CC6: Metabolic Diseases Flashcards
What is the mechanism behind MCAD deficiency? What are the symptoms?
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.
Why is clinical presentation of MCAD often seen in the liver?
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.
What is Jamaican vomiting sickness?
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.
What is the mechanism behind carnitine deficiencies? What are the symptoms?
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.
Describe Zellwegers disease. What are the symptoms?
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.
What are the mechanisms and symptoms of Type I von Glerke disease?
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.
What are the mechanisms and symptoms behind type III Cori’s disease?
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.
What are the symptoms and mechanisms behind type V McArdle’s disease?
How can this disease be detected?
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].
Describe the mechanisms and symptoms behind G-6-P dehydrogenase deficiency
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.
How is G-6-P dehydrogenase deficiency related to contraction of malaria?
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.
What are the symptoms and mechanisms behind PKU disease?
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.
Describe the two theories thought to explain the mechanism behind PKU disease
- 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.
- Transport hypothesis: phenylalanine at high concentrations outcompetes other molecules for uptake into the brain.
What is tyrosinemia I disease? How is it treated?
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.
Why are only some tissues affected by an inborn error?
- A specific pathway is only active in certain tissues.
- Some tissues have higher dependence on a specific fuel that 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.
What is the difference between catabolic and anabolic?
Catabolic: breaking things down for the synthesis of energy
Anabolic: building things up via the synthesis of storage molecules
Describe the Cori cycle.
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.
Describe the glucose-alanine cycle (Cahill cycle).
Amino groups and lactate from muscle are transported to the liver for gluconeogenesis. The resulting glucose can then be transported back to the muscle.
What is the key molecule involved in cytosolic, and mitochondrial metabolism? List the pathways they are involved in.
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
Describe the Krebs cycle. What is the yield? How is it regulated?
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)
- Feedback inhibition of key enzymes by the products of the reaction to prevent overproduction of ATP and reduced cofactors.
- Substrate availability.
- Hormones and other signaling molecules e.g., insulin and calcium.
- Chronic regulation involves an increased number of mitochondria.
Why is calcium used to regulate metabolic pathways, such as the Kreb cycle?
Calcium increase signals that there’s an increase in muscle contractility, and hence the muscle is going to require extra energy production.
Why don’t red blood cells undergo the Krebs cycle or the electron transport chain?
They don’t have mitochondria.
How is glycolysis regulated?
- Glucose uptake (GLUTs)
- Energy state of the cell e.g., PFK1 is inhibited by high ATP levels
- Indirect hormone regulation e.g., F-6-P can be converted into F2,6bP which activates PFK1.
- Feedforward stimulation e.g., F1,6bP stimulates pyruvate kinase.
- Allosteric factors
- Covalent modifications - hormonal control
- Translocation of proteins
What’s the difference between GLUT1, GLUT2, and GLUT4?
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
How are glycogenesis and glycogenolysis regulated?
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.
How is gluconeogenesis regulated? How is it tissue specific?
+ 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.
How is fatty acid oxidation regulated?
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.
Describe de novo lipogenesis. How is it regulated?
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.
Describe ketolysis and ketogenesis. Where do they occur? How are they regulated?
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.
Which pathway can amino acids be fed into? How are they used in the fed vs fasted state?
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).
Which tissues prefer the following substrates for fuel, and why:
- Fatty acids
- Glucose
- Amino acids
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)
What are glucogenic vs ketogenic amino acids?
Glucogenic: can be metabolised to produce glucose through gluconeogenesis.
Ketogenic: can be metabolised to produce ketone bodies.
Some amino acids can be both!
Give the pros and cons to fatty acid and glucose metabolism for energy production.
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
