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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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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, 2016 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, 2016 at 19:44
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The main point is specified above - that Krebs is a cycle. It starts with a 4-carbon molecule (oxaloacetate), adds 2 carbons (acetyl from acetyl Co-A) to make a 6-carbon (citrate) and burns off 2 carbos as CO2 in a set of steps until it gets back to the 4-carbon starting point (oxaloacetate) to add another Acetyl.

If you siphon off any of the components of that cycle there's no feed to the next step and the cycle stops.

the second point is that Krebs cycle enzymes are inside mitochondria, and gluconeogenesis enzymes are outside in the cytosol. It is within Mitochondria that Acetyl is snipped off fatty acid chains (i.e. 2 carbons at a time) and linked to CoA and enters Krebs.

As a general point, most molecules cannot exit (or enter) mitochondria without a specific protein that will carry that specific molecule across the membrane, so there has to be a specific gene for that function.

So any specific molecules in Krebs have to have a gene to exit the (two) mitochondrial membranes. Humans don't have genes for that.

(NB - you can generate a small amount of glucose from fat from (a) the 3-carbon Glycerol that joins 3 fatty acids together and (b) the few odd-number fatty acid chains that will leave a 3-carbon molecule after a load of 2-carbons are snipped off)

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    $\begingroup$ Welcome to Biology.SE! This looks like a good answer, but answers are much more likely to receive a favorable response if you cite supporting references (primary literature is best). This allows non-experts to verify your answer and provides a starting point for further learning. A good example of how to format references. (NB: Standards have increased from when the accepted answer was posted.) ——— You may also want to take the tour and then consult the help center pages for additional advice on How to Answer effectively on this site. Thank you! $\endgroup$
    – tyersome
    Jan 6, 2022 at 22:16
  • $\begingroup$ (+1) As I understand things, the basic problem is that for each acetyl-CoA (a two-carbon compound) entering the TCA cycle, two carbons are lost as CO2 for each round of the cycle. Thus there can be no net synthesis of any carbon compound from acetyl-CoA via the TCA cycle. This is not true of the glyoxylate bypass where the CO2-losing steps are effectively bypassed, and this pathway is often a prerequisite for growth on acetate as sole carbon source (This is what so impressed Hans Kornberg). $\endgroup$
    – user338907
    Jan 6, 2022 at 23:01
  • $\begingroup$ See Tricarboxylic Acid Cycle and Glyoxylate Bypass, for example. Plants (and bacteria) can make glucose from acetyl-CoA if they have the enzymes of the glyoxylate pathway. More can be found in Kornberg's papers (Hans Kornberg, that is) on the glyoxylate cycle. $\endgroup$
    – user338907
    Jan 6, 2022 at 23:05
  • $\begingroup$ Please do not refer to the Krebs Tricarboxylic Acid Cycle as "Krebs". This is not standard practice (I have never heard it before) and appears disrespectful to the memory of Hans Krebs (although I imagine that was unintended). "The Krebs Cycle" is acceptable, although people use the name "Tricarboxylic Acid Cycle" or "Citric Acid Cycle" because Krebs was also responsible for elucidating another metabolic cycle — "The Urea Cycle". $\endgroup$
    – David
    Jan 6, 2022 at 23:30
  • $\begingroup$ Your emphasis on loss of C2 via carbon dioxide is a useful clarification/extension of the accepted answer. However, your remarks about mitochondria are incorrect. Oxaloacetate (OAA) is a constituent of the TCA cycle and is normally produced from fumarate in the mitochondrion. In "normal" oxidative metabolism it condenses with Acetyl CoA to complete the cycle. However if there is direct or indirect input of OAA from amino acids it can act as a gluconeogenic precursor through conversion to PEP by PEP carboxykinase. To do this it is exported to the cytoplasm as malate via a malate transporter. $\endgroup$
    – David
    Jan 7, 2022 at 11:33

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