i)

The lack of reciprocal regulation in metabolic pathways can result in futile cycles and would end with
an overall energy loss. If the final product of one pathway is required, a simultaneous unregulated
opposite pathway would use up the product and reconvert it back into its precursors, reducing the
efficacy at which the system produces the desired product. It can also cause a dangerous amount of
a metabolite to accumulate – high blood glucose levels can cause damage to cells due to its ability to
upset osmotic balance and must be converted to other forms in excess.

In glycolysis and gluconeogenesis, reciprocal regulation can be dictated by either metabolites or

energy charges. A major factor in metabolite reciprocal regulation is fructose – 2,6 – bisphosphate.
This molecule performs many functions.

When energy is required, glycolysis is favoured to convert glucose into pyruvate. As a signalling
molecule, it can influence the 3rd reaction in glycolysis. It can stimulate the glycolytic reaction
(fructose – 1 – phosphate → fructose – 1,6 – bisphosphate) while inhibiting the reverse reaction for
gluconeogenesis. Furthermore, F2,6P allosterically stimulates pyruvate kinase in a feedforward loop,
encouraging the production of pyruvate from phosphoenolpyruvate.

The hormone insulin would also be produced from pancreatic beta cells. This initiates a signal
pathway, activating protein phosphatases to dephosphorylate fructose – 2,6 – bisphosphatase. This
inhibits fructose bisphosphatase 2 and activates PFK1, allowing glycolysis to predominate.

When energy and biosynthetic intermediates are in excess, gluconeogenesis is favoured to produce
glucose from pyruvate. Glucagon levels rise instead of insulin, triggering a cyclic AMP signal cascade.
This causes protein kinase A to phosphorylate fructose bisphosphatase 2, activating it. This results in
the production of fructose – 6 – phosphate from the dephosphorylation of fructose – 2,6 –
bisphosphate. In addition, PFK2 is inhibited, mitigating the synthesis of fructose – 2,6 – bisphosphate
and its stimulation of glycolysis would be inhibited, causing gluconeogenesis to be favoured.

ii)

Glycogen is a polysaccharide comprised of glucose monomers

bound by 1,4 glycosidic bonds to form straight chains and 1,6
glycosidic bonds to form branches, depicted on the right. This
creates an efficient sugar storage which must be reciprocally
regulated to maintain safe blood glucose levels.
 Like in glucose synthesis and catabolism, glycogen metabolism
is also heavily reciprocally regulated by hormones like insulin,
glucagon and epinephrine.

The final reaction in glycogen synthesis is catalysed by

glycogen synthase, shown on the left. In the fed state, excess
blood glucose is transported to muscles, adipose tissue and the
heart via the GLUT4 transporter, which requires insulin. During
this state, the pancreatic beta cells produce insulin to
stimulate tissue uptake of glucose and glycogen synthesis in
the liver. Insulin also inactivates glycogen synthase kinase.
Glycogen synthase kinase phosphorylates glycogen synthase
and inactivates it. Protein phosphatase 1 activates glycogen
synthase via dephosphorylation and glycogen synthase is kept
dephosphorylated due to the inactivated glycogen synthase
kinase.

The breakdown of glycogen into its residues is catalysed by glycogen phosphorylase. In the fasting
state, glucagon is released from pancreatic alpha cells, triggering a cyclic AMP signal cascade. This
causes protein kinase to phosphorylate phosphorylase kinase, activating it, which phosphorylates
glycogen phosphorylase, activating it and stimulating glycogen degradation in the liver. Epinephrine
is also released from adrenal glands when the fight or flight mechanism is activated and glycogen is
broken down into glucose – 1 – phosphate, which is converted into glucose – 6 – phosphate and fed
into the glycolysis pathway to produce ATP.