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In glycolysis, glucose is converted to glucose 6-phosphate so it can not diffuse out of the membrane. Then it is converted to fructose 6-phosphate.
Why is this? Perhaps it makes it less stable so it is easier to break down into pyruvate?
That is just a guess, is anyone able to provide more information about this?
Avoiding diffusion is one reason to phosphorylate glucose, the other is that it is removed from the osmotic balance between inside and outside of the membrane, so it can be transported at a high rate.
The Glucose-6-phosphate can then be used as a substrate for different pathways, namely glycolysis and the pentose phosphate way, and (depending on the organism) also be converted into glycogen and starch for further storage.
The reason for the phosphorylation lies further downstream in glycolysis: The isomerization by the glucose phosphate isomerase and the subsequent second phosphorylation into Fructose-1,6-biphosphate make the conversion and dedication of the molecule into the glycolysis irreversible.
Fructose-1,6-biphosphate is then cleaved by the aldolase into two C3-units: Dihydroxyacetone phosphate (DHAP) and Glyceraldehyde 3-phosphate (GA-3-P). GA-3-P is converted into DHAP, so that downstream only one metabolite needs to be processed.
If there is no glucose there is no need for glycolysis: I deduce from this truism that – at some early stage in the evolution of metabolism – a pathway resembling gluconeogenesis must have arisen before glycolysis. This is just another way of stating the obvious fact that autotrophy must have preceded heterotrophy.
If the aldolase reaction for triose → hexose evolved around glyceraldehyde 3-phosphate/dihydroxyacetone phosphate then perhaps the involvement of fructose 1,6-bisphosphate was dictated by the underlying chemistry of the aldolase condensation, and the steps to glucose followed from there. Note that the main carbon fixation pathway in photoautotrophs does indeed use this process: carbon fixation by RuBisCO generates 3-phosphoglycerate and the subsequent action of triosephosphate isomerase and aldolase generates fructose 1,6-bisphosphate.
So, my main point is that seeking the underlying design principles in the glycolytic pathway may be futile: glycolysis represents the catabolic use of a sequence of reactions that originally evolved for the purpose of anabolism.
Disclaimer: I have probably read this idea somewhere but I have no recollection of where. If anyone can point to an authoritative version of this please do so.
Clarifying the question
The pathway of glycolysis starts a hexose (glucose), but at a certain point — the aldolase reaction — two molecules of a triose are generated, then interconverted to the same triose, after which the pathway continues to pyruvate, generating net ATP. These triose molecules each carry a phosphate, which, as the poster mentions, prevents them diffusing through the cell membrane, so the hexose precursor needs to carry two phosphates. Thus the question “why is fructose formed?” can be restated as:
“Why is the hexose precursor of the two triose phosphates fructose 1,6-bis phosphate, and not simply glucose 1,6-bis phosphate?”
Short Answer
The chemical structure of glucose is not suitable to form a bis-phosphate compound that can yield interconvertable triose phosphates in the biochemical reactions the cell employs.
Fuller Answer with Chemical Details
First consider the linear and cyclized structures of relevant phosphate derivatives of glucose and fructose:
Glucose 1,6-bis phosphate may be unfamiliar: it is found in cells in low amounts and may have some regulatory function. Inspection shows that, because the aldehydic group is at the 1-position of glucose, a phosphate can only be added at that position after cyclization generates an alcohol there. Once glucose 1,6-bis phosphate has been formed it cannot convert to a straight-chain structure, unlike fructose 1,6-bis phosphate where the ketonic group is in the 2-position. (Hence none is shown.) This is the key point.
Now let us turn to the triose–hexose interconversion, which is necessary for both glycolysis and gluconeogenesis, which ever originated first. This has two requirements:
Requirement 1 is satisfied most easily in biological systems by an aldol condensation such as the aldolase reaction (also found in the Calvin cycle) in which the nucleophilic carbon of an enolate attacks the carbon of an aldehyde.
Requirement 2 can be satisfied by the isomerization of an aldehyde (like glyceraldehyde 3-phosphate) to a ketone (like dihydroxyacetone phosphate).
The fact that a ketone like dihydroxyacetone phosphate has the potential to form an enolate (shown above) explains the particular suitability of these trioses in relation to the aldose reaction:
[Taken from Chemistry Libre Texts.]
The initial product of this reaction is, of necessity, a linear hexose 1,6 bis-phosphate — with the fructose as the hexose as its carbonyl is at C2. After the fructose 1,6-bis phosphate has lost the phosphate at the C1 position it can isomerize to glucose 6-phosphate (with the C1 position free to form an aldehyde) in a similar manner to the triose phosphate isomerization.
So it is not just the symmetry of fructose (noted by the poster in a comment) that is important — but the structure of glucose itself. Glucose 1,6-bis phosphate is not, of course, the only sugar that can become ‘locked’ in its cyclic form. For example, the deoxy-ribose rings in the backbone of DNA cannot linearize because the bases are attached to the C1ʹ where the aldehydic group was originally.
