Cystine vs Cysteine for cellular health

Key learnings: 

• What are the ingredients to produce glutathione?
• Differences between cystine and cysteine, and why they matter 
• How do they contribute to glutathione production?

What seems to be a typo actually holds the secret for delivery of the main building block for glutathione inside the cell. We break down the differences between these two amino acids and explain their function in glutathione production.  

Found in every cell of your body, glutathione is a powerful and essential antioxidant. Antioxidants remove damaging free radicals in the body, reducing oxidative stress. 

This antioxidant is unique as it is not from the foods you eat, but is actually produced by your own body. Glutathione is made up of three building blocks called amino acids which are cysteine, glutamate (which forms glutamic acid) and glycine.

In the body there are different types of amino acids: essential, non-essential and conditionally essential. A non-essential amino acid can be produced by the body; an essential amino acid cannot, and must be sourced from dietary intake. Moreover, some non-essential amino acids are termed ‘conditionally essential,’ as depending on dietary intake of precursor amino acids and other factors their rate of production can be limited. When limited production of a non-essential amino acid occurs, this is when they become essential to the diet.

The building blocks for glutathione production are non-essential amino acids. However, glycine and cysteine can be conditionally essential amino acids.

Glutathione has three main roles:

• To be an antioxidant defense
• To detoxify metabolic products
• Is involved in the regulation of important cell processes

In order to maintain sufficient levels of glutathione, a high amount of cysteine is required due to it being the rate limiting amino acid in the production of glutathione. This means that the production of glutathione is dependent on the levels of cysteine present in the cell.

There are three ways of producing cysteine present in the body.

1. Cysteine absorption
2. Breakdown of a cystine molecule
3. Converting methionine into cysteine through a reaction pathway (1)

We will cover factors one and two, beginning with the differences between Cysteine and cystine. Later, we will highlight their role in glutathione production.

But first of all, what are cystine and cysteine?

Both are sulphur-containing amino acids that are used in a number of different reaction pathways, one of which is to produce glutathione in the body. However, there are major differences between the two amino acids.

Structure

Cystine is made up of two cysteine molecules which have been oxidised and are bonded together with a disulphide bond. This means cystine is a more stable molecule than cysteine as the disulphide bond strengthens the overall structure of the amino acid.

Cysteine, on the other hand, is a single non-essential amino acid which the body can create using the essential amino acid methionine as a precursor. (2)

Absorption

After digestion cysteine is absorbed in the gastrointestinal (GI) tract with 25% of it being used up by surrounding cells. Because it later faces spontaneous breakdown in the bloodstream, the supplementation of cysteine has demonstrated not to be an effective way to boost glutathione production. (3,4)

Cysteine supplementation also has dangerous consequences if too much is consumed, as high concentrations present in the body can become toxic. This includes the precursor N-acetylcysteine which has been associated with users becoming clammy, coughing up blood and experiencing inflammation of the mouth and lips. Overall, cysteine or N-acetylcysteine are not ideal supplements to enhance glutathione production. (4,5)

However, unlike cysteine, cystine is an ideal precursor to be used to increase glutathione levels. By acting as a delivery system of cysteine, it is not utilized by cells in the GI tract upon digestion or catabolized in the blood. Therefore, cystine successfully provides two molecules of cysteine, which overall increases the bioavailability of cysteine for cells. (4)

Cellular uptake

A number of cells uptake cystine using an antiporter called System xc-, a transporter that allows the movement of two substances simultaneously in opposite directions. In order to import one cystine molecule into the cell, another amino acid (glutamate) is exported out of the cell.

Once cystine is present in the cell it is then reduced back to cysteine, resulting in two cysteine amino acids per each cystine molecule. This cystine-glutamate antiporter has been identified in the brain, spinal cord and pancreas. It has been linked to a range of central nervous system functions including release of neurotransmitter and the operation of the barrier between the blood and the brain. (2,6)

On the other hand, Cysteine can be directly transported into the cell by ASC and EAAC1 transporters. (7,8)

Role in glutathione production

Two ATP dependent reactions stand between the building blocks and the product they create. The first reaction joins glutamate to cysteine and forms an intermediate. The linkage that joins them protects glutathione from being broken down by digestive enzymes within the cell.

The second reaction joins glycine onto the intermediate and creates glutathione. During this process, the rate limiting amino acid is cysteine — this means that a large amount of cysteine is required to be present inside the cell for the process to start.

In order to gain a large enough amount of cysteine, cells can directly use cysteine transported in from the ASC/EAAC1 transporters or they can use cystine transported in from the cystine-glutamate antiporter. 

Although in theory either cysteine or cystine can be used to produce glutathione, one study suggested that increased cysteine uptake by supplementation does not significantly change glutathione levels. Therefore, to increase glutathione levels cystine is the preferred supplementation. (9,10,11,12)

Where do I find cystine and cysteine?

Cysteine is abundant in most high protein foods such as meat, fish and grains. Although cysteine is easily accessible, the low bioavailability of it hinders its effectiveness at enhancing glutathione levels in the body. There are dietary supplements of cysteine, however, they are not effective at increasing levels of glutathione due to their spontaneous breakdown in the blood. 

However, there are other ways to boost the production of glutathione.

Dietary oral supplements of cysteine are now available on the market which do not have to be administered invasively but have been shown to enhance the synthesis of glutathione in those who are deficient. (4) 

By maintaining high amounts of cysteine, the body will have excess amounts present in the cell which will trigger the body to store it as glutathione.

Native undenatured whey protein is also an effective source of cystine, the precursor to cysteine. Therefore, consuming native undenatured whey protein can elevate your levels of glutathione.

References

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2. Yu, X., & Long, Y. C. (2016). Crosstalk between cystine and glutathione is critical for the regulation of amino acid signalling pathways and ferroptosis. Scientific Reports, 6.
3. Bauchart-Thevret, C., Stoll, B., & Burrin, D. G. (2009). Intestinal metabolism of sulfur amino acids. Nutrition Research Reviews, 22(2), 175–187.
4. Winter, A. N., Ross, E. K., Daliparthi, V., Sumner, W. A., Kirchhof, D. M., Manning, E., Linseman, D. A. (2017). A Cystine-Rich Whey Supplement (Immunocal®) Provides Neuroprotection from Diverse Oxidative Stress-Inducing Agents In Vitro by Preserving Cellular Glutathione. Oxidative Medicine and Cellular Longevity, 2017, 1–15.
5. Sansone, R. A., & Sansone, L. A. (2011). Getting a knack for nac: N-acetyl-cysteine. Innovations in Clinical Neuroscience, 8(1), 10–14.
6. Bridges, R. J., Natale, N. R., & Patel, S. A. (2012). System x c- cystine/glutamate antiporter: An update on molecular pharmacology and roles within the CNS. British Journal of Pharmacology, 165(1), 20–34.
7. Smith, Q. R. (2018). Transport of Glutamate and Other Amino Acids at the Blood-Brain Barrier. The Journal of Nutrition, 130(4), 1016S-1022S.
8. Hayes, D., Wießner, M., Rauen, T., & McBean, G. J. (2005). Transport of L-[14C]cystine and L-[14C]cysteine by subtypes of high affinity glutamate transporters over-expressed in HEK cells. Neurochemistry International, 46(8), 585–594.
9. Noctor, G., Arisi, A. C. M., Jouanin, L., Valadier, M. H., Roux, Y., & Foyer, C. H. (1997). The role of glycine in determining the rate of glutathione synthesis in poplar. Possible implications for glutathione production during stress. Physiologia Plantarum, 100(2), 255–263.
10. Banjac, A., Perisic, T., Sato, H., Seiler, A., Bannai, S., Weiss, N., … Bornkamm, G. W. (2008). The cystine/cysteine cycle: A redox cycle regulating susceptibility versus resistance to cell death. Oncogene, 27(11), 1618–1628.
11. Forman, H. J., Zhang, H., & Rinna, A. (2009). Glutathione: overview of its protective roles, measurement, and biosynthesis. Molecular Aspects of Medicine, 30(1–2), 1–12.
12. Van Haaften, R. I. M., Haenen, G. R. M. M., Evelo, C. T. A., & Bast, A. (2003). Effect of vitamin E on glutathione-dependent enzymes. Drug Metabolism Reviews, 35(2–3), 215–253.