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Problem 1

Using the summary metabolic pathway chart, work out the routes for the following metabolic transformations. In each case, indicate the stages at which metabolites are transferred between intracellular compartments or between different cell types. Try to also identify any key regulatory events.

  • A) Dietary glucose into triacylglycerol stored in adipose tissue, after a high carbohydrate meal
    • CHO (Dietary carb) --> TAG in adipose tissue (storage)
    • Glucose goes: Intestines --> blood (via intestinal mucosal cells)
    • Need to get to liver for glycolysis (which occurs in the cytoplasm). This produces pyruvate
    • Glucose --> Pyruvate (via glycolysis in cytoplasm of liver cells)
    • Insulin levels increase after a high-carb meal (this, along with decreased glucagon, stimulates glycolysis)
    • Pyruvate --> Acetyl-CoA (mitochondrial matrix, after transport of pyruvate across inner membrane)
    • Need to synthesis fatty acids in the cytoplasm to make TAG.
    • Mitochondrial acetyl CoA --> cytoplasmic acetyl-CoA (as citrate; uses oxaloacetate)
    • Now we’re in the cytoplasm
    • Acetyl-CoA --> Long-chain acyl-CoA (fatty acid synthase, in cytoplasmic compartment)
    • Long chain acyl-CoA --> triacylglycerol (in liver still – needs to get to adipose tissue)
    • Attach triacylglycerol to lipoproteins:
    • Liver triacylglycerol --> adipose tissue triacylglycerol (lipoproteins in blood)
  • B) Skeletal muscle protein into acetyl-CoA in neuronal cells (via blood glucose) during a 2-day fast
    • Hydrolysis of muscle protein --> amino acids (rate of breakdown fastest after 2-3 days)
    • Skeletal muscle amino acids --> liver amino acids (via blood. Not all amino acids are precursors to GNG).
      • Can use (for example):
        • Alanine (--> pyruvate as keto acid)
        • Aspartate (--> oxaloacetate as keto acid)
        • Glutamate (--> alpha-ketoglutarate as keto acid)
    • Amino --> alpha-ketoacids (and amino group --> urea cycle)
    • Keto acids --> other ketoacids (see above for examples), which are intermediates in TCA cycle and GNG (aminotransferases, pass on amino group)
    • Glucose synthesised via GNG in liver cytoplasm (GNG stimulated by high glucagon and low insulin and fructose-1,6-bisP)
    • Liver glucose --> brain glucose (via blood; glucose can go through the blood and we don’t have to do anything to it)
    • Glucose --> pyruvate --> acetyl-CoA in neuronal cells
  • C) Triacylglycerol from adipose tissue into acetyl-CoA in neuronal cells during prolonged starvation
    • TAG from adipose tissue --> acetyl-CoA in neuronal cells during prolonged starvation
    • Hydrolysis of TAG in adipose tissue by hormone sensitive lipase (stimulated by high glucagon:insulin ratio)
    • Adipose tissue fatty acids --> liver fatty acid (via blood in albumin – as the adipose tissue cannot make lipoproteins)
    • Fatty acid --> fatty acyl-CoA (in the cytoplasmic compartment of liver cell).
    • Need to get to the mitochondrial matrix (carnitine transport system)
    • Fatty acyl-CoA --> acetyl-CoA (via beta oxidation in mitochondrial matrix; also NADH and FADH2)
    • Need to transport this acetyl-CoA to the brain. This is done as ketones (can only be made in the mitochondria; can only be converted back in the mitochondria)
    • Acetyl-CoA --> ketone bodies (which are water soluble; still inside the mitochondria)
    • Liver ketone bodies --> Brain ketone bodies (via blood)
    • Ketone bodies --> acetyl-CoA (in the mitochondria of neuronal cells)

Problem 2

The enzyme HMG-CoA reductase catalyses the second reaction in cholesterol biosynthesis and is the major control point in the pathway. It is an integral membrane protein in the endoplasmic reticulum with its active site in the cytoplasmic compartment. Assuming that this enzyme is phosphorylated by protein kinase A, predict the effect of phosphorylation on the enzyme activity. Assuming that it is also an allosteric enzyme, suggest compounds that might be expected to be allosteric inhibitors or activators.

  • Phosphorylation of enzymes that are anabolic = inactivate
  • Phosphorylation of enzymes that are catabolism = activate
  • Allosteric inhibitors
    • AMP and ADP (AMP is a better inhibitor)
    • Cholesterol
  • Allosteric activators
    • ATP
    • NADH or NADPH
    • Acetyl-CoA

Problem 3

Why cannot fatty acids be used as or converted into precursors for GNG (while glucose can be converted into fatty acids)

  • ???After TCA cycle, there is no product by which to return to GNG (lose 2 carbons as CO2 = net 0 carbons)

Problem 4

Assume that the energy released from triacylglycerol and glycogen catabolism is 40 and 18 kJ/g respectively. Assume also that someone’s average energy expenditure is 8000 kJ/day. Calculate the number of days for which the individual’s energy requirements could be supplied by 1 kg of stored triacylglycerol from adipose tissue and 1 kg of stored glycogen in the liver. Remember that stored glycogen is two-thirds water and only one-third glycogen itself. How many days would it take this individual to use up 10kg of stored triacylglycerol assuming they consume no macronutrients and maintain constant energy expenditure?

  • TAG = 40 kJ/g
  • Glycogen = 18 kJ/g
  • Per day we need 8000 kJ/day
  • 1/3 of stored weight of “glycogen” is actually glycogen (rest is water)
  • Fat: 1kg (1000)(10)(10000)
  • Glycogen: 1kg(1000)(1/3)
  • TAG = 40 * 1000/8000 = 5 days
  • Glycogen = 1/3* 18*1000/8000 = 0.75 days
  • Part 2: TAG = 50 days