August 23, 2020
In a preprint* published Friday, researchers from Germany, Denmark, and the UK published a paper suggesting that SARS-CoV-2, the coronavirus that causes COVID-19, relies heavily on sugar to be able to replicate.
These results raise the possibility that sugar intake fuels the growth of the virus and could be a major determinant of viral load.
Explaining this requires some biochemistry. If you aren't familiar with the biochemistry of the “pentose phosphate pathway,” please consider watching my 42-minute lesson on it on YouTube. The “background” section below is a much briefer crash course.
Additionally, if you feel like you need visuals to understand the biochemistry below, please watch the YouTube video I made explaining today's newsletter with slides.
If you don't need a biochemistry refresher, you can skip the “background” section. If you would prefer not to dive into the biochemistry at all, skip down to “The Bottom Line.”
Background: The Pentose Phosphate Pathway
The pentose phosphate pathway uses glucose to produce NADPH and ribose 5-phopshate.
NADPH is a derivative of the B vitamin niacin (vitamin B3) that is used for the recycling of glutathione, which contributes to antioxidant defense; cytochrome P450 activity, which contributes to detoxification; the recycling of vitamin K and folate; and the synthesis of fatty acids, cholesterol, neurotransmitters, and DNA nucleotides.
Ribose 5-phosphate is used for the synthesis of DNA, RNA, and all of the major energy shuttles within the cell, such as coenzyme A, ATP, NADH, NADPH, and FADH2.
The pentose phosphate pathway starts by taking glucose 6-phosphate out from the glycolytic pathway. First, glucose 6-phosphate is converted into a 5-carbon sugar while producing NADPH. This is the “oxidative phase.” Next, in the “non-oxidative phase,” the resulting 5-carbon sugars can exit the pentose phosphate pathway one of two ways: either by generating ribose-5-phosphate for the synthesis of DNA, RNA, and the other molecules I just listed, or by rearranging themselves into 3-carbon and 6-carbon sugars that return to glycolysis.
In the oxidative phase, electrons and energy from glucose are invested into the energy-poor NADP+ to generate the energy-rich form of the molecule, NADPH. In the non-oxidative phase, five carbon sugars are generated that can be used to synthesize molecules from scratch, what we call de novo.
Notice that NADPH occurs in the list of molecules that can be synthesized de novo. The non-oxidative phase allows a new molecule of NADPH to be produced from its component parts. That one molecule will be used to invest energy in other processes many times. Each time it will become NADP+ and need to be recycled in the oxidative phase, where energy will be invested into it to regenerate NADPH. Generally speaking, the oxidative phase would be used to recycle NADP+ to NADPH far more often than the non-oxidative phase would be used to produce a 5-carbon sugar that would become part of a brand new NADPH molecule.
When the cell needs more NADPH than ribose 5-phosphate, it returns the sugars to glycolysis to form a continuous loop, where glucose 6-phosphate generates NADPH, the 5-carbon sugars rearrange to form 3-carbon and 6-carbon sugars, those return to glycolysis, they reform glucose 6-phosphate, and the loop runs again.
When the cell needs a balance of NADPH and ribose 5-phosphate, glucose 6-phosphate is constantly siphoned off to produce both NADPH and 5-carbon sugars without any return of the sugars to glycolysis.
If the need for 5-carbon sugars exceeds the need for NADPH, the glucose metabolites can leave glycolysis at later steps to bypass the oxidative phase. More specifically, glucose 6-phosphate is converted to fructose 6-phosphate, which is converted in several steps to glyceraldehyde 3-phosphate. Fructose 6-phosphate and glyceraldehyde 3-phosphate can leave glycolysis to enter the non-oxidative phase of the pentose phosphate pathway and generate ribose 5-phosphate without the need to generate NADPH.
If the cell mainly needs NADPH and ATP, the sugars proceed through the oxidative part of the pathway, then return to glycolysis, and rather than running a loop, the sugars finish glycolysis to be burned for energy.
What We Would Expect From a Viral Infection
Although there are DNA viruses, SARS-CoV-2 is an RNA virus that needs to produce RNA within its host in order to replicate. We would therefore expect it, and RNA viruses in general, to increase the demand for ribose 5-phosphate to use for RNA synthesis.
While NADPH is used to synthesize the building blocks of DNA, which our own cells would need to make when dividing, it is not used to synthesize the building blocks of RNA, which RNA viruses such as SARS-CoV-2 need to make when replicating. That doesn't rule out that the virus would use NADPH for some processes, but it does suggest that there is a general lopsided need of viruses for the non-oxidative part of the pathway.
Moreover, we humans use NADPH to recycle glutathione, which is known to have antiviral effects towards HIV, herpes simplex virus type 1, influenza A, murine leukemia virus (which infects mice), dengue virus serotype 2, and hepatitis C virus, and probably prevents SARS-CoV-2 from entering cells.
Therefore, an RNA virus would be expected to disproportionately depend on the non-oxidative phase of the pathway and to “prefer” the host be bad at using the oxidative phase.
In other words, the virus's “preferred” program of metabolism would be that we avoid the oxidative phase of the pentose phosphate pathway and send sugars straight through the non-oxidative phase to produce lots of ribose 5-phosphate.
SARS-CoV-2 Hijacks The Pentose Phosphate Pathway
The paper we are discussing today showed that SARS-CoV-2 depends on the pentose phosphate pathway for replication:
They had previously shown that inhibiting the first two steps of glycolysis with a compound called 2-deoxyglucose stopped SARS-CoV-2 from replicating in isolated cells. While this could be considered a dependence on glycolysis, there is another interpretation: the first step in glycolysis produces glucose 6-phosphate, which enters the oxidative phase of the pentose phosphate pathway; the second step produces fructose 6-phosphate, which enters the non-oxidative phase of the pentose phosphate pathway. Both of these steps allow the pentose phosphate pathway to produce 5-carbon sugars.
In this paper, they showed that SARS-CoV-2 infection increases the production of two enzymes: transketolase and transaldolase. Both of these enzymes are part of the non-oxidative phase, and they are used either to return the 5-carbon sugars to glycolysis when more NADPH than ribose 5-phosphate is needed, or to siphon off sugars from glycolysis for the non-oxidative phase when more ribose 5-phosphate than NADPH is needed.
Transketolase needs thiamin (vitamin B1) as a cofactor, and the inactive thiamin analogue benfooxythiamin can be used to inhibit the enzyme. In this paper, benfooxythiamin inhibited SARS-CoV-2 replication. Using 2-deoxyglucose and benfooxythiamin together produced even more powerful inhibition of viral replication. In fact, the two together achieved nearly complete inhibition of viral growth.
The authors' interpretation was that SARS-CoV-2 hijacks the pentose phosphate pathway to use ribose 5-phosphate for RNA synthesis.
However, I don't think we can completely rule out that it is hijacking the pathway to get NADPH. 2-deoxyglucose would block the use of glucose 6-phosphate for NADPH production, and benfooxythiamin would block the return of 5-carbon sugars to glycolysis, which allows the cycle to run as a loop for enhanced NADPH generation.
Nevertheless, I see three arguments that favor their interpretation:
As I noted above, we would expect RNA viruses to be dependent on ribose 5-phosphate, but not NADPH, for replication.
The combination of 2-deoxyglucose and benfooxythiamin nearly completely wiped out viral replication. While the pentose phosphate pathway is the only source of newly produced ribose 5-phosphate, there are other minor sources of NADPH (such as isocitrate dehydrogenase and malic enzyme) that could step up to the plate when the pentose phosphate pathway is inhibited. If NADPH were the limiting factor, the effectiveness of the two inhibitors should have been less complete.
Glucose 6-phosphate dehydrogenase (G6PDH) deficiency is a genetic disorder impacting about eight percent of the world's population, and it specifically impairs the oxidative part of the pathway. As described in this letter, G6PDH-deficient cells are more vulnerable to infection with other coronaviruses, and Black and Asian groups with higher susceptibility to COVID-19 also have higher proportions of G6PDH deficiency. In the Al-Ahsa area of Saudi Arabia, G6PDH deficiency was strongly overrepresented in pediatric COVID-19 cases, especially in boys: in the general population of that area, only 23% of males and 13% of females are deficient, but in pediatric COVID-19 cases 80% of boys and 36% of girls were deficient. These results suggest that the oxidative phase of the pentose phosphate pathway is protective.
In the context of all the available evidence, this study supports the specific importance of the non-oxidative phase of the pentose phosphate pathway in fueling viral growth.
The Authors' View
The authors used their findings to explain how poor glucose control in diabetics is a risk factor for poor outcomes in COVID-19.
They then wrote, “the findings also demonstrate that the simultaneous inhibition of different metabolic pathways [meaning the oxidative and non-oxidative pathways using 2-deoxyglucose and benfooxythiamin] has potential as an antiviral treatment strategy for SARS-CoV-2-infected individuals.”
Their title, “Targeting pentose phosphate pathway for SARS-CoV-2 therapy” suggests they view the potential therapeutic value of the inhibitor cocktail as the major implication of their paper.
This strikes me as potentially dangerous. While in isolated cells this might blunt infection without any obvious harm, I would expect systemic blockade of the pentose phosphate pathway to risk hemolytic anemia and respiratory stress by impairing glutathione recycling. I found the paper more interesting because of its implications for sugar intake.
Fructose and Glucose Are Different
Ordinary table sugar consists of sucrose, which is a half glucose and half fructose. High-fructose corn syrup consists of a mix of glucose and fructose. Starch, by contrast, is entirely made up of glucose. So, the difference between sugar and starch is that most sugar contains roughly half fructose.
Although fructose is mainly metabolized in the liver, there is still plenty of it that will enter the bloodstream after consuming sugar. For example, in one study, the consumption of 25 grams of sucrose increased serum fructose 10-fold from 20 uM to 200 uM, and increased serum glucose 50% from 6 mM to 9 mM. In the absence of sucrose consumption, the glucose levels in the blood are 300 times the fructose levels. After sucrose consumption, the glucose levels are only 45 times the fructose levels. Glucose is always the major sugar in the blood, but, on a relative basis, sucrose increases serum fructose far more than it increases serum glucose.
Fructose in the blood has access to all the internal organs. In the lung, fructose is metabolized to fructose 1-phosphate, and then to dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, which then enter glycolysis.
Glyceraldehyde 3-phosphate can then enter the pentose phosphate pathway, but only through the non-oxidative phase. That allows it to generate ribose 5-phosphate, but not NADPH.
One exception: glyceraldehyde 3-phosphate can generate glucose 6-phosphate during gluconeogenesis, and that would allow a way for fructose to enter the oxidative phase of the pentose phosphate pathway. However, eating sugar usually stimulates enough insulin to suppress gluconeogenesis. Under conditions where liver glycogen is depleted, the demand for glucose will be high enough for fructose to be used for gluconeogenesis, but under most other conditions the insulin would largely prevent that from happening.
Furthermore, glucose enters glycolysis or the pentose phosphate pathway in a fashion that is regulated by the need to use the two pathways. In the absence of such a demand, glucose will just form glycogen. By contrast, fructose enters these pathways in a completely unregulated fashion according to the abundance of fructose. Fructose can therefore push forward the non-oxidative phase of the pentose phosphate pathway to produce an abundance of 5-carbon sugars, without being able to support NADPH production.
In 1986, Richard Veech published a paper comparing the effect of sugar and starch on different pentose phosphate pathway metabolites. Veech had gotten his start under Sir Hans Krebs, who won the 1953 Nobel prize for discovering what we now call “the Krebs cycle.” Veech was also “the unknown scientist behind the ketogenic diet craze” who passed away at 84 earlier this year, according to an obituary.
In his 1986 paper, he compared rats fed standard diets that were 60% carbohydrate, mainly as starch, to 48 hours fasting, and to animals that fasted 48 hours and then refed on a diet that had the starch replaced with sugar. The ribose 5-phosphate levels within their livers were increased 13% by fasting, and increased six-fold by refeeding on sugar.
The NADPH/NAPD+ ratio was increased about 80% on sugar, but NADPH is used to synthesize fatty acids, and refeeding on sugar-rich diets increase the synthesis of fatty acids 60-fold in rats. So the increase in NADPH is probably largely fed into fatty acid synthesis, while the 6-fold greater ribose 5-phosphate levels would be available to feed viral growth were an infection present.
As such, the ability of fructose to push forward the production of 5-carbon sugars would be expected to fuel the growth of RNA viruses, including SARS-CoV-2.
In other words, fructose executes the virus's preferred program of metabolism by pushing sugars through the non-oxidative phase of the pentose phosphate pathway, bypassing the oxidative phase, to produce ribose 5-phosphate without producing as much NADPH.
Fasting increased the ribose 5-phosphate slightly, by 13%, which is a very small effect. Carbohydrate restriction would probably do something similar. This suggests that fasting, and by extension carbohydrate restriction, would not be a way to starve the virus of ribose 5-phosphate. However, restricting sugar might be a way to avoid dumping fuel onto the fire of viral growth.
Is There Any Human Evidence?
I searched pubmed, biorxiv.org, medrxiv.org, and ssrn.com for papers looking at the association between sugar intake, low-carbohydrate diets, or ketogenic diets and COVID-19. All I could find were papers on how the medical administration of ketogenic diet was adapting to lockdown or showing how sugar intake changed during lockdown. I could not find anything investigating whether any of these dietary factors correlated with COVID-19 incidence, severity, or mortality.
This can and should be studied.
The Bottom Line
Although there is no human evidence thus far, there is a strong biochemical argument suggesting that fructose, but not glucose, would provide extra fuel to the growth of RNA viruses, including SARS-CoV-2.
Glucose and fructose can both support viral growth through the pentose phosphate pathway. However, fructose disproportionately feeds the part of the pathway that fuels viral growth, while glucose also feeds the part of the pathway used to support antioxidant defense and the recycling of vitamin K and folate.
The paper reviewed today showed that inhibiting this pathway virtually completely abolishes the ability of SARS-CoV-2 to infect isolated cells. Blocking this pathway in a live human risks impairing the recycling of glutathione, which would hurt certain parts of the antiviral defense, risk hemolytic anemia, and contribute to respiratory distress.
However, cutting sugar out of the diet, or strictly moderating it, may allow the pathway to support the needs of our cells without throwing fuel on the fire of viral growth.
While biochemical evidence from isolated cells does not necessarily translate into human health outcomes, we already have plenty of reasons to limit the amount of sugar in our diet. Eating a diet that moderates natural sugars and cuts out most added sugars is a good thing to do, and may just help protect against COVID-19.
Stay safe and healthy,
Chris
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*Footnotes
* The term “preprint” is often used in these updates. Preprints are studies destined for peer-reviewed journals that have yet to be peer-reviewed. Because COVID-19 is such a rapidly evolving disease and peer-review takes so long, most of the information circulating about the disease comes from preprints.