What to do about sky-high pyroglutamate?

What to do about sky-high pyroglutamate?


Brad says, “Working with a clinician at California
Center for Functional Medicine, a DUTCH Test revealed pyroglutamate levels of 3,359 micrograms
per.” I think you have those units wrong, 3,059
something. “And 2,884 in follow-up tests, the highest
level the lab has ever seen. Normal range is 43 to 85.” Wow. Okay. This is very high. “Clinician suspects mitochondrial dysfunction
and/or problems with glutathione pathway. I have also Genova Organix and ION test results. Thoughts?” No Brad, those units are still wrong because
you have a unit of mass against a unit of mass. It’s got to be unit of mass against a unit
of volume. But it doesn’t matter. I don’t need the units to answer your question. Pyroglutamate, its other name is 5-oxoproline. It is something that is primarily produced
when you are synthesizing glutathione, but you do not have enough of the second step
in glutathione synthesis to keep up with the first step. Let me explain that in a little more detail. Glutathione is the master antioxidant of a
cell. It’s also critically important for detoxification. It’s also critically important for lung function,
especially keeping mucus fluid and especially keeping the airways dilated. Asthma is largely a local deficiency of glutathione
in the lung. For example, congestion would probably involve
low levels of glutathione in the lung. A lot of lung diseases involve low levels
of glutathione. Glutathione is also extremely important in
cellular repair and cell division. It also regulates hundreds of proteins. Glutathione is super important. What is it? It’s a tripeptide which means that it’s made
from three amino acids. Those three amino acids are glutamate, cysteine,
and glycine. In the first step of glutathione synthesis,
you join glutamate to cysteine, and you make gamma-glutamylcysteine. That requires magnesium. It requires ATP. It requires insulin. It also is strongly regulated by the need
for glutathione. If you have oxidative stress, you’re going
to do that more than if you didn’t have oxidative stress because you need more glutathione. The glutathione, when you have enough, will
stop that step because you have enough. There’s a negative feedback loop there. Also, many of the polyphenols and fruits and
vegetables through what we call hormesis, which means a little bit of bad is good for
you, those are the polyphenols that we consider antioxidants. Our bodies consider toxins and they’re good
for us in part because they upregulate glutathione synthesis, so they also will stimulate that
enzyme. Now, in the second step, you join glycine
to the gamma-glutamylcysteine to make glutathione. That also requires magnesium. It also requires ATP. It requires glycine. As I’ve covered in many things that I put
out, we all probably need a little bit more glycine, especially if we eat a lot of animal
products because animal proteins are very rich in methionine which increases the need
for glycine. Also, because it appears that glycine synthesis,
we make our own glycine, was that that pathway even evolved to satisfy the need for small
invertebrates. For people like us who have dramatically more
collagen as a component of our tissues because of our skin and bones especially, we fall
short of what we need for glycine synthesis by up to 10 to 60 grams a day depending on
the person. Pyroglutamate is something that elevates when
that first step goes forward and then the body says, “Oh, wait, I can’t do the second
step. What am I going to do with this gamma-glutamylcysteine?” It recycles it. The process of recycling it, it makes pyroglutamate
and that winds up in your urine. What we know this tells us is that the first
step of glutathione synthesis is exceeding the capacity for the last step. Why wouldn’t the last step go forward? Well, you could have a profound deficiency
in glycine, but you could see that pretty easily because you said you also have Genovia
ION panel. The Genova ION panel will have glycine. If it was the plus 40 amino acids, it would
also have sarcosine. The glycine levels are low, that’s a big clue
that the problem is because glycine is missing. If the sarcosine levels are elevated, then
that gives you further clues about why the glycine is low. That would indicate that you’re overmethylating
the glycine, and that’s why you’re losing it. If the glycine is not low, then glycine being
low isn’t your problem. That suggests that you have a problem with
the enzyme. It does not suggest that you have a deficiency
of magnesium or ATP or insulin or anything else that I was just talking about because
those would all impact the first step. It’s only glycine or the enzyme. If it’s not glycine, you probably have a glutathione
synthetase deficiency, which is the enzymatic deficiency that could cause that. Barring that, it’s theoretical you could just
have an extremely overactive first step. You don’t have a defective second step. You just are producing the first step so massively
outpacing the second step, the same thing happens. But I think that you would know that if you
look at your glutathione levels. Probably, if the pyroglutamate is the highest
the lab has ever seen, probably the glutathione levels are really, really low. Brad, I don’t remember the range on that. Can you put the range? You could have extraordinary oxidative stress
upregulating the first step, but then your glutathione levels are going to look like
crap. Okay. His glycine is on the lowish end, but it’s
not that low. Look, maybe you need more glycine, but your
glycine isn’t low enough to cause orders of magnitude higher pyroglutamate. It’s almost certainly the case that you have
a glutathione synthetase deficiency, unless you have extraordinary levels of oxidative
stress. I think that would be easy to test for because
I just can’t imagine that your glutathione levels —
I guess it’s not that easy to test for because if you have a glutathione synthetase defect,
you’re going to have bad glutathione levels. If you have a tremendous amount of oxidative
stress, you’re also going to have low glutathione levels. If you have low glutathione levels, that’s
going to cause a tremendous amount of oxidative stress. I take back what I said about being easy to
figure out. I think it’s easy to figure out by doing an
enzymatic assay for glutathione synthetase. You are speaking with you said the clinician. I would ask the clinician to get you a glutathione
synthetase test. He’s working with Amy Nett at CCFM, which
is the California Center of Functional Medicine. I don’t know what her experience is with this. I mean, she’s not a clinical geneticist. You could just ask her if she can run that
test for you. If she can, then she can do it. If she can’t, then she would probably need
to refer you to a clinical geneticist. There’s a lot fewer of those than most doctors,
but they’re around. I think if it’s not a glutathione synthetase
defect, then it becomes a lot harder to figure out what it is because it probably means you
have massive oxidative stress from somewhere and there’s a lot of things that could cause
that. That would be a potential Pandora’s box of
questions that would come out of that. But definitely the first step would be to
look at glutathione synthetase. I hope that helps, Brad.

3 Replies to “What to do about sky-high pyroglutamate?”

  1. hello chris could you do an explicit video on raw and cook in all his nuances, potential degradation of nutrients,bio availability changing, formation of "toxic" compounds,enzymes, you would clear up the smoke on this topic

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