Glutathione 101, Part 1: Cysteine Misbehaves, But Glutathione Saves

I’ve written a lot about our good friend glutathione on this blog (here and here), and I’ll be writing about him quite a bit more in the future.  When it comes to boosting glutathione status, a nutrient-dense diet rich in traditional foods is the best adjunct to dietary and lifestyle strategies aimed at increasing the metabolic rate, so this blog is a great place to explore the great goodness of this trusty little tripeptide of ours.  In my last post, one reader expressed surprise that I listed protection against the toxicity of the amino acid cysteine as one of the functions of glutathione.  This calls for a crash course that brings to mind each component of glutathione’s goodness so we can better understand how edible superheroes like raw milk, raw fruits and vegetables, bone broth, and liver work their biochemical magic.

Glutathione Guards Cysteine Under His Wing

Glutathione knew that one of his great purposes in life was to wage a courageous battle against the misuse of electrons.  He had never been the type to be mired down in superficiality and dubious dichotomies, so he never cared whether this misuse led to oxidative stress or reductive stress, nor did he care whether free radicals had instigated the misuse of these electrons or if the culprits were at their core truly radical-free.

His most profound insight, however, came to him when he considered the nature of his arch-enemy, cysteine.  He looked in the mirror one day and realized that all along the enemy had been within himself.  “Nay,” he said to cysteine, “I shall no longer be at enmity with you.  I shall be a father to you, and you shall be my son, and I will hold you close within my bosom.”

Glutathione, you see, is called a tripeptide because he’s composed of three amino acids, each bound together by a peptide bond that magnesium and ATP have infused with energy.  These amino acids are glutamate, cysteine, and glycine.

GSH1

If we peer into the human cell, we see that free cysteine concentrations are conspicuously low (1):

Free-Cysteine2

It may seem at first glance that cysteine is rare in the cell and hard to find. In reality, however, each glutathione contains one cysteine, so what these results really show is that glutathione has guarded the cellular cysteine well, holding over 99 percent of the non-protein cysteine close to his breast.

Cysteine Misbehaves

We can get a sense of why this might be by sprinkling some free cysteine on a dish of cells and watching what happens.  Take brain cells, for instance.  Bringing the concentration of free cysteine up to roughly match that shown above for free glycine kills off 70 percent of the cells (3).

Or we could play a little trick on E. coli.  This little bugger is usually quite resistant to hydrogen peroxide, but scientists have a way of fixing that (4).  Here’s the trick.  First, grow the E. coli in a broth deprived of cysteine for a while so that it actively seeks out every bit of cysteine it can find; then, suddenly, add normal concentrations of cysteine.  The E. coli won’t know what hit it.  Before it has a chance to adjust, it’ll sop up all the cysteine you give it.  Add hydrogen peroxide to the mix, and virtually all the bacteria die within ten minutes.

Could we be headed for disaster simply by eating cysteine?  Probably not, unless we eat megadoses unobtainable from food.  Here’s what happens to rats when they eat megadoses of cysteine (5):Cys-Decreases-GSH1

We don’t see a major effect until the dose reaches 1000 mg per kilogram of body weight.  At this dose, glutathione is a goner:  the depletion surpasses 90 percent.  To obtain this amount of cysteine from food, however, you would have to eat about fifty pounds of pork every day.  Just ain’t gonna happen.

It is nevertheless fascinating that cysteine even could deplete glutathione, since glutathione is made from it.  Taken together, these results are a testament both to the potential toxicity of cysteine and to the amazing ability of biological systems to safely manage their cysteine.  After all, only tiny amounts are needed to kill brain cells grown in laboratory dishes, but impossibly large amounts are needed to cause serious harm to a live animal.

We owe the greater part of our gratitude for this amazing ability to our good friend glutathione.  By taking cysteine under his wing and holding him close to his breast, glutathione shields him from the many opportunities he would have for mischievous behavior when swimming through the stormy seas of youth in the presence of questionable characters like free iron and copper. To better understand this protection, let’s first take a look at how cysteine gets into trouble when glutathione’s not around.

Cysteine Heads for Troubled Waters

Cysteine is a complex character, but we can imagine him in simplified form by devoting our attention to just three key body parts, shown below.  Although it might be cruel to imagine that poor cysteine has no feet, it will help us understand how glutathione keeps him from getting into trouble if we imagine the sulfhydryl group as his head and the carboxyl and amino groups as his hands.  We will soon find it important that the sulfhydryl group is composed primarily of sulfur.

Cysteine3

Drop the cysteine into some water, and something funny happens.  First, the hydrogen way on the left floats all the way over to the right.  It leaves the carboxyl group and joins the amino group.  Since hydrogen carries a positive charge, this leaves cysteine’s left hand with a negative charge and endows his right hand with a positive charge.

So far nothing too peculiar has happened.  But a few percent of the cysteine will undergo a more radical transformation: the loss of a hydrogen from the sulfhydyl group, cysteine’s head.  When cysteine loses this hydrogen it’s as if he lost his mind.

Sulfhydryl-Ionized1

In the ever so slightly alkaline environment of the cell, the proportion of free cysteine transformed in this way at any given instant increases to six percent (6).

The loss of this hydrogen exposes cysteine’s most prized possession: his highly reactive electron.  The whole reason sulfur plays such an important role in biology is because of its penchant for transferring electrons, and its role in cysteine’s sulfhydryl group is no different.  But that also means that cysteine can get in a lot of trouble if he doesn’t transfer electrons carefully, and when glutathione is gone and metals like iron and copper escape the close watch of the proteins to which they are are normally bound, boy do these hooligans get into some mischief.  Scientists still aren’t sure exactly how these characters interact, but it seems to be something like this (2):

Trouble1

Since cysteine’s head and left hand each have one negative charge, together they can interact with iron, copper, or other similar metals that have two positive charges.  The role of cysteine’s positively charged right hand is unclear, but it may help push his left hand into the correct position or indirectly give greater strength to his left hand’s negative charge.  What is clear is that cysteine needs both hands to make mischief.  Any derivatives of cysteine that tie up one or the other hand (such as N-acetyl-cysteine), tie up both hands (such as glutathione), or put extra distance between his right and left hands (such as homocysteine) are incapable of promoting the same type of molecular mischief (2, 5, 7, 8).

Scientists have yet to agree on the precise mechanisms by which these hoodlums cause trouble, probably because they do so in the midst of the night like most other hoodlums.  Some scientists suggest that cysteine transfers an electron to iron, making it capable of turning hydrogen peroxide into the much more damaging hydroxyl radical.  Others suggest that copper is the primary culprit, and that copper helps transfer electrons from cysteine to oxygen, first generating superoxide, and subsequently generating hydrogen peroxide and the hydroxyl radical.  Regardless of the exact mechanism, cysteine’s interaction with trace metals causes enough damage to kill brain cells, so we’re talking about some serious mischief.

Once cysteine loses its prized electron during all this commotion, it becomes a free radical and neutralizes itself by butting heads with another cysteine that’s been through the same ordeal.  Collapsing on each other, they stick, forming cystine disulfide (notice the different spelling). It’s called a “disulfide” because two sulfur atoms, one from each cysteine, have now stuck together.

Cystine2

Although the proportion of cysteine that has its prized electron exposed at any given moment is only a few percent, this few percent oxidizes so rapidly that, in the absence of the high concentrations of glutathione we find inside cells, this few percent is constantly replaced and virtually all of the cysteine gets siphoned off into mischief-making.  We can see this simply by looking at human blood, where over 90 percent of the free cysteine exists as its oxidized disulfide form (9).

There’s nothing intrinsically wrong with the formation of these disulfides, however.  As we will see in future posts in this series, the formation of disulfides is an important system of communication.  Glutathione’s mission is not to prevent their formation entirely, but to prevent their misuse and to promote their proper use.  Allowing them to form spontaneously without any guidance would cause not only the copious production of destructive oxidants, but would also lead to devastating breakdowns in the body’s communication systems.  Thanks a great deal to glutathione, we largely escape this fate.

Having taken a closer look at cysteine’s misbehavior, we can now understand how glutathione can be his savior.

Glutathione Saves

When cysteine passes through the digestive tract, the intestines and liver extract the greater portion of it.  Exactly how much these organs extract probably depends on how much cysteine we consume, and it has never to my knowledge been precisely quantified in humans.  In pigs, they take up between forty and eighty percent of dietary cysteine (9).  They use it first to synthesize proteins and glutathione.  According to their need, they may use it to synthesize coenzyme A as well.  They convert the rest to taurine and sulfate.  In humans, high intakes of cysteine increase urinary sulfate excretion (10) but do not increase the flux of cysteine through the blood (11).  This suggests that these organs quickly and efficiently take up excess dietary cysteine so they can either store it as glutathione or irreversibly degrade it to other more stable byproducts.

Once our cells degrade cysteine to taurine or sulfate, the cysteine is irrecoverable.  Storing cysteine as glutathione, by contrast, is like depositing it into a bank account.  The liver releases glutathione into the general circulation, and our cells use an enzyme stuck to their outer surface to grab hold of that glutathione and harvest cysteine for themselves.  In fasting humans, about half of the cysteine that passes through the blood comes from glutathione (12).  Injecting them with glutathione results in a huge flux of cysteine through the blood, roughly equal to the amount of glutathione injected.  This suggests that our bodies tightly regulate the glutathione concentration of the blood, and that when the liver provides glutathione over and above this regulated level, it does so at least in part to transport cysteine to other tissues.

As we will see in future posts in this series, our bodies probably regulate blood levels of cysteine and glutathione because they serve as important communication signals that are capable of turning the functions of proteins up or down, switching their functions on or off, or otherwise changing the nature of their functions.

Our conclusion for today, however, is that our good friend glutathione guards cysteine safely in his bosom, preventing him from adventuring off into capricious escapades in troubled waters where mischief is the order of the day and where delinquent trace metals will encourage him to abuse our precious oxygen through the wanton and promiscuous transfer of electrons.  Glutathione has looked upon these electrons and has seen that their transfer is good; in future posts in this series, we will see how glutathione ensures that these electrons be transferred not towards our destruction but towards our radiant health, for the benefit of all.

Read more about the author, Chris Masterjohn, PhD, here.

References

1. Luo JL, Hammarqvist F, Andersson K, Wernerman J. Skeletal muscle glutathione after surgical trauma. Ann Surg. 1996;223(4):420-7.

2.  Yang EY, Campbell A, Bondy SC. Configuration of thiols dictates their ability to promote iron-induced reactive oxygen species generation. Redox Rep. 2000;5(6):371-5.

3.  Wang, XF, Cynader MS.  Pyruvate released by astrocytes protects neurons from copper-catalyzed cysteine neurotoxicity.  J Neurosci. 2001;21(10):3322-31.

4.  Park S, Imlay JA.  High levels of intracellular cysteine promote oxidative DNA damage by driving the fenton reaction. J Bacteriol. 2003;185(6):1942-50.

5.  Estrela JM, Saez GT, Such L, Vina J. The effect of cysteine and N-acetyl cysteine on rat liver glutathione (GSH). Biochem Pharmacol. 1983;32(22):3483-5.

6.  Bannai S. Transport of cystine and cysteine in mammalian cells. Biochim Biophys Acta. 1984;779(3):289-306.

7.  Kachur AV, Koch CJ, Biaglow JE.  Mechanism of copper-catalyzed autoxidation of cysteine.  Free Radic Res. 1999;31(1):23-34.

8.  Hsu CC, Huang CN, Hung YC, Yin MC.  Five cysteine-containing compounds have antioxidative activity in Balb/cA mice.  J Nutr. 2004;134(1):149-52.

9.  Bauchart-Thevret C, Cottrell J, Stoll B, Burrin DG.  First-pass splanchnic metabolism of dietary cysteine in weanling pigs.  J Anim Sci. 2011;89(12):4093-9.

10.  Courtney-Martin G, Rafii M, Wykes LJ, Ball RO, Pencharz PB.  Methionine-adequate cysteine-free diet does not limit erythrocyte glutathione synthesis in young healthy adult men.  J Nutr. 2008;138(11):2172-8.

11.  Hiramatsu T, Fukagawa NK, Marchini JS< Cortiella J, Yu YM, Chapman TE, Young VR.  Methionine and cysteine kinetics at different intakes of cystine in healthy adult men.  Am J Clin Nutr. 1994;60(4):525-33.

12.  Fukagawa NK, Ajami AM, Young VR.  Plasma methionine and cysteine kinetics in response to an intravenous glutathione infusion in adult humans.  Am J Physiol. 1996;270(2 Pt 1):E209-14.

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