Metabolism 1- Glycolysis

• Metabolism

  • All chemical reactions that maintain the living state of cells and organisms.
  • NEEDED for basic functions of all organs and tissues.
• Anabolism

  • assimilation of molecules and complex structures from building blocks of life
  • REQUIRES energy
• Catabolism

  • breakdown of molecules to obtain the anabolic “building blocks” of life and substrate for energy
  • breakdown of molecules to yield energy
• what are the most common metabolic diseases

  diabetes; obesity; fatty liver disease; hemochromatosis; mitochondrial disease
• Energy for metabolism

  • Comes from the sun
  • plant synthesise macromolecules- using energy from sunlight
  • catabolic pathways→ oxidise macromolecules, producing energy
  • anabolism pathways→ ATP used to drive biosynthesis reactions
• REDOX reactions

  ARE involve transfer of electrons from one species to another
• Oxidation

  species that loses electrons
• Reduction

  species that gain electrons
• Glucose

  • most common carbohydrate
  • half all organic carbon is three polysaccharides (sugar polymers) [found]:
  • Starch [plants]
  • Cellulose [plants]
  • Glycogen [animals → stored in muscle and liver]
  • Primary energy source
  • oxidised to CO2 and H2O
  • required by most cells
  • glucose from blood to maintain function
  • Brain (accounts for 20% of O2/ glucose requirement at rest BUT only represents 2% of body weight)
  • all cancer
• storage of glucose

  Glucose stored as an inert polysaccharide as glycogen
• Glucotoxity

  mammalian cells/ tissue CANNOT tolerate chronic hyperglycaemia (diabetes)
• Glycolysis -> purpose

  • production of ATP
  • provision of building blocks for synthetic reactions
• Glycolysis -> stage 1

  glucose is trapped and destabilised
• Glycolysis -> stage 2

  Aldolase generates two interconvertible three-carbon molecules are formed
• Glycolysis -> stage 3

  generation of ATP
• Glycolysis -> control points

  1. Hexokinase- substrate entry

  2. Phosphofructokinase- rate of flow

  3. Pyruvate Kinase- product exit
• Phosphofructokinase

  Key enzyme controlling rate of substrate movement along glycolytic pathway
• Phosphofructokinase: fill missing in table

  will increase glycolysis when energy is needed

  
• Phosphofructokinase: fill a, b, c in table

  A-- slow glycolysis if energy abundant

  B-- Slows downstream pyruvate entry to TCA cycle if energy is abundant

  C-- Slows glycolysis if too much lactic acid id being produced

  
• Phosphofructokinase-> control

  By energy charge

  • ATP/ AMP ration is called energy charge
  • if all adenylate nucleotides are shape of ATP, cell is FULLY CHARGED
  • if cell only contained AMP and Pi, it is DISCHARGED
• Anaerobic (lactic Acid Fermentation)

  • Lactate has long term considered a toxic by-product of low O2.
  • HIGH serum lactate is very dangerous DUE to generation of lactic acidosis (drop in pH)
  • Recognised that there are many physiological roles for lactate, including signalling and protein modifications (lactylation)
  • NADH used to ferment pyruvate to lactic acid (lactate)
  • NADH is re-generated at beginning of stage 3 of glycolysis
• The Warburg Effect

  Up-regulation of glycolysis in cancer cells
• Treating Cancer-> By targeting glycolysis

  • 2-Deoxy-glucose
  • competitive inhibitor. Blocks further metabolism of G6P
  • 3-Bromopyruvate
  • Competitive inhibitor. Blocks production of 1,3-bisphosphoglycerate
  • Dichloroacetate
  • Promotes conversion of lactic acid to pyruvate. By re-engaging mitochondrial metabolism it slows glycolytic rate. Cells can no longer sustain nucleotide synthesis and so cannot grow.