Glycolysis is a metabolic pathway found universally in biological systems. It is the metabolic pathway which converts glucose via a series of reactions to 2 molecules of pyruvate. As a result of these reactions, a small amount of ATP and NADH are produced. Most of the metabolic energy derived from glucose comes from the entry of pyruvate into the citric acid cycle and oxidative phosphorylation. These pathways occur under aerobic conditions. Under anaerobic conditions, pyruvate can be converted to lactate in muscle or ethanol in yeast.

Among the important findings determined as part of the elucidation of the glycolytic pathway were:

• The finding by Hans Buchner and Eduard Buchner that fermentation, the conversion of sucrose to ethanol, could occur in the absence of a living cell.
• The finding of a hexose bi-phosphate intermediate (fructose 1-6 biphos) in glycolysis
• The activities required for the reactions to occur were composed of a heat-labile, non-dialyzable substance (enzymes) and a heat-stable, dialyzable substance (coenzymes).
• Many scientists, including Gustav Embden, Otto Meyerhof, Carl Neuberg, Jacob Parnas, Otto Warburg, Gerty Cori, and Carl Cori, contributed to the complete determination of the pathway.
• Glycolysis is formally known as the Embden-Meyerhof-Parnas Pathway.

Glycolysis takes place in the cytoplasm of the cell. The goal of the initial reactions of glycolysis is to convert glucose into fructose 1,6-bisphosphate. This traps glucose in the cell as glucose 6-phosphate and forms a phosphorylated compound (fructose 1,6- bisphosphate) that can be cleaved into phosphorylated 3-carbon intermediates - DHAP & 3PGALD. These 3-carbon units can then be used to generate ATP by substrate level phosphorylation and by making pyruvate & NADH for the citric acid cycle and oxidative phosphorylation.

The first step in glycolysis is the phosphorylation of glucose by ATP to form glucose 6-phosphate. This reaction, catalyzed by the enzyme hexokinase, traps glucose in the cell.

The second step in glycolysis is the isomerization of glucose 6-phosphate to fructose 6-phosphate. This converts the sugar from a 6-membered pyranose to the 5-membered furanose structure and involves the conversion of an aldose into a ketose. This reaction is catalyzed by the enzyme phosphoglucose isomerase.

The third step in glycolysis is a second phosphorylation to form fructose 1,6-bisphosphate catalyzed by the enzyme phosphofructokinase. Phosphofructokinase is an allosteric enzyme controlled by ATP and other metabolites. The importance of the control of phosphofructokinase will be discussed in a later lesson.

Up to this point no energy in the form of ATP has been generated by glycolysis. Two ATP's have been used. The second stage of glycolysis involves the cleavage of the 6-carbon fructose 1,6-bisphosphate to 3-carbon sugars followed by isomerizations. The generation of 3-carbon units from the 6-carbon sugar is catalyzed by the enzyme aldolase. In this reaction, dihydroxyacetone phosphate and glyceraldehyde 3-phosphate are generated. The glyceraldehyde 3-phosphate generated in this reaction can continue directly in the glycolytic pathway. Dihydroxyacetone phosphate must be converted to glyceraldehyde 3-phosphate in order to continue in the pathway. This isomerization is catalyzed by the enzyme triose phosphate isomerase. At equilibrium most of the 3-carbon sugar is in the form of dihydroxyacetone phosphate. However, the removal of glyceraldehyde 3-phosphate in further glycolytic reactions allows the formation of more glyceraldehyde 3-phosphate from dihydroxyacetone phosphate, shifting the equilibrium of the reaction.

The next reaction of glycolysis generates a high potential phosphorylated compound, 1,3-bisphosphoglycerate. This compound is formed from glyceraldehyde 3-phosphate by the action of the enzyme glyceraldehyde 3-phosphate dehydrogenase. In this reaction, inorganic phosphate (P_i) is incorporated into the C-1 position forming an acyl phosphate with NAD⁺ serving as the electron acceptor. The high energy potential of 1,3-bisphosphoglycerate is used to form ATP from ADP and P_i. This reaction is carried out by phosphoglycerate kinase. These reactions result in the formation of NADH and ATP. All of the reactions can be seen in the diagrams in Panel 4-1 on page 112 of the first edition of ECB by Alberts, et al, 1998. 

The last part of glycolysis involves the formation of pyruvate and more molecules of ATP. This is accomplished by a rearrangement of 3-phosphoglycerate to form 2-phosphoglycerate followed by a dehydration to form phosphoenolpyruvate (PEP). The final nearly irreversible reaction is the formation of ATP and pyruvate catalyzed by the enzyme pyruvate kinase.

Pyruvate is the precursor molecule for:
        1. lactic acid ferementation (anaerobic respiration)
        2. alcohol fermentation
        3. aerobic respiration (tricarboxylic acid cycle - Krebs cycle)

 

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