Question

Explain, using electron-pushing arguments, why glycolysis must go through the Glucose 6-Phosphate to Fructose 6-Phosphate step (i.e. a C1 aldehyde to a C2 ketone).
Focus on the subsequent aldolase-catalysed reaction and explain why Glucose 1,6 bisphosphate would not be able to go through the aldolase reaction.

Answer 1

In the glycolytic pathway, glucose 6-phosphate, a six-carbon sugar, is isomerized to fructose 6-phosphate. Two steps after the isomerization reaction, the six-carbon sugar is cleaved to form two three-carbon sugars. The isomerization reaction is critical for the subsequent cleavage reaction that results in formation of two three-carbon sugars in the glycolytic pathway. Cleavage of a C–C bond does not progress at a reasonable rate in the absence of chemical assistance from functional groups on adjacent carbons.

Reasons why it is important:

1. Breaking C-C bond is energetically unfavorable and can only proceed if a functional group with electronegative atoms adjacent to the cleavage site to stabilize the reaction intermediates.
2. To cleave C-C bond, a nucleophilic carbon attacks the adjacent electrophilic carbon. The isomerization reaction moves the carbonyl group to C-2, thus making it a nucleophile that can attack C-3 to generate two three-carbon sugars.

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