Amino acids and energy production

I wasn’t sure where to put this. It is general background information about metabolism, but since it is directly relevant to energy production in PWME and hence fatigue, I put it here.

Recently I needed to refresh my memory about how some amino acids are broken down for energy.

I thought I would make a summary of this since several recent studies have shown that defects in other energy production pathways mean that PWME may increasingly rely on amino acids as an energy source - see for example the Fluge and Mella and Armstrong studies.

So for people who like to know how things work, the summary shows the different places that amino acids feed in to energy pathways and explains why different amino acids have different metabolic effects.

First a few basic concepts.

Normally around 10% of our energy comes from breakdown of amino acids. The vast majority comes from breakdown of glucose (derived from carbohydrates) and fatty acids (derived predominantly from triglycerides).

At the heart of energy production is the Kreb’s cycle, AKA the Citric acid cycle (CAC), AKA as the Tricarboxyllic acid (TCA) cycle (citrate is a tricarboxylic acid, ie it contains three carboxyl groups - COOH).

Glucose and fatty acids are broken down to feed into the cycle at a single (different) entry point while amino acids are broken down to substances with multiple entry points.

This diagram from Wikipedia shows the multiple points for amino acid feed-in.



Note that glucose feeds in at pyruvate, after undergoing a multi-step process known as glycolysis.

Fatty acids feed in at acetylCoA after undergoing a multi-step process known as beta oxidation.

Note also that two related pathways are illustrated which help to explain the different metabolic effects of some amino acids.

These additional pathways are gluconeogenesis and ketogenesis.

Gluconeogenesis, as the name implies, is the synthesis of glucose from non-carbohydrate carbon sources. In the diagram it is shown by the arrow from pyruvate to oxaloacetate and then to phosphoenolpyruvate. From this point, the glucose synthetic pathway is glycolysis in reverse.

This is an energy expensive pathway that is invoked when glucose supplies, which are absolutely required by certain cell types, become limiting (such as during starvation, fasting, vigorous exercise or low carbohydrate intake).

The initiating enzyme is pyruvate carboxylase, which converts pyruvate to oxaloacetate.

There are additional substrates for gluconeogenesis which are not shown in the diagram. These include:-
i) lactate and alanine which are sent from exercising muscles to the liver for conversion to pyruvate and then to glucose (look up the Cori cycle and glucose-alanine cycle to understand this better) ;

ii) glutamine which in the kidney and small intestine is converted to alpha ketoglutarate and hence via the Kreb’s cycle to oxaloacetate and eventually glucose

iii) the glycerol backbone of triglycerides, which in the liver feeds into the reverse glycolysis pathway.

Ketogenesis, as the name implies, is the production of ketones from fatty acids and some amino acids. The starting point is acetylCoA which is converted in the liver to acetoacetate and then the other ketone bodies, viz beta hydroxybutyrate and acetone. It is shown in the diagram as a reversible loop from acetylCoA.

Ketogenesis is invoked when cellular conditions limit the production of Kreb’s cycle intermediates such as oxaloacetate and acetylCoA accumulates. Unavailability of glucose is the common trigger or excess breakdown of fatty acids.

The ketones can be sent from the liver to cells in need of energy; there the ketones are converted back to acetylCoA and used in the Kreb’s cycle.

So now we can see that amino acids can be categorised in three ways depending on their metabolic effects, ie whether they end up as acetylCoA and hence feed ketogenesis, or whether they end up as pyruvate or Kreb’s cycle intermediates and so feed gluconeogenesis. Some do both.

Ketogenic: Leu, Lys

Ketogenic and Glucogenic: Phe, Trp, Tyr, Ile

Glucogenic: Ala, Arg, Asp, Asn, Cys, Glu, Gln, His, Met, Pro, Ser, Val, Thr

Note that in some animals Thr is also ketogenic, but not in humans.

If you want to know more detail of the individual amino acid catabolic pathways, illustrations can be found here and here; the latter site also has a detailed discussion of gluconeogenesis, ketogenesis and the control thereof.

Fluge and Mella, in their seminal paper characterising the energy defects in ME/CFS, further subdivided the glucogenic category into those which were converted to pyruvate (their category 1) and those which replenished intermediates in the Kreb’s cycle – the anapleurotic amino acids (their category 3).

Their category 2 amino acids were those with ketogenic potential (regardless of whether they were also glucogenic).

They did this because it fitted the pattern of amino acid usage in the women with ME/CFS who they studied. Blood levels of category 2 and 3 amino acids were reduced, indicating increased usage, while category 1 amino acids were unaffected.

They concluded that this pattern of usage indicated a problem with pyruvate to acetylCoA conversion; in face of this difficulty, amino acids which didn’t feed into this step were increasingly used to compensate.

They then showed that the pyruvate dehydrogenase complex (PDH), which catalyses the pyruvate to acetylCoA conversion, is inhibited in ME/CFS.

This was a result of upregulation of genes coding for several enzymes which inhibit PDH, viz SIRT4, members of the PDH kinase family of enzymes (PDK) and the transcription factor PPRD.

What is driving this upregulation is not yet known.

One small practical spin-off of these studies is that it might be worthwhile considering supplementation of some or all of the amino acids which are not broken down to pyruvate as a means of boosting energy production.

There was some discussion of this strategy in another place with mixed success reported.

I have tried it, also with mixed success. It definitely helps with energy but you may need to experiment with the amino acid mixture. I became a little depressed if I continued too long with an essential amino acid mixture. Pulsing is better.

I interpreted this to mean some interference with neurotransmitter balance. This in turn might reflect too much leucine interfering with uptake of neurotransmitter precursors such as phenylalanine and tyrosine, since they used the same transporter (the large, neutral amino acid transporter).

ETA Tryptophan, another important neurotransmitter precursor, uses this transporter also.

 

I tried whey protein and it provides a shot of energy and reduces PEM duration and severity. Pricey but effective.
When i say shot i don't mean normal person functioning but better then average for me

 

Thanks for starting this thread. I’m afraid I find the detailed science almost impossible to follow but I am trying!

I tried whey too and it really did seem to increase my energy. I found it made me feel unwell in other ways though and wondered if it was all the extra crap in the product I was taking- I eventually found a product that was just organic whey and nothing else. It still made me feel unwell with awful digestion problems, and a marked increase in joint pains and migraines (can’t be certain the last two were down to whey as I get random spikes in these anyway).

My stomach upset on whey was so bad I cut out dairy altogether and I now take a vegan protein powder that I mix myself as it’s cheaper. I’m currently taking a mix of pea, soya isolate, sunflower seed and coconut. I whizz it up with a banana, courgette and spinach. It’s delicious!!

I’ve noticed that I tend to feel more energetic if I have my protein smoothie in the morning with a coffee and then wait as long as possible before eating anything else, anything between 2 and 5 hours. I don’t know if there’s any science to this- I did it originally as I’m trying to lose weight but noticed I felt better.

I am just about to try incorporating another smoothie later in the day as I was doing this with the whey. Might start another thread on protein shakes but may not manage so if anybody else is interested please go for it?

 

@alicec,

thanks for starting this thread. your writing is clear and concise. I have been experimenting with taking amino acids and lately taking branch chain amino acids (bcaa). when I consume bcaa's in water, bit later like maybe 10 minutes, I feel a tingling sensation especially on my cheeks and extremities. nothing disturbing or long lasting ....I just have noticed it. So do you guess that some neuropathic pathways are getting activated?

you have any comments on branch chain amino acids versus a general amino acid mixture?

 

It's been 20 years since I read some stuff on neurotransmitters.From what I remember the proportion of branched chain amino acids to aromatic amino acids might affect the rate at which tryptophan or tyrosine enters the brain.The synthesis of serotonin seems to be proportional to tryptophan availability(carbohydrates also seem to favour tryptophan entering the brain I don't remember how-in addition to the previously mentioned ration of BCAA with aromatic ring amino acids tryptophan bound to albumin which has a bigger affinity for the blood brain barrier seem to determine tryptophan availability).According to the articles I had read then serotonin is more likely to cause sleepiness than happiness.
It's important to mention that excess tyrosine instead of increasing dopamine synthesis results in the synthesis of octopamine which is a false neurotransmitter which replaces noradrenaline while it has a fraction of its effectiveness.
Don't ask me to explain any of the above,it's surprising that I remember what I remember.The studies into the rate of synthesis of neurotransmitters and the availability of precursor amino acids date from the 70s.I don't know if there has been any new research into this topic.If any amino acids make you feel worse there is probably an explanation.

 

Do you know if there are foods that would be good sources of these amino acids?

 

Sorry I somehow missed this post.

Maybe but I would be just guessing about what this means.

All three - leu, ile and val - feed in independently of pyruvate so should theoretically be helpful.

All three would compete for uptake into the brain with the aromatic amino acid precursors to neurotransmitters but whether this is a good or bad thing might depend on other things.

In this study looking at just this question, athletes given BCAAs had improved mood. This was thought to be a result of depletion of BCAAs (as a result of activity) leading to increased trp entering the brain, increased serotonin synthesis leading to central fatigue. Repletion of the BCAAs was stimulatory and beneficial.

I imagine that response is very much an individual thing. So if the BCAAs help with energy and don't adversely affect mood, keep going!

I'm a bit inclined to mood disturbance so was a bit worried about BCAAs alone. I can't tolerate whey so thought I'd try an essential amino acid mix which contains phe and trp in addition to BCAAs (and a few others). I got a bit depressed if I took the mixture too long.

It could be of course that I didn't need any more phe and trp and was now getting too much. I have intended to try BCAAs alone but haven't done it yet.

It is worth experimenting with amino acid/protein sources to see if energy can be boosted. Which one is best will be very individual I think.

 

Yes it does. See the link in my post above.

 

With proteinaceous foods you'd be getting a mixture, some of the ones you wanted, some that you didn't. You could maybe look for an analysis of proteins which are rich in the amino acids you want - I don't have any particular information on this.

 

If phe is phenylalanine that amino acid too might be a precursor in the synthesis of dopamine.I don't think studies into phenylanine as a precursor were done because the team from MIT which did the studies with tyrosine and the synthesis of dopamine seemed to have a preference for tyrosine because it is an one step reaction while phenylalanine is a two step reaction.(I am quoting from memory,I am not a chemist).I think that it might have been interesting to do the same experiments with phenylalanine as well eg supplying different amounts of the amino acid to the experimental animals and then measuring the amounts of neurotransmitter produced each time.
Interestingly tyrosine did not result in an increase on the production of dopamine and the researchers repeated the experiment exposing the animals to cold and imposed immobility in order to get an increase in the synthesis of dopamine(those conditions result in the increase of the rate of synthesis).I even remember the phrase''in normal circumstances the enzyme tyrosine hydroxylase is saturated by its substrate''.That's why an excess in the supply of tyrosine can result in the synthesis of octopamine a false neurotransmitter since the excess tyrosine that can not be used by tyrosine hydroxylase, ends up being used by another enzyme in another biosynthetic pathway.

 

Not might, it is. The pathway goes phe>tyr>dopa>dopamine>noradrenaline>adrenaline.

Perhaps the studies you referred to concentrated on the tyr>dopa step because this is the rate-limiting step in the pathway.

 

In the experiments that I read tyrosine was given to guinea pigs not phenylalanine.It was a team from MIT Wurtman was the one name I remember.I found out about phenylalanine being in the same pathway from a japanese paper but I don't remember exactly what it was about.
Do you get the same effect if you take tyrosine compared to taking phenylalanine?

 

I've never taken either in isolation so couldn't comment.

 

By lots of experiments with foods of differing ratios of amino acids. Wheat, for example, is unusually high in proline. Foods that had a high ratio of another amino acid compared to proline didn't bother me, which allowed me to eliminate some candidates. As an extra check, I tried consuming the same amount of proline from different foods, and experienced the same severity of symptoms from all of them. No one offers proline as an inexpensive pure supplement, so I couldn't test it that way, and I didn't see any need to buy lab-grade proline when that extra verification wouldn't change anything.

I went through the same process to identify a sensitivity to what I believe was palmitic acid some years ago. I solved that with supplemental carnitine, but the problem went away before I could get a reasonably pure source of palm oil.

As another unusual response to a single nutrient, cis-linoleic acid reduces the number of times I wake fully during the night. Conjugated linoleic acids (from ruminant meats and dairy) have the same effect, but they contain the cis isomer too, so I think that's why they work the same.

I only had one unusual response to a mineral: iodine. It had a beneficial effect, and since T2 (3-5 diiodothyronine) had exactly the same effect, I expect the iodine boosted production of T2, which was responsible for the improvement. I needed one small dose every 21 days. More didn't help, but if I missed that dose, I felt worse on day 22.

Human are a whole bunch of responses to individual molecules.

 

I cannot think of any possible mechanism for becoming sensitive to proline. The immune system would not respond to it. I don't think any receptors are going to respond to it abnormally. It is an interesting concept but I find it hard to believe it could be validated.

 

It seems that proline is a weak glutamate receptor agonist but I don't see how this would change to produce an acquired intolerance.

 

Amino acids have featured in ME/CFS e.g. Chris Armstrong did some MRI work and found some depleted (he suggested these were consumed for energy i.e. even though glucose was high) and some elevated (suggesting they weren't used). Fluge and Mella followed that up around 2016 by suggesting that PDH was not working; therefore, amino acids entering the citric acid cycle reliant on PHD weren't used and amino acids not relient on PDH were consumed.

Then there's the whole thing of intracellular levels --- e.g. tryptophan bistability ---- roll on the GWAS (Chris Ponting's) study ---- might give some clues and throw out some suggestions.

 

Some weird stuff re amino acids* when diet is low the body increases consumption of them - suppose that links to ME/CFS as starvation but can't see how relates to proline reduction/sensitivity
*https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0093597