Session 2: Energy Production from Carbohydrates (2) Flashcards
What are some regulatory mechanisms of glycolysis?
Substrate availability, product inhibition, feedback inhibition (allosteric), allostery, covalent modification of enzymes.
What is the name of the lactic acid cycle?
Cori cycle
Summarise what happens in the lactic acid cycle (Cori cycle).
Lactate released into the blood is taken up by the liver, oxidised to pyruvate, and converted to glucose via gluconeogenesis.
How do you define the Cori cycle?
The cycling of lactate and glucose between peripheral tissues (muscle) and liver.
In what scenarios is lactate utilisation impaired?
Liver disease, vitamin deficiencies (e.g. thiamine), high alcohol intake, enzyme deficiencies.
How much lactate is produced without exercise every day (g)?
40-50g/day
How much lactate is produced WITH exercise every day (g)?
30g/5 minutes
What are some examples of fructose metabolism disorders and what are the causes?
Essential fructosuria = caused by fructokinase deficiency; fructose intolerance = caused by aldolase deficiency.
What are the products of sucrose metabolism?
Fructose + glucose
What are the products of lactose metabolism?
Galactose + glucose
What are some causes of Galactosaemia (deficiency of galactose)?
Galactokinase deficiency = non-classic galactosaemia; GALT deficiency = classic galactosaemia.
What are symptoms of galactosaemia?
Poor feeding, vomiting, diarrhoea.
What is the clinical presentation of Glucose-Phosphate Dehydrogenase Deficiency (G6PDH deficiency)?
Haemolytic anaemia, fatigue, pale colour of skin, shortness of breath, jaundice.
What are the names given to the insoluble aggregates that attach to RBC membranes in G6PDH deficiency?
Heinz bodies
What is the consequence of attachment of Heinz bodies to RBC membranes?
This leads to destruction of RBCs and causes haemolysis by the spleen.
What are some common triggers of G6PDH deficiency?
Certain chemicals in medications (e.g. antimalarials such as primaquine), antibiotics, certain foods (fava beans), and infections.
Why is there a need for regeneration of NAD+ that isn’t reliant on oxidative phosphorylation?
RBCs have no mitochondria; kidney medulla, lens & cornea have fewer mitochondria; absence of oxygen during vigorous exercise or poorly oxygenated tissues.
The rate of lactate production = the rate of lactate __________.
utilisation
What are plasma lactate concentrations determined by?
Production of lactate, utilisation of lactate, disposal of lactate (by kidneys).
What is considered high lactate (lactic acidosis) in the blood?
> 5mM
What are the major enzymes involved in fructose metabolism?
Fructokinase, aldolase.
Where is fructose metabolised?
In the liver.
What is the process of fructose metabolism?
Fructose is phosphorylated to fructose-1-P by fructokinase enzyme.
Fructose-1-P is cleaved by aldolase enzyme into 2 constituents…
1) Glyceraldehyde = this is converted to glyceraldehyde-3-phosphate
2) DHAP = this is converted to glyceraldehyde-3-phosphate
Glyceraldehyde-3-phosphate then enters glycolysis
Cause/pathogenesis of fructose intolerance?
Aldolase deficiency leads to fructose 1,6-bisphosphate accumulation in the liver, causing liver damage and hypoglycaemia.
What are the symptoms of fructose intolerance?
Poor feeding in babies, nausea, vomiting, abdominal pain.
What is the standard treatment for fructose metabolism disorders?
Elimination of sucrose and fructose from diet.
Where is galactose metabolised?
In the liver.
What are the main enzymes involved in galactose metabolism?
Galactokinase, galactose-1-phosphate uridyl transferase (GALT).
What is the process of galactose metabolism?
Galactose is phosphorylated by Galactokinase into galactose-1-phosphate, which is converted to glucose-1-phosphate by GALT. Then, converted to glucose-6-phosphate
What is non-classic galactosaemia?
Galactokinase deficiency leading to accumulation of galactose and galactitol.
What is classic galactosaemia?
GALT deficiency leading to accumulation of galactose-1-phosphate and galactitol.
What are the pathological consequences of galactose metabolism disorders?
Cataracts due to galactitol accumulation; brain and liver damage.
What is the standard treatment for galactose metabolism disorders?
Dietary restrictions of lactose and galactose.
What are the two phases of the pentose phosphate pathway?
Oxidative phase:
Glucose-6-phosphate oxidised to ribulose-5-phosphate.
This is catalysed by glucose-6-dehydrogenase enzyme
Non-oxidative phase:
Rearrangement of glycolic intermediates
Ribulose-5-phosphate converted to either F-6-P (Fructose-6-phosphate) or G-3-P (Glyceraldehyde-3-phosphate)
What is the major enzyme involved in pentose phosphate pathway catalysis?
Glucose-6-dehydrogenase enzyme.
What are the primary functions of the pentose phosphate pathway?
Production of NADPH+ and H+, intermediates for glycolysis, and C5 sugars for nucleotides.
What is the importance of the pentose phosphate pathway?
Provides NADPH+ and H+ reducing power, maintains a reduced state in glutathione, protects cells from oxidative damage.
What is G6PDH deficiency and its impact?
Glucose-6-phosphate dehydrogenase deficiency is a deficiency of the enzyme that catalyses the pentose phosphate pathway.
Impact:
- Reduced and low levels of NADPH+ and H+ produced (less reducing power)
- RBCs most severely affected as pentose pathway in these cells is the ONLY way of generating ATP (no mitochondria - no oxidative phosphorylation).
- Oxidative damage as glutathione is in an oxidised state (GSSG)
- Haemoglobin and other proteins become cross-linked by disulphide bonds (bridges) which are formed by oxidised S atoms (S-S)Deficiency of glucose-6-phosphate dehydrogenase; leads to reduced NADPH+ and H+, oxidative damage, and haemolysis.
What is the name of the insoluble aggregates formed from the cross-linking by disulphide bonds in RBCs (G6PDH deficiency)?
Heinz bodies.
What happens when Heinz bodies attach to the RBC membrane?
Haemolysis by the spleen.
What are the symptoms of G6PDH deficiency?
Asymptomatic unless triggered; symptoms include haemolytic anaemia, fatigue, pallor, dyspnea, jaundice.
Where does the catabolism of galactose occur?
In the liver.
Name the reduced form of galactose that accumulates in tissues in galactosaemia.
Galactitol.
Name the metabolic pathway whose altering may lead to oxidative damage and the formation of Heinz bodies in erythrocytes.
Pentose phosphate pathway.
What is bilirubin?
An orange-yellow pigment formed in the liver by the breakdown of hemoglobin and excreted in bile.
What does abnormally high levels of bilirubin in the blood lead to?
Hyperbilirubinemia causes jaundice (yellow discolouration of the sclera and skin).
Propose an explanation for the presence of Heinz bodies in a patient’s erythrocytes.
Heinz bodies are produced from G6PDH deficiency, leading to oxidative damage and cross-linking of proteins.
Can anaemia and jaundice be related - how?
Anaemia causes RBC degradation, leading to bilirubin accumulation and jaundice.
What is the role of glucose-6-phosphate dehydrogenase enzyme?
Enzyme that catalyses the first step of the pentose phosphate pathway.
Why can’t people with glucose 6 phosphate dehydrogenase deficiency (G6PDH) take antimalarial drugs such as primaquine?
People with G6PDH deficiency struggle to produce enough NADPH in the Phosphate Pentose Pathway (PPP).
NADPH is needed to maintain glutathione protein in a reduced state which protects the RBC from oxidative damage by ROS - that’s what help keeps the structure of the RBC intact.
Primaquine oxidises glutathione which leads to oxidative damage of the RBC - which leads to the production of Heinz bodies.
Is galactose a normal constituent of urine?
No.
How could you account for the presence of galactose in a patient’s urine?
Blood concentration above renal threshold or kidney damage.
What are the metabolic consequences of an absence of galactose-1-phosphate uridyl transferase enzyme?
Accumulation of galactose and galactose-1-phosphate, leading to abnormal metabolism.
Why do galactosaemic patients develop cataracts?
Cross-linking of lens proteins leads to opacity (cataract).
Are the metabolic consequences of an absence of galactokinase similar to those of an absence of galactose-1-phosphate uridyl transferase?
No, absence of galactokinase leads to less severe consequences.
What is the standard treatment of a patient with galactosaemia?
Dietary restriction of galactose/lactose; replace with artificial milk.
How much lactate is produced every day WITHOUT exercise?
40-50g/day.
In what pathological situations is lactate production common?
Shock, congestive heart disease, arterial disease.
Examples of situations in which production of lactate is elevated?
Strenuous exercise, hearty eating, shock, congestive heart disease, arterial disease.
Examples of situations in which production of lactate is depleted?
Liver disease, vitamin deficiencies, high alcohol intake.
What is hyperlactatemia?
2-5 mM in blood, below renal threshold, no change in blood pH.
Which are the three regulatory steps of glycolysis?
Reactions 1, 3 and 10: Hexokinase, Phosphofructokinase, Pyruvate kinase.
Define lactic acidosis and why it may occur
Lactic acidosis is the elevation of lactate that affects the buffering capacity of the plasma (i.e., there is a fall in plasma pH due to accumulation of lactic acid).
Increased lactate can be due to increased lactate production during e.g., strenuous exercise (up to 10g/min), hearty eating, shock and congestive heart disease.
Increased lactate can also be due to decreased utilisation of lactate which occurs during e.g., liver disease, enzyme deficiencies (thiamine deficiency), and increased alcohol intake
Case study
A male infant aged 4 weeks was admitted to hospital. He was a small, and lethargic baby with hepatomegaly and splenomegaly; jaundice was absent on admission, but had been observed the week prior. One week later urine and blood were positive for galactose.
Galactose-1-phosphate uridyltransferase (GPT) were present in the blood at low levels. At 8 weeks ocular examinations revealed faint central opacity and a difference in light refraction in the left eye.
What’s the diagnosis?
Galactosaemia
Case study
21-year-old male, working as a tour guide was admitted to A&E because of severe jaundice. History revealed he had taken as a prophylactic measure, an antimalarial, Primaquine, to protect himself. The day after intake of Primaquine he noticed yellowish discolouration of his face progressing down to the lower extremities.
Past history revealed a previous admission when he was 12 years old for the same complaint, when he was given Sulphonamides for a UTI.
Laboratory examinations revealed low haemoglobin, RBC’s showed Heinz Bodies.
What’s the diagnosis?
G6PDH deficiency
