BIOCHEM & CLINICAL

• Krebs cycle

  Also called the tricarboxylic acid cycle or citric acid cycle
• Hans Krebs


  The person who founded and developed the Krebs cycle
• Glycolysis pathway

  1. Convert glucose into pyruvate

  2. Generate 2 NADH and 2 net ATP
• Transition step

  1. Add coenzyme A to pyruvate

  2. Generate 2 NADH and 2 CO2
• Acetyl CoA


  The molecule that enters the Krebs cycle
• Oxaloacetate (OAA)


  A 4-carbon fragment that combines with acetyl CoA
• Krebs cycle

  1. Acetyl CoA and OAA combine to form citrate

  2. Citrate is converted to isocitrate

  3. Isocitrate is converted to alpha-ketoglutarate with release of CO2 and production of NADH

  4. Alpha-ketoglutarate is converted to succinyl CoA with release of CO2 and production of NADH

  5. Succinyl CoA is converted to succinate

  6. Succinate is converted to fumarate

  7. Fumarate is converted to malate

  8. Malate is converted back to oxaloacetate
• Citrate synthase


  The enzyme that combines acetyl CoA and OAA to form citrate
• High ATP levels

  Allosterically inhibit citrate synthase
• High NADH levels

  Allosterically inhibit citrate synthase
• High citrate levels

  Allosterically inhibit citrate synthase
• High succinyl CoA levels

  Allosterically inhibit citrate synthase
• Low ATP levels

  Allosterically stimulate citrate synthase
• Aconitase


  The enzyme that converts citrate to isocitrate
• Aconitase is reversible, allowing conversion of isocitrate back to citrate
• Fluoroacetate can inhibit aconitase by forming fluorocitrate
• Isocitrate dehydrogenase

  Converts isocitrate to alpha-ketoglutarate, releasing CO2 and producing NADH
• High ATP levels

  Allosterically inhibit isocitrate dehydrogenase
• Low ATP levels

  Allosterically stimulate isocitrate dehydrogenase
• High calcium levels

  Allosterically stimulate isocitrate dehydrogenase
• Alpha-ketoglutarate dehydrogenase

  Converts alpha-ketoglutarate to succinyl CoA, releasing CO2 and producing NADH
• High succinyl CoA levels

  Allosterically inhibit alpha-ketoglutarate dehydrogenase
• High NADH levels

  Allosterically inhibit alpha-ketoglutarate dehydrogenase
• High calcium levels

  Allosterically stimulate alpha-ketoglutarate dehydrogenase
• k sonic away we don't need to do that anymore there's either too much ATP there's too much any DHS there's too much energy produced in the cell stop
• the next ones are the next ones a little weird but it's not crazy see these NADH es if you start generating too much NADH s that can also tell this enzyme to shut down
• NADH inhibiting enzyme

  1. NADH comes over

  2. Inhibits enzyme

  3. Stops converting alpha-keto glutarate into succinylcoA

  4. Because there's already too much NADH
• calcium is also going to work in this step - so you're going to have nadh who is going to be inhibiting this enzyme succinylcoA which is going to be inhibiting this enzyme and then what else is going to be working in this stuff calcium calcium's going to be stimulating this enzyme here
• we generated co2 by decarboxylation we generated some NADH s out of this reaction because we have the alpha keto glutarate hydrogenase
• if there's too much succinylcoA from too much krebs cycle activity it's going to inhibit this enzyme to stop this Candace Krebs cycle from continuing to occur
• if there's too much NADH s that are being generated it'll also inhibit this enzyme tell it not to continue to give her because we already have too much any DHS and too much ATP
• calcium is helping to activate this enzyme so we can speed up the ATP production
• Alpha ketoglutarate

  An important component of the enzyme histone demethylase
• Histone demethylases remove methyl groups from histone proteins, which control gene expression
• A mutant form of alpha ketoglutarate dehydrogenase can convert alpha ketoglutarate into 2-hydroxyglutarate, which can inhibit histone demethylase and lead to uncontrolled cell growth and tumor formation
• Converting succinylcoA to succinate

  1. Release coenzyme A

  2. Generates GDP and inorganic phosphate

  3. ADP converts GDP and phosphate to ATP

  4. Succinyl-CoA synthetase enzyme catalyses this
• Succinate dehydrogenase

  • Part of the electron transport chain
  • Converts succinate to fumarate, generating FADH2
• Mutations in succinate dehydrogenase can lead to pheochromocytoma, a tumor in the adrenal medulla
• Converting fumarate to malate

  Enzyme fumarase adds water to convert fumarate to malate
• Deficiency in fumarase can lead to leiomyomas, tumors in smooth muscle tissue