No.

Contact Our BIO-INNOVATION CENTER

L-Ergothioneine
A Stable, Safe, and Powerful Natural Antioxidant
NAGASE & CO. is working on fermentative production of the natural antioxidant
ergothioneine (Figure 1), which is stable, safe, and can be transported to the brain as
well.

What is Ergothioneine?
Ergothioneine (EGT), a rare amino acid, is a naturalcompound with excellent antioxidant properties. Certain
mushrooms (in the class basidiomycetes), fungi such as
Aspergillus oryzae, Streptomyces species, andcyanobacteria are the only organisms capable ofproducing EGT. Humans cannot synthesize EGT in thebody, therefore must eat mushrooms or foods fermented
by A. oryzae to obtain it.
EGT was discovered in 19091, so it has been known forsome time, but in recent years it has been found to haveinteresting properties, and there is evidence that it ispromising against diseases involving the brain, thenervous system, and aging.

OHN

ONH N+S ThionegroupFig. 1. L-Ergothioneine (EGT)Longevity Vitamin
Dr. Bruce Ames (of the famous Ames test) is the leading researcher in aging and proposed“longevity vitamins” as a new group of vitamins which though are not required for survival, but
are vital compounds to maintain health in the long term. Ames also noted how EGT may
contribute to maintaining mitochondrial activity, and suggested it as a potential longevity
vitamin2. With the longer lifespans of the modern era, healthy longevity has become a major
concern, and longevity vitamins are likely to become progressively more important.
Clinical research hassuggested that EGT is vital toPotential Targets of❶❸healthy longevity. The decline❷
L-Ergothioneine❹
in mental and physicalcapability due to aging is① Parkinson’s Disease❺known as frailty. In a
② Cognitive impairment
comparison of EGT levels② Depression
between people with high frailty④ Cataract, Retinopathy
and low frailty, those who were
⑤ UV-induced skin aging
frailer had lower EGT levels3.
(Wrinkle, Blotches)This indicates that EGT can❾⑥ Cardiovascular disease
help to battle aging. It has also⓫
⑦ Liver disease
been reported in a comparison❻(Fatty liver, Fibrosis)⓬between countries that the⑧ Kidney disease
countries which consume the❼most EGT may have the⑨ Complications ofdiabetes
longest lifespans4.
❽⑩ Pre-eclampsia❿⑪ Cancer⑫ Frailty

1No.
1. Excellent Antioxidant Properties
EGT is an excellent antioxidant, with a capacity for neutralizing reactive oxygen species(ROS) 3 to 30 times higher (depending on the type of ROS) than glutathione, the mostcommon antioxidant in the body5. These powerful antioxidant properties are due to a uniquepart of the structure of EGT, the thione group (Figure 1). Since oxygen molecules are a type ofradical, many antioxidants become unstable when oxygen is present. Since EGT has a thione
radical, it reacts quickly to strong ROS such as hydroxyl radicals and singlet oxygen, but hasvery low reactivity with oxygen, and avoids breaking down even over long periods in thepresence of oxygen. It is also very stable when exposed to heat or acid6and is highlysafe7.

2. Discovery of the Ergothioneine Transporter
The primary reason that EGT has received attention in recent years is due to the discovery in2005 of the ergothioneine transporter (ETT) for the uptake of EGT into cells in humans8. As
mentioned above, only some microorganisms can produce EGT, but it is now known that EGTis used via ETT in various lifeforms including plants, fish, and mammals. ETT has been foundin various tissues in humans, and it has been reported that maintaining a high concentration(approximately 2 mM) of EGT in a cell will protect the cell from oxidative stress6.

i.

Mitochondria are an important organelle that consume oxygen to produce energy (ATP),but as a result they are destined to be susceptible to oxidative stress. A decline inmitochondria function is closely related to various diseases and aging. Studies haveshown large amounts of ETT in the membrane of this vital organelle9.

ii.

One of the cell types where the most ETT occurs is in red blood cells, the transporters ofoxygen, and red blood cells have been found to have high concentrations of EGT10.
Approximately 100-500 μM of EGT is found in human blood, but in some people this canexceed 1000 μM (unpublished data).

iii. ETT is also found in skin tissue, and it has been reported that there is a particularly large
amount of ETT in epidermal cells, so they tend to accumulate EGT more easily11. It isbelieved that the reason epidermal cells are able to accumulate EGT easily is to resist
oxidative stress due to ultraviolet rays.

iv. Despite EGT being highly water soluble, it can pass through the blood-brain barrier and is
known to accumulate in the central nervous system as well. Oxidative stress and theonset of neurodegenerative diseases are closely related, and there have been multiple
studies showing the effectiveness of EGT in preventing neurodegenerative diseases12, 13.

As described above, it is interesting physiologically that there is a high occurrence of ETT incells and organelles which are susceptible to oxidative stress, allowing for EGT, a powerfulantioxidant, to accumulate easily. ETT is also known to occur more frequently in inflamedareas (making it easier to absorb EGT to fight inflammation).

2

No.
3. Inducing Differentiation in Stem Cells
Recent research has shown that EGT can promote the differentiation of stem cells. For
example, providing EGT to neural stem cells can encourage them to differentiate into neurons.
Studies have indicated the possibility of promoting nerve reconstruction by ingesting EGT if
nerve damage occurs13, 14.

Potential Effects of Ergothioneine
EGT is a promising agent in preventing neurodegenerative diseases (Alzheimer's,Parkinson's), depression, skin aging due to ultraviolet rays (wrinkles and discoloration),
cataracts, and glycative stress. However, EGT levels in cells decline with age12. Therefore, it
may be possible to prevent various diseases caused by aging by actively increasing EGTintake.

NAGASE & CO., LTD’s Ergothioneine
Production Technology
As explained above, EGT is a very appealing
substance, but with existing methods such as
extracting it from mushrooms, it is difficult to mass
produce it in stable quantities at a low cost. Byutilizing the Streptomyces (N-STePP®) smart cell
technology which NAGASE has established throughyears of research, NAGASE aims to develop a
revolutionary fermentative production process tomake ergothioneine from inexpensive sugar15.

The NAGASE BIO-INNOVATION CENTER is committed to developing processes for efficiently
producing a wide range of compounds with proprietary fermentation technologies.

Contact Our BIO-INNOVATION CENTER© 2018-2022 NAGASE & CO., LTD.

3

No.

REFERENCES
1. Tanret C. Sur une base nouvelle retiree du seigle ergote, l'ergothioneine. Compt.Rend. (1909) 149: 222-224
2. Ames B. N. Prolonging healthy aging: Longevity vitamins and proteins Proc. Natl. Acad. Sci. USA. (2018) 115(43) 10836-10844
3. Kameda M. et al. Frailty markers comprise blood metabolites involved in antioxidation, cognition, andmobility. Proc. Natl. Acad. Sci. USA. (2020) 117(17): 9483–9489
4. Beelman R. B. et al. Is ergothioneine a ‘longevity vitamin’ limited in the American diet? J. Nut. Sci. (2020) 9:
1-5
5. Franzoni F. et al. An in vitro study on the free radical scavenging capacity of ergothioneine: comparison withreduced glutathione, uric acid and trolox. Biomed Pharmacotherapy. (2006) 60: 453-457
6. Cheah IK. et al. Ergothioneine; antioxidant potential, physiological function and role in disease. BiochimBiophys Acta. (2012) 1822(5): 784-793
7. Chu W. EFSA classes antioxidant l-ergothioneine safe for kids and pregnant women. (2017) 15-NOV
8. Grundemann D. et al. Discovery of the ergothioneine transporter. Proc. Natl. Acad. Sci. USA. (2005)
102(14): 5256–5261
9. Lamhonwah AM. et al. Novel localization of OCTN1, an organic cation/carnitine transporter, to mammalian
mitochondria. Biochem Biophys Res Commun. (2006) 345(4): 1315-1325
10. Kobayashi D. et al. Expression of organic cation transporter OCTN1 in hematopoietic cells during erythroid
differentiation. Exp Hematol. (2004) 32(12): 1156-1162
11. Markova NG. et al. Skin cells and tissue are capable of using L-ergothioneine as an integral component of
their antioxidant defense system Free Rad Biol Med. (2009) 46: 1168–1176
12. Cheah IK. et al. Ergothioneine levels in an elderly population decrease with age and incidence of cognitivedecline; a risk factor for neurodegeneration?

Biochem Biophys Res Commun. (2016) 478(1): 162-167

13. Nakamichi N. et al. Food-derived hydrophilic antioxidant ergothioneine is distributed to the brain and exerts
antidepressant effect in mice. Brain Behavior (2016) 6(6)14. Ishimoto T. et al. Organic cation transporter-mediated ergothioneine uptake in mouse neural progenitor cells
suppresses proliferation and promotes differentiation into neurons. PLOS ONE (2014) 9(2): e89434
15. Ergothioneine production method. WO2019163767A(2017)4