Process of Glycogenesis (With Diagram) | Biochemistry

In this article we will discuss about the process of glycogenesis.

The process of formation of glycogen from glucose in the tissues is called glyco­genesis. Different tissues of the living orga­nisms store carbohydrate as glycogen. The steps of glycogenesis are as follows (Fig. 8.83).

1. Glucose is phosphorylated to glycose-6- phosphate by the enzyme hexokinase (glucokinase) in presence of a phosphate donor, ATP.

Glucose + ATP hexokinase→ Glycose-6-phosphate + ADP

2. Glycose-6-phosphate is transformed into glucose-1-phosphate, catalysed by the enzyme phosphoglucomutase.

3. Glucose-1-phosphate is converted to UDP-glucose by the enzyme UDP-glucose pyrophosphorylase in the presence of UTP (Fig. 8.81). The pyrophosphate (PPi) is immediately hydrolysed by inorganic pyrophosphatase, releasing energy. Thus the overall reaction is very exergonic and essentially irreversible.

4. Glycogen synthase (synthetase) transfers the glucosyl residue from UDP-glucose to the C₄OH at the non-reducing end of a glycogen molecule, forming an α 1, 4 glycosidic bond. It is fact that glycogen synthase cannot unite to UDP-glucose, but it can only extend and existing chain (Fig. 8.82).

So, glycogen synthase needs a primer, which is a protein called glyco­genic Glycogenin contains eight gluco­syl units linked via a 1-4 linkages, which are added to the protein by itself (i.e., autocatalysis). Glycogen synthase can extend this molecule only.

Each glycogen synthase can extend this molecule only. Each glycogen granule contains only a single glycogenin molecule at its core. Glycogen synthase enzyme is becoming active when it comes in contact with glycogenin. On the other hand glyco­genin limits the size of the glycogen granule.

5. An enzyme, called branching enzyme [amylo-(1, 4′ → 1, 6′) transglycosylase] transfers a part of the 1, 4′-chain (about seven glucose unit) to a more interior site in the glycogen molecule and reattaching it by forming α¹, 6¹ glucosidic bond with a branching point (Fig. 8.59).

Glycogen degradation (Catabolism):

Breaking of glycogen to form glucose is called glycogen degradation.

The process requires two enzymes; the action of them is as follows:

1. Glycogen phosphorylase (or phosphorylase) degrades glycogen by breaking α 1, 4′ glycosidic bond. This enzyme release glucose units one at a time from non-reducing end of the glycogen molecule and produce glucose-1-phosphate. For this reaction, inorganic phosphate (P_i) is also required.

This reaction is an example of phosphorolysis, i.e., breakage of a covalent bond by the addition of a phosphate group.

The limitation of glycogen phospho­rylase enzyme is that, it can remove only those glucose residues that are more than five units apart from branch point.

2. Glycogen de-branching enzyme removes the α 1-6′ glycosidic bonds and allows glyco­gen phosphorylase to continue its function.

3. Phosphoglucomutase converts glucose-1-phosphate to glucose-6-phosphate.

4. Glucose-6-phosphate is converted to glucose in liver by the enzyme glucose-6-phosphatase. This glucose then diffuses to circula­tion to maintain blood glucose concentration.

In muscle glucose-6-phosphate is meta­bolised immediately through glycolysis. It is to be noted that muscle does not contain glucose-6-phosphatase enzyme, so no ques­tion of glucose diffusion from muscle cells into blood stream.

Gluconeogenesis:

Synthesis of glucose from non-carbohydrate precursors, including lactate and pyru­vate, citric acid cycle intermediates the car­bon skeletons of most amino acids and glyce­rol, is called gluconeogenesis. The liver is the main site of gluconeo­genesis.

The other organs with little capabi­lity of gluconeogenesis are kidney, brain and muscle. In liver cells, the first enzyme of glu­coneogenesis, pyruvate carboxylase, is located in the mitochondrial matrix. The last enzyme, glucose-6-phosphatase is bound to the smooth endoplasmic reticulum. The other enzymes of the pathway are located in the cytosol.

Apparently gluconeogenesis appears to be a reversal of glycolysis. In glycolysis, glucose is metabolised to pyruvate and in gluconeo­genesis pyruvate is metabolised into glucose. Indeed, some of the reactions of glycolysis are reversible and so the two pathways of these reactions have these steps in common.

But three steps in glycolysis are essentially irreversible; those catalysed by the enzymes hexokinase, phosphofructokinase (PFF) and pyruvate kinase. All these reactions are ATP mediated and drives glycolysis forward towards pyruvate formation. In gluconeoge­nesis these three steps are reversed by using other reactions (Fig. 8.85). Therefore, gluco­neogenesis is not a simple reversal of glyco­lysis.

Precursors for gluconeogenesis:

1. Glycerol enters into the gluconeogenesis pathway through dihydroxy acetone phos­phate.

2. Lactate, pyruvate, citric acid cycle inter­mediates and the carbon skeleton of amino acids are at first converted into oxaloacetate.

Steps of gluconeogenesis:

1. The enzyme pyruvate carboxylase converts pyruvate to oxalacetate by carboxylation (Fig. 8.85). This enzyme is located in mitochondrial matrix and uses biotin as an activated carrier of CO₂, the reaction occur in two stages:

E-biotin + ATP + HCO₃^– → E-biotin-CO₂ + ADP + P_i

E-biotin – CO₂ + Pyruvate → E-biotin + Oxaloacetate

2. Phosphoenolpyruvate carboxykinase (PEPCK) enzyme simultaneously decarboxylates and phosphorylates oxalacetate to form phosphoenol puruvate (PEP), releasing CO₂ and using GTP.

Therefore, it is apparent that reversal of pyru­vate to PEP needs the input of a substantial amount of energy, one ATP for the pyruvate car­boxylase step and one GTP for the PEPCK step.

3. PEP is then converted to fructose-1, 6- bisphosphate in a series of steps that are a direct reversal of those in glycolysis described earlier. This sequence of reactions uses one ATP and one NADH for each PEP molecule metabolised.

4. Fructose 1, 6-bisphosphate is dephosphorylated to form fructose 6-phosphate by the enzyme fructose 1, 6-bisphosphatase.

Fructose 1, 6-bisphosphate + H₂O → Fructose 6-phosphate + P_i

5. Fructose 6-phosphate is converted to glucose-6-phosphate by the glycolytic enzyme phosphoglucoisomerase.

6. Glucose 6-phosphate is converted to glucose by the enzyme glucose 6-phosphatase, present in SER.

Glucose 6-phosphate + H₂O → Glucose + P_i

Energetics:

Energy is required to synthesise glucose by gluconeogenesis. Two 3 carbon pyruvate molecules are required to synthesise one hexose glucose.

Hence, energy required in different steps is as follows: