Lecture 3: Anaerobic Glucose Breakdown - Fermentation Flashcards
What are the two major metabolic pathways of energy for cells?
Glycolysis and oxidative phosphorylation (OXPHOS) are two major metabolic pathways to provide energy for cells.
- Glycolysis converts glucose into pyruvate via a series of metabolic reactions independant of oxygen and occurring in the cytosol
- In OXPHOS phosphorylation of ADP to ATP is dependent on the oxidative reactions occurring in the mitochondria.
What are situations in which oxygen may be lacking?
periods of heavy work, or in cancer tumors where many cells pile up
- the combination of glycolysis and fermentation (glucose to pyruvate to lactate) produces ATP
How is NAD+ regenerated back into glycolysis?
- pyruvate to lactate
- microbiota production of ethanol
both systems coupled to oxidation of NADH to NAD+
What is the reaction for fermentation of pyruvate to lactate?
Pyruvate is reduced to lactate coupled to the oxidation of NADH to NAD+ enzyme lactate dehydrogenase (LDH)
LDH
lactate dehydrogenase
- Enzyme for fermentation to lactate
Lactic acidosis
lactic acid build-up/ accumulation in the vlood stream
- drop in blood pH
- produced when oxygen levels are low in cells within the areas of the body where metabolism takes place
Cori Cycle
Active muscle uses glycogen (and available glucose) for energy, generating lactate via anaerobic glucose breakdown (glycolysis). During recovery, the lactate is transported to the liver and converted to glucose via gluconeogenesis. The glucose is released into the bloodstream and returned to the muscles to replenish glycogen reserves.
Oxygen debt
Oxygen debt occurs when the body reaches a state of anaerobic respiration during intense exercise. When a person engages in high levels of physical activity, the body cannot distribute oxygen to the cells at a sufficiently rapid pace to keep up with the oxygen demand therefore breathing is elevated to replenish oxygen levels and support oxidative phosphorylation in the liver.
Energetics of anaerobic glycolysis
Where does fermentation to alcohol (ethanol) commonly occur?
- Making alcoholic beverages such as beer
- Naturally in the body microbiota
Fermentation to ethanol reaction
2-step process with the enzymes pyruvate decarboxylase and alcohol dehydrogenase
- CO2 produced is responsible for allowing bread to rise and for the carbonation of champagne and beer.
What kind of enzyme in pyruvate decarboxylase?
thiamine pyrophosphate (TPP)-dependant enzyme
- cofactor
What does ethanol ingestion inhibit?
Inhibits gluconeogenesis
- alcohol dehydrogenase produces NADH, shifting the lactate dehydrogenase equilibrium away from pyruvate towards lactate as it causes pyruvate to be excessively converted to lactate resulting in less pyruvate being available for gluconeogenesis.
- induces a form of apparent hypoxia even in normal oxygen conditions.
What can be added to alcohol in order to mitigate hypoglycemia?
Adding sugar
How does fermentation occur in the liver during alcohol consumption?
Fermentation is normal in the vigorously exercised muscle, but not in the liver. So ethanol exposure induces fermentation in an organ that does not normally use fermentation to sustain the glycolysis part of glucose oxidation (the liver likely uses mitochondrial respiration to restore NAD+ levels needed for the glycolysis part of glucose oxidation).
Amount of endogenous alcohol production
Endogenous alcohol production by fermentation by the microorganisms in the gut is about 3 grams / day.
- The concentration of ethanol in the blood of the portal vein is ~0.5 mM.
- The Km for alcohol dehydrogenases ~1mM.
- The legal limit for blood alcohol level is 18 mM.
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Pasteur effect
The inhibition of fermentation by molecular oxygen
- a sudden change from anaerobic to aerobic metabolism.
Glucose oxidation in anaerobic vs. aerobic conditions
- In anaerobic conditions, glucose oxidation is partial (glycolysis → glucose to pyruvate) and ends in fermentation (production of either lactate or ethanol), which regenerates NAD+ that is used by glycolysis to keep going.
- yields only 2 ATP / glucose
- Under aerobic conditions, O2 suppresses fermentation and glucose oxidation is complete (glucose to CO2 and H2O). Glycolysis yields only
- yields 30-32 ATP / glucose
Fermentation vs. putrefaction
- Fermentation is an anaerobic microbial process that converts sugars into acids, gases and alcohols.
- Putrefaction is an anaerobic process that decomposes dead plant and animal matter due to specific germs living under anaerobic conditions.
Pasteurization
Pasteurization’ prevents fermentation through boiling the broth to kill the anaerobic microbes (thus also preventing putrefaction).
- sterilization
Warburg manometer
Measures the oxygen consumption of tissue by measuring changes in gas volume.
Warburg effect
tumours of nearly all types carry out glycolysis at much higher rates (~10x) than normal tissues.
- observation that most cancer cells produce energy predominantly not through the ‘usual’ citric acid cycle and oxidative phosphorylation in the mitochondria as observed in normal cells, but through a less efficient process of ‘anaerobic glycolysis’ consisting of high level of glucose uptake and glycolysis followed by lactic acid fermentation taking place in the cytosol, not the mitochondria, even in the presence of abundant oxygen.
What is the medical significance of Warburg effect?
Most tumour cells grow under hypoxic (low oxygen) conditions, because they lack the blood supply to provide adequate levels of oxygen. Tumours use glycolysis to produce 2 ATP per glucose while fermentation ensures adequate levels of NAD+ are available for glycolysis to proceed in the tumor cells. Blocking fermentation slows down tumour cells’ growth.
