Explain using electron-pushing arguments why glycolysis must go through G6P to F6P step (C1 aldehyde to C1 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.

To understand why glycolysis must go through the G6P to F6P step, let's first go over the electron-pushing arguments and the subsequent aldolase-catalyzed reaction.

In the first step of glycolysis, glucose (a 6-carbon sugar) is phosphorylated by hexokinase to form glucose 6-phosphate (G6P). G6P serves as the starting point for the subsequent reactions in glycolysis.

The electron-pushing arguments:

1. Stabilization of the aldehyde group: In glucose, the carbonyl group at C1 is an aldehyde. The aldehyde is relatively unstable due to electron withdrawal from the highly electronegative oxygen atom. By converting the aldehyde to a ketone in fructose 6-phosphate (F6P), the molecule gains stability through resonance delocalization of the electron density.

2. Easier hydration: The ketone group in F6P is more easily hydrated to form an enediol intermediate compared to an aldehyde. This is because the ketone is less reactive toward nucleophiles, resulting in a lower activation energy for hydration.

Now, let's move on to the aldolase-catalyzed reaction. In glycolysis, fructose 1,6-bisphosphate (FBP), which is formed from F6P, undergoes cleavage by aldolase into two 3-carbon fragments: dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate (GAP). This step is crucial for subsequent metabolism.

Why glucose 1,6-bisphosphate would not be able to go through the aldolase reaction:

Glucose 1,6-bisphosphate lacks the necessary structural arrangement for the aldolase enzyme to catalyze the cleavage. The enzyme recognizes the specific conformation and stereochemistry of FBP to perform the reaction. The carbon chain in FBP is optimally positioned for the formation of an enolate intermediate, which then allows for the cleavage of the carbon-carbon bond. In contrast, glucose 1,6-bisphosphate has a different arrangement, making it unable to undergo the necessary aldolase-catalyzed cleavage.

In summary, the conversion of G6P to F6P in glycolysis through electron-pushing arguments facilitates stabilization and easier hydration, while the subsequent aldolase-catalyzed reaction can only occur with fructose 1,6-bisphosphate due to its specific structural arrangement.