Cell division

growth → division → growth

• → differentiate
• → repeat (stem cells)

Redox regulation is very important for anabolism and catabolism

• NAD+/NAD(H): catabolic reactions, provides protons.
  • normally high NAD/NADH ratio
• NADP+/(NADPH): anabolic reaction, for maintaining redox state of the cell. Can help reduce oxidized molecules.
  • NADP+(NADPH) is produced from NAD+(NADH) by NAD+ kinase (NADK)

Glucos metabolism

• normal body range is approx. 5mM

• A lot of molecules can be produced from glucose

• Warburg effect: glucose addiction of cancer cells

• catabolism (both are not mutually exclusive):

  • mitochondrial respiration
  • fermentative glycolysis
  • higly conserved
  • glycolysis = 2 ATP mito resp = 36-38 ATP

• Glycolysis:

  • three irreversible steps → regulated

  

  • General pathway regulation:
    • enzyme concentration (hours)
    • enzyme activity (allosteric regulation (ms) or covalent modification (s))
    • substrate availablity (immediately)
  • **Pyruvate kinase (**10th step of glycolysis)
    • converts PEP → pyruvate, uses ATP
    • genes + isoforms
      • PKM (muscle) → M1 (muscle, heart brain), M2 (cancer + embryonic development)
      • PKM1 tetramere is constitutively active
      • PKM2 is inactive dimer/activer tetramere —> acitve state it produces ATP, inactive it has a moonlight function:
        • dimer has moonlight function (noncanonical): can go into the nucleus → alter gene transcription by phosphorylating, relevant because cancer cells need a lot of building blocks which can be produced this way
    • regulation:
      • pyruvate inhibits

cancer metabolism

• disorganized proliferation → dysplasia → high metabolic demant

• Warburg effect: cancer cells produce lactate from oxygen, even in the presence of O2.

• PET scans use the uptake of radioactive glucose for tumor localization.

• anaerobic glycolysis is a hallmark of highly proliferative cells.

  • yeast/bacteria produce ethanol instead of lactate in anaerobic conditions. Upon starvating they can take up these and use it for energy.

• Tumors, why?

  • Avoidance of ROS production

    • ROS are mainly produced in mito’s.
    • ROS is not necessarily toxic, especially in low or short exposure (this might even be needed for cell division)
    • Also, mitochondrial activity is required for cancer cells: mito DNA shows. Primary tumors in mice without mito’s grow smaller + horizontal transfer of mito’s.
    • so: mito’s are required in cancer

  • Cope with hypoxia

    • Some tumors grow around a vessel, but the outside cells might become hypoxic.
    • However, not all tumors grow in this manner and not all cells have the same oxygen tension whilst the warburg effect is in almosts all tumors.

  • Immune escape

    • lactate released H+, making the environment acid.

    

    • lactate dehydrogonase converts pyruvate → lactate (so high [] make low pH)
    • high levels of ldh increased tumor growth → however, this difference is gone in immunocompromised mice: low pH causes inactivation of T cells + NK cells.

  • NAD/NADH balance

    • pyruvate to lactate restores NAD+ which supports glycolytic flux + anabolic reactions: because LDH makes NADH → NAD+.
    • this is usefull because of branching → more production of other building block than ATP.

    

• Consequences of Warburg effects

  • (Lower ATP production)

  • Less TCA imput → shortage

    • citrate for FFA
    • oxaloacetate for amino acids

  • Anaplerosis: replenishing th epool of TCA intermediates

    • Glumatine extra important for cancer cells
    • In tumors → backwards out of glutamine so synthesis of lipids and AZn (replenishes TCA cycle)