin
Melatonin
56
Name compounds that require glycine for its synthesis
histamine
57
Name a compound that require glutamate for its synthesis
GABA
58
Name a compound that require arginine for its synthesis
Nitric oxide
59
Name a compound that require serine for its synthesis
Sphingosine
60
What are the two main pathways that facilitate removal of nitrogen from amino acids?
Transamination
| Deamination
61
How can amino acids be used in oxidative metabolism?
amino acids must have their amino group removed so that only carbon skeletons remain
62
What is transamination?
swaps the amino group (NH2) on an amino acid for a carboxyl group (C=O) through alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The reactions are reversible.
63
What does alanine aminotransferase (ALT) do?
catalyses the movement of the amino group from alanine to alpha-ketoglutarate, producing pyruvate and glutamate.
64
What does aspartate aminotransferase (AST) do?
catalyses the movement of the amino group from aspartate to alpha-ketoglutarate, producing oxaloacetate and glutamate.
65
What is deamination?
the liberation of the amino group as free ammonia, which is eventually turned into urea through the urea cycle.
Mainly occurs in liver
66
What coenzyme is needed by all aminotransferases?
Pyridoxal phosphate – derivative of vitamin B6
67
What are plasma ALT and AST levels measured routinely for?
Liver function test
68
Name enzymes that can deaminate amino acids
Amino acid oxidases
Glutaminase
Glutamate dehydrogenase
69
What is urea?
a molecule in the body with a high nitrogen content that is chemically inert in humans
produced primarily following deamination of glutamate in the liver which releases ammonia. Ammonia is toxic to human cells, it is converted to urea which is released in the urine.
70
How many enzymatic reactions does the urea cycle consist of and where do they take place?
four enzymatic reactions: one mitochondrial and three cytosolic.
The process involves 5 liver enzymes.
71
How does a high protein diet affect the urea cycle?
a lot of amino acids to metabolise
Enzymes for the urea cycle are upregulated, so the increased amount of protein can be metabolised faster and so no ammonia builds up.
72
How does a low protein diet or starvation affect the urea cycle?
down-regulation of these enzymes because they are not needed to metabolise protein
73
What is refeeding syndrome?
Nutritional support given to severely malnourished patients
74
What happens when too much protein is consumed within 4-7 days after the malnutrition period?
massive attempted synthesis of glycogen, fat and protein in cells and causes largely deranged levels of potassium, magnesium and phosphorus in the blood.
enzymes are overwhelmed and cannot convert ammonia into urea fast enough causing ammonia to build up (hyperammonaemia).
75
What are the risk factors for malnutrition?
BMI<16
Unintentional weight loss > 15% in 3-6 months
10 days or more with little or no nutritional intake
76
What are the symptoms caused by defects in the urea cycle?
```
Vomiting
Lethargy
Irritability
Mental retardation
Seizures
Coma
```
77
What is the biochemical basis of ammonia toxicity?
Readily diffusible
Extremely toxic to the brain
Blood levels needs to be kept low (25-40 umol/L)
78
What are the potential ammonia toxicity effects?
Interference with amino acid transport and protein synthesis
Disruption of cerebral blood flood
pH effects (alkaline)
interference with metabolism of excitatory amino acid nt
alteration of BBB
interference with TCA cycle
79
Describe the glutamine transport mechanism of amino acid nitrogen form tissues to the liver for disposal
Ammonia combined with glutamate to form glutamine
Glutamine transported to liver or kidneys where it is cleaved by glutaminase to glutamate and ammonia
Ammonia fed into urea cycle in liver and excreted in urine by kidneys
80
Describe the alanine transport mechanism of amino acid nitrogen form tissues to the liver for disposal
Amine groups transferred to glutamate by transamination
Pyruvate transaminated by glutamate to form Alanine
Amino group fed by via glutamate into urea cycle for disposal
81
What is Phenylketonuria (PKU)?
Autosomal recessive. Affected on gene on Chr12
a deficiency in phenylalanine hydroxylase = phenylalanine cannot be converted to tyrosine.
Phenylalanine builds up in the blood, and with transamination, so do phenylketones (as phenylalanine is a ketogenic amino acid).
Phenylketones in urine= musty smell
82
What are the symptoms of PKU?
developmental delay, small head, seizures and hypopigmentation
83
What are the treatments for PKU?
low phenylalanine, high tyrosine diet
avoid artificial sweeteners
avoid high protein foods e.g. meat, milk, egg
84
What is Homocystinuria?
Autosomal recessive disorder
Defect in cystathionine beta-synthase
methionine cannot properly be broken down, so homocysteine builds up in the blood, and is oxidised to homocystine (two homocysteines bound together).
Homocystine is excreted in the urine
85
What are the symptoms of homocystinuria?
lens dislocation, skeletal deformities, and defective connective tissue
86
What is the treatment of homocystinurias?
Low- methionine diet
Avoid milk, meat, fish, cheese, eggs, nuts
Cystine, Vit B6, betaine, B12 and folate supplement
