Metabolic Pathways

• Types of metabolism

  • Anabolism: building up of cell macromolecules from precursor molecules
  • Catabolism: breaking down of energy containing nutrients into energy depleted end products
• ATP

  Hydrolysis of phosphoanhydride bonds releases energy
• Coenzyme A


  1. CoA + H2O -> X + CoA-SH (thiol)
• Redox Energy

  NAD+ (oxidised) and NADH (reduced)
• Net loss of -2 ATP in Preparatory Phase of Glycolysis
• Net gain of 2 ATP & 2 NADH in Payoff Phase of Glycolysis
• Three Irreversible Steps in Gluconeogenesis

  • Conversion of Pyruvate to PEP
  • Conversion of F-1,6-bisP to F-6-P
  • Conversion of G-6-P to Glucose
• Gluconeogenesis


  Metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates
• Fermentation in Yeast

  Pyruvate from glycolysis has CO2 removed by pyruvate decarboxylase -> makes acetaldehyde -> alcohol dehydrogenase reduces this into ethanol (NADH is oxidised to NAD+)
• Fermentation in Animals

  Pyruvate from glycolysis is reduced by lactate dehydrogenase (NADH is oxidised to NAD+) -> produces lactate
• Cori Cycle


  Muscle contraction powered by glycogen -> broken down into glucose via glycogenolysis -> anaerobic glycolysis occurs -> fermentation produces lactate -> lactate exported from muscle cells, into bloodstream and liver -> liver converts lactate to glucose using ATP -> glucose travels back through blood stream and to muscles
• Glycogenolysis


  The process by which glycogen is converted to glucose-1-phosphate (G1P) and then to glucose-6-phosphate (G6P) to enter the glycolytic pathway
• Glycogen


  • Branched polysaccharide, forming open helical structure (easy access) - storage form of carbohydrate in the body
  • Liver Glycogen: source of blood glucose, critical during fasting
  • Muscle Glycogen: cannot give rise to blood glucose, used to power muscle contraction for extended periods of time
• GlycogenolysisEnzymes


  • Glycogen phosphorylase -> removes terminal nonreducing end -> glucose 1-phosphate formed
  • Debranching transferase enzyme -> chains shortened -> recognises short branch -> moves 3 sugars to nonreducing end of adjacent chain
  • Debranching glycosidase enzyme -> removes last glucose as free glucose
  • Phosphoglucomutase -> converts glucose 1-phosphate to glucose 6-phosphate (which can enter glycolysis)
• Glycogenesis


  1. UDP-Glucose Pyrophosphorylase -> synthesises UDP-glucose from UTP and synthesised glucose-1-phosphate and pyrophosphate (PPi)

  2. Glycogen Synthase -> recognises nonreducing end -> transfers UDP-glucose to nonreducing end -> leaving glucose and releasing UDP

  3. Glycogen Branching Enzyme -> catalyses transfer of a block of glucose residues from nonbranching end of a glycogen branch

  4. Glycogenin -> both primer on which new chains are synthesised and enzyme that catalyses
• PDH Complex


  First control point of Krebs cycle - Catalyses removal of CO2 from pyruvate to form Acetyl-CoA
• Oxidative Phosphorylation


  Process of transforming redox energy under aerobic conditions during Glycolysis and the Citric Acid Cycle (NADH & FADH2) into chemical energy in the form of ATP
• Chemiosmotic Model


  The transfer of electrons down an electron transport system through a series of oxidation-reduction reactions releases energy
• Electron Transport Chain

  • Flow of electrons through complexes in inner mitochondrial membrane & subsequent pumping of protons from the matrix into the intermembrane space creates a proton gradient that is used to drive ATP synthesis
  • Intermembrane Space: P Side (positive - with H+)
  • Matrix: N Side (comparably more negative)
• Coenzyme Q


  • Lipophilic inner mitochondrial membrane dwelling mobile electron carrier that transfers electrons from Complex I and Complex II to Complex III
  • Ubiquinone: Oxidised form (Q)
  • Ubiquinol: reduced form (QH2)
  • Semiquinone: partially reduced (QH) - can also exist as radical
• Cytochrome C


  • Small soluble protein residing in intermembrane space that accepts electrons from Complex III and donates them to Complex IV
  • Contains prosthetic group Heme C with central Fe3+ -> reduced to Fe2+ after accepting an e- from Complex III -> return to Fe3+ when e- is donated to Complex IV
• ATP Synthase

  • Uses H+ gradient formed via the pumping of protons by Complexes I, III & IV to drive the unfavourable synthesis of ATP from ADP + Pi
  • F0 (stalk) - spans inner mitochondrial membrane - has a, b and c subunits in mammals
  • F1 (head) - matrix side of inner membrane - has α, β, γ, δ and ε subunits
• ATP Synthesis

  1. Results from the rotational catalysis mechanism (120°)

  2. Proton motive force causes rotation of the γ subunit as the H+ is pumped through the F0 component -> ADP in β-ADP conformation shifts to β-ATP conformation favouring ADP to convert to ATP -> β-empty conformation moves to β-ADP conformation & picks up ADP
• ~4 Protons required to synthesize 1 ATP
• Process of PDH Complex:

  Pyruvate bound -> removal of CO2 catalysed -> bound to TPP and moves to next active site -> Acyl lipoyllysine group acts as swinging arm to put up Acetyl group (was pyruvate) -> move to next active site to combine with CoA -> forms Acetyl-CoA which is released
• Complexes that are Proton Pumps:

  • I
  • III
  • IV
• ATP Yield for NADH & FADH2: ~4 Protons required to synthesize 1 ATP

  • 10 protons pumped into IMS per NADH -> 10/4 = 2.5 ATP per NADH
  • 6 protons pumped into IMS per succinate (FADH2) -> 6/4 = 1.5 ATP per FADH2
• Energy Gain Glycolysis:

  • Net gain of 2 ATP
  • Net gain of 2 NADH
  • ~ 5 ATP per glucose
• Energy Gain Krebs Cycle: (per glucose)

  • 2 ATP
  • 10 NADH (2 cytosolic, 8 mitochondrial)
  • 2 FADH
  • 2 GTP

  30-32 ATP in total
• Proton Use

  • Phosphate translocase (symporter) -> each phosphate moved into matrix requires 1 H+ to move with it (3 ATP with each cycle -> 3 H+ needed)
  • Yeast: require 10 protons required to turn ATPsynthase through one cycle to produce 3 ATP
  • (10 + 3) / 3 = 4.3333 protons per ATP
  • Mammals: require 8 protons required to turn ATPsynthase through one cycle to produce 3 ATP
  • (8 + 3) / 3 = 3.6667 protons per ATP