The process of gluconeogenesis starts from various possible precursors - plausible entry points like, Pyruvate, OAA, Fumarate, Propionate (as succinate) and alpha-KG. It is important to note that, acetyl-coA is not an entry point for Gluconeogenesis.
Entry points shown as blue circles.
The most common reason cited for this is the irreversibility of the enzyme, pyruvate dehydrogenase. Since it is irreversible, Acetyl coA can't get back to pyruvate to go on forming glucose.
But, Acetyl CoA naturally enters the Krebs cycle, so why can't it go ahead and form glucose via gluconeogenesis using one of the Krebs intermediates?
I have had this doubt for very long and tried to come up with an explanation to satisfy myself but I still don't know if it is valid.
So here it goes. All the entry points to gluconeogenesis (mentioned before) are an addition to the Krebs cycle. They get on the boat, sail along, get off at oxaloacetate and leave. They don't bother the boat in any other way. Even Pyruvate, forms oxaloacetate via pyruvate carboxylase and then gets on the boat for gluconeogenesis.
On the other hand, Acetyl coA would be a part of the Krebs cycle itself. It is not adding anything to it (2 carbons that are added are lost as CO2). So an Acetyl CoA added, can't leave as OAA. It would be analogous not sailing on the boat but eating it down itself. Slowly, it would lead to a decay and loss of the intermediates Krebs cycle and it would come to a standstill (?)
Is this explanation right? Are there any other ways to explain why irreversibility of PDH results in this?
Although acetyl-coA can enter gluconeogenesis via pathways like glyoxylate cycle (not in humans) and pathways to make pyruvate from acetone (not economical) to form glucose, the question is why it can not do so directly via the Krebs cycle.
Image: Harper's Biochemistry, 29th Edition.