Respiration

• Life is a Battle Against Entropy
• Natural tendency of universe is towards disorder (entropy)
• Cells must create and maintain order
• Only possible with input of energy
• Cells obtain energy


  Oxidising organic molecules in an ordered series of enzyme-catalysed reactions - metabolic pathways - coupled to the formation of ATP
• ATP


  The energy currency for all cells
• Energetically unfavourable reactions are coupled to hydrolysis of ATP - ATP hydrolysis drives unfavourable reactions
• Cellular Respiration


  • Lipids
  • Proteins
  • Carbohydrates in the diet --> digestion --> fatty acids and glycerol, amino acids and sugars in cells --> oxidation --> ATP, NADH and other activated carrier molecules
• Sugars are a particularly important source of energy
• Cells oxidise glucose


  In a series of enzyme catalysed steps, gradually releasing energy and capturing it in activated carrier molecules
• Oxidation


  Gain of O2, loss of H2 or loss of e-
• Glycolysis


  1. Major metabolic pathway for sugar oxidation. In cytosol of cells

  2. 6C glucose converted into 2 3C molecules of pyruvate

  3. Glycolysis is anaerobic. Glucose is oxidised as e- are removed from carbons

  4. In part 1, 2 ATPs are used to drive unfavourable reactions

  5. In part 2, a 6C sugar is cleaved into 2 3C sugars

  6. In part 3, 2 pyruvates, 2 NADHs and 4 ATPs are formed

  7. Net gain: 2 ATPs and 2 NADHs per glucose
• ATP


  Energy is released when ATP is hydrolysed to ADP and inorganic phosphate (Pi) or when Pi is used to phosphorylate another molecule
• Functions of ATP


  • Carrying energy
  • Building block of DNA and RNA
  • Part of Coenzyme A
  • Cyclic AMP, a signalling molecule
  • Synthesise NADH
• NADH and NADPH


  • Very similar; one phosphate difference between them
  • Both synthesised from vitamin B3 (niacin) and ATP
  • Activated carrier molecules
  • NADH and NADPH are the reduced forms - electron and proton rich
  • NAD+ and NADP+ are the oxidised forms - electron and proton poor
  • NADH and NADPH transfer high energy electrons between molecules
  • NADH participates in catabolic pathways
  • NADPH participates in anabolic pathways
• Anaerobic Energy Generation


  1. In presence of O2, pyruvate is transported into mitochondria and converted into CO2 and acetyl coenzyme A. Acetyl group is oxidised to CO2 and H2O

  2. When O2 limited, pyruvate converted into lactate (muscle) or ethanol and CO2 (yeast). NADH is oxidised to NAD- to allow glycolysis to continue
• Tumours prioritise lactate production over oxidative phosphorylation (aerobic respiration)
• Malignant tumours reproduce very quickly (metastasise), consuming large amounts of glucose and producing large amounts of lactate (this is the Warburg effect)
• This unusual biology can be detected by the whole body CT scan of a non-Hodgkin's lymphoma patient
• Cells need to maintain a high ATP/ADP ratio, even in times of starvation
• Food Molecules are Stored in Special Reservoirs


  • Sugars are stored as glycogen in animals
  • Sugars are stored as amylose and amylopectin (starch) in plants
  • Fatty acids are stored as triglycerides in specialised cells - adipoccytes
• Glycogen


  Present as small granules in the cytoplasm of many cells, especially liver and muscle, and is used during short periods of fasting
• Adipose tissue


  Can be white or brown. Brown contains many more mitochondria
• Oxidation of a gram of dry fat


  Yields about twice as much energy as a gram of dry sugar
• Fats as stored in the body

  Yield about 6 times as much energy as glycogen
• Glycogen binds a lot of water and fats don't, so fats are energy-dense
• Glycogen degradation and synthesis

  Rapidly synthesised and degraded according to need
• Glycogen breakdown


  If blood contains insufficient food molecules, glycogen is broken down into glucose-1-phosphate and then into glucose-6-phosphate (no ATP required) which enters glycolysis at Step 2
• Glycogen synthesis


  If there is an excess of ATP or glucose, glucose monomers are used to synthesise glycogen and fatty acids in the liver
• Glucose entry into cells

  Glucose enters cells *only* through transport proteins embedded in the cell membrane
• Glucose transport


  Diffuses through transporters following its concentration gradient
• Glucose transporters


  • Different glucose transporters in different tissues, each with a different KM
• GLUT2 in liver and pancreas


  The high KM of GLUT2 means the liver and pancreas are more able to respond to increases in [glucose] than other tissues
• In the fed state

  Liver and pancreas will take up glucose more quickly
• GLUT3 in brain


  When [glucose] is low, GLUT3 is still working near Vmax, ensuring the brain receives a steady supply of glucose, despite the low [glucose]
• Hexokinase and glucokinase


  The GLUTs allow glucose to enter cells, hexokinase and glucokinase ensures it stays there
• Blood [glucose] ~ 5mM at rest, higher following a meal
• Hexokinase in most tissues

  KM ~ 0.1mM, it's inhibited by its product, glucose 6-phosphate (G6P)
• Hexokinase-containing cells


  Rate of phosphorylation is always maximised (due to the low KM), this maintains a large concentration difference between blood and cytosol, allowing glucose to flow down its concentration gradient into the cell
• Only when G6P is high


  The rate reduces (feedback inhibition) allowing ATP to be used for other functions