#Warburg effect Glycolysis

1. JIMMA UNIVERSITY
INSTITUTE OF HEALTH
FACULTY OF HEALTH SCIENCES
MEDICAL BIOCHEMISTRY

2. Warburg Effect, Reverse Warburg Effect, the
Pasteur Effect And Luebering–Rapoport
pathway
Done by: Reshad Nuredin

3. OUT LINE
• Warburg Effect
• Reverse Warburg Effect
• the Pasteur Effect
• Luebering–Rapoport pathway

4. Objectives
At the end of this presentation, the students
will able to:
 Describe Warburg effect
 Explain the significance of reverse Warburg effect
 Understand the Pasteur effect
 Understand and explainLuebering–Rapoport pathway

5. Warburg Effect
• Ever since its discovery (1924) the Warburg effect
(aerobic glycolysis) remains an unresolved puzzle:
• why the aggressive cancer cells “prefer” to use the
energetically highly inefficient method of burning the
glucose at the cellular level?
• While in the course of the last 90 years several
hypotheses have been suggested, to this date there is
no clear explanation of this rather unusual effect.

6. Cont….
• Even though it is commonly assumed that Warburg
effect is a consequence of carcinogenesis,
• another hypothesis could be brought up that the
cellular switch to aerobic glycolysis may represent
the very point in time when a normal cell becomes
cancerous.
• Furthermore, this switch may happen at the point
where the fate of pyruvic acid is determined,
• caused by the inadequate supply of enzymes that
promote citric as opposed to lactic acid cycle.

7. Cont….
• Despite the fact that cancer cells prefer lactate
production from glucose, and rely less on
mitochondria, which is way more efficient at
producing ATP, very high rates of glycolysis can
generate ATP rapidly and in enough amounts to
provide the cancer cell with the energy it needs.
• Very high rates of glycolysis can generate more ATP
than levels of ATP made by a slower process in
mitochondria in a given period of time

8. Cont…
• Complete metabolism of glucose in the presence of
oxygen to water and carbon dioxide generates a
hypothetical yield of 36 to 38 ATPs per glucose
molecule.
• only 2 ATPs per glucose molecule when glucose is
converted to lactate and is not metabolized further by
mitochondria.(Devic S,2016)

9. Cont….

10. Cont..

11. cont…..

12. Cont…

13. Cont…
• Aerobic glycolysis relies more on cytosolic glucose
metabolism than on mitochondrial metabolism (Krebs
cycle, electron transport, oxidative phosphorylation).
• The major source of reactive oxygen species (ROS)
in cells is the electron transport chain (especially
Complex I and Complex II).
• The enhanced aerobic glycolysis in cancer cells may
therefore protect them from free radical damage by
minimizing flux through the electron transport chain.

14. Cont…
• NADPH, produced from the pentose phosphate
pathway, also protects cells from free radical damage
by maintaining reduced glutathione (GSH), which
protects cells from reactive oxygen species.
• So increased flux through glycolysis (and therefore
pentose phosphate pathway) would make more
NADPH to keep the glutathione system working and
protecting cancer cells from ROS damage.

15. The Warburg effect in cancer cells. As shown in this diagram, the Warburg effect is mainly
induced by mitochondrial dysfunction. NADPH: nicotinamide adenine dinucleotide phosphate;
ROS: reactive oxygen species; UCPs: uncoupling proteins; PEP: phospho-enolpyruvate;
GLUTs: glucose transporters; HK: Hexokinase; G6P: glucose 6 phosphate; MCTs:
monocarboxylate transporters; PPP: pentose phosphate pathway; PFK1:

16. Cont……..
• However, even the acceptance of the aerobic
glycolysis being a more adequate glucose metabolism
pathway for cancer cells.
• the question of a hen or an egg remains:
• is the Warburg effect just a consequence,
or could it be the very cause of carcinogenesis

17. Cont…..

18. Reverse Warburg Effect
• The reverse Warburg effect postulates that lactate
production in cancers is at least partly related to non-
cancer cells (stromal cells) close to the cancer cells
supplying the cancer cells with lactate.
• The theory is that cancer cells signal (“educate”)
normal stromal cells to enhance their glycolysis and
produce lactate and secrete the lactate for use by the
cancer cells.

19. Cont..
• Lactate has been shown to have numerous signaling
functions and may be important in angiogenesis (new
blood vessel formation), which occurs commonly in
cancers, allowing cancer cells to maintain a high
blood supply.
• Lactate can also be used as a fuel by cancer cells

20. The reverse Warburg effect. Cancer cells induce oxidative stress in neighboring fibroblasts by
secreting reactive oxygen species (ROS), triggering aerobic glycolysis and production of high energy
metabolites, especially lactate and pyruvate, which are in turn transported through ‘lactate shuttle’ to
sustain the anabolic need of adjacent cancer cells. In this process, many events occur such as loss of
Cav-1 in stroma cells, upregulation of mono-carboxylate transporters (MCTs) in both, etc. These
changes mean more than biomarkers of increased aerobic glycolysis in stroma cells, but are involved
in some regulatory pathways which drive tumor progression, metastasis and even drug resistance

21. Oxidative stress-mechanism in the reverse Warburg effect

22. the Pasteur Effect
 The effect was discovered in 1857 by Louis Pasteur,
who showed that aerating yeasted broth causes
yeast cell growth to increase, while conversely,
fermentation rate decreases.
• The effect can be explained; as the yeast being
facultative anaerobes can produce energy using two
different metabolic pathways.

23. Cont…..
• While the oxygen concentration is low, the product
of glycolysis, pyruvate, is turned into ethanol and
carbon dioxide , and the energy production efficiency
is low (2 moles of ATP per mole of glucose ).
• If the oxygen concentration grows, pyruvate is
converted to acetyl CoA that can be used in the citric
acid cycle.
• Under anaerobic conditions, the rate of glucose
metabolism is faster, but the amount of ATP
produced is smaller.

24. Cont…..
• When exposed to aerobic conditions, the ATP and
Citrate production increases and the rate of glycolysis
slows, because the ATP and citrate produced act as
allosteric inhibitors for phosphofructokinase 1, the
third enzyme in the glycolysis pathway.
• From the standpoint of ATP production then, it is
advantageous for yeast to utilize the citric acid cycle
in the presence of oxygen, as more ATP is produced
from less glucose. (Boulton ,1996)

25. Luebering–Rapoport pathway
• The Luebering–Rapoport pathway (also called the
Luebering–Rapoport shunt) is a metabolic pathway in
mature erythrocytes.
• It involving the formation of 2,3-
bisphosphoglycerate (2,3-BPG), which regulates
oxygen release from hemoglobin and delivery to
tissues.

26. Cont..
• Through the Luebering–Rapoport pathway
bisphosphoglycerate mutase catalyzes the transfer of
a phosphoryl group from C1 to C2 of 1,3-BPG,
giving 2,3-BPG.
• 2,3-bisphosphoglycerate, the most concentrated
organophosphate in the erythrocyte, forms 3-PG by
the action of isphosphoglyceratephosphatase.

27. Cont…
• The concentration of 2,3-BPG varies proportionately
with the pH, since it is inhibitory to catalytic action of
bisphosphoglyceromutase (Bellingham,1973).

28. Cont….

29. Cont…
Role in hemoglobin(Hb):
• 2,3-BPG is not a waste molecule in RBC. lt combines
with hemoglobin(Hb) and reduces Hb affinity with
oxygen.
• Therefore, in the presence of 2,3-BPG,
oxyhemoglobin unloads more oxygen to the tissues.
• Adult Hb-A1: 2,3-BPG concentration is high, affinity
to O2 less and unloading/dissociation is more.
• Hb-F: 2,3-BPG concentration is low, affinity to O2 is more,
and unloading/dissociation is less.

30. Cont…
Role in hypoxia:
• Increase in erythrocyte 2,3-BPG is observed in
hypoxic conditions, high altitude, anemic conditions.
• In all these cases, 2,3- BPG will enhance the supply of
oxygen to the tissues.

31. Cont…
Inherited enzyme deficiency:
• Glycolysis in the erythrocytes is linked with 2,3-BPG
production and oxygen transport.
• In the deficiency of the enzyme hexokinase, glucose
is not phosphorylated, hence the synthesis and
concentration of 2,3-BPG are low in RBC.
• The hemoglobin exhibits high oxygen affinity in
hexokinase-defective patients.

32. Cont…
• On the other hand, in patients with pyruvate kinase
deficiency, the level of 2,3-BPG in erythrocytes is
high, resulting in low oxygen affinity.

33. References
1.Devic S. (2016). Warburg Effect a Consequence or the Cause of
Carcinogenesis?. J Cancer; 7(7): 817-822.
2. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB.
The biology of cancer: metabolic reprogramming fuels cell
growth and proliferation. Cell Metab. 2008; 7:11-20.
2. BARKER, J., KHAN, M. & SOLOMOS, T. (1964). Mechanism of
the Pasteur Effect. Nature 201, 1126–1127
3. Bellingham A. J. And Grimes A. J. (1973) . RED CELL
2,3‐DIPHOSPHOGLYCERATE, 555-562