Glutamine and Viral Infections.

[Ema]

Human fibroblasts infected with human cytomegalovirus (HCMV) were more viable than uninfected cells during glucose starvation, suggesting that an alternate carbon source was used.

We have determined that infected cells require glutamine for ATP production, whereas uninfected cells do not. This suggested that during infection, glutamine is used to fill the tricarboxylic acid (TCA) cycle (anaplerosis).

In agreement with this, levels of glutamine uptake and ammonia production increased in infected cells, as did the activities of glutaminase and glutamate dehydrogenase, the enzymes needed to convert glutamine to α-ketoglutarate to enter the TCA cycle.

Infected cells starved for glutamine beginning 24 h postinfection failed to produce infectious virions. Both ATP and viral production could be rescued in glutamine-starved cells by the TCA intermediates α-ketoglutarate, oxaloacetate, and pyruvate, confirming that in infected cells, a program allowing glutamine to be used anaplerotically is induced.

Thus, HCMV infection activates the mechanisms needed to switch the anaplerotic substrate from glucose to glutamine to accommodate the biosynthetic and energetic needs of the viral infection and to allow glucose to be used biosynthetically.

Full text here.

 

[Ema]

@Hip, have you read this paper?

 

[Hip]

Interesting stuff, Ema. The paper says about cytomegalovirus:

Infectious virions are not produced under glucose-free or glutamine-free conditions

So if you wanted to inhibit cytomegalovirus, a low glutamine diet might help. High glutamine foods include:

beef, chicken, fish, dairy products, eggs, vegetables like beans, beets, cabbage, spinach, carrots, parsley, vegetable juices and also in wheat, papaya, brussel sprouts, celery, kale and fermented foods like miso.

Source: here.

The paper says cytomegalovirus-infected cells need glutamate for viral replication, as the infected cells need to convert glutamate into alpha-ketoglutarate, which they do using two enzymes, glutaminase (GLS) and glutamate dehydrogenase (GDH), via the following pathway:

Glutamine ------(GLS)------➤ Glutamate ------(GDH)-----➤ Alpha-Ketoglutarate

The above pathway is from figure 1. Once glutamine is converted into alpha-ketoglutarate, it can enter the Krebs cycle (citric acid cycle). The paper suggests that:

Why does HCMV require such an increase in glutamine metabolism? ... HCMV does not want glucose to be metabolized for energy in the citric acid cycle but instead maintains it for synthetic purposes such as fatty acid synthesis

So any supplements or drugs which can inhibit the enzymes glutaminase or glutamate dehydrogenase might be useful in fighting cytomegalovirus infection.



It looks like epigallocatechin gallate (EGCG) from green tea inhibits glutamate dehydrogenase, and it looks like salicylate (an active metabolite of aspirin) is also an inhibitor.

CB-839 and UPGL00004 are both potent glutaminase inhibitors, but only available for research.

 

[Ema]

alpha-ketoglutarate, it can enter the Krebs cycle (citric acid cycle).

I wonder if taking AKG instead of glutamine could be helpful too. It's used in the Deanna Protocol for ALS at fairly high doses as well.

The increase in AKG enables their mitochondria to produce enough energy to keep cells alive, despite their exposure to an unhealthy amount of extracellular glutamate. AKG usually does not pass through the cell membranes in normal healthy cells. Based on our experience, we found that the permeability of the cell membrane in diseased or damaged cells changes and allows AKG to permeate the cells. Due to the fact that AKG only enters diseased cells, the substance only goes where it is needed.

I'm conflicted though because Dominic D'Agostino has said that taking supplemental glutamine even in the presence of cancer is unlikely to cause harm (though one should exercise prudence in that case). Taking high amounts of glutamine has seemed to increase my energy levels and reduce my overall pain, presumably by forcing an increase of GABA as well.

But this all certainly makes it seem like taking supplemental glutamine in the face of a viral infection like CMV is not a good idea at all. Hmmm.

 

[Hip]

I wonder if taking AKG instead of glutamine could be helpful too.

I would not have thought so, as it is the alpha-ketoglutarate that cytomegalovirus needs to build more viral particles.