L7: metabolism Flashcards
(7 cards)
what is metabolism
A linked series of reactions
Often these enzymes facillitating metabolism are spatially co located
Greek for “change”
Series of linked chemical reactions within cells - required to sustain life.
Extraction of energy and reducing power from environment - catabolic
Macromolecule synthesis from sim
building blocks - anabolic
Can be split into two:
Breaking down complex molecules for simple building blocks with the creation of energy - catabolism
Reverse- simple building blocks to create complex macromolecules like proteins, dna, lipids - anabolism
Pathways are integrated.
the warbug effect
In the presence of oxygen, cancer cells produce high levels of lactate, higher than normal tissues. Normally in oxygen - no fermentation, no conversion of glucose to pyruvate and lactate, usually in oxygen absence.
The Warburg effect
Warburg nanometer- looks at rate of gaseous prod overtime. Thin section of tissue, healthy or cancerous, placed and made various observations e.g: prod of co2 from glucose or lactate prod.
Cancer cells- glucose subverted through glycolysis into lactate prod
Correct
Preferentially consume glucose and produce lactate in presence of oxygen: aerobic glycolysis
Incorrect
Effect attributed to faulty/dysfunctional mitochondria
Increased lactate: the cause of cancer
Postulated that cancer can be cured by neutralisation of the lactic acid
Why is anaerobic glycolysis beneficial?
Controversial even today!
Energy
Maintain ATP:ADP ratio for energetically unfavourable reactions
– Ox Phos = 15x more ATP! Cancer cells need atp to rapidly proliferate
Glycolytic flux (flow/conversion of glucose to lactic acid) , however, is increased 10-50x in cancer
ATP generation is faster for aerobic glycolysis vs ox phos
High glucose uptake is a selective advantage over other cells
Selection pressures on tumour cells, the ones that survive have this growth advantage.
biomass
Cell division requires doubling of biomass. Double organelles, double proteins etc. for daughters to split. Not just biomass leads to double, prod of biomass through reduction of nad to nadh to drive complex macromolecule synthesis. Nad required to prod lipids, proteins, nucleic acids and atp. Need to regen that nad to keep dividing. One way- simple conversion of pyruvate to lactic in fermentation or warburg effect - aerobic glycolysis.
why is anaerobic glycosis benefical
Why Anaerobic Glycolysis Is Beneficial in Tumour Cells
1. PKM2 Regulation and Glycolytic Flux
Pyruvate kinase M2 (PKM2) is an enzyme that catalyzes the final step in glycolysis:
Phosphoenolpyruvate (PEP) → Pyruvate
In normal tissues, PKM2 exists in its tetrameric (4-subunit) form, which is highly active, efficiently converting PEP to pyruvate.
In tumour cells, PKM2 often shifts to a dimeric (2-subunit) form, which is less active.
👉 Why this matters:
Slowing this final step of glycolysis creates a backlog of glycolytic intermediates.
These intermediates can then be diverted into anabolic pathways to:
Build nucleotides
Synthesize amino acids
Produce lipids
This supports rapid cell growth and division, which tumours require.
⚡ Avoiding Oxidative Phosphorylation (OXPHOS) and Reducing ROS
OXPHOS, the mitochondria’s energy production pathway, is efficient but creates reactive oxygen species (ROS) as byproducts.
ROS can cause DNA, protein, and lipid damage, triggering cell stress or death.
👉 Tumour cells prefer aerobic glycolysis (glycolysis even in the presence of oxygen) because:
It limits mitochondrial electron flow, reducing ROS production.
Less ROS = less oxidative stress and greater cell survival.
🛡️ Antioxidant Production via the Pentose Phosphate Pathway (PPP)
Glycolysis intermediates (like glucose-6-phosphate) are shunted into the oxidative branch of the PPP.
This produces:
NADPH: a reducing agent that acts as a powerful antioxidant
Ribose-5-phosphate: for nucleotide synthesis
👉 NADPH protects cells by:
Supporting glutathione regeneration (via reduction of glutathione disulfide to glutathione, the main cellular antioxidant)
Helping detoxify ROS
Contributing to cysteine synthesis, a key amino acid in glutathione formation
✅ Result: Tumour cells increase glycolysis not just for energy but to:
Support biosynthesis
Minimize oxidative damage
Produce NADPH and antioxidants for survival
glutamine
Alternative carbon sources to fuel cancer: glutamine
Amino acid taken up by ASCT2
Converted to glutamate via glutaminase in mitochondria
Feeds TCA cycle and ox phos through conversion to α-ketoglutarate: intermediate of tca cycle so instead of relying glucose to pyruvate to tca, can use these to keep tca running and electrons feeding to etc.
Role in redox homeostasis through glutathione production
fatty acids
Alternative carbon sources to fuel cancer: fatty acids
Lipids taken up from the plasma or mobilised from lipid droplets
Transported into the mitochondria through CoA-carnitine recycling
Fatty-acyl chains are oxidised over four steps - beta ox?, reducing the chain by 2C, producing NADH, FADH2 and acetyl-CoA
Acetyl-CoA fed into the TCA cycle for ATP synthesis
Fatty acid synthesis
Tumours are highly ‘plastic’ – there is flexibility
Fatty acids required for membrane synthesis and energy storage
Fatty acid synthesis is one mechanism to achieve this
Occurs in cytosol, not mitochondria and has distinct mechanism
Growing chain increased by 2C from acetyl-CoA. Elongation stops at palmitate (C16)
Performed by fatty acid synthase, a multienzyme complex, covalently attached (7 catalytic sites!)
role of oncogenes
Acetate also increased - can read on this
As well as ocnogenic signalling cotrol metabolic processes. P53 inhibits transcription and translation of glycolytic enzymes when p53 active. If lose p53 in 50% of cancers, process goes array. Prod of glycolytic intermediates in the presence of dna damage.
Myc and Hif- check what they do
