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Review article http://dx.doi.org/10.1016/j.apjtb.2017.08.005
L
-theanine: A potential multifaceted natural bioactive amide as health supplement
Rajsekhar Adhikary, Vivekananda Mandal
*
Plant and Microbial Physiology and Biochemistry Laboratory, Department of Botany, University of Gour Banga,
Malda 732 103, W.B., India
ARTICLE INFO
Article history:
Received 11 Jul 2017
Received in revised form 27 Jul 2017
Accepted 14 Aug 2017
Available online xxx
Keywords:
Bioactive amide
Bioavailability
L
-theanine
Lifestyle associated diseases
Pharmacokinetics
ABSTRACT
Natural bioactive compounds from plants are of great importance in modern therapeutics,
which are used to prepare antibiotics, growth supplements or some other therapeutics.
L
-
theanine is such a bioactive amide amino acid presented in different plants and fungi,
especially in tea. Theanine has influential effects on lifestyle associated diseases, such as
diabetes, cardiovascular disorders, hypertension, stress relief, tumor suppression,
menstruation and liver injury. This amino acid can maintain normal sleep and improve
memory function and nullify effect of the neurotoxins. The rate of bioavailability and its
medium of ingestion in the body is one of the great concerns for its additional antioxidant
properties. Pharmacokinetics of the bioactive compound and its mode of action are
described herewith. The biosynthesis and industrial synthesis are also reviewed to pro-
mote accelerated production of this bioactive compound in the pharmaceutical industries.
1. Introduction
Bioactive compounds of natural origin have great importance
in common days for herbal medicines, antibiotics preparation,
health supplements or some other therapeutic uses. Theanine is
one of such important non-essential amide bioactive amino acids
presented in tea (Thea sinensis, Theaceae), Ilex guayusa
(Aquifoliaceae) and Boletus badius (Basidiomycetes). The
average contents of
L
-theanine throughout the tea plants range
from 1.2 to 6.2 mg/g fresh weight. Chemically theanine is
L
-
g
-
glutamyl ethylamide or 5-N-ethyl-glutamine, with two chimeric
forms, which is principally synthesized in the root of tea and
accumulated in the leaves that are consumed as beverages.
Theanine acts on so many physiological processes of human
system in specified and limited doses
[1,2]
.
The different physiological disorders include different life-
style associated diseases, one of which is diabetes. In India,
diabetes is one of the potential epidemics with more than 62
million peoples currently suffering from this disease. In 2000,
India ranked (31.7 million) top in the world with the highest
prevalence of diabetes mellitus, followed by China (20.8
million) and United States (17.7 million). The prevalence of
diabetes is predicted to double globally from 2000 to 2030 with
a maximum increase in India followed by China and United
States
[3,4]
.
Apart from diabetes, cardio-vascular diseases (CVD) and tu-
mor for both malignant and benign are the great challenges in
modern medical therapies. World Health Organization (WHO)
have targeted 25% reduction of all non-communicable diseases
(NCD) which cause 82% death worldwide, including cardio-
vascular diseases, cancer, chronic respiratory diseases and dia-
betes. WHO also targeted 25% decrease in hypertension in young
as well as elder. To combat and successfully complete the targets,
it is necessary to search a proper potent health supplement and
theanine may be one of the potent options in medical science
[5]
.
In modern therapeutics, bioavailability of the bioactive
compound is a great concern for preparation of novel antibiotics
or health supplements. The high bioavailability and alleviation
of many physio-biological complications of human health make
theanine suitable for its acceptance as therapeutic and health
supplement. It can alleviate many physio-biological complica-
tions of human health. Advances in pharmacokinetics, pharma-
cological and physiological functions and biosynthesis of
theanine are reviewed and summarized in this article. Industrial
production of the bioactive compound has a huge financial
prospect to flourish the economics health of a nation
[6]
.
*Corresponding author: Vivekananda Mandal, Department of Botany, University
of Gour Banga, Malda 732 103, W.B., India.
Tel: +91 9679 008986
Fax: +91 03512 223666
E-mail: vivekugb@gmail.com (V. Mandal).
Peer review under responsibility of Hainan Medical University. The journal
implements double-blind peer review practiced by specially invited international
editorial board members.
Contents lists available at ScienceDirect
Asian Pacific Journal of Tropical Biomedicine
journal homepage: www.elsevier.com/locate/apjtb
Asian Pac J Trop Biomed 2017; ▪(▪): 1–61
2221-1691/Copyright © 2017 Hainan Medical University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://
creativecom mons.org/li censes/by-nc -nd/4.0/).
Please cite this article in press as: Adhikary R, Mandal V, L-theanine: A potential multifaceted natural bioactive amide as health supplement, Asian Pac J Trop Biomed (2017), http://dx.doi.org/10.1016/
j.apjtb.2017.08.005
2. Statement of interest
Tea, which is the second most consumed beverage in the
world, contains considerable amount of theanine (1.0%–2.5%)
in dry weight of leaves, which is consumed regularly through the
preparation of green tea. Beneficial bioactive property helps to
cure several biological disorders in a cost-effective manner and
act as a potential health supplement. Industrial production of
theanine has high market value and carries economic impor-
tance. The present study emphasized on the economic impor-
tance of this bioactive compound and its efficacy against
different biological and histopathological as well as psychiatric
anomalies. This review suggests the intake of Theanine both as
drugs and green tea in considerable doses and quantities
respectively in present stressful environment to live healthier
and more joyful.
3. Biosynthesis
L
-theanine contains molecular formula C
7
H
14
N
2
O
3
with
molecular weight of 174.20 Da and carries melting point of 214–
215
C. The odorless, slightly sweet tasted white crystalline
L
-
theanine is transparent, colorless, water soluble in nature. The-
anine biosynthesis in tea starts with the amino acid and alanine
presented in higher amount in root, with the enzyme alanine
decarboxylate and produces ethylamine mostly found in leaves.
Another free amino acid is glutamic acid, mainly found in stem,
reacts with ethylamine to produce theanine. Leaves of tea act as
sink of theanine although roots are the source of the free non-
essential amide amino acid theanine (Table 1)
[7]
.
4. Bioavailability
Theanine especially
L
-theanine when ingested either in
capsulated form or an aqueous solution of tea, is distributed not
only in human plasma level but also in the other tissues, and is
metabolized in the form of glutamate and ethylamine, because
their concentrations in plasma level are increased and found in
the urine
[8]
. Metabolic fate of
L
-theanine in rat model, after
infestation of
L
-theanine, glutamic acid and ethylamine is
found in the plasma and also in urine in dose dependent
manner
[9,10]
.In vitro, synthesis of theanine, large amount of
glutamic acid and ethylamine are produced after
L
-theanine
incubation with either glutaminase or
g
-glutamyl
transpeptidase (GGT)
[11]
. Incubation of
L
-theanine with
homogenate from rats' kidney, increased concentration of
ethylamine and glutamic acid were observed
[9,12]
, whereas
not from small intestine, liver, and brain. In the metabolic
aspect,
L
-theanine is metabolized in vitro to equimolar
amounts of ethylamine
[11]
. After intake of 24 h as capsule or
tea, the mean excretion of
L
-theanine refers 47 and 54% of
ingested one. Thus, the bioavailability of
L
-theanine remains in
between 47% and 54%
[8]
.
5. Pharmacokinetics of theanine
Theanine is chemically a chiral compound with two isomers,
L-form and D-form. In natural production, especially in tea, only
L
-theanine is found whereas in synthetic both isomers are pro-
duced. In physiological responses, there are significant differ-
ences between ‘L’and ‘D’forms.
L
-theanine is more readily absorbed than
D
-theanine. It has
been shown that if equal amount of ‘L’and ‘D’form is given
separately to mammals, ‘L’form has almost three times more
absorption capacity than ‘D’form in the plasma level. Also, if
these two forms of this bioactive compound are given at a time
in equal content, the amount of uptake of
L
-theanine content is
much higher than
D
-theanine
[1]
.
L
-theanine and
D
-theanine have mutual antagonism when
they are administered in the system at a time. ‘D’form inhibits
absorption of ‘L’form in the body
[13]
.
Though these two forms of amino acid have lost from the
urinary route,
D
-theanine excretes more readily than
L
-theanine,
and the rate of excretion is about 10–15 times more in ‘D’form
than that of L form, while both are consumed either through
orally or injected in peritoneum in equal amount that resulted the
body becomes readily dehydrated
[13,14]
.
In plasma
D
-theanine degradation occurs more quickly than
L
-theanine. Both ‘D’and ‘L’theanine are partially degraded into
ethylamine and glutamic acid, which is catalyzed by a
phosphate-independent glutaminase in the kidney
[13]
.
Structurally theanine is similar to the excitatory neurotrans-
mitter glutamate which binds to glutamate receptors with weak
interaction in the micromolar range, including the
a
-amino-3-
hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kai-
nate receptors, and to a lesser extent, the N-methyl-
D
-aspartic
acid (NMDA) receptor
[15–18]
. Theanine acts antagonistically of
the former two sites
[16]
and as an agonist of the latter site
[19]
,
binds to group I metabotropic glutamate receptors (mGluRs)
[15,20]
and has an inhibitory activity on glutamine transporters
which accordingly blocks the reuptake of glutamine and
glutamate
[18,21,22]
. Finally, theanine elicits umami or savory
taste results direct binding and activates the T1R1 + T1R3
heterodimer or umami (savory) taste receptor
[23,24]
.
6. Mode of action of
L
-theanine
Theanine is basically non-toxic for all mammalian cells to a
certain level of intake and there has been no adverse effect in
physiological and histopathological characteristics
[1,25]
.
Theanine in ‘L’form has very unique mode of action in the
mammalian systems, as mentioned below.
Table 1
Amino acids content value of different plant parts (
m
mol/g fresh tissues ± SD) of 6 months old seedling of tea.
Organ Ethylamine Alanine Theanine Glutamic acid Glutamine Aspartic acid Asparagine
Cotyledons 0.55 ± 0.35 2.26 ± 0.68 11.38 ± 0.81 1.79 ± 0.58 1.42 ± 0.57 1.39 ± 0.09 0.28 ± 0.05
Roots 0.66 ± 0.12 3.05 ± 0.16 39.00 ± 4.74 1.68 ± 0.32 1.56 ± 0.21 0.91 ± 0.13 0.20 ± 0.02
Leaves 0.88 ± 0.07 0.55 ± 0.06 14.96 ± 1.95 2.3 ± 0.36 1.00 ± 0.05 1.77 ± 0.26 0.44 ± 0.15
Stems 0.44 ± 0.02 0.95 ± 0.17 33.85 ± 3.68 2.39 ± 0.59 8.19 ± 1.14 1.64 ± 0.75 0.44 ± 0.02
Fresh weights (g) per organs are as follows: Cotyledons, (1.11 ± 0.18); roots, (1.05 ± 0.03); leaves (0.52 ± 0.08); stems, (0.53 ± 0.02)
[7]
.
Rajsekhar Adhikary, Vivekananda Mandal/Asian Pac J Trop Biomed 2017; ▪(▪): 1–62
Please cite this article in press as: Adhikary R, Mandal V, L-theanine: A potential multifaceted natural bioactive amide as health supplement, Asian Pac J Trop Biomed (2017), http://dx.doi.org/10.1016/
j.apjtb.2017.08.005
L
-theanine increases dopamine and serotonin production in
the brain
[26]
and induces relaxation through the enhancement of
alpha wave activity in brain.
L
-theanine, as chemotherapeutic agent, competitively inhibits
glutamate transport into the infected tumor cells, can also
decrease intracellular glutathione (GSH) levels. The efflux of
chemotherapeutic agents (e.g. doxorubicin, idarubicin, cisplatin,
irinotecan) are inhibited by theanine, which causes them to
accumulate in tumor cells and to protect normal cells from
damage by these drugs through its antioxidant property and
maintaining cellular GSH level
[22,27–29]
.
L
-theanine can counteract the stimulatory effect of caffeine.
In rats, after caffeine administration intravenously with theanine
at the same dose, the stimulant effect of caffeine was blunted.
Whereas given by normal dose of caffeine with a smaller dose of
theanine administration resulted in excitatory effects of caffeine,
which suggested a dose specific dual activity of theanine
[30]
.
A dose-dependent hypotensive effect was occurred in sponta-
neously hypertensive rats injected with
L
-theanine in vivo
[31]
whereas structurally similar to theanine, glutamine administration
made unaltered blood pressure
[32]
.
7. Dosesand physiological effects applied for
L
-theanine
in mammals
Functionally
L
-theanine especially crossing the blood brain
barrier, is measurable in a range from 30 min and up to 5 h after
ingestion
[10,11,33]
, which is metabolized in the kidneys to
glutamate and ethylamine
[34]
. Recent studies referred
anxiolytic effect of single dose of theanine up to 200–250 mg
per day and it may be extended up to 1 250 mg/day
[9,12,35–37]
.
But there is no such specified dosage of
L
-theanine suggested
for enhanced immune system functions in mammalian systems.
8. Physiological effects of
L
-theanine
L
-theanine has multifaceted physiological effects on human
health. A brief account of these effects is mentioned below.
8.1. Neuroprotection
Theanine helps to protect neural damage and improve function
by reduction of cerebral infarction by inhibiting different neuro-
logical functions like catalase (CAT), superoxide dismutase
(SOD), and succinate dehydrogenase (SDH) activity, thus reduces
glutathione (GSH) and oxidative damage of neuronal cells
[36–38]
.
It protects brain from cerebral ischemia
[39]
, and prevents brain
injury mediated by glutamate receptor agonist
[40]
and inhibits
cerebral cortical neuron involvement in delayed neuronal death
(DND). Neuroprotective role by regulation of group I mGluR
through stimulating the expression of phospholipase C-
b
1
(PLC-
b
1) and phospholipase C-
g
1 (PLC-
g
1)
[20]
by
L
-theanine,
resulted in decrease in efficacy of neurotoxin-induced neurotox-
icity, oxidative stress and also Parkinson's (PD) and Alzheimer's
diseases (AD). DNA fragmentation and nerve cell (SH-SY5Y)
apoptosis are also reduced by
L
-theanine
[41–43]
.
8.2. Hypotensive activity
In adults,
L
-theanine can serve as a hypotensive agent with
anti-stress activity, acting on suppression of cortical neuron
excitement, reduction of anxiety and control rising of blood
pressure in high stress condition
[34]
. Theanine showed
hypotensive effect on spontaneous hypertensive rat
[44,45]
.
L
-
theanine showed the hypotensive activity made by the increase
of 5-hydroxytryptamine (5-HT) levels through the regulation
of peripheral nerves and vascular system. Theanine is accumu-
lated in the animal brain and reduce the levels of brain 5-HT and
its metabolite 5-hydroxy indole acetic acid (5HIAA)
[46]
.
8.3. Anti-diabetic effects
Diabetes is principally occurred by the abnormality of zinc
metabolism, which is important for protecting heart suffering
from diabetic myocardial complications from oxidative stress.
Supplements of zinc are very crucial for treatment to prevent
cardiac-oxidative damage and delay diabetic cardiomyopathy.
Theanine-zinc compound makes a zinc complex and acts as a
zinc supplement to maintain hypoglycaemic effect
[47,48]
.
8.4. Anti-fatigue effects
L
-theanine causes rise of the concentrations of dopamine (DA)
and hepatic glycogen, and reduction of concentrations of 5-HT
and serum urea are resulted in the alleviation of physical fatigue.
Prolonged theanine treatment reduces 5-HT, serum urea and
lactate, as well as increases DA and hepatic glycogen levels
[49]
.
8.5. Anti-tumor effects
First, Theanine inhibits biosynthesis of the glutamate trans-
port protein and intracellular glutathione, resulting in less
glutathione doxorubicin conjugate (GS-DOX) of the multidrug
resistance-associated protein-5/GS-X (MRP5/GS-X) pump, and
less intercellular transport of doxorubicin (DOX), which is
beneficial in effect of anti-tumor drugs
[28,50]
.
L
-theanine
enhances anti-tumor effects of cisplatin on mouse M5076 cells
[9]
, and it shows significant suppressive effects on tumors with
combination of Irinotecan hydrochloride, whereas irinotecan
hydrochloride alone has no anti-tumor effect.
Second,
L
-theanine relieves the toxic side effects induced by
some anticancer drugs through reduction of the activity of enzyme
glutathione peroxidase and lipid peroxidation levels induced by
the drug DOX, results less super oxidative stress
[29,35]
.
And thirdly, theanine derivatives inhibit tumor growth by
targeting epidermal growth factor receptor/vascular endothelial
growth factor receptor-Akt/nuclear factor-kappa B (EGFR/
VEGFR-Akt/NF-kappa B) signaling pathways, which involves
in controlling the survival and proliferation of cells.
L
-theanine
derivatives ethyl 6-fluorocoumarin-3-carboxylyl
L
-theanine
(TFC) and ethyl 6-nitrocoumarin-3-carboxylyl
L
-theanine (TNC)
can effectively inhibit the cell growth of lung cancer by targeting
these pathways
[51,52]
.
8.6. Anti-depressant effects
L
-theanine has a convincing effect on anxiety and depression.
Intake of
L
-theanine after weaning prevents mice from stress-
induced impairments of hippocampal long-term potentiation
(LTP) and improves recognition memory
[53]
. The antidepressant
mechanism of
L
-theanine involving heart rate reduction and
salivary immunoglobulin A (s-IgA) decrease responses to an
acute stress task. The reduction in heart rate and s-IgA mediate
attenuation of the sympathetic nerve activation or suppression
of the excitation of cortical neuron
[53–56]
.
Rajsekhar Adhikary, Vivekananda Mandal/Asian Pac J Trop Biomed 2017; ▪(▪): 1–63
Please cite this article in press as: Adhikary R, Mandal V, L-theanine: A potential multifaceted natural bioactive amide as health supplement, Asian Pac J Trop Biomed (2017), http://dx.doi.org/10.1016/
j.apjtb.2017.08.005
8.7. Anti-oxidant activity
L
-theanine can oxidize LDL cholesterol to some extent. Lipid
peroxidation marker mediated assay of malondialdehyde inhibit
LDL oxidation with theanine in vitro, although the effect was
weaker than the potent antioxidant effect of green tea poly-
phenols
[57]
.
8.8. Improving immunity
L
-theanine with
L
-cystine can enhance serum IgG and
antigen-specific IgM levels. A combined administration of
L
-
theanine and
L
-cystine in the human system
[58]
enhances the
immunity to influenza vaccine in elderly persons with low
hemoglobin by orally
[59]
and also alleviates post-gastrectomy
inflammation and promotes recovery after surgery during the
perioperative period
[60]
.
8.9. Alleviation of liver injury induced by alcohol
Excessive alcohol uptake causes liver injury, increases free
radicals and lipid peroxide (LPO) levels, and declines the ac-
tivity of glutathione peroxidase. To alleviate alcohol-induced
liver injuries, theanine increases aldehyde dehydrogenase and
alcohol dehydrogenase activity, declines cytochrome P450 CYP
2E1
[61]
.
L
-theanine improves the hepatic indices by raising the
activities of CAT, GSH and SOD with a reduction of MDA level
in the liver. Moreover, administration of
L
-theanine significantly
ameliorates the hepatic function and declines the level of tumor
necrosis factor-
a
in the liver
[62,63]
.
8.10. Protective effects on the cardiovascular system
Consumption of
L
-theanine improves vascular function and
decreases the risk of cardiovascular disease. The protective ef-
ficacy of the compound can reduce serum cholesterol
[64]
, rise
artery vasodilation and production of nitric oxide
[65]
, and
protect brain from cerebral ischemic injury. Alleviation of
serum cholesterol levels can reduce the risk of coronary heart
disease (CHD) by the application of
L
-theanine, which can
significantly decrease the levels of abdominal adipose, liver
cholesterol, serum neutral fat and cholesterol
[64]
.
8.11. Improvement of memory
L
-theanine promotes the maturity of nervous centralis during
the neural maturation period, which is beneficial for brain
development
[11,12]
, ameliorates learning and memorizing ability
by elimination of acquired memory disorders, oxidative stress,
and improves the brain
a
-wave
[66]
. Cognitive functions can
be enhanced by bioactive compound through the rise of brain
neurotransmitters such as dopamine, 5-hydroxytryptamine (5-
TH), glycine and
g
-aminobutyric acid (GABA)
[67,68]
.
8.12. Reduction of menstrual discomfort
The menstrual discomfort can be reduced by
L
-theanine
considerably. The target population with premenstrual syn-
drome, have experienced reduction of menstrual discomfort with
the intake of
L
-theanine
[69]
.
8.13. Maintenance of normal sleep
L
-theanine helps to maintain normal sleep for better brain
development and thus results in better mental and cognitive
health. The effect was examined on a target population and
considered beneficial for maintenance of normal sleep
[69]
.
9. Side effects of
L
-theanine
L
-theanine in mammalian system is generally well tolerated,
and has a high LD
50
value (5000 mg/kg) and it is non-mutagenic
or non-carcinogenic agent in animal cells or bacteria.
10. Market demand and artificial preparation of
L
-theanine
Artificial chemical synthesis of
L
-theanine (purity
level 98%) comes from food-grade
L
-glutamic acid and eth-
ylamine with the solvent system as purified water and ethanol.
The major source of theanine is tea containing 1.0%–2.5% of
dry weight of leaves and the average daily demand is 667–
1 668 mg/day in United States according to Taiyo International,
Inc. by JHEIMBACH LLC. To mitigate the huge demand, large
scale production is very essential for smooth supply of
L
-the-
anine as a food supplement. Though there are some other fungal
sources, but the theanine content is very low compared to tea
leaves. For large scale production, the most accepted three
processes are stated here.
The first production procedure was adopted and patented by
Taiyo International, Inc. by JHEIMBACH LLC where biolog-
ical or green synthesis of the bioactive compound was carried
out. It includes a treated organism which is aerobically cultured
in a glucose and yeast extract medium. Glutamine, ethylamine,
and glutamic acid are derived from raw materials, as well as
ammonia produced during the reaction, as impurities. The other
compounds, if presented, can be detected by the HPLC. But the
disadvantage is the total production system is completely
dependent on glutamic acid which is produced by bacterial
culture of Bacillus subtilis or Bacillus amyloliquefaciens and the
production is quite low.
The second large and facile production system of
L
-theanine
was as followed:
g
-Benzyl glutamate prepared by dissolving in
pyridine and trityl chloride (1.28 eq) was added to the solution
[70]
. To some successive treatments
L
-theanine was obtained as
white crystals through the crystallization of the residue by the
treatment of hot ethanol, and followed by re-crystallization of
ethanol–water treatment. Though in this chemical synthesis
method we get targeted product in a crystalline form, the pro-
duction method is very much time consuming.
Another efficient method of industrial production through
chemical synthesis process was developed by Zhejiang Tianrui
Chemicals Co., Ltd., where the required time is not exhaustive,
the whole system is well balanced, and a patent was awarded on
this production system.
11. Conclusion and future direction
L
-theanine, a non-essential bioactive amino acid, is very
much beneficial to sustain in the stressful environment. Simul-
taneous intake of different medicine and food supplement may
reduce the health damage in a considerable limit. The mitigating
Rajsekhar Adhikary, Vivekananda Mandal/Asian Pac J Trop Biomed 2017; ▪(▪): 1–64
Please cite this article in press as: Adhikary R, Mandal V, L-theanine: A potential multifaceted natural bioactive amide as health supplement, Asian Pac J Trop Biomed (2017), http://dx.doi.org/10.1016/
j.apjtb.2017.08.005
activity of
L
-theanine against non-communicable diseases like
cancer, cardiovascular disorder, respiratory anomalies, and dia-
betes may be useful in the current situation. High blood pressure
and the others complications can be reduced by using
L
-theanine
in a constant dose as food supplement. Pharmacokinetics,
bioavailability and mode of action in mammalian system are
discussed in this review. In accordance to the benefits of
L
-
theanine, the industrial production system and the probable
effective system is discussed elaborately in this content. The
consumption of
L
-theanine can reduce the chance of application
of different drugs which have different critical side effects.
Summarily in this review the beneficial role of the bioactive
compound serves as a good heath supplement in daily con-
sumption of higher combating power for both male and female.
In this regards,
L
-theanine will become a very effective supple-
ment in development of food and drugs in modern days.
Conflict of interest statement
We declare that we have no conflict of interest.
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j.apjtb.2017.08.005