About the definition of ketogenic amino acid

Question

I am studying biochemistry and have been looking at metabolic network diagrams showing the different intermediates of glycolysis and the citric acid cycle that amino acids can be converted to. I have gone over a list of which amino acids are considered ketogenic and which are considered glucogenic. I was surprised that Serine, Glycine, Cysteine, and Alanine are not considered ketogenic as they can be converted to pyruvate and pyruvate can be turned to acetyl-CoA, so that these 4 amino acids seem like they can then be used for ketogenesis. I then looked at the definition of ketogenic amino acids on Wikipedia and it says "A ketogenic amino acid is an amino acid that can be degraded directly into acetyl-CoA".

The question is if there's some reason this is the definition of ketogenic amino acids; it seems to make more sense to me to classify Serine, Glycine, Cysteine, and Alanine as ketogenic due to what I said.

Thank you.

Answer 1

The fundamental 'problem' with acetyl-CoA is that it cannot be converted to glucose via the tricarboxylic acid (TCA) cycle: a two-carbon compound (acetyl-CoA) enters the TCA cycle, but two carbons are lost as CO$_2$ during each round of the cycle (in the two decarboxylation steps, ie in the reactions catalyzed by isocitrate dehydrogenase and by the alpha-ketoglutarate dehydrogenase complex).

There is no 'net gain' of carbon when acetyl-CoA is 'burned' in the TCA cycle.

This is why animals cannot convert even-number fatty acids (even-chain fatty acids) to glucose, and a basic principle of animal nutrition is that triglycerides, with the exception of the glycerol backbone, cannot be converted to glucose.

This, is seems to me, is also the key to understanding the difference between 'ketogenic' and 'glucogenic' amino acids.

Amino acids that directly give rise to acetyl-CoA (or acetoacetyl-CoA) cannot be converted to glucose but that can be converted to ketone bodies (such as D-3-hydroxybutyrate) are referred to as ketogenic amino acids.

Pyruvate can be converted to glucose (via glucneogenesis), and amino acids that may be converted to pyruvate are considered glucogenic. A very good example is alanine which may be converted to pyruvate simply by transamination (alanine aminotransferase).

Alanine is a key protein-derived glucose precursor, especially in times of starvation (Felig, 1975). A commentary on the discovery of this key finding is given in this citation classic

In addition, amino acids that may be converted to TCA intermediates that in turn may be converted to phosphoenolpyruvate (and are thus precursors of glucose) are considered glucogenic (Lehninger, Biochemistry, 2nd Ed, 1975, p629).

We need to be aware that propionate (a three-carbon compound) is glucogenic (and this is particularly important in ruminants): it is even-chain fatty acids (and their CoA derivatives) that are non-glucogenic.

Furthermore, an amino acid may be both ketogenic and glucogenic.

1. Only leucine and lysine (LK) are exclusively ketogenic
2. Tryptophan, Isoleucine, Phenylalanine, and Tyrosine (WIFY) are both glucogenic and ketogenic
3. The other 14 'protein' amino acids are glucogenic

See D'Mello (2003) for a great ref (it must be good, he's from Scotland).

The catabolism of the branched-chain amino acids (Ile, Leu, Val) provide an example of each type (Harper et al., 1984):

• The catabolism of isoleucine gives rise propionyl-CoA and acetyl-CoA and is both glucogenic and ketogenic.
• Leucine catabolism yields acetoacetate and acetyl-CoA (ketogenic)
• Valine catabolism yields succinyl-CoA (glucogenic)

A quote from Metzler (2001) may help to clarify the origin of the terms.

According to a long-used classification amino acids are ketogenic if (like leucine) they are converted to acetyl-CoA (or acetyl-CoA and acetoacetate).

When fed to a starved animal, ketogenic amino acids cause an increased concentration of acetoacetate and other ketone bodies in the blood and urine.

On the other hand, glucogenic amino acids such as valine, when fed to a starved animal, promote the synthesis of glycogen

... isoleucine is both ketogenic and glucogenic, a fact that was known long before the pathway of metabolism was worked out.

Thus, in feeding experiments, a glucogenic amino acid gives rise 
to the synthesis of glycogen, whereas a ketogenic amino acid does not
(but does give rise to an increase in the concentration of ketone bodies)`

We may note that plants can circumvent 'the acetyl-CoA problem' as they have the enzymes of the glyoxylate cycle, where the two decarboxylation steps of the TCA cycle are 'bypassed' (the key enzymes are malate synthase and isocitrate lyase) [and plants can convert acetyl-CoA to glucose].

It is also of interest, maybe, that both arginine and taurine (not one of the 20, of course) are essential in cats (see D'Mello, 2003). Arginine is required because of an inability to synthesis ornithine and a single Arg-free meal may cause a cat to become comatose due to the build-up of NH$_3$ (see D'Mello, 2003; Bequette, 2003) , and taurine is required to prevent retinal degeneration (see D'Mello, 2003; Bequette,2003). In addition, cats need high levels of Phe/Tyr for melanin biosynthesis, otherwise hair color may change from black to red-brown (see Bequette, 2003)

Reference

Some key references given above are from the following book:

Amino Acids in Animal Nutrition (2003) Edited by J.P.F. Mello, CABI Publishing, 2nd Edition

1. D'Mello, J.P.F (2003) Amino Acids as Multifunctional Molecules by J.P.F. D'Mello (Chapter 1)
2. List Bequette, B.J. (2003) Amino Acid Metabolism in Animals:an Overview (Chapter 4)

In Addition (Taurine in Cats)

1. Carnivores Herbivores and Omnivores in Blondes in Venetian Paintings, the Nine-Banded Armadillo, and Other Essays in Biochemistry by Konrad Bloch

Answer 2

“The question is if there’s some reason this is the definition of ketogenic amino acids”

The answer from @user1136 covers the biochemistry of the degradation of ketogenic and glucogenic amino acids. However it doesn’t answer this part of the question directly, which is what I shall use my answer to add. Just as we may classify amino acids as hydrophobic or hydrophilic if we are interested in their function in proteins, this classification as related to a particular context. At least in part, this is:

The provision of glucose, especially for the brain, during starvation and pathological states such as diabetes

Whether or not so-called glucogenic amino acids could in principle be converted to acetyl CoA, the regulatory mechanisms controlling the pathways ensure that it will be converted to glucose via gluconeogenesis — which is the raison d’être for the breakdown of amino acids during starvation.

Although certain tissues can use other fuels instead of glucose, the brain and the erythrocytes have an absolute requirement for glucose. In the case of the erythrocyte the product of glucose oxidation, lactic acid, can be recycled via the liver. However this is not the case for nervous tissue. So an alternative classification might be glucogenic or non-glucogenic. However the fact that the ketone bodies produced by non-glucogenic amino acids have important positive and negative functions themselves (alternative fuel, but can cause acidosis) presumably led to the use of the term, ketogenic.

Footnote: Context and Experimental Evidence

The experimental evidence for the breakdown products of individual amino acids came from feeding experiments, so that it might be argued that the context of starvation I assert is incorrect, especially given the contemporary fad for ketogenic diets and the like. However as regards evolutionary and clinical importance, I would argue that starvation is what matters.

Further reading

There is more information about gluconeogenesis in starvation in my answer to this SE Question.

There is a useful answer by @Don_S to another SE question concerning the use of glucose and ketone bodies by the brain.

Section 30.3 of Berg et al. 5e (unfortunately no longer available on NCBI Bookshelf) deals with amino acid breakdown and the use of glucose or ketone bodies during starvation.