Why can't fat be converted into Glucose?

[manohman]

So the reason cited is that beta oxidation/metabolism of fats leads to formation of acetyl coa, a 2 carbon molecule, and that because of that it cannot be converted back into glucose.

Why exactly is that the case?

If Glucogenic amino acids can be converted into citric acid cycle intermediates and then turn back into glucose via gluconeogensis, then why cant Fatty Acids which yield Acetyl Coa. Can't you just have Acetyl Coa enter the citric acid cycle and produce the same intermediates that the glucogenic amino acids creat?

---

Members don't see this ad.

 

[Czarcasm]

So the reason cited is that beta oxidation/metabolism of fats leads to formation of acetyl coa, a 2 carbon molecule, and that because of that it cannot be converted back into glucose.

Why exactly is that the case?

If Glucogenic amino acids can be converted into citric acid cycle intermediates and then turn back into glucose via gluconeogensis, then why cant Fatty Acids which yield Acetyl Coa. Can't you just have Acetyl Coa enter the citric acid cycle and produce the same intermediates that the glucogenic amino acids creat?

Both glucose and fatty acids can be stored in the body as either glycogen for glucose (stored mainly in the liver or skeletal cells) or for FA's, as triacylglycerides (stored in adipose cells). We cannot store excess protein. It's either used to make other proteins, or flushed out of the body if in excess; that's generally the case but we try to make use of some of that energy instead of throwing it all away.

When a person is deprived of nutrition for a period of time and glycogen stores are depleted, the body will immediately seek out alternative energy sources. Fats (stored for use) are the first priority over protein (which requires the breakdown of tissues such as muscle). We can mobilize these FA's to the liver and convert them to Acetyl-CoA to be used in the TCA cycle and generate much needed energy. On the contrary, when a person eats in excess (a fatty meal high in protein), it's more efficient to store fatty acids as TAG's over glycogen simply because glycogen is extremely hydrophilic and attracts excess water weight; fatty acids are largely stored anhydrously and so you essentially get more bang for your buck. This is evolutionary significant and why birds are able to stay light weight but fly for periods at a time, or why bears are able to hibernate for months at a time. Proteins on the other hand may be used anabolically to build up active tissues (such as when your working out those muscles), unless you live a sedentary lifestyle (less anabolism and therefore, less use of the proteins). As part of the excretion process, protein must be broken down to urea to avoid toxic ammonia and in doing so, the Liver can extract some of that usable energy for storage as glycogen.

Also, it is worth noting that it is indeed possible to convert FA's to glucose but the pathway can be a little complex and so in terms of energy storage, is not very efficient. The process involves converting Acetyl-CoA to Acetone (transported out of mitochondria to cytosol) where it's converted to Pyruvate which can then be used in the Gluconeogenesis pathway to make Glucose and eventually stored as Glycogen. Have a look for yourself if your interested: http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002116.g003/originalimage (and this excludes the whole glycogenesis pathway, which hasn't even begun yet).

TLDR: it's because proteins have no ability to be stored in the body, but we can convert them to glycogen for storage during the breakdown process for excretion. Also, in terms of energy, it's a more efficient process than converting FA's to glycogen for storage.

 

[soccerman93]

This is where biochem comes in handy. Czarcasm gives a really good in depth answer, but a simpler approach is to count carbons. The first step of gluconeogenesis(formation of glucose) requires pyruvate, a 3 carbon molecule. Acetyl Co-A is a 2 carbon molecule, and most animals lack the enzymes (malate synthase and isocitrate lyase) required to convert acetyl co-A into a 3 carbon molecule suitable for the gluconeogenesis pathway. The ketogenic pathway is not efficient, as czarcasm pointed out. While acetyl co-A can indeed be used to form citric acid intermediates, these intermediates will be used in forming ATP, not glucose. Fatty acid oxidation does not yield suitable amounts of pyruvate, which is required for gluconeogenesis. This is part of why losing weight is fairly difficult for those that are overweight, we can't efficiently directly convert fat to glucose, which we need a fairly constant supply of. Sorry, that got a little long-winded

 

[Nsvlb]

The end product of glycolysis (opposite of gluconeogenesis) is pyruvate (a three carbon molecule). Pyruvate then gets converted into Acetyl-CoA (a two carbon molecule) by an enzyme called pyruvatedehydrogenase after which it can enter the krebb's cycle.
The problem is that there is no enzyme which does the opposite of pyruvatedehydrogenase, i.e. there's no enzyme which can convert Acetyl-CoA into pyruvate. And since pyruvate is the substrate of gluconeogenesis, Acetyl-CoA could never participate in it.

This is also the reason why amino acids which get broken down to acetyl-CoA or acetoacetyl-CoA are called ketogenic and those which are broken down to alpha-ketoglutarate, succinyl-CoA, fumarate, oxaloacetate or pyruvate are called glucogenic.

 

[Gurby]

Never say never. It is possible, we humans are just lacking a few key enzymes. Other organisms can do it: https://en.wikipedia.org/wiki/Glyoxylate_cycle

 

[betterfuture]

Though odd # fatty acids have the ability to be converted to glucose in humans, right? But generally, there is no enzyme that converts acetylCoA into pyruvate in humans, but I guess its complex and less efficient.

 

[aldol16]

Though odd # fatty acids have the ability to be converted to glucose in humans, right? But generally, there is no enzyme that converts acetylCoA into pyruvate in humans, but I guess its complex and less efficient.

They do, but it's not the acetyl-CoA monomers that are converted to glucose. It's the odd-numbered carbon unit left over that's converted to glucose, namely propionyl-CoA. You carboxylate it into succinyl-CoA and then you're in business.

 

[Domek]

Sorry for reviving this one but I had a similar question today, and I wanted to add on to these answers in case anyone else checks this thread for the same reason...

Simply put, amino acids that are glucogenic enter the TCA cycle at the a-ketoglutarate step and leave as oxaloacetate. In other words, it's actually oxaloacetate that's being used as a substrate for gluconeogenesis.

Why is it impossible to do this with acetyl-CoA? Because in order to enter the TCA cycle in the first place, acetyl CoA must combine with oxaloacetate. So, by the time you generate your oxaloacetate from acetyl-CoA, you've consumed an oxaloacetate in the process. Using acetyl-CoA as a substrate for gluconeogenesis is inefficient because all you've done is spin the TCA cycle for no reason. You're not getting any new substrates out of it.

This answer seemed more intuitive to me so I thought it might help someone out.

 

[desperadoflakes]

Sorry for reviving this one but I had a similar question today, and I wanted to add on to these answers in case anyone else checks this thread for the same reason...

Simply put, amino acids that are glucogenic enter the TCA cycle at the a-ketoglutarate step and leave as oxaloacetate. In other words, it's actually oxaloacetate that's being used as a substrate for gluconeogenesis.

Why is it impossible to do this with acetyl-CoA? Because in order to enter the TCA cycle in the first place, acetyl CoA must combine with oxaloacetate. So, by the time you generate your oxaloacetate from acetyl-CoA, you've consumed an oxaloacetate in the process. Using acetyl-CoA as a substrate for gluconeogenesis is inefficient because all you've done is spin the TCA cycle for no reason. You're not getting any new substrates out of it.

This answer seemed more intuitive to me so I thought it might help someone out.

To be sure, not all amino acids enter the citric acid cycle as a-ketoglutarate (only about 5 of them do). Different amino acids enter the TCA at different points, and some enter as pyruvate. Lysine and leucine actually can ONLY enter as Acetyl-CoA (just like fatty acid oxidation), so these two amino acids are strictly ketogenic (can only be used for fatty acid synthesis or ketogenesis). Some of the amino acids are strictly glucogenic, and some are both. The most important one to know about IMO is alanine, from which most amino acid metabolism for gluconeogenesis occurs. An important part of amino acid metabolism is transamination, mediated by a different enzyme for each amino acid. For alanine, it looks like:

Alanine + alpha-ketoglutarate --> Pyruvate + glutamate
The enzyme is alanine aminotransferase. You could think of it like the amino group on the alanine and the carbonyl on aKG switching spots.

Usually what happens next is the following reaction:
Glutamate + Oxaloacetate --> Aspartate + a-Ketoglutarate

Either glutamate or aspartate can undergo a DEamination, yielding either aKG or OAA respectively, and the urea will then shuttle towards the urea cycle.