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YEAR 1 - Biochemistry and Medical Genetics (Anton) > 10. Biochemistry: Integrative Aspects, Defence and Disease > Flashcards

10. Biochemistry: Integrative Aspects, Defence and Disease Flashcards

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1
Q

What are some important factors to consider in metabolic integration?

A
  1. How the specific pathways fit into each other
  2. How the different organelles are involved in this integration
  3. How the different organs are integrated to give us whole body metabolism
  4. How this is all controlled
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2
Q

What are the main catabolic pathways?

A
  • Glycolysis
  • Fatty acid oxidation
  • Ketolysis
  • Glycogenolysis
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3
Q

What are the main anabolic pathways?

A
  • Glycogenesis
  • Lipogenesis
  • Gluconeogenesis
  • Ketogenesis
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4
Q

Draw a diagram to show the integration of these pathways:

  • Glycogenolysis
  • Glycogenesis
  • Glycolysis
  • Gluconeogenesis
  • Proteolysis
  • De novo lipogenesis
  • Fatty acid oxidation
  • Oxidative phosphorylation
  • Ketolysis
  • Ketogenesis

[IMPORTANT]

A
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5
Q

Practice metabolic integration by testing yourself on how to get from one metabolite to another.

A
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6
Q

What are the two important metabolic “hubs” that mutliple pathways feed from and to?

A
  • Acetyl-CoA
  • Glucose-6-phosphate
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7
Q

What metabolic pathways can feed into and out from acetyl-CoA? [IMPORTANT]

A

Feed in:

  • Glycolysis
  • Lipolysis + Beta oxidation
  • Ketogenic amino acids

Feed out:

  • Lipogenesis
  • Ketogenesis (+ cholesterol production)
  • TCA cycle
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8
Q

What metabolic pathways can feed into and out from glucose-6-phosphate? [IMPORTANT]

A

In the middle of:

  • Glycolysis (between glucose and pyruvate)
  • Gluconeogenesis (between pyruvate and glucose)

Feed in:

  • Glycogenolysis

Feed out:

  • Glycogenesis
  • Pentose phosphate pathway
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9
Q

How are the 2 major metabolic hubs connected?

A

Acetyl-CoA is produced from G6P in glycolysis.

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10
Q

Draw a diagram to show the flux in and out of the 2 main metabolic hubs (acetyl-CoA and G6P) in the fed state in the liver.

A
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11
Q

Draw a diagram to show the flux in and out of the 2 main metabolic hubs (acetyl-CoA and G6P) in the fasted state in the liver.

A
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12
Q

What two structures enable compartmentalisation of metabolism?

A
  • Organelles
  • Membranes
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13
Q

What are some advantages and disadvantages of metabolic compartmentalisation?

A
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14
Q

Describe the compartmentalisation of gluconeogenesis.

A
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15
Q

Describe the compartmentalisation of very long chain fatty acid oxidation.

A
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16
Q

What is the advantage of metabolic control between tissues (e.g. tissue cycles)?

A
  • Allows tissue specialisation
  • Allows a “signal” such as a hormone to be generated in one location and act on peripheral tissues
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17
Q

Which organ is typically involved in cell cycles?

A

Liver

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18
Q

Draw a diagram to show the inter-organ relationships in metabolising fatty acids.

A
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19
Q

On which principle does regulation of flux through metabolic pathways in response to changes in the physiological state happen?

A

Control involves changing the activity of the enzymes or their levels, which can be divided into:

  • Acute -> Seconds to minutes to occur
  • Chronic -> Hours to days to occur
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20
Q

What are the 2 forms of acute regulation of the flux through a metabolic pathway in response to the physiological state of the body? Give an example of each.

A

Internal signal:

  • This is usually allosteric, involving an intracellular marker of the need for that pathway
  • e.g. Inhibition of phosphofructokinase by ATP, and activation by AMP

External signal:

  • This is usually covalent (e.g. phosphorylation)
  • Often signals via a cell surface receptor and induces an internal response
  • e.g. Hormones: Adrenaline, Insulin and Glucagon
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21
Q

What is the advantage of external regulation (i.e. via hormones) of metabolic pathways?

A

It allows the same signal to regulate multiple metabolic pathways simultaneously.

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22
Q

What things about the physiological state of the body can hormones signal?

A
  • The whole body’s nutritional status
    • Blood substrate excess = Fed state
    • Blood substrate deficiency = Fasted state
  • The whole body’s energy needs
    • “Fight or flight” response requires more ATP
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23
Q

What are the main metabolic responses that hormones can induce in distant cells in response to changes in the physiological state?

A
  • Taking substrate from blood into tissue
  • Returning substrate from tissue to blood
  • Diverting substrate within tissue into energy-generating pathways
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24
Q

For insulin, state:

  • Where it is secreted
  • What its release is stimulated by
  • What it signals
  • What its general effects are
A
  • Secreted by β-cells of the pancreas in the fed state
  • Stimulated by increased blood glucose, certain amino acids and certain fatty acids
  • Signal of substrate excess/fed state
  • Tells tissue to promote fuel storage and inhibit fuel breakdown
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25
Q

For glucagon, state:

  • Where it is secreted
  • What its release is stimulated by
  • What it signals
  • What its general effects are
A
  • Secreted by α-cells of the pancreas in the fasted state
  • Stimulated by low glucose
  • Signal of substrate deficiency/fasted state
  • ONLY ACTS ON LIVER
  • Signal to liberate glucose into blood from liver (to fuel other tissues)
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26
Q

For adrenaline, state:

  • Where it is secreted
  • What its release is stimulated by
  • What it signals
  • What its general effects are
A
  • Secreted by the adrenal gland
  • Stimulated and signals the fight or flight response
  • Tell tissues to divert substrates towards making ATP
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27
Q

What is another name for the fed state?

A

Post-prandial state

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28
Q

Which anabolic pathways does insulin stimulate and which catabolic pathways does it inhibit?

A

Stimulates anabolic effects:

  • Glucose uptake and glycolysis
  • Glycogenesis
  • De novo lipogenesis
  • Fatty acid uptake by adipose and storage
  • Protein synthesis

Inhibits catabolic effects:

  • Gluconeogenesis glucose production and release
  • Glycogenolysis
  • Fatty acid mobilisation from adipose (and consequent fatty acid oxidation in peripheral tissues)
  • Ketogenesis
  • Protein breakdown
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29
Q

Draw a diagram to summarise the effects of insulin on glucose metabolism.

A
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30
Q

Draw a diagram to summarise the effects of insulin on fatty acid metabolism.

A
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31
Q

What does chronic control of the flux through metabolic pathways in response to changes in the physiological state involve?

A

Changes in the translation and transcription of the enzymes involved in the pathways.

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32
Q

Chronic control of metabolic pathways in response to the physiological state occurs by regulating the trascription and translation of the enzymes involved in the pathways. What are some triggers for this regulation?

A

Mostly hormones, but also:

  • External signals -> e.g. Decreased oxygen delivery to the tissues (hypoxia)
  • Internal signals -> e.g. Increased fat within the tissue
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33
Q

How do glucocorticoids, glucagon and insulin allow chronic control of metabolism by altering the transcription and translation of enzymes?

A
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34
Q

Why is it important to avoid futile cycling of pathways in metabolism? How is this done? [EXTRA]

A

Problems:

  • Wastes energy
  • Wastes metabolites
  • Generates heat

It is avoided by reciprocal regulation of opposite pathways.

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35
Q

Is it advantageous for a cell to be using multiple fuels at once?

A

No, it is important for the cell to save more precious fuels.

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36
Q

What is the glucose-fatty acid cycle? [EXTRA]

A
  • It is a mechanism to prevent both glucose and fatty acids being used as a metabolic fuel simultaneously
  • When fatty acids are being used for metabolism, this results in down-regulation of glucose metabolism
  • This is done via the enzyme PDH (pyruvate dehydrogenase), which inhibits glycolysis
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37
Q

What cells release insulin?

A

Beta cells of the pancreas

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38
Q

What are the two main types of diabetes mellitus you need to know about?

A
  • Type 1 (insulin-dependent)
  • Type 2 (insulin-independent)
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39
Q

How common is diabetes and which form is more common?

A
  • 1 in 11 adults had diabetes worldwide in 2015 = 415 million people
  • 90% have type 2 diabetes.
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40
Q

At what age does type 1 diabetes mellitus typically start and what mechanism causes it?

A
  • 1 to 25 years old
  • Auto-immune destruction of the pancreatic β-cells
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41
Q

At what age does type 2 diabetes mellitus typically start and what mechanism causes it?

A
  • Typical onset > 40 years
  • Insulin resistance -> Defective sensitivity of peripheral tissues to insulin
  • Accompanied by defects in insulin secretion
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42
Q

How is the prevalence of the two types of diabetes mellitus changing?

A

Both are increasing, but type 2 is increasing at a greater rate.

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43
Q

Is diabetes genetic or environmental?

A

Both types of diabetes have a genetic and an environmental component.

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44
Q

What is the stage between diabetes and non-diabetes?

A

Impaired glucose tolerance (a.k.a. pre-diabetes)

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45
Q

What is the normal plasma glucose concentration when fasting? [IMPORTANT]

A

4mM to 6mM

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46
Q

Explain the glucose tolerance test. [IMPORTANT]

A
  • It is a test used to diagnose diabetes mellitus
  • A 75g glucose drink is given to a patient
  • Two hours later, the plasma glucose levels are measured:
    • 4.5 - 6.0mM is the control range (not diabetes)
    • 7.8 - 11mM indicates pre-diabetes
    • >11.1 indicates diabetes
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47
Q

What glucose concentration indicates diabetes mellitus after 2 hours in the glucose tolerance test?

A

More than 11.1mM

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48
Q

What fasting glucose concentration is typical of diabetes mellitus?

A

More than 7mM

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49
Q

What cell is this and what are the black spots?

A
  • Beta cell in the pancreas
  • The black granules are insulin
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50
Q

How is insulin stored in granules in beta cells?

A
  • It is stored as preproinsulin, which is then cleaved to proinsulin
  • Proinsulin is then cleaved to insulin
  • Insulin is then ready for release
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51
Q

Describe the mechanism behind insulin release from beta cells of the pancreas.

A
  • When there is high blood glucose, lots enters through GLUT2 channels into the beta cells
  • This glucose is metabolised by mitochondria, raising ATP and lowering ADP concentrations
  • The ATP causes ATP-sensitive potassium channels in the membrane to close, depolarising the membrane
  • This causes voltage-sensitive calcium channels to open, increasing intracellular calcium
  • The Ca2+ causes exocytosis of insulin granules
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52
Q

Describe what can be seen in this histological stain.

A

It is a pancreatic islet:

  • Pink = β-cells stained for insulin
  • Brown = α-cells stained for glucagon
  • Blue = δ-cells stained for somatostatin
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53
Q

Explain what can be seen in these histological slides.

A
  • The slide on the left is a control pancreatic islet
  • The slide on the right is a pancreatic islet in type 1 diabetes (with the beta cells destroyed)
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54
Q

Explain what can be seen in these histological slides.

A
  • The slide on the left is a control pancreatic islet
  • The slide on the right is a pancreatic islet in type 1 diabetes (with the beta cells destroyed)
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55
Q

For diabetes mellitus, describe the changes of these metabolites in the blood:

  • Insulin
  • Glucose
  • Lipids
  • Ketones
A
  • Low insulin -> Hypoinsulinaemia
  • High glucose -> Hyperglycaemia
  • High lipids -> Hyperlipidaemia
  • High ketones -> Hyperketonaemia
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56
Q

Are the effects of diabetes mellitus limited to just the blood profile changes in insulin, glucose, lipids and ketones?

A

No, because:

  • Concentrations of substrates and hormones now reaching all peripheral tissues (liver, muscle, adipose) changes
  • This affects the metabolic pathways that are activated/inhibited in this tissues.
  • Therefore, primary β-cell defect causes secondary effects on all tissues
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57
Q

What are the anabolic and catabolic effects of insulin?

A
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58
Q

Compare the metabolic effect of starvation and diabetes mellitus. [EXTRA]

A
  • They are the SAME, since in both cases there is a lack of insulin.
  • However, diabetes mellitus, there is high blood glucose, while in starvation there is not!
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59
Q

Describe the mechanisms affecting blood glucose concentration in diabetes mellitus.

A

There is no insulin or lack of sensitivity, so the body thinks it is starving, even though it is not. After a meal, not only is glucose coming in from the GI tract, there is also increased glucose concentration due to:

  • Increased gluconeogenesis
  • Decreased glycolysis
  • Decreased glucose uptake into tissues
  • Increased use of alternative fuels (e.g. ketone bodies)
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60
Q

Describe the mechanisms affecting blood fatty acid and ketone body concentration in diabetes mellitus.

A

There is no insulin or lack of sensitivity, so the body thinks it is starving, even though it is not. Therefore:

  • Increased lipolysis in adipose tissue
  • Increased ketogenesis in the liver from fatty acids
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61
Q

Draw a table to show the effects of insulin (fed state) and diabetes mellitus on the following pathways, as well as the effect that these changes in diabetes have on the normal blood concentration of metabolites:

  • Glycogenolysis
  • Gluconeogenesis
  • Lipolysis
  • Ketogenesis
  • Proteolysis
  • Glucose uptake
  • Glycolysis and glucose oxidation
  • Adipose fatty acid uptake
  • De novo lipogenesis
  • Protein synthesis
A
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62
Q

How does insulin increase glucose uptake into tissues? [EXTRA]

A

Stimulates GLUT4 transporters.

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63
Q

How does insulin increase glucose oxidation and glycolysis? [EXTRA]

A
  • Stimulating phosphofructokinase
  • Stimulating pyruvate dehydrogenase
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64
Q

How does insulin increase adipose fatty acid uptake? [EXTRA]

A

Stimulates LPL (lipoprotein lipase)

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65
Q

How does insulin increase de novo lipogenesis? [EXTRA]

A

Stimulates acetyl-CoA carboxylase.

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66
Q

How does insulin decrease glycogenolysis? [EXTRA]

A

Inhibits glycogen phosphorylase.

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67
Q

How does insulin decrease gluconeogenesis? [EXTRA]

A
  • Inhibits fructose 1,6-bisphosphatase
  • Inhibits transcription of many gluconeogenic proteins
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68
Q

How does insulin decrease lipogenesis and fatty acid oxidation? [EXTRA]

A
  • Inhibits HSL (hormone-sensitive lipase)
  • Increases concentration of malonyl-CoA (which inhibits CPT1) via its action on acetyl-CoA carboxylase
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69
Q

How does insulin decrease ketogenesis? [EXTRA]

A
  • Decreases fatty acid delivery
  • Decreases gluconeogenesis
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70
Q

What are the major metabolic disturbance in diabetes mellitus that are listed in the spec? [IMPORTANT]

A
  • Polyuria
  • Polydipsia
  • Dehydration
  • Fatty acid mobilisation
  • Ketoacidosis
  • Hyperglycaemia
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71
Q

What is polyuria?

A

Where the body urinates more than usual and passes excessive or abnormally large amounts of urine each time you urinate.

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72
Q

Why does diabetes mellitus cause polyuria?

A
  • When glucose exceeds the renal threshold (>12 mmol/l), it cannot be fully reabsorbed by the kidneys, and is excreted in the urine
  • This makes the urine hyperosmolar
  • Therefore, additional water is excreted
  • This results in dehydration and thirst
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73
Q

What is ketoacidosis and what is the danger?

A
  • A metabolic state caused by uncontrolled production of ketone bodies that cause a metabolic acidosis.
  • While ketosis refers to any elevation of blood ketones, ketoacidosis is a specific pathologic condition that results in changes in blood pH and requires medical attention.
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74
Q

Describe the levels of glucose, NEFAs and fatty acids in the blood in diabetes ketoacidosis. [EXTRA?]

A
  • Glucose = >20mM
  • NEFAs = 2-4mM
  • Ketone bodies = 10-20mM
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75
Q

Describe how diabetic ketoacidosis occurs in diabetes.

A
  • Insulin is not produced or there is insulin insensitivity, so peripheral tissues are not supplied with glucose
  • Ketone bodies are produced as an alternative fuel
  • They are acidic
  • Overwhelms bicarbonate buffering system, leading to acidosis
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76
Q

What are the symptoms of diabetic ketoacidosis and why?

A
  • Increased ventilation (Kussmaul respiration) -> This is to try and exhale more CO2 and raise the pH
  • Smell of acetone
  • Dehydration
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77
Q

What is polydipsia?

A

Excessive thirst.

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78
Q

Why does diabetes cause dehydration and polydipsia (excessive thirst)?

A

It results from polyuria, which is caused by:

  • Glucose in the urine increasing the osmotic potential and increasing water in the urine
  • Increased ketone bodies need to be excreted too, so there are larger volumes of urine
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79
Q

What are some of the complications of diabetes mellitus? [EXTRA]

A
  • Cardiovascular disease
  • Nephropathy
  • Retinopathy
  • Neuropathy
  • Amputation -> Diabetes can affect the nerves, muscles and circulation in feet and hands, leading to amputation
  • Depression and Dementia
  • Complications in pregnancy
  • Sexual dysfunction
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80
Q

How can blood glucose be monitored in type 1 diabetes? What are the pros and cons of each?

A
  • Blood glucose meters using a drop of blood
    • Damages fingers over time
    • Only gives a reading of glucose at one point in time
  • Continuous glucose monitoring (interstitial fluid)
    • Gives a reading of glucose over time
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81
Q

How can type 1 diabetes be treated?

A
  • Insulin injections
    • Both short acting and long acting insulin analogues
  • Insulin pumps -> Subcutaneous insulin infusion
  • Islet transplantation
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82
Q

Draw a graph to show how glucose and insulin vary throughout the day in a non-diabetic person.

A
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83
Q

Draw a graph to show how insulin concentration varies throughout the day in a type 1 diabetic and non-diabetic (with injections).

A

It can be seen that in diabetes, the insulin remains in the system for a long time after the meal, which can cause problems with hypoglycaemia.

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84
Q

What are the benefits of subcutaneous insulin infusion (insulin pumps) as a treatment for type 1 diabetes?

A
  • The allow slower and continuous infusion of insulin, not just large spikes that remain in the system for a long time.
  • This reduces the risks of hypoglycaemia after a meal.
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85
Q

What are some potential future treatments for type 1 diabetes? [EXTRA]

A
  • Closed circuit loops (sensing glucose and infusing appropriate insulin automatically)
  • Islet encapsulation advances
  • Vaccines to prevent diabetes development
  • Pancreatic transplantation
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86
Q

Describe briefly the mechanism underlying the development of type 2 diabetes.

A

Peripheral tissues lose their sensitivity to insulin:

  • In response to carbohydrate the pancreas has to secrete more insulin to cause the same normalisation of blood glucose (hyperinsulinaemia)
  • Can progress to the β-cell not being able to produce this increased amount of insulin (hypoinsulinaemia)
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87
Q

What are some of the risk factors for type 2 diabetes?

A
  • Obesity (80% overall risk = exercise and lifestyle)
  • Genetics and ethnicity
  • Age
  • Social deprivation
  • Gestational diabetes (both for mother and offspring)
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88
Q

We do not know the exact mechanism of how type 2 diabetes develops. What are some of the main proposed mechanisms?

A
  • Adipokines (adipose-derived inflammatory cytokines) secreted from enlarged adipose tissue
  • Intracellular lipid accumulation in peripheral tissues = Lipotoxicity
  • High glucose = Glucotoxicity
  • Adipose derived hormones
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89
Q

How can type 2 diabetes be treated?

A

Lifestyle:

  • Improvements in diet
  • Improvement in exercise

Pharmacology:

  • Metformin -> Improves insulin sensitivity
  • Sulphonylureas -> Increases insulin secretion
  • Acarbose -> Slows starch digestion
  • Incretins -> GLP1 analogues and DPP4 inhibitors -> Increase insulin secretion
  • SGLT2 inhibitors -> Increase glucose renal excretion
  • Insulin injections if β-cell function decreases
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90
Q

Metformin can be used to treat type 2 diabetes. How does it work?

A

Increases sensitivity to insulin.

91
Q

Sulphonylureas can be used to treat type 2 diabetes. How does it work?

A

Increases insulin secretion.

92
Q

Acarbose can be used to treat type 2 diabetes. How does it work?

A

Slows the digestion of starch.

93
Q

Incretins (GLP1 analogues and DPP4 inhibitors) can be used to treat type 2 diabetes. How do they work?

A

Increase insulin secretion.

94
Q

SGLT2 inhibitors can be used to treat type 2 diabetes. How do they work?

A

Increase renal glucose excretion.

95
Q

Insulin can be used to treat type 2 diabetes. When is it used?

A

It is used when the pancreatic beta cells can no longer produce insulin.

96
Q

Name some common diseases that have abnormal metabolism as part of their effects.

A
  • Cancer
  • Heart disease
  • Stroke
  • Diabetes
  • Liver disease
97
Q

Describe the relationship between metabolism and disease.

A
  • Many diseases affect the metabolism in the body
  • BUT ALSO metabolism changes can lead to disease too
98
Q

What are inborn errors of metabolism?

A

Genetic diseases that cause a mutation in a metabolic protein that changes its function.

99
Q

How do inborn errors of metabolism affect the child before birth?

A

Maternal comensation usually occurs before birth.

100
Q

Draw a summary of all of the inborn errors of metabolism you need to know.

A
101
Q

What are two inborn errors of metabolism that are routinely tested for in the heel prick test?

A
  • Phenylketonuria
  • Medium-chain acyl-CoA dehydrogenase deficiency
102
Q

Draw the pathway that describes metabolic disease in molecular terms.

A
103
Q

Is it easy to diagnose a metabolic disease on the basis of the levels of different metbaolites?

A
  • In this diagram, the enzyme converting B to C is defective.
  • You would expect the concentrations of A and B to increase, and the concentrations of C, D, E and F to fall.
  • However, this is only the case if:
    • A and B are not involved in other metabolic pathways (G and H)
    • C, D, E and F are not produced by any other pathways (J)
  • There is also the possibility that the mutated enzyme will start producing metabolite K instead, which accumulates in the cell
104
Q

What is MCAD? What are the symptoms of MCAD deficiency?

A
  • MCAD is medium-chain acyl-CoA dehydrogenase enzyme
  • It catalyses the first step in beta oxidation of medium-chain FAs
  • Deficiency means that you can’t break down fatty acids during fasting:
    • No ketogenesis while fasting -> Hypoketoticon fasting
    • Fasting hypoglycaemia -> Since more dependent on glucose
    • Vomiting, lethargy, seizure, coma and death
105
Q

What does MCAD stand for?

A

Medium-chain acyl-CoA dehydrogenase

106
Q

How common is MCAD deficiency and when does it present?

A
  • Most common inherited inborn error in fatty acid metabolism -> Frequency 1/19,000 -1/14,000
  • Onset during infancy
  • Sudden, unexpected death in 25%
107
Q

What is the importance of carnitine? What are the symptoms of carnitine deficiency?

A
  • Carnitine is involved in the carnitine shuttle, which is required to bring fatty acyl-CoA into the mitochondria for beta oxidation
  • In carnitine deficiency:
    • Cardiomyopathy (since fats are the main fuel for the heart, so the heart enlarges)
    • Fatty infiltration of organs
    • Muscle weakness
    • Hypoglycaemia (since need to shift to using glucose)
108
Q

Where does carnitine come from?

A

It comes from the diet and is also synthesised by the body.

109
Q

What does carnitine deficiency occur?

A

It is a mutation in a transporter that moves carnitine into the cell, so even if there is lots of carnitine in the blood, it is not available at the mitochondrial membrane.

110
Q

What is the importance of peroxisomes? What are the symptoms of peroxisomal disorders?

A
  • Peroxisomes catalyse initial steps in oxidation of very long-chain fatty acids, prior to transport to the mitochondria
  • Also involved in anti-oxidant defence, and certain paths of amino acid metabolism and lipid synthesis
  • Symptoms:
    • Hyptonia (low muscle tone) and seizures
    • Abnormal facial presentations
    • Hepatomegaly, renal cysts, adrenal hypoplasia
    • Neonatal onset, usually death within months
111
Q

What is the main type of peroxisomal disorder and how does it occur?

A
  • Zellwegers disease -> Defect in import of proteins into peroxisome
  • The peroxisomes exist as normal but there is no proteins within them
112
Q

What are the main inborn errors of fatty acid metabolism?

A
  • MCAD deficiency
  • Carnitine deficiency
  • Peroxisomal disorders
113
Q

What is the importance of glucose-6-phosphate dehydrogenase? What are the symptoms of glucose-6-phosphate dehydrogenase deficiency?

A
  • G6PD is involved in the pentose phosphate pathway, which generates:
    • NADPH -> For synthesis of antioxidants and in lipid synthesis
    • Ribose sugars -> For RNA synthesis
  • Symptoms of deficiency:
    • Mostly asymptomatic throughout life
    • Usually presents as drug-induced or infection-induced acute haemolytic anaemia
    • The haemolysis is also seen following the ingestion of fava beans (broad beans)
114
Q

How common is glucose-6-phosphate dehydrogenase deficiency?

A

The most common human enzyme defect -> Affects >400 million people worldwide

115
Q

What is the inheritance type for glucose-6-phosphate dehydrogenase deficiency?

A

It is X-linked.

116
Q

Why does G6PD deficiency lead to haemolytic anaemia?

A
  • It is because the drugs / infection / fava beans lead to oxidative stress
  • As the sufferer is less able to generate NADPH, they cannot overcome the oxidative stress
  • RBC are particularly susceptible as they have high levels of oxygen, and no organelles making other antioxidants
117
Q

What three things can induce haemolytic anaemia in individuals with glucose-6-phosphate dehydrogenase deficiency?

A
  • Fava beans
  • Drugs
  • Infection
118
Q

Why is G6PD deficiency so common?

A
  • The distribution of sufferers, matches very closely with the distribution of malaria
  • It is thought that G6PD deficiency therefore offers a level of protection against malaria
119
Q

Draw a summary of how glycogen breakdown occurs.

A
120
Q

What are 3 important glycogen storage disorders and what enzyme defect does each involve?

A
  • Type I (Von Gierke’s disease) -> Glucose-6-phosphatase deficiency
  • Type III (Cori’s disease, Forbe disease) -> Debranching enzyme deficiency
  • Type V (McArdle’s disease) -> Muscle phosphylase deficiency
121
Q

What is Von Gierke’s disease (Type I glycogen storage disease) and what are the symptoms?

A
  • Glucose-6-phosphatase deficiency
  • Glucose-6-phosphatase is usually used to convert G6P to glucose in the liver
  • With the deficiency, glycogenolysis and gluconeogenesis cannot happen

Symptoms of deficiency:

  • Glycogen accumulation -> Enlarged liver and kidneys
  • Hypoglycaemia
  • Lactic acidaemia (since the Cori cycle can’t function, so blood lactate rises)
122
Q

What is Cori’s disease (Type III glycogen storage disease) and what are the symptoms?

A
  • Debranching enzyme deficiency
  • Debranching enzyme usually removes glucose monomers from glycogen in both muscles and liver

Symptoms of deficiency:

  • Difficult to distinguish from Type I GSD by physical examination -> Enlarged liver and kidneys
  • The structure of both liver and muscle glycogen is abnormal -> Results in an increased amount of glycogen with short outer branches
123
Q

What is McArdle’s disease (Type V glycogen storage disease) and what are the symptoms?

A
  • Glycogen phosphorylase deficiency (ONLY of muscle isoform, not liver)
  • Glycogen phosphorlyase is normally involved in removing G1P from glycogen, which can then be converted to glucose

Symptoms of deficiency:

  • Enlarged glycogen granules in muscle
  • Exercise intolerance and painful cramps -> During exercise, the muscle can’t use glycogen for ATP production
124
Q

Draw the pathway for the breakdown of phenylalanine.

A
125
Q

What is phenylketonuria and what are the symptoms? [IMPORTANT]

A
  • Unable to metabolise phenylalanine
  • Due to a deficiency in phenylalanine monooxygenase

Symptoms:

  • Severe neurological problems if untreated soon after birth
  • Neurological damage –low IQ, behavioural difficulties
126
Q

Which enzyme is deficient in phenylketonuria?

A

Phenylalanine monooxygenase (a.k.a. hydroxylase)

127
Q

Describe the mechanism, by which phenylketonuria produces its symptoms.

A
  • Phenylketonuria involves a deficiency of phenylalanine monooxygenase, so that phenylalanine cannot be broken down (first of all to tyrosine)
  • This leads to a build up of phenylalanine
  • Some of the phenylalanine is converted to phenylpyruvate and then phenyllactate
  • It is suggested that symptoms on the brain occur by two mechanisms:
    • Phenylpyruvate and phenyllactate are toxic metabolites
    • Phenylalanine at high concentrations outcompetes other metabolites for transport into the brain
128
Q

What is the treatment for phenylketonuria?

A

Phenylalanine-free diet/low protein diet.

129
Q

What are some different diseases that occur due to deficiencies along the phenylalanine metabolism pathway?

A
130
Q

What is tyrosinaemia I, what are the symptoms and treatment?

A
  • It is a deficiency in the enzyme that converts fumaryloacetoacetate to fumarate and acetoacetate (at the end of phenylalanine metabolism)
  • This results in a build up of fumaryloacetoacetate, which is converted to succinyl acetone -> This leads to cancer and liver disease
  • Treatment was once done by a low-protein and low-phenylalanine diet, but then NTBC was developed, which blocks the pathway further upstream
131
Q

What is galactosaemia, what are the symptoms and treatment?

A
  • Galactose-1-phosphate uridyltransferase is involved in galactose metabolism
  • Deficiency in galactose-1-phosphate uridyltransferase causes galactosaemia

Symptoms of deficiency, when ingesting lactose:

  • Vomiting and failure to thrive
  • Delayed development
  • Severe liver disease
  • Cataracts
  • Learning difficulties (even with treatment)

Treatment:

  • Galactose-free diet
132
Q

What is hereditary fructose intolerance and what metabolic effects does it have?

A
  • Fructose-1-phosphate aldolase is involved in fructose metabolism, by converting fructose-1-phosphate to glyceraldehyde
  • Deficiency in fructose-1-phosphate aldolase:
    • Sequesters inorganic phosphate -> Hypophosphataemia
    • F-1-P also inhibit the “traditional” aldolase in glycolysis/gluconeogenesis and inhibits glycogen phosphorylase -> Decreased gluconeogenesis and glycogenolysis
133
Q

What are the symptoms of hereditary fructose intolerance?

A
  • Hypophosphataemia -> Due to sequestering of phosphate in fructose-1-phosphate
  • Hypoglycaemia -> Due to inhbition of gluconeogenesis and glycogenolysis

Symptoms of acute exposure:

  • Sweating
  • Dizziness
  • Nausea
  • Seizures
  • Coma

Symptoms of chronic exposure:

  • Failure to thrive
  • Vomiting
  • Drowsiness
  • Hepatomegaly
134
Q

Why is fructose intake arguably worse than glucose?

A
  • Glucose uptake is regulated by insulin –fructose uptake bypasses this regulation
  • In liver, fructose metabolism bypasses phosphofructokinase in glycolysis = key regulated step in glycolysis
  • Taken together -> Uptake and metabolism are less regulated
  • This may explain why fructose disappearance from the blood is twice as fast as for glucose.
135
Q

Why do inborn errors of metabolism usually only affect certain tissues?

A
  • A specific pathway is only active in certain tissues
  • Some tissues have higher dependence on a specific fuel than others
  • The IEM may affect a tissue-specific isoform of the enzyme
  • Some tissues may have less capacity to “flex their metabolism” to a different fuel, or to tolerate the consequences of a restricted pathway
136
Q

What are xenobiotics?

A
  • Chemical substances found within an organism that are not naturally produced or expected to be present within the organism.
  • It can also cover substances that are present in much higher concentrations than are usual.
137
Q

Which organs have the role of metabolising xenobiotics?

A
  • Liver (primarily)
  • GI tract
  • Kidney
  • Lungs
138
Q

Summarise the role of liver metabolism.

A

Conversion of toxic, lipophilic compounds to polar, more water-soluble derivatives for excretion.

139
Q

What are the two parts of the liver’s detoxification mechanism? What happens in each?

A

Phase I:

  • Increases polarity of the drug by transforming or removing the functional groups

Phase II:

  • Addition of endogenous compounds to the drug, further increasing polarity and preparing them for excretion.
140
Q

Compare the types of reaction in phase I and II of liver metabolism.

A
  • Phase I -> Oxidation and reduction (and hydrolysis)
  • Phase II -> Conjugation
141
Q

Phase I of drug metabolism typically involves the reveal of which functional group?

A

Hydroxyl (-OH)

142
Q

What are some of the main phase I reaction types?

A
  • Hydroxylation
  • Oxidation
  • Reduction
  • Hydrolysis
  • N-de-alkylation
  • Oxidative deamination
143
Q

What are the intermediates of liver detoxification like?

A

They are often reactive oxygen species that can cause secondary damage and must soon undergo phase II reaction.

144
Q

Does liver metabolism always make the substances less toxic than before?

A

No, sometimes it can make it more toxic.

145
Q

What are the two main divisions of drug metabolising enzymes (DMEs)?

A
  • Phase I enzymes -> Responsible for oxidation, reduction and hydrolysis
  • Phase II enzymes -> Responsible for conjugation
146
Q

Aside from the liver, where else are drug metabolising enzymes found?

A

Small intestine and blood

147
Q

What are some major classes of phase I enzymes? [EXTRA]

A
  • Dehydrogenases
  • Mono-oxygenases -> Cytochrome P450s
  • Reductases
  • Hydrolases
148
Q

What are the main categories of enzymes that carry out oxidation in phase I of metabolism? When is each used?

A
  • Specific monooxygenases -> Used to oxidise specific molecules
    • Monoamine oxidase (MAO)
    • Alcohol dehydrogenase
  • General, mixed-function monooxygenases -> Used to metabolise everything else
    • Cytochrome P450s
149
Q

Through which enzyme does most of liver detoxification go in phase I? What sort of enzyme is this?

A

Cytochrome P450s -> These are mono-oxygenase enzymes with a low specificity for drugs

150
Q

What type of enzyme are cytochrome P450s? [EXTRA]

A

Mono-oxygenase -> This means they are electron donors

151
Q

What is an unwanted side effect of oxidation/reduction reactions in phase I of liver metabolism?

A

They can activate innocuous xenobiotics to give carcinogens and other toxic molecules.

152
Q

Describe an example of the activation of xenobiotics to carcinogens.

A
  • When benzene is metabolised by cytochrome P450s, it forms benzene epoxide as an intermediate
  • If this is close to DNA, it can tag onto DNA and act as a carcinogen.
153
Q

How can phase I of liver metabolism be clinically exploited?

A

Prodrugs can be activated by the oxidation/reduction reactions.

154
Q

What cofactor do cytochrome P450s use?

A

NADPH

(Since the cytochromes P450s are mono-oxygenases and are therefore electron donors)

155
Q

Aside from drug metabolism, what other processes do cytochrome P450s play a role in?

A
  • Steroid production
  • Bile acid production
156
Q

Write the equation for the reaction that cytochrome P450s catalyse. [EXTRA?]

A
157
Q

How does drug metabolism respond to changes in the levels of drugs in the body?

A

Major enzymes and other components of phase 1 and 2 metabolism can be induced by transcription factors activated by the presence of drugs.

158
Q

How does alcohol modify drug metabolism? [Details are EXTRA]

A

Ethanol can induce the cytochrome P450 system. However, these enzymes have a broad specificity, so this has many side effects:

  • Increased metabolism and decreased half life of:
    • Warfarin, phenytoin, phenobarbital, propranolol
  • Increased activation and hepatotoxicity of:
    • Paracetamol, isoniazid, cocaine, carbon tetrachloride, various carcinogens
159
Q

What are the two types of monoamine oxidases?

A
  • MAO-A
  • MAO-B
160
Q

What are monoamine oxidases and where are they found?

A
  • A family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group.
  • Found on the outer membrane of mitochondria.
  • Expressed in most tissues.
161
Q

Write the equations for the reactions catalysed by MAO.

A

1: RCH2NH2 + O2 → RCH = NH +H2O2
2: RCH=NH+H2O → RCH= O + NH3

162
Q

What are molybdenum hydroxylases? [EXTRA]

A
  • This class includes three groups: aldehyde oxidases (AOs), xanthine oxidases/dehydrogenases (XDH).
  • They are phase I enzymes involves in drug metabolism.
163
Q

In phase II of drug metabolism in the liver, conjugation occurs. What types of reaction does this involve?

A

Oxidation/Reduction reactions

164
Q

What is the purpose of phase II drug metabolism reactions?

A

To conjugate groups to the drug that make it even

165
Q

What are some of the different molecules that drugs can be conjugated with in phase II of drug metabolism?

A
  • Glucuronic acid
  • Glycine
  • Glutathione
  • Sulfate
  • Methyl group
  • Acetyl group
166
Q

What enzyme is responsible for the majority of phase II conjugation reactions in the liver?

A

UDP-Glucuronosyltransferases (UGT)

167
Q

What is the role of UDP-glucuronosyltransferases (UGT)?

A
  • Enzymes that catalyze the transfer of sugars (glucuronic acid, glucose, and xylose) to a variety of acceptor molecules (aglycones).
  • This is as part of phase II reactions.
168
Q

Where are UDP-glucuronosyltransferases (UGT) found?

A
  • Luminal side of the ER
  • In the liver, kidney and intestine
169
Q

What conjugation does the spec mention specifically for phase II reactions?

A

Conjugation with glucuronic acid

170
Q

In phase II of liver metabolism, what may sugars be attached at?

A
  • Aromatic and aliphatic alcohols
  • Carboxylic acids
  • Thiols
  • Primary, secondary, tertiary, and aromatic amino groups
  • Acidic carbon atoms
171
Q

What is glucuronidation an important step in the elimination of?

A
  • Bilirubin
  • Bile acids
  • Steroid hormones
  • Thyroid hormones
  • Retinoic acids
  • Biogenic amines such as serotonin
172
Q

Draw the mechanism for glucoronidation. State what the enzyme for this is.

A
  • Enzyme: UDP-Glucuronosyltransferases (UGT)
  • X is a nucleophilic site
173
Q

What are acyl glucuronides and what is their clinical importance?

A
  • Carboxylic acids conjugated with glucuronide
  • Many of these are considered to be reactive electrophilic metabolites
  • These can reaction with proteins leading to covalent drug/protein adducts.
  • A number of acyl glucuronides lead to idiosyncratic hepatotoxicity that is considered to be immune-mediated.
174
Q

Draw a diagram to show how benzene might be metabolised, ready for excretion.

A
175
Q

How do metabolites move into and out of liver cells?

A

There are many influx and efflux pumps.

176
Q

How can drug interactions occur with relation to transporters?

A

One drug can affect the metabolism of another by inhibiting the influx or efflux pumps on the surface of liver cells.

177
Q

How is bilirubin metabolised in phase II in the liver? How is this clinically relevant?

A
  • It can only be glucuronidated by UGT1A1
  • Mutations in this enzyme result in high levels of unconjugated bilirubin in the blood, which can lead to neurotoxicity:
    • Crigler-Najar syndrome
    • Gilbert syndrome
178
Q

What is the primary site of alcohol metabolism?

A

Liver

179
Q

What are the toxic effects of alcohol due to?

A
  • Acetaldehyde (CH3-CHO)
  • NADH
180
Q

What are the three major metabolic effects of alcohol? [IMPORTANT]

A
  • Hypoglycaemia
  • Lactic acidosis
  • Hyperuricaemia (excess of uric acid in the blood)
181
Q

What carries out first pass metabolism of alcohol?

A

The stomach.

182
Q

What factors affect the absorption of alcohol?

A
  • Concentration of alcohol
  • Blood flow at site of absorption
  • Irritant properties of alcohol
  • Rate of ingestion
  • Fed/fasted state
183
Q

Why are women more affected by alcohol?

A
  • Women generally have a smaller volume of distribution for alcohol than men because of their higher percentage of body fat.
  • Women will have higher peak blood alcohol levels than men when given the same dose of alcohol as g per kg body weight but no differences occur when given the same dose per liter of body water.
184
Q

What three enzymes catalyse the first step of alcohol metabolism and where in the cell is each found?

A
  • Alcohol dehydrogenase -> Cytosol
  • Cytochrome P450 mono-oxygenase -> ER
  • Catalase -> Peroxisomes
185
Q

Where is alcohol dehydrogenase (ADH) found?

A

Cytosol of liver cells

186
Q

What is the equation for the reaction catalysed by alcohol dehydrogenase (ADH)? [EXTRA]

A

CH3-CH2OH + NAD+ → CH3-CHO + NADH + H+

187
Q

What is the function of alcohol dehydrogenase?

A
  • It functions to:
    • Oxidise endogenous alcohol produced by microorganisms in the gut
    • Oxidise exogenous ethanol and other alcohols consumed in the diet
    • Oxidise substrates involved in steroid and bile acid metabolism.
  • The enzyme has broad substrate specificity, oxidising many primary or secondary alcohols
188
Q

What trace mineral does alcohol dehydrogenase contain?

A

Zinc

189
Q

Aside from gender differences, what might account for different alcohol tolerances between people?

A

Differential expression and activity of isoforms of alcohol dehydrogenase may account for differences in alcohol metabolism between individuals.

190
Q

Where is catalase and in what part of the cells?

A
  • In the brain and liver (mostly significant in the brain)
  • In peroxisomes
191
Q

What reactions does catalase catalyse? What is its function?

A
  • Main role as an antioxidant:
    • H2O2+ H2O2 -> H2O + O2
  • More minor role in alcohol metabolism (limited due to limited peroxide):
    • CH3-CH2OH + H2O2 -> CH3-CHO + 2H2O
192
Q

What are the two major products of the first step of alcohol metabolism?

A
  • Acetaldehyde (CH3CHO)
  • NADH
193
Q

What enzyme catalyses the second step of alcohol metabolism?

A

Aldehyde dehydrogenase

194
Q

What does aldehyde dehydrogenase do?

A
  • Catalyses the removal of acetaldehyde produced by the first step of alcohol metabolism
  • Acetylaldehyde + NAD+ + H2O → Acetate + NADH + H+
195
Q

How many types of aldehyde dehydrogenase are there? Which is the main one involved in alcohol metabolism? [EXTRA]

A
  • Four main classes of the enzyme -> I to IV
  • Type II is the main type
196
Q

Where is aldehyde dehydrogenase found?

A

The main type found in alcohol metabolism is in the mitochondria.

197
Q

What is the typical ratio of NAD+ to NADH in liver cells? How is this altered by alcohol metabolism and what is the effect of this? [EXTRA]

A
  • Typically there is a lot more NAD+ than NADH
  • Liver metabolism produces NADH, which changes this ratio
  • This has profound effects on other liver metabolic pathways which require NAD+ or are inhibited by NADH
  • This NADH must therefore be removed
198
Q

How is NADH produced by alcohol metabolism removed? [EXTRA?]

A
  • Lactate dehydrogenase (in the cytosol)
    • Pyruvate + NADH -> Lactate + NAD+
  • 3-Hydroxybutyrate dehydrogenase (in mitochondria)
    • Acetoacetate + NADH -> Beta-hydroxybutyrate + NAD+

These reactions get rid of the NADH produced by alcohol metabolism, maintaining the low ratio of NADH to NAD+.

199
Q

Where is lactate dehydrogenase found and what reaction does it catalyse in relation to alcohol metabolism?

A
  • In the cytosol of the liver
  • It catalyses the removal of NADH produced by alcohol metabolism
  • Pyruvate + NADH -> Lactate + NAD+
200
Q

Where is 3-hydroxybutyrate dehydrogenase found and what reaction does it catalyse in relation to alcohol metabolism?

A
  • It is found in mitochondria of the liver
  • It catalyses the removal of NADH produced by alcohol metabolism
  • Acetoacetate + NADH -> Beta-hydroxybutyrate + NAD+
201
Q

How can alcohol consumption lead to the side effect of lactic acidosis? [IMPORTANT]

A
  • Alcohol consumption is often related to a poor diet that is low in thiamine
  • Thiamine is a precursor to many important molecules, including those involved in the conversion of pyruvate to acetyl-CoA
  • Therefore, thiamine deficiency means that the build up of pyruvate is directed towards lactate rather than the TCA cycle, leasing to lactic acidosis
202
Q

How can alcohol consumption lead to the side effect of hypoglycaemia? [IMPORTANT]

A
  • Decreased glucose sensitivity
    • Alcohol impairs the brain’s awareness low blood glucose -> So less oral intake
  • Decreased gluconeogenesis
    • Alcohol metabolism produces NADH
    • This stimulates the conversion of pyruvate into lactate, instead of into gluconeogenesis
    • Also, ethanol inhibits growth hormone that favours gluconeogenesis from free fatty acids
  • Decreased insulin sensitivity
203
Q

Describe why some Asian people have a lower tolerance to alcohol.

A
  • 50% Chinese/Japanese experience flushing, hypotension and tachycardia on ingesting alcohol
  • Due to type II enzyme variant in which glu 497 is replaced by lys → reduced activity.
  • Variant enzyme may give aversion to alcohol because of unpleasant reaction when acetaldehyde accumulates
  • However, if individual continues to drink regardless, there is an increased risk of liver cell damage due to toxic effects of acetaldehyde
204
Q

What products/intermediates of alcohol metabolism are damaging to the liver?

A

Acetaldehyde is toxic to the liver if not removed.

205
Q

Draw the mechanism for aldehyde dehydrogenase action.

A
206
Q

Why is acetaldehyde toxic to the liver? [IMPORTANT]

A
  • Mitochondrial dysfunction -> Lipid peroxidation
  • Increased collagen synthesis
  • Appearance of neo-antigens
  • Decreased microtubule function -> Altered transport and secretion

This can occur due to acetaldehyde binding to lysine residues on proteins.

207
Q

Draw a diagram to summarise the metabolism of alcohol.

A
208
Q

Describe what happens to the acetate produced by alcohol metabolism.

A

It is converted to uric acid:

  • CH3-CHO → CH3COOH
  • CH3COOH + ATP + CoASH → CH3CO-SCoA + AMP + PPi
  • AMP → IMP → hypoxanthine → uric acid
209
Q

How can alcohol metabolism lead to hyperuricaemia and what are the consequences of this?

A
  • The acetate produced by alcohol metabolism is converted to give uric acid, which builds up in the blood
  • This can lead to gout, which is characterised by recurrent attacks of a red, tender, hot, and swollen joint.
210
Q

What is methanol metabolised to and how? What is the significance of this?

A
  • It is metabolised to formaldehyde
  • By alcohol dehydrogenase

Formaldehyde is what specimen are preserved in for DR. This means that even a small amount of methanol can cross link proteins and can be fatal.

211
Q

In general, why are aldehydes bad?

A

They can cross-link a lot of proteins, damaging them.

212
Q

How can methanol poisoning be treated an why?

A

By a large dose of ethanol, which outcompetes the methanol for the alcohol dehydrogenase binding site. Thus, no formaldehyde is produced.

213
Q

Which antibiotics do not mix with alochol? [EXTRA]

A
214
Q

What are two harmful reactive oxygen species formed by the body that you need to know about? What is the formula of each?

A
  • Superoxide -> O2-
  • Hydrogen peroxide -> H2O2
215
Q

Describe the formation of superoxide and hydrogen peroxide, plus their derivatives.

A
  • They are produced by:
    • 15% by mitochondrial electron transport chain
    • 45% by endoplasmic cytochrome P450 system
    • 35% by peroxisomal H2O2 generation
    • 5% by cytosolic reactions
  • O2- can be further reduced to H2O2 or it can generate ONOO-.
  • H2O2 can also generate an OH radical.
216
Q

What are the two vitamins with anti-oxidant properties that you need to know about? [IMPORTANT]

A
  • Vitamin C
  • Vitamin E
217
Q

Where in the cell does vitamin C act as an anti-oxidant?

A

Cytosol

218
Q

Where in the cell does vitamin E act as an anti-oxidant?

A

Membranes

219
Q

What is the most important anti-oxidant molecule except for vitamins C and E?

A

Glutathione

220
Q

What are the three main anti-oxidant enzymes?

A
  • Superoxide dismutase
  • Catalase
  • Glutathione peroxidase
221
Q

Describe how the three main anti-oxidant enzymes work together. [IMPORTANT]

A

Superoxide dismutase:

  • 2O2- + 2H+ → H2O2 + O2

Catalase:

  • 2H2O2 → 2H2O + O2

Glutathione peroxidase:

  • 2GSH + H2O2 → GSSG + 2H2O
222
Q

What trace elements do different isoforms of superoxide dismutase contain?

A
  • Cu/Zn in cytosol
  • Mn in mitochondria
223
Q

What is the most reactive harmful oxygen species?

A

OH- (hydroxide)

224
Q

Summarise the major oxidant and antioxidant systems in the cell.

A

YEAR 1 - Biochemistry and Medical Genetics (Anton) (8 decks)

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