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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. enter image description here

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.

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    $\begingroup$ Well, I'm not sure I'm reading you're boat analogy right, but it sounds like you're on the right track. The problem is that acetyl-CoA enters the TCA cycle by condensing with oxaloacetate in the citrate synthase reaction. Therefore, you need 1 oxaloacetate for each acetyl-CoA added. Now, if the citrate formed goes on to oxaloacetate which is then removed for gluconeogenesis, there is no oxalocatete left for the next citrate synthase reaction. The reactions do not balance. Therefore, an anaplerotic substrate like glutamine or asparate is needed to replenish the lost oxaloacetate. $\endgroup$ – Roland Sep 27 '16 at 22:23
  • $\begingroup$ @Roland — Please follow the instructions that come up in the comment box and refrain from answering questions in comments. $\endgroup$ – David Sep 28 '16 at 7:33
  • $\begingroup$ @Roland Thanks! Why don't you post it as an answer so that I can mark it answered? $\endgroup$ – Polisetty Sep 28 '16 at 21:25
  • $\begingroup$ Sorry, haven't had time for Biology SE for a while. My comment is now posted as an answer. $\endgroup$ – Roland Oct 21 '16 at 9:01
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The problem is that acetyl-CoA enters the TCA cycle by condensing with oxaloacetate in the citrate synthase reaction. Therefore, you need 1 oxaloacetate for each acetyl-CoA added. Now, if the citrate formed goes on to oxaloacetate which is then removed for gluconeogenesis, there is no oxalocatete left for the next citrate synthase reaction. The reactions do not balance. Therefore, an anaplerotic substrate like glutamine or asparate is needed to replenish the lost oxaloacetate.

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    $\begingroup$ Maybe it's also useful to note that organisms that have the glyoxylate shunt can bypass the decarboxylation steps in the TCA cycle, and in fact can use 2-carbon substrates like acetate (that enter through acetyl-CoA) for gluconegenesis and growth. (en.wikipedia.org/wiki/Glyoxylate_cycle) $\endgroup$ – Victor Chubukov Oct 21 '16 at 18:07
  • $\begingroup$ Yes, but I think the OP is already aware of this; see the last paragraph of the question. $\endgroup$ – Roland Oct 21 '16 at 19:44
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There is also this paper that shows alternative pathways in silico that could be used to convert FAs to glucose, but at a high energetic cost to the human host. https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1002116

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    $\begingroup$ Hi and welcome to Bio.SE! Thanks for providing this answer with citation! Could you also provide a quick summary or quote from the relvant part(s) of the paper in case your link goes "dead" one day? Also, providing the actual citation further helps your post to be helpful in the future even if the link goes dead. Thanks a lot! $\endgroup$ – theforestecologist Mar 4 at 21:22

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