Chemistry Reference
In-Depth Information
respectively. Both of these amino acids are used extensively in the biosynthesis of other amino acids and in
nucleotide biosynthesis. Succinyl CoA is used together with glycine in the synthesis of porphyrins, while citrate is
the starting point of both fatty acid and cholesterol biosynthesis. However, all of these biosynthetic pathways require
free energy, so cycle intermediates which have been siphoned off must be replaced. These so-called anaplerotic
reactions (filling up, Greek, ana,up
รพ
plerotikos, to fill) are also illustrated in
Figure 5.13
.
It is clear that, to avoid metabolic chaos, biosynthetic pathways cannot use the same enzyme machinery as the
corresponding catabolic ones. Sometimes, as in the synthesis of glucose from pyruvate (gluconeogenesis), this
implies the use of alternative enzymes for only a few specific steps in the pathway, sometimes, as in the
biosynthesis of fatty acids, the pathway is localised in a different cellular compartment from the catabolic
pathway, and uses different enzymes. We now discuss each of these pathways in turn.
SELECTED CASE STUDIES: GLUCONEOGENESIS AND FATTY ACID BIOSYNTHESIS
Glucose is extremely important in metabolism, both as a fuel and as a precursor of essential structural carbo-
hydrates and other biomolecules. The brain, like red blood cells, is almost completely dependent on glucose as an
energy source. However, the capacity of the liver to store glycogen (the body's reserve of glucose) is only
sufficient to supply the brain with glucose for about half a day under conditions of fasting or starvation. Under
these conditions, the needs for glucose must be met by gluconeogenesis, the synthesis of glucose from non-
carbohydrate precursors. These include lactate and pyruvate, produced by glycolysis, but also citric acid cycle
intermediates themselves as well as all but two of the twenty protein amino acids. All of these molecules have in
common that they can be converted to oxaloacetate, the starting material for gluconeogenesis. There is no pathway
for the net conversion of acetyl CoA into oxaloacetate in animals. Since most fatty acids are oxidised completely
to acetyl CoA, they cannot serve as glucose precursors either.
7
As illustrated in
Figure 5.10
, seven of the ten enzymes of the glycolytic pathway are used in gluconeogenesis,
and the three which are not, as we might expect, are those which catalyse essentially irreversible steps in
glycolysis. The first two, hexokinase and phosphofructokinase, which use ATP in the glycolytic pathway are
replaced by hydrolytic reactions catalysed, respectively, by glucose-6-phosphatase
8
and fructose-1,6-bisphos-
phatase, which remove the phosphoryl groups as inorganic phosphate. The conversion of pyruvate to phospho-
enolpyruvate is more complex, first because the reaction is energetically extremely unfavourable, and second
because the pyruvate, required for gluconeogenesis is localised within the mitochondrial matrix, whereas the
enzymes of the glycolytic pathway are in the cytosol. The solution (
Figure 5.14
) involves the energy-dependent
FIGURE 5.14
Conversion of pyruvate to oxaloacetate and then to phosphoenolpyruvate.
carboxylation of pyruvate within the mitochondria by pyruvate carboxylase, to form oxaloacetate. Oxaloacetate is
then exported to the cytosol, either as malate or as aspartate, as described below. In the cytosol, it is converted to
phosphoenolpyruvate again in an energy-dependent process, this time involving GTP (
Figure 5.14
)
, by the enzyme
7. Hence, the old, yet true, dictum that you can make fat from sugar, but you cannot make sugar from fat.
8. Glucose-6-phosphatase is found only in liver and kidney, and allows these tissues to supply glucose to other organs of the body, like the
brain, which have little or no reserves of carbohydrates.
