Glycolysis vs Gluconeogenesis: Key Differences, Enzymes & Regulatory Steps Explained

What is Glycolysis? 

Glycolysis is the splitting of the 6-carbon compound glucose to form two products, depending upon the process occurs aerobically or anaerobically. 

Glycolysis - Products  

Every glucose molecule is generated.

• Aerobic glycolysis - 2 Pyruvates and 7 ATPs.
• Anaerobic glycolysis - 2 Lactate and 2 ATPs.

Significance of Glycolysis

Glycolysis is the only pathway that generates ATPs even in the absence of oxygen.

Glycolysis - Cells Dependent  

• Physiologically, the following cells are dependent on glycolysis for ATP production, as they lack mitochondria
  • RBCs
  • Retinal cells
  • Corneal cells

• White muscle fibres: Due to a lack of fresh blood supply during isometric contractions. Any blood vessel entering the muscle gets constricted due to muscular contraction. They won't get a fresh supply of oxygen, nor do they have myoglobin (a Storage form of oxygen). Thus, they depend on anaerobic glycolysis.
• Renal medulla: In ischaemic or hypoxic damage to the kidney, the renal medulla is affected the most as it receives relatively low blood supply. It has low O₂ supply and relies more on glycolysis.

Difference of Glycolysis in Anaerobic Cells (RBCs) and Aerobic Cells (Neurons)

Steps of Glycolysis  

Step-01: Glucose → Glucose 6 Phosphate.

• Glucose enters the cell. 
• The first enzyme to act on is Glucokinase or Hexokinase. 
• This enzyme utilises 1 high-energy phosphate (ATP) for conversion. 

Step-02: Glucose 6 Phosphate (G6P) ⇄ Fructose 6 Phosphate (F6P).

• Phosphate Hexose Isomerase enzyme is involved.

Step-03: Fructose 6 Phosphate (F6P) → Fructose 1,6 bisphosphate.

• Phosphofructokinase I uses one ATP for the conversion.

Steps 01 - 03 are named the investment phase because 2 ATPs are utilised. 

Further steps are considered in the Harvest phase (ATPs are generated).

Step-04: Fructose 1,6 bisphosphate → Glyceraldehyde 3 Phosphate + Dihydroxyacetone Phosphate.

• Aldolase A is important in glucose glycolysis.
• Aldolase B is important in fructose glycolysis.

Step-05: Glyceraldehyde 3 Phosphate ⇄ Dihydroxyacetone Phosphate.

• The enzyme involved is Phosphate Triose Isomerase.

Step-06: 2 Glyceraldehyde 3 Phosphate → 2 1,3 bisphosphoglycerate. 

• Glyceraldehyde 3 Phosphate dehydrogenase enzyme is involved.
• This reaction is an example of oxidative phosphorylation.
• Gives two hydrogens to NAD to form 2 NAD → 2 NADH.

.

Step-07: 2 1,3 Bisphosphoglycerate → 2 3-Phosphoglycerate.

• An example of substrate-level phosphorylation.
• Enzyme - Phosphoglycerate kinase.
• 2 ATPs are generated directly.

Step-08: 2 3-Phosphoglycerate → 2 2-Phosphoglycerate.

• Enzyme - Phosphoglyceromutase.

Step-09:  2 2-Phosphoglycerate → 2 Phosphoenolpyruvate.

• Enolase acts by removing a water molecule.

Step-10: 2 Phosphoenolpyruvate → 2 Pyruvates.

• Catalysed by pyruvate kinase.
• An example of substrate-level phosphorylation.
• 2 ATPs are generated directly.

What happens when the same process occurs anaerobically?

It has two impacts: 

• NADH cannot enter ETC; thus, the process lacks 5 generated ATPs. NAD cannot be regenerated, causing NAD deficiency and making Glyceraldehyde 3 Phosphate dehydrogenase enzyme inactive; further glycolysis is arrested.

• To counteract these limitations, in anaerobic cells, Lactate dehydrogenase converts Pyruvates into Lactates by regenerating NAD. 

Facts About Glycolysis

1. The products of aerobic glycolysis are 2 Pyruvate and 7 ATPs.

2. The products of anaerobic glycolysis are 2 Lactate and 2 ATPs.

3. The rate-limiting enzyme of glycolysis is Phosphofructokinase I.

4. Arsenate inhibits phosphoglycerate kinase.

5. Glyceraldehyde 3-phosphate dehydrogenase is inhibited by iodoacetate.

GLUCONEOGENESIS

This process is a reversal of glycolysis, where two molecules of pyruvate are combined to form glucose (irreversible steps of glycolysis). It takes place in the liver and kidneys. 

Steps Involved in Gluconeogenesis

There are four steps with three enzymes 

Pyruvate kinase: It is a two-step process

• Step-01: Pyruvate → oxaloacetate (OAA) in the presence of pyruvate carboxylase.

• Step-02: Oxaloacetate→Phosphoenolpyruvate in the presence of PEPCK (phosphoenolpyruvate carboxykinase).
  • PEPCK uses GTP as its coenzyme. 

• Step-03 PFK-1: 

• Hexokinase/ Glucokinase: Step 04

Enzymes Involved in Gluconeogenesis

There are four enzymes involved in gluconeogenesis

• Pyruvate carboxylase 
• PEPCK
• Fructose-1,6-bisphosphatase
• Glucose-6-phosphatase (In Liver and Kidney only)
• The first three enzymes are present in all the tissues
• Conversion of two molecules of pyruvate to one molecule of glucose: 11 ATP.

 Facts for the Regulation of Glycolysis and Gluconeogenesis

• Common Allosteric regulator (fructose 2,6-bisphosphate).
• Fructose 2,6 bisphosphate is a stimulator of glycolysis (PFK-1). 
• Fructose 2,6 bisphosphate is an inhibitor of gluconeogenesis (Fructose 1,6 bisphosphatase). 
• Fructose 2,6 bisphosphate is the product of a tandem enzyme(bifunctional enzyme with both phosphorylation and dephosphorylation functions) - PFK2.
• Fructose 2,6-bisphosphatase activity is stimulated by phosphorylation.

Important MCQS 

Q1: A neonate presented with hemolytic anaemia. A peripheral smear revealed that it's a case of non-spherocytic hemolytic anemia. Pyruvate kinase activity was remarkably low (0.675 U/g Hb). Which of the following explains hemolytic anaemia in this condition?

1. High 2,3 BPG production
2. Low 2,3 BPG production
3. High ATP production
4. Failure of the Sodium Potassium ATPase pump  

Answer: Failure of the Sodium Potassium ATPase pump  

Q2: Which of the following is a product of anaerobic glycolysis?

1. 2 Pyruvate 10
2. 2NAD
3. 7 ATP
4. 2 ATP  

Answer: 2 ATP

Q3: All of the following cells are dependent on glycolysis except?

1. Neurons
2. RBC
3. Renal medulla
4. Red muscle fibres 

Answer: Red muscle fibres 

Q4: Glucose is trapped inside the cells as

1. ? D-glucopyranose (The most common physiological form of glucose).
2. UDP glucose
3. Glucose 6 phosphate 
4. Fructose 6-phosphate

Answer: Glucose 6 phosphate 

Q5: The irreversible steps of glycolysis are all except

1. Pyruvate kinase
2. Phosphoglycerate kinase 
3. Hexokinase
4. Phosphofructokinase

Answer: Phosphoglycerate kinase 

Q6: The steps in which oxidative phosphorylation occurs in glycolysis are:

1. Pyruvate kinase
2. Phosphoglycerate kinase
3. PFK
4. Glyceraldehyde 3 Phosphate Dehydrogenase  

Answer: Glyceraldehyde 3 Phosphate Dehydrogenase 

Q7: In anaerobic glycolysis, lactate is formed

1. For the generation of ATP
2. For the regeneration of lactate
3. For the regeneration of pyruvate
4. For the regeneration of NAD  

Answer: For the regeneration of NAD  

Q8: The significance of the Rapoport-Luebering Shunt is

1. ATP production
2. Lactate formation
3. Source of fatty acids
4. 2, 3 BPG production 

Answer: 2, 3 BPG production 

Q9: The enzyme involved in the Rapoport-Luebering Shunt is

1. Phosphoglycerate kinase
2. Bisphosphoglycerate kinase
3. Bisphosphoglycerate mutase 
4. Phosphoglycerate mutase

Answer: Bisphosphoglycerate mutase 

Q10: Fructose 1, 6 bisphosphatase is seen in: 

1. Liver 
2. Skeletal muscle 
3. a & b 
4. none

Answer: Liver

Q11: Fructose 1, 6 bisphosphatase is seen in: 

1. Liver 
2. Skeletal muscle 
3. a & b 
4. none

Answer: Both a and b

Q12: Malate shuttle is used in: 

1. Glycolysis 
2. Gluconeogenesis 
3. Citric acid cycle 
4. None of the above

Answer: Gluconeogenesis

Q13: The tandem enzyme that regulates glycolysis and gluconeogenesis is 

1. PFK1 
2. PFK2 
3. Fructose 1,6 bisphosphatase 
4. Pyruvate carboxylase

Answer: PFK2

Q14: In a well-fed state, which of the following enzyme activities will be high?  

1. Pyruvate carboxylase 
2. PFK2 
3. Fructose 1,6 bisphosphatase 
4. Fructose 2,6 bisphosphatase

Answer: PFK2

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