Metabolism
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Is fructose fattening?
Key points from this exercise:
The main regulation of glycolysis is the reaction catalysed by phosphofructokinase, which is inhibited by ATP, citrate and phosphoenolpyruvate.
Normal intracellular concentrations of ATP lead to about 90% inhibition of phosphofructokinase. As ADP begins to accumulate in the cell as the result of ATP utilisation, the reaction of adenylate kinase leads to formation of AMP and ATP from ATP. AMP overcomes the inhibition of phosphofructokinase by ATP, leading to a rapid increase in the rate of glycolysis.
Phosphoenolpyruvate is a key intermediate in gluconeogenesis, and as it accumulates in the cytosol it acts to inhibit phosphofructokinase and so inhibit glycolysis.
Citrate provides the source of acetyl CoA in the cytosol for fatty acid synthesis.
Although it is a symmetrical molecule, citrate behave asymmetrically, because it is chanelled directly from the active site of citrate synthase onto aconitase. It is only when aconitase is saturated that citrate is free to leave citrate synthase, go into free solution and be transported into the cytosol. This ensures that citrate is not used for fatty acid synthesis when it is needed for citric acid cycle activity.
In the cytosol citrate is cleaved by citrate lyase, providing acetyl CoA for fatty acid synthesis and oxaloacetate.
Oxaloacetate does not enter mitochondria. In the cytosol it is reduced to malate(at the expense of NADH. Malate is then oxidised and decarboxylated to pyruvate, linked to reduction of NADP to NADPH. This provides half the NADPH needed for fatty acid synthesis (the other half comes from the pentose phosphate pathway). Pyruvate enters the mitochondrion and is carboxylated to oxaloacetate (at the cost of 1 mol of ATP per mol of pyruvate carboxylated).
Fructose enters glycolysis by formation of fructose 1-phosphate (catalysed by fructokinase). Fructose 1-phosphate is then cleaved by aldolase to yield dihydroxyacetone phosphate and glyceraldehyde. It thus by-passes the regulatory step in glycolysis catalysed by phosphofructokinase. Glycolysis from fructose is not regulated,a nd the result is formation of more pyruvate, then more citrate, than is needed for ATP synthesis. This excess citrate is exported from mitochondria and provides an uncontrolled source of acetyl CoA for fatty acid synthesis.