Glycolysis

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Glycolysis

Glycolysis is a fundamental metabolic pathway that breaks down glucose (a 6-carbon hexose sugar) into two molecules of pyruvate (a 3-carbon compound), releasing energy in the form of ATP and NADH. It occurs in the cytoplasm and functions under both aerobic and anaerobic conditions.

It is also known as the Embden–Meyerhof–Parnas (EMP) pathway, named after its discoverers. This pathway consists of 10 enzyme-catalyzed steps, divided into two phases:

I Preparatory Phase (Investment Phase / Glucose Activation Phase)-

•        ATP is consumed, hence also known as the investment phase.

•        Also called the glucose activation phase.

•        In this phase, two molecules of ATP are invested, and the hexose chain is cleaved into two triose phosphates.

•        During this, phosphorylation of glucose and its conversion to glyceraldehyde-3-phosphate take place

Step  1:

Glucose+ATP→Glucose-6-phosphate+ADP
The first step of glycolysis involves the phosphorylation of glucose, which means a phosphate group from ATP is added to glucose to form glucose-6-phosphate. This reaction is catalyzed by the enzyme hexokinase (or glucokinase in the liver). This step also uses one molecule of ATP, starting the investment phase of glycolysis

Step 2:

Glucose-6-phosphate → Fructose-6-phosphate

In this step, the enzyme phosphoglucose isomerase converts glucose-6-phosphate into fructose-6-phosphate by rearranging the molecular structure from an aldose to a ketose sugar. This is an isomerization reaction and prepares the molecule for the next phosphorylation.

Step 3:

Fructose-6-phosphate +ATP→ Fructose-1,6-bisphosphate +ADP

This is a key regulatory and irreversible step of glycolysis catalyzed by the enzyme phosphofructokinase-1 (PFK-1). Here, another ATP is used to add a second phosphate group to the molecule, forming fructose-1,6-bisphosphate. This step is the rate-limiting step and is tightly regulated by energy levels in the cell. High levels of ATP inhibit PFK-1, while AMP and ADP activate it. This ensures glycolysis only proceeds when energy is needed.

Step 4:

Fructose-1,6-bisphosphate → Glyceraldehyde-3-phosphate + Dihydroxyacetone phosphate

In this cleavage step, the six-carbon sugar fructose-1,6-bisphosphate is split into two three-carbon molecules: glyceraldehyde-3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP) by the enzyme aldolase.  

Step 5:

Dihydroxyacetone phosphate  → Glyceraldehyde-3-phosphate

The enzyme triose phosphate isomerase rapidly converts dihydroxyacetone phosphate into a second molecule of glyceraldehyde-3-phosphate. Although both DHAP and G3P are triose sugars, only G3P continues through the rest of glycolysis. This step ensures that all carbon atoms from glucose are funneled through the same reactions as we advance, maximizing energy extraction efficiency.


II. Pay-off Phase (Energy Extraction Phase)- 

  • ATP is produced. Hence also called the energy extraction phase.
  • During this phase, conversion of glyceraldehyde-3-phosphate to pyruvate and the coupled formation of ATP take place.

Step 6:

Glyceraldehyde-3-phosphate  + NAD⁺ + Pi → 1,3-bisphosphoglycerate + NADH + H⁺

Each molecule of G3P undergoes an oxidation reaction catalyzed by glyceraldehyde-3-phosphate dehydrogenase, producing 1,3-bisphosphoglycerate, a high-energy compound. In this step, NAD⁺ is reduced to NADH, which is later used in aerobic conditions to generate more ATP via oxidative phosphorylation. An inorganic phosphate (Pi), not from ATP, is added to G3P, making this one of the few substrate-level phosphorylation preparations without using ATP.

Step 7:

1,3-bisphosphoglycerate + ADP → 3-phosphoglycerate + ATP

The high-energy phosphate group from 1,3-bisphosphoglycerate is transferred to ADP to form ATP, a process catalyzed by phosphoglycerate kinase. This is the first ATP-generating step of glycolysis (substrate-level phosphorylation). Since each glucose yields two G3P molecules, two ATPs are generated here, compensating for the two ATPs used earlier.

Step 8:

3-phosphoglycerate → 2-phosphoglycerate

This is a simple rearrangement step catalyzed by phosphoglycerate mutase, where the phosphate group is moved from the 3rd carbon to the 2nd carbon. This rearrangement is necessary to prepare the molecule for the formation of the next high-energy intermediate in the pathway.

Step 9:

2-phosphoglycerate → Phosphoenolpyruvate (PEP) + H₂O

The enzyme enolase catalyzes the dehydration of 2-phosphoglycerate, removing a water molecule and creating phosphoenolpyruvate (PEP). PEP is a very high-energy compound, and this reaction primes the molecule for the final step of glycolysis where ATP will be generated again.

Step 10:

Phosphoenolpyruvate + ADP → Pyruvate + ATP

In the final step, pyruvate kinase catalyzes the transfer of a phosphate group from PEP to ADP, forming ATP and pyruvate, the end product of glycolysis. This is the second substrate-level phosphorylation step, yielding two more ATP molecules (one per PEP). This step is irreversible and also regulated based on the energy needs of the cell.

ATP Yield in Glycolysis (Aerobic Condition)

Phase

Step/Reaction

Enzyme

ATP Produced

ATP Consumed

Investment Phase

Glucose → Glucose-6-phosphate

Hexokinase

0

1

Fructose-6-phosphate → Fructose-1,6-bisphosphate

Phosphofructokinase-1 (PFK-1)

0

1

Subtotal (Investment)

0

2 ATP

Payoff Phase

1,3-Bisphosphoglycerate → 3-Phosphoglycerate (×2)

Phosphoglycerate kinase

2

0

Phosphoenolpyruvate → Pyruvate (×2)

Pyruvate kinase

2

0

2 NAD⁺ → 2 NADH (via G3P dehydrogenase)

G3P Dehydrogenase

6 ATP

0

Subtotal (Payoff)

10 ATP

0

Net ATP Gain

10 – 2 = 8 ATP

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