Metabolism of Carbohydrates

Glycogenolysis

Glycogenolysis is the breakdown of glycogen into glucose-1-phosphate (G-1-P), which is then converted
to glucose-6-phosphate (G-6-P) before going through glycolysis (the breakdown of glucose through a
series of reactions to form pyruvic acid). Note that glycogenolysis feeds into glycolysis with the
formation of glucose-6-phosphate. The process of glycogenolysis is is controlled by the enzyme
phosphorylase.

The glucose formed when removed from a glycogen molecule is glucose-1-phosphate, which means that
the glucose has a phosphate group attached at the carbon-1 position. This is achieved because ATP is
involved:

Glycogen(n) + ATP → Glycogen(n−1) + G-1-P + ADP.

The G-1-P is then converted to G-6-P, whereby the phosphate group is moved from carbon-1 to carbon-6
before undergoing glycolysis. Glycogenolysis is a process that must be capable of happening rapidly,
since it provides an important and major source of energy during prolonged physical activities. This
implies that glycogenolysis needs to be ‘switched on’ almost instantaneously.

Glycolysis

Glycolysis is a process where a six-carbon compound, glucose, is converted to two three-carbon

compounds (i.e. two pyruvates), which are then converted to two two-carbon compounds (acetyl-CoA)
with the liberation of carbon dioxide, and then into the Tricarboxylic acid cycle (TCA cycle), where it is
completely oxidized to carbon dioxide and water. The conversion of glucose to pyruvate is through a
series of ten reactions (Figure-1)

Note that glucose is first phosphorylated to Glucose-6-phosphate (G-6-P) by the enzyme hexokinase
(although the liver uses glucokinase). This happens immediately as glucose enters the cell and utilizes an
ATP molecule. Hexokinase is more specific than glucokinase. The G-6-P is then converted to fructose-
6-phosphate and then, in the third reaction, the F-6-P is converted to fructose-1,6 diphosphate. This
reaction involves the enzyme phosphofructokinase (PFK). PFK is the regulatory enzyme for glycolysis
The next phase of glycolysis involves splitting the F-1,6 diphosphate (which, remember is a six-carbon
compound) into two three-carbon compounds, dihydroxyacetone phosphate (DHAP) and
glyceraldehyde 3-phosphate. The DHAP is then converted to glyceraldehyde 3-phosphate – so in
effect there are now two glyceraldehyde 3-phosphates, which are in turn converted to 1,3-
diphosphoglycerate. In the latter process, an NADH (Nicotinamide-adenine-dinucleotide hydrogen) is
formed from NAD(Nicotinamide-adenine-dinucleotide), NADH being the reduced form of NAD. The 1,3
di-phosphoglycerate is then converted to 3-phosphoglycerate in a process that produces ATP, before
being converted to 2-phosphoglycerate and then to phosphoenolpyruvate (PEP). The final stage sees the
formation of pyruvate and another ATP from PEP.

Carbohydrates: Glycolysis

Figure-1
Examination of glycolysis
The Examination of glycolysis shows that after an initial use of two ATPs (reactions 1 and 3), a further
four ATPs are produced (remember that in reactions 5 and 9 there are two reactants from the initial
glucose molecule). So there is a net yield of two ATP. In addition, two NADH are formed from two
NAD, and these can either be re-oxidized from aerobic events in the mitochondria (each producing three
ATP or from the conversion of pyruvic acid to lactic acid. The production of lactic acid ensures that
glycolysis continues if aerobic re-oxidation of NAD from NADH is not possible. The latter tends to occur
during very high intensity bouts of exercise. Regeneration of NAD is essential if glycolysis is to continue.
The formation of lactic acid occurs when significant amount of pyruvate are formed in glycolysis.
The ‘link’ reaction; production of acetyl-CoA:
The pyruvate formed as the end result of glycolysis passes into the mitochondria and is converted to
acetyl-CoA in the so-called ‘link’ reaction. This reaction involves the formation of acetyl-CoA from
pyruvate with the production of carbon dioxide.
The key regulatory enzyme is known as pyruvate dehydrogenase (PDH). In essence, the three-carbon
pyruvate is converted to the two-carbon acetyl-CoA. The formation of acetyl-CoA provides the
crossroads between carbohydrate and fat oxidation, and so the control of PDH is seen as an important
factor in the regulation of fat and carbohydrate metabolism.
Another important factor is that NADH is formed from NAD and later this provides ATP.

Tricarboxylic acid cycle (TCA cycle) or Krebs cycle:

Acetyl-CoA formed during the link reaction, enters the TCA cycle, whereby it attaches to a four-carbon
compound, oxaloacetic acid (OAA). The combination of the four-carbon OAA and the two-carbon
acetyl-CoA results in the formation of the six-carbon, citric acid (or citrate). This cyclic sequence of
reactions is found in every cell type that possesses mitochondria

The function of the TCA cycle is to convert the two-carbon acetyl-CoA to carbon dioxide and water and
to produce energy (ATPs). Figure-2 highlights some key events in the TCA cycle, and shows that citrate is
converted to isocitrate, then to succinyl-CoA and then to alpha-ketoglutarate. The formation of alpha-
ketoglutarate produces NADH, as does the next reaction to succinyl-CoA. The cycle is catalyzed by a
series of enzymes and yields reducing equivalents (H+)

Succinyl-CoA then forms fumarate in a reaction that produces a Flavin-adenine-dinucleotide-hydrogen

(FADH2). Fumarate then forms malate, and then malate forms OAA, with the production of another
NADH. So, the net effect of the TCA cycle is to produce three NADH, one FADH2 and one ATP. Each
NADH results in the formation of three ATPs via oxidative phosphorylation whilst the FADH is re-oxidized
to form two ATPs via oxidative phosphorylation.
 Tricarboxylic acid cycle

Figure-2
The hexose monophosphate shunt (Pentose phosphate pathway)

The hexose monophosphate shunt provides an alternate pathway for the use of glucose-6-phosphate. It
is an important pathway because it generates reducing equivalents carried by NADP+ and because it
generates a phosphorylated ribose for use in nucleotide synthesis It is estimated that approximately
10% of the glucose-6-phosphate generated from glucose is metabolized by the shunt
Gluconeogenesis

The provision and maintenance of normal blood glucose levels in the absence of food involves not only
glycogenolysis but the synthesis of glucose from noncarbohydrate precursors. This process, called
gluconeogenesis. Gluconeogenesis occurs primarily in the liver and kidney. Most tissues lack the full
complement of enzymes needed to run this pathway. In particular, the enzyme phosphoenolpyruvate
carboxykinase (PEPCK) is not found or is in short supply. The other reactions use the same enzymes as
glycolysis. The capacity to synthesize glucose in times of need is absolutely essential to survival. Blood
glucose must be maintained so that those tissues, i.e., brain, that have an absolute requirement for this
fuel can continue to function. Although gluconeogenesis is essential, it must be carefully controlled so
that excess glucose is not produced. The process is energetically very expensive. If it were not closely
regulated, undue protein catabolism with its associated ammonia load could be devastating because it
uses as substrates the carbon chains of deaminated amino acids. Fortunately, a number of fail-safe
controls that do not allow this to occur are in place.

Gluconeogenesis can use the carbon skeletons from a number of metabolites of glucose (lactate,
pyruvate, and some of the triose phosphates) and also those from deaminated amino acids. Not all of
the amino acids enter the gluconeogenic sequence at the same place. Shown in Table 1 are the amino
acids that serve as substrates for glucose synthesis. Some enter as pyruvate, whereas others enter the
Krebs cycle at various points.