CC6: Metabolic Diseases

Question 1

What is the mechanism behind MCAD deficiency? What are the symptoms?

Answer 1

MCAD deficiency means you can’t break down fatty acid chains longer than 8 carbons during fasting. Normally, the liver would take up FAs to generate ketones. Without this process, the brain becomes starved of ketones and so keeps using glucose, causing hypoglycemia, coma and eventually death.

Question 2

Why is clinical presentation of MCAD often seen in the liver?

Answer 2

The liver takes up fatty acids during fasting to generate acetyl CoA which is diverted into ketone body synthesis. In MCAD, they can’t break down the fatty acids and so a build up of fatty deposits is often seen in the liver in cases of sudden deaths. Without ketone bodies, the brain is starved and becomes hypoketotic.

Question 3

What is Jamaican vomiting sickness?

Answer 3

This is a disease caused by consuming unripe ackee fruit which poisons a key enzyme in B-oxidation, blocking the pathway. This presents in similar symptoms to MCAD deficiency but at a much faster rate.

Question 4

What is the mechanism behind carnitine deficiencies? What are the symptoms?

Answer 4

This disease is due to a mutation in the carnitine transporter, preventing FA from being shuttled into the mitochondrial matrix. This results in FAs being stored in other organs, and thickening of the heart chambers because there’s less energy for the heart as well as reduced ketogenesis.

Muscle weakness is due to the muscles eventually requiring FAs to generate ATP, and many show hypoglycemia due to a compensatory shift to glucose metabolism that is to the detriment of the rest of the body.

Question 5

Describe Zellwegers disease. What are the symptoms?

Answer 5

A defect in the import of proteins into the peroxisome, which catalyses the initial steps in oxidation of some FAs, causing hypotonia (poor muscle tone) and seizures, abnormal facial presentations, and usually death within months.

Question 6

What are the mechanisms and symptoms of Type I von Glerke disease?

Answer 6

A deficiency in G-6-Pase (only in the liver ER), resulting in the liver and kidneys becoming enlarged due to excess glycogen that can’t be broken down because G-6-P isn’t active to increase blood glucose from glycogen.

This causes hypoglycemia, and the Cori cycle can’t function so lactate levels rise causing acidification of the blood.

Question 7

What are the mechanisms and symptoms behind type III Cori’s disease?

Answer 7

A deficiency in the debranching enzyme which removes the branches from glycogen. This causes a build up of abnormal glycogen with lots of short branches that causes damage to organs, especially the liver and muscles.

Difficult to distinguish from type I von Glerke disease by physical examination.

Question 8

What are the symptoms and mechanisms behind type V McArdle’s disease?

How can this disease be detected?

Answer 8

A muscle phosphorylase deficiency which means muscle glycogen can’t be broken down, but blood glucose and liver function isn’t compromised.

This results in enlarged glycogen granules in the muscle, but the muscle can’t then use the glycogen for ATP production in response to exercise, often causing painful cramps and exercise intolerance.

Detected using 31-P magnetic resonance spectroscopy on muscle at rest and during exercise. Individuals with the disease can’t regenerate ATP from ADP in response to acute exercise so there will be a spike in [ADP].

Question 9

Describe the mechanisms and symptoms behind G-6-P dehydrogenase deficiency

Answer 9

Without this enzyme, you cannot produce enough NADPH, which is a source of antioxidant protection. This often only presents due to drugs/infection as these lead to oxidative stress which can’t be overcome. As red blood cells have no other organelle to produce NADPH, but contain high levels of oxygen, they will often burst.

Question 10

How is G-6-P dehydrogenase deficiency related to contraction of malaria?

Answer 10

This disease is very common as the distribution of sufferers matches very closely with the distribution of malaria. It’s thought that this deficiency offers a level of protection against malaria due to reduced red blood cells.

As G6PD deficiency leads to increased oxidative stress in red blood cells, this may in turn have a negative influence on the parasite. As such, individuals who possess this mutation have some protection against malaria.

Question 11

What are the symptoms and mechanisms behind PKU disease?

Answer 11

A disease where someone is unable to metabolise phenylalanine due to deficiencies in phenylalanine monooxygenase.

If left untreated soon after birth, it causes serious neurological problems, hence why babies are screen within the first 7 days of being born.

Question 12

Describe the two theories thought to explain the mechanism behind PKU disease

Answer 12

1. Toxic metabolite theory: the new metabolites phenylpyruvate and phenyllactate are responsible, which aren’t normally seen in normal humans. Thus, it’s not actually phenylalanine causing the issue, but it’s the met-metabolites.
2. Transport hypothesis: phenylalanine at high concentrations outcompetes other molecules for uptake into the brain.

Question 13

What is tyrosinemia I disease? How is it treated?

Answer 13

A rare autosomal recessive metabolic disorder characterised by the lack of a key enzyme needed to break down tyrosine. This can result in cancer and severe liver disease.

It can be treated with a low tyrosine diet and liver transplantation. A drug is also used that blocks the tyrosine degradation pathway further upstream, as this has less severe liver damage symptoms.

Question 14

Why are only some tissues affected by an inborn error?

Answer 14

1. A specific pathway is only active in certain tissues.
2. Some tissues have higher dependence on a specific fuel that others.
3. The IEM may affect a tissue-specific isoform of the enzyme.
4. Some tissues may have less capacity to ‘flex their metabolism’ to a different fuel, or to tolerate the consequences of a restricted pathway.

Question 15

What is the difference between catabolic and anabolic?

Answer 15

Catabolic: breaking things down for the synthesis of energy
Anabolic: building things up via the synthesis of storage molecules

Question 16

Describe the Cori cycle.

Answer 16

When glycogen is broken down via glycolysis, the lactate formed during this process diffuses from the muscle into the capillaries and is transported to the liver.

The liver cells oxidise lactate to pyruvate, which may be reconverted to glucose by gluconeogenesis.

This glucose may be exported from the liver and thus made available again to the muscle for energy or storage as glycogen.

Question 17

Describe the glucose-alanine cycle (Cahill cycle).

Answer 17

Amino groups and lactate from muscle are transported to the liver for gluconeogenesis. The resulting glucose can then be transported back to the muscle.

Question 18

What is the key molecule involved in cytosolic, and mitochondrial metabolism? List the pathways they are involved in.

Answer 18

Cytosolic: G-6-P
- Glycolysis
- Gluconeogenesis
- Pentose phosphate pathway
- Glycogenesis
- Glycogenolysis

Mitochondria: acetyl CoA
- Oxidative phosphorylation
- Ketogenesis
- Ketolysis
- De novo lipogenesis
- Fatty acid oxidation
- Proteolysis

Question 19

Describe the Krebs cycle. What is the yield? How is it regulated?

Answer 19

Integration of 1 acetyl CoA results in the synthesis of:
- 2 CO2 molecules
- 1 substrate-level phosphorylation (formation of GTP/ATP)
- 4 reduced cofactor molecules (for oxidative phosphorylation)

1. Feedback inhibition of key enzymes by the products of the reaction to prevent overproduction of ATP and reduced cofactors.
2. Substrate availability.
3. Hormones and other signaling molecules e.g., insulin and calcium.
4. Chronic regulation involves an increased number of mitochondria.

Question 20

Why is calcium used to regulate metabolic pathways, such as the Kreb cycle?

Answer 20

Calcium increase signals that there’s an increase in muscle contractility, and hence the muscle is going to require extra energy production.

Question 21

Why don’t red blood cells undergo the Krebs cycle or the electron transport chain?

Answer 21

They don’t have mitochondria.

Question 22

How is glycolysis regulated?

Answer 22

1. Glucose uptake (GLUTs)
2. Energy state of the cell e.g., PFK1 is inhibited by high ATP levels
3. Indirect hormone regulation e.g., F-6-P can be converted into F2,6bP which activates PFK1.
4. Feedforward stimulation e.g., F1,6bP stimulates pyruvate kinase.
5. Allosteric factors
6. Covalent modifications - hormonal control
7. Translocation of proteins

Question 23

What’s the difference between GLUT1, GLUT2, and GLUT4?

Answer 23

GLUT1: in most tissues, low Km
GLUT2: liver, pancreas; high Km as these will receive a large hit of glucose after eating
GLUT4: insulin-sensitive tissues; induces translocation

Question 24

How are glycogenesis and glycogenolysis regulated?

Answer 24

These processes involve either glycogen synthase or glycogen phosphorylase. Both are regulated by:
- Adrenaline
- Glucagon (liver only)
- Insulin

GP is also regulated by calcium and AMP in the muscle only.

Question 25

How is gluconeogenesis regulated? How is it tissue specific?

Answer 25

+ Glucagon (phosphoenolpyruvate carboxylase, F1,6bP) - Glucagon (pyruvate kinase) + Citrate (F1,6bP) + Acetyl CoA (pyruvate carboxylase) This only occurs in the liver, so G-6-Pase and glucagon receptor expression confers cell specificity to hepatocytes.

Question 26

How is fatty acid oxidation regulated?

Answer 26

Key site of regulation is the carnitine shuttle, as there's no transporter for fatty acyl CoA so carnitine is added for transport and later removed within the mitochondria. These shuttles are controlled by malonyl CoA.

Question 27

Describe de novo lipogenesis. How is it regulated?

Answer 27

Takes a non-fatty acid source to generate TAGs by first converting them into acetyl CoA. This generates malonyl CoA which inhibits fatty acid oxidation to prevent futile cycling. - Occurs mostly in the liver, but other tissues will still use it to create malonyl CoA for FA oxidation regulation. - Acetyl CoA is regulated by palmitoyl CoA, citrate, and energy levels.

Question 28

Describe ketolysis and ketogenesis. Where do they occur? How are they regulated?

Answer 28

In ketogenesis, TAGs are broken down through the FA oxidation pathway and, within the liver, acetyl CoA is diverted into ketone production rather than into the Krebs cycle. Ketone bodies can then be broken down again to provide acetyl CoA as an alternative fuel source via ketolysis. Ketogenesis: Liver Ketolysis: most oxidative tissues Ketolysis is regulated by substrate availability and ketone body concentration within the blood.

Question 29

Which pathway can amino acids be fed into? How are they used in the fed vs fasted state?

Answer 29

Can be fed into different points of the Kreb cycle depending on their carbon skeleton. Fed state: carbon skeletons are used to make ATP or storage as either TAGs or glycogen. Fasted state: used by the liver to make either glucose or ketones, depending on the carbon skeleton (i.e., glucogenic or ketogenic, or both).

Question 30

Which tissues prefer the following substrates for fuel, and why: - Fatty acids - Glucose - Amino acids

Answer 30

Fatty acids: - Heart - Skeletal muscle - Liver - Renal cortex These have a good oxygen supply, many mitochondria, oxidative metabolism and a high ATP requirement. Glucose: - Brain - RBCs - Renal medulla - Skeletal muscle These have poor oxygen supply and few/no mitochondria (excluding the brain), and are anaerobic. Amino acids: - Liver (all except leu, ileu, and val) - Gut (gln, glu, asp) - Renal cortex (gln) - Muscle (leu, ileu, val)

Question 31

What are glucogenic vs ketogenic amino acids?

Answer 31

Glucogenic: can be metabolised to produce glucose through gluconeogenesis. Ketogenic: can be metabolised to produce ketone bodies. Some amino acids can be both!

Question 32

Give the pros and cons to fatty acid and glucose metabolism for energy production.

Answer 32

FAs: - More energy rich - Good for storage - Needs lots of oxygen Glucose: - Less energy rich - More hydrated, so larger and therefore less desirable as energy storage - More oxygen efficiency and can generate ATP anaerobically

Question 33

Why do fats make more energy than glucose?

Answer 33

Fats produce far more reduced cofactors that can enter the ETC in B-oxidation, compared to the amount glucose produces in glycolysis and the TCA cycle.

Question 34

What are the advantages and disadvantages of hormonal control of metabolism?

Answer 34

+ 1 signal can control multiple tissues + 1 signal can control multiple metabolic pathways + 1 signal can mediate immediate and delayed responses - hormones are typically extracellular, so a signaling cascade is required - intracellular signaling delays the response time

Question 35

How is insulin used in metabolism?

Answer 35

Secreted by B cells of the pancreas in the fed state, stimulated by an increase in blood glucose, certain amino acids and certain FAs. This is a signal of the fed state, stimulating anabolic pathways whilst inhibiting catabolic pathways.

Question 36

Describe the signaling pathway that occurs in B-cells to secrete insulin.

Answer 36

The pancreas takes up glucose which enters the B-cells via GLUT2. This triggers glycolysis and increases the [ATP]. Increased [ATP] closes ligand-induced K channels, but opens VG calcium channels. The influx of calcium then causes insulin release.

Question 37

Describe the signaling cascade induced in muscle, adipose, and liver cells by insulin.

Answer 37

Insulin binds its receptor and triggers activation of PI3K. PI3K converts PIP2 into PIP3. PIP3 activates PDK1, activating Akt. Akt then goes on to increase GLUT4 transporters within the membrane for increased glucose uptake. Insulin also induces activation of enzymes involved in glycolysis.

Question 38

How does insulin stimulate glycogenesis?

Answer 38

It activates glycogen synthase whilst inactivating glycogen phosphorylase.

Question 39

How does insulin inhibit fatty acid oxidation?

Answer 39

Indirectly, by stimulating the de novo lipogenesis pathway to increase malonyl CoA which inhibits FA oxidation by blocking the carnitine shuttle.

Question 40

How does insulin impact: - ketogenesis and ketolysis - protein breakdown - transcription

Answer 40

Decreases ketogenesis and ketolysis Suppresses protein breakdown Controls transcription of over 150 genes as there's multiple insulin TFs.

Question 41

How is glucagon involved in metabolism regulation? How is glucagon release triggered?

Answer 41

Glucagon is secreted by the a-cells of the pancreas in the fasted state, simulated by low glucose levels. It only acts on the liver as a signal to liberate glucose into the blood from the liver to fuel other tissues. In a-cells, low ATP results in calcium influx and inducement of glucagon granule release.

Question 42

How does glucagon impact gluconeogenesis?

Answer 42

It activates it, by activating PKA which decreases F-2,6-bP and thus decreases activity of enzymes involved in glycolysis. It can also increase the synthesis of enzymes involved in gluconeogenesis.

Question 43

How does glucagon regulate glycogenolysis?

Answer 43

In the hepatocyte, glucagon activates glycogen phosphorylase whilst inhibiting glycogen synthase to promote glycogenolysis and inhibit glycogenesis.

Question 44

How does glucagon regulate fatty acid oxidation?

Answer 44

It increase oxidation by decreasing malonyl CoA levels to upregulate the carnitine shuttle. Not all of the acetyl CoA made in glycolysis can undergo the Krebs cycle, and so it undergoes ketogenesis.

Question 45

What physiological changes occur in the fasted state? What promotes these changes?

Answer 45

1. Muscle reduces glucose use, so there's more available for the brain and RBCs. 2. Muscle increases FA use. 3. Adipose tissue responds by increasing FA release via lipolysis. It's the absence of insulin that promotes these changes, not the increase in glucagon.

Question 46

What is the Randle cycle?

Answer 46

The cycle proposes that if fat is most abundant, the cell should stop using glucose to save it for other cells. If glucose is most abundant, the cell should stop using fat.

Question 47

How does insulin regulate lipid metabolism in the fed state?

Answer 47

Insulin promotes uptake, storage, and synthesis of lipids in various tissues. 1. Insulin promotes uptake of non-esterified FAs (NEFAs) from the blood. 2. Insulin stimulates synthesis of TAGs in adipose tissue. 3. Insulin promotes TAG storage. 4. Insulin inhibits NEFA oxidation in muscle and liver tissue by reducing the activity of enzymes involved in B-oxidation e.g., CPT1 and HSL.

Question 48

Compare type I and type II diabetes. How are they diagnosed?

Answer 48

Type I: insulin-dependent; typical onset from 1-25 years old due to autoimmune destruction of pancreatic B-cells. Type II: non-insulin dependent; typical onset >40 years due to insulin resistance in peripheral tissues. Insulin is produced in greater amounts to overcome this, but it can impair insulin secretion from B-cells. Diagnosis involves monitoring plasma glucose concentrations after a glucose spike.

Question 49

Summarise the metabolic effects of type I diabetes.

Answer 49

A lack of insulin means the body thinks it's starving, promoting catabolism and inhibiting anabolism, but the body is in the fed state. Changes in blood profile: - Low insulin - Hyperglycaemia - Hyperlipidaemia - Hyperketonaemic

Question 50

What is diabetic ketoacidosis?

Answer 50

Diabetes means that the body constantly thinks it's in the fasted state due to a lack of insulin. In an effort to obtain energy from other sources, the body starts to break down fats for fuel, leading to the production of ketones as a byproduct. High levels of ketones in the blood can can acidify the blood, hence the name ketoacidosis.

Question 51

What are the long-term complications of diabetes?

Answer 51

Cardiovascular disease Nephropathy (kidney disease) Retinopathy Neuropathy Amputation Depression and dementia Complications in pregnancy

Question 52

What are the treatment options for type I and type II diabetes?

Answer 52

Type I: - glucose monitoring - insulin injections - insulin pumps - islet transplantation Type II: - lifestyle improvements - drugs e.g., insulin injections or metformin (improves insulin sensitivity)

Question 53

What future treatments are hoped to be used for type I diabetes?

Answer 53

1. Closed circuit loops (sense glucose and automatically infuse the appropriate insulin) 2. Islet encapsulation advances 3. Childhood vaccines to prevent diabetes development in high risk individuals 4. Pancreatic transplantation

Question 54

What mechanisms are thought to drive type II diabetes? What are the metabolic consequences?

Answer 54

Peripheral tissue may become resistant to insulin because of: - adipokines secreted from enlarged adipose tissue - intracellular lipid accumulation (lipotoxicity) - high glucose (glucotoxicity) - adipose-derived hormones Insulin induces targets but not to the same extent, causing a whole body metabolic shift away from glucose use towards FA use. However, there is still some insulin present so gluconeogenesis and ketogenesis aren't increased as much as seen in type I.

Question 55

Why do some people argue that diabetes is a fat disease, and not a glucose disease? What 3 mechanisms are driven by intracellular fats?

Answer 55

Many metabolic complications of type I diabetes actually stem from excessive rates of FA delivery from adipose to the liver and muscle, due to insulin not being there to inhibit lipolysis, etc. 1. The Randle cycle - the excess fat drives a decrease in glucose use within cells. 2. PPARa TF - senses the fat and transcribes genes for fat metabolism and storage. 3. Lipid-induced insulin resistance - an intermediate in TAG synthesis can prevent insulin signaling, driving insulin resistance.

Question 56

What determines why different tissues have different demands for oxygen?

Answer 56

ATP requirements of the tissue Metabolic preference for aerobic vs anaerobic Mitochondrial number in the tissue

Question 57

What is hypoxia? Give 2 physiological and 2 pathological examples.

Answer 57

A decrease in oxygen concentration. Physiological: altitude; in utero within the developing foetus. Pathological: myocardial infarction (restricted blood flow); anaemia (poor oxygen transport)

Question 58

Compare acute and chronic hypoxia.

Answer 58

Acute = induces an immediate response via covalent and allosteric mechanism. Chronic = induces a slower response via transcriptional mechanisms. A heart attack involves both of these mechanisms i.e., restricted blood flow to the heart over many years, and an acute MI causes sudden vessel blockage.

Question 59

What reaction does adenylate kinase catalyse?

Answer 59

ADP + ADP --> ATP + AMP Acts as an emergency reaction to scavenge energy when there's low oxygen levels for oxidative phosphorylation (i.e., hypoxia).

Question 60

How is AMPK involved in the response to hypoxia?

Answer 60

In response to hypoxia, AMPK is activated by high [AMP] to promote cell survival: + stimulates glucose uptake, glycolysis, and glycogenolysis to generate ATP in the absence of oxygen + stimulates FA oxidation and uptake + stimulates p53 to inhibit the cell cycle and potentially promote autophagy - decreases anabolic pathways

Question 61

How does AMPK increase glucose uptake? How does this differ to the insulin response, and what does this mean for potential therapies?

Answer 61

Phosphorylates the GLUT4 inhibitor, Rab GTPase, allowing for GLUT4 to move to the membrane. AMPK acts on a different pool of GLUT4 than insulin, so there's a potential for the insulin GLUT4 to be targeted in diabetes without impacting AMPK signaling.

Question 62

How does AMPK upregulate glycolysis, and what is the fate of pyruvate in hypoxic conditions?

Answer 62

Phosphorylates enzymes involved in glycolysis to upregulate them. Under hypoxic conditions, pyruvate is converted into lactate to provide NAD+. This is the cause of chest pain during a heart attack.

Question 63

How does AMPK increase glycogen breakdown?

Answer 63

Inactivates glycogen synthase.

Question 64

How does AMPK reduce de novo lipogenesis and upregulate FA oxidation?

Answer 64

Inhibits an enzyme to reduce malonyl CoA concentration, removing inhibition on the carnitine shuttle for FA oxidation.

Question 65

Why is AMPK activation not a long-term solution to acute hypoxia?

Answer 65

The heart consumes the most amount of oxygen per gram than any other organ in the body as it requires large amounts of ATP. This ATP demand is impossible to fulfill in the absence of oxygen, so AMPK is only suitable for very short-term hypoxia.

Question 66

How is hypoxia-inducible factor involved in chronic hypoxia?

Answer 66

HIF is a TF that binds to hypoxic response elements that are aimed at ensuring cell survival during hypoxia and restoring normoxia. In hypoxia, subunit HIF-a escapes normal degradation and moves into the nucleus to bind HIF-B and induce transcription. It senses decreased oxygen levels by the hydroxylation state of proline residues, as this doesn't occur in hypoxia and is how HIFa escapes degradation.

Question 67

How does HIF impact metabolism during chronic hypoxia?

Answer 67

+ upregulates glycolysis + upregulates glycogen content - inhibits PDH to block oxidative phosphorylation - reduces FA oxidation as this requires lots of oxygen - reduces the ETC by reducing complex IV activity

Question 68

How is HIF being looked into for an anaemia treatment?

Answer 68

Many pharmaceutical companies are developing compounds that activate HIFa as this can increase RBC numbers (HIFa is trying to improve oxygen transport).

Question 69

What is VO2 max?

Answer 69

The maximal aerobic capacity - a measurement of maximum oxygen consumption during physical activity.

Question 70

What are the 3 main energy systems required to meet metabolic demand (i.e., muscle ATP regeneration)?

Answer 70

1. Glycolytic 2. Mitochondrial respiration 3. Phosphagen (synthesising ATP from other phosphate products e.g., ADP+ADP)

Question 71

Describe the relationship between substrate utilisation and exercise intensity/duration.

Answer 71

Low intensity: relies on fats because there's time to oxidise them High intensity: carbohydrates as these are quicker to produce ATP, and it's easy to access from glycogen stores. Very high intensity: anaerobic metabolism, causing production of lactate and causes muscle fatigue, and creatine phosphate to quickly produce ATP during short bursts of intense exercise.

Question 72

Why is muscle glycogen a preferred substrate for high-intensity exercise?

Answer 72

Carbohydrate metabolism can produce ATP up to three times faster than fat metabolism, which is why carbohydrate availability is crucial for high-intensity exercise. Glycogen is also stored in the muscles themselves so is closer to the site of energy production.

Question 73

What are the 3 levels of metabolic regulation? Give examples for each.

Answer 73

1. Hormonal e.g., insulin and glucagon (and adrenaline) 2. Allosteric e.g., calcium which allosterically activates muscle glycogenolysis following muscle contraction, and activation of glycolysis enzymes. 3. Substrate-level e.g., Randle cycle

Question 74

Describe 2 processes that may lead to increased glycogenolysis during exercise. Which of these is primarily required to meet energetic needs during an all-out sprint?

Answer 74

1. Calcium release via muscle contraction, activating glycogen phosphorylase to increase glycogen breakdown. 2. Adrenaline release through sympathetic nervous system stimulation, activating glycogen phosphorylase. Calcium is primarily required for high-intensity exercise, whereas adrenaline is primarily used during moderate-intensity exercise.

Question 75

What is the role of creatine in metabolism?

Answer 75

Creatine is stored in the muscle cells as phosphocreatine. During high-intensity exercise, phosphocreatine can donate its phosphate group to ADP to rapidly produce ATP.

Question 76

What is the Warburg effect, and why does it occur?

Answer 76

Cancer cells primarily undergo anaerobic glycolysis, producing lactate, even in aerobic conditions. It is useful to cancer cells because: 1. There's more 'carbon' for the biosynthesis of fatty acids and nucleotides, especially the synthesis of NADPH via PPP. Cancer cells are prone to generating lots of ROS species, so high [NADPH] is important. 2. Lactate accumulation creates a hostile environment to fend off the immune system.

Question 77

How is glutamine addiction achieved through oncogenic signaling?

Answer 77

Overexpression of the myc oncogene can lead to glutamine addiction in cancer cells as it upregulates expression of high-affinity glutamine transporters, and other vital enzymes in 'glutaminolysis'.

Question 78

Why is NADPH important for oxidative stress control?

Answer 78

It provides reducing power needed to regenerate antioxidants, such as glutathione and thioredoxin.

Question 79

Which metabolic pathways yield NADPH? Which of these is the main NADPH contributor in cancer cells?

Answer 79

1. PPP 2. THF pathway to synthesise purine bases (main contributor) 3. TCA cycle

Question 80

What are oncometabolites and why do these induce cancer?

Answer 80

Oncometabolites are metabolites that accumulate in cells due to mutations in genes encoding metabolic enzymes. These can cause metabolic rewiring and epigenetic reprogramming, especially pseudohypoxia (HIFa accumulates). - Mutant isocitrate dH leads to accumulation of 2-hydroxyglutarate, although the role of this isn't completely understood. - Succinate dH mutations result in succinate accumulation that can promote angiogenesis. - Fumarase mutations results in accumulation of fumarate and a predisposition to renal carcinomas.

Question 81

Is the Warburg effect a cause of cancer, or a result of cancer? How do we know this?

Answer 81

Oncogenic signaling causes the Warburg effect. By adding a radioactive fluorine to glucose molecules, these will get trapped in the cell, so we have observed an increase in glucose uptake in cancer cells compared to WT cells.