T2 L6: Regulation of carbohydrate metabolism

• What is gluconeogenesis?

  glucose synthesis from non-carbohydrate precursors, eg:

  • lactate (glycolysis)
  • amino acids
  • glycerol (fat metabolism - NOT fatty acids)

  occurs in liver and kidney

  maintains blood sugar when glucose isn't available to preserve glucose-dependent cerebral function and red cell metabolism
• What are the requirements for gluconeogenesis?

  • a source of carbon -> provided by lactate, amino acids, glycerol
  • a source of energy -> provided by fatty acid metabolism (lipolysis)
• The urea cycle

  increased gluconeogenesis always coupled with increased urea synthesis

  amino acids -> transaminated -> lose ammonia (toxic to cells, need to be eliminated)

  ammonia -> liver -> urea -> bloodstream -> kidneys -> excreted

  reaction produces fumarate which can be converted to oxaloacetate (substrate for gluconeogenesis)
• What enzyme catalyses the conversion fructose 1,6 bisphophate to fructose 6 phosphate in gluconeogenesis?

  Fructose 1,6 bisphosphatase
• Glycolysis and gluconeogenesis are opposing processess, so need to be recpirocally regulated.
• What are the 3 energetic allosteric regulators of glycolysis?

  ATP, AMP, H+
• How is glycolysis regulated by ATP?

  inhibits

  sign of high energy levels
• How is glycolysis regulated by AMP?

  activates

  sign of low energy levels (ATP depletion)
• How is PFK-1 regulated by H+ ions?

  H+ increased during anoxia bc of lactic acid production

  inhibits glycolysis to prevent cellular pH falling too low
• In which tissue can PFK-1 regulation by H+ ions be overcome and by what substance?

  heart

  high AMP (activates glycolysis)

  results in cardiomyocyte dmg, chest pain
• What are the 3 nutrient allosteric regulators of PFK-1?

  • Fru 6 P
  • Fru 2,6 BP
  • citrate
• How does Fru 6 P regulate PFK-1 allosterically?

  activates

  sign of high rates of glucose entry / glycogen breakdown

  stimulates glycolysis to allow utilisation

  
• How does Fru 2,6 BP regulate PFK-1 allosterically?

  most potent allosteric activator known

  sign of high rates of glucose entry / glycogen breakdown

  stimulates glycolysis

  
• How does citrate regulate PFK-1 allosterically?

  inhibits

  signals TCA cycle overload (more acetyl CoA than can be oxidised)

  or fatty acid oxidation overload

  signals need to conserve glucose so inhibits glycolysis
• How is F 2,6 BP produced and what is its purpose?

  F 6 P -> PFK-2 -> F 2,6 BP

  most potent activator known

  massively activates PFK-1 to drive glycolysis

  potent inhiitor of F 1,6 BPase

  
• What is F 2,6 BP inactivated by and how?

  dephosphorylation by F 2,6 BPase

  back into F6P
• How does phosphorylation affect PFK2 in the liver?

  inhibits
• How does phopshorylation affect F 2,6 BPase in the liver?

  activation
• How do PFK 1 and F 2,6 BP exist in the liver?

  single tandem enzyme with two active sites
• How is fructose 2,6 bisphosphate in liver affected by hormones?

  glucagon -> cAMP -> activates cAMP protein kinases. they phosphorylate:

  • PFK2 (inactivated - less F 2,6 BP made)
  • F 2,6 BPase (activated - dephosphorylates F 2,6 BP)

  overall result: lower levels of F 2,6 BP; reduces PFK-1 activity; inhibits glycolysis
• How is gluconeogenesis activated?

  increased fatty acid oxidation -> incareased acetyl CoA levels

  acetyl CoA:

  • activates pyruvate carboxylase
  • inhibits pyruvate dehydrogenase

  so favour gluconeogenesis over glycolysis
• How does hormonal regulation of gluconeogenesis work?

  short term stimulants: glucagon & adrenaline

  long term stimulants: glucagon, glucocorticoids, thyroid hormones

  acute inhibitors: insulin, supression of lipolysis and gluconeogenic enzymes