DIVERSE POTENTIAL AND PHARMACOLOGICAL STUDIES OF ARGININE

Abstract

Arginine is metabolically flexible amino acid with major role in protein synthesis and detoxification of ammonia. It is involved in several metabolic pathways for the production of biologically active compounds such as creatine, nitric oxide, ornithine, glutamate, agmatine, citrulline and polyamines. Regarding this all, we review the crucial role of arginine in metabolism, diversified prospective uses and pharmacological applications. Arginine plays an important role in the treatment of tumorigenesis, asthama, gastric, erectile dysfunction, apoptosis, melanoma and congestive heart failure. Ability to produce nitric oxide offers various applications as in the prevention of age and hair loss. It serves as a precursor of creatine with ergogenic potential. The ability to increase endogenous growth hormone makes arginine a preferred supplement for the improvement of physical performance. In the present study details about the pharmacological applications of arginine based on modern scientific investigations have been discussed. There are immense properties hidden in arginine that need to be explored using the scientific investigations to make it beneficial for the medicine and human health. More research is needed to evaluate the role of arginine supplementation on exercise performance and training adaptations in healthy and diseased populations before taking any conclusions.

Full text

J P P
JOURNAL OF PROTEINS AND PROTE OMICS
6(3), 2015, pp. 237-243
Corresponding Author: Nidhi Srivasta va
E-mail: nidhiscientist@g mail.com
Received: May 14, 2015
Accepted: August 21, 2015
Published: August 25, 2015
Review Article
DIVERSE POTENTIAL AND PHARMACOLOGICAL STUDIES OF ARGININE
Anju Meshram and Nidhi Srivastava*
Department of Bioscience and Biotechnology, Banasthali University, Banasthali- 304 022, Rajasthan, India
Abstract: Arginine is metabolically flexible amino acid with major role in protein synthesis and detoxification of
ammonia. It is involved in several metabolic pathways for the production of biologically active compounds such
as creatine, nitric oxide, ornithine, glutamate, agmatine, citrulline and polyamines. Regarding this all, we review
the crucial role of arginine in metabolism, diversified prospective uses and pharmacological applications. Arginine
plays an important role in the treatment of tumorigenesis, asthama, gastric, erectile dysfunction, apoptosis,
melanoma and congestive heart failure. Ability to produce nitric oxide offers various applications as in the
prevention of age and hair loss. It serves as a precursor of creatine with ergogenic potential. The ability to increase
endogen ous growth hormone makes arginine a prefer re d supplement for the improvement of physical
performance. In the present study details about the pharmacological applications of arginine based on modern
scientific investigations have been discussed. There are immense properties hidden in arginine that need to be
explored using the scientific investigations to make it beneficial for the medicine and human health. More research
is needed to evaluate the role of arginine supplementation on exercise performance and training adaptations in
healthy and diseased populations before taking any conclusions.
Keywords: Arginine; nitric oxide; pharmacology; metabolism
Introduction
L-Arginine is a basic natural amino acid engaged
in several metabolic pathways within the human
body (Figure 1). Glutamine is an important
precursor for de nove synthesis of arginine in
humans (Ligthart-Melis et al., 2008). Arg is a
substrate for protein synthesis but also modulates
cellular biochemical functions via conversion to
a number of biologically active compounds such
as urea, polyamines, proline, glutamate, creatine
and agmatine (Morris, 2006). Arg is utilized by a
vast variety of metabolic pathways that produce
a variety of biologically active compounds such
as nitric oxide, creatine phosphate, ornithine, and
citrulline (Tong and Barbul, 2004).
The maintenance of plasma arginine levels is
primarily dependent upon its synthesis in the
kidney and dietary intake. Dietary arginine is not
essential in healthy adult humans, demonstrating
the utility of the kidney in this regard. However,
it becomes ‘essential’ in conditions of starvation,
in ju ry or s tress (Barbul , 1986). Arginin e
supp lementa tion is therefore bene ficial in
path o physiolog ic set tings where systemic
arginine levels decrease, such as in models of
wound healing, lymphocyte respo nses and
mitogenesis (Satriano 2004). Arginine is finding
a wide range of applications in production of
proteins. Arginine has been used for many years
to assist protein refolding. This effect was ascribed
to aggregation suppression by arginine of folding
intermediates during protein refolding (Tsumoto
et al., 2005).
Arg i nine has various p h armacological
applications such as tumorigenesis, asthama,
gastric, erectile dysfunction, apoptosis, melanoma

238 Journal of Proteins and Proteomics
and congestive heart failure. Remarkable uses of
Arg can be seen in the prevention of hair loss,
anti-aging, role in cell division, improvement of
memory and cognitive functions.
Arginine sources
Arginine can be manufactured by the human
body, and does not need to be obtained directly
through the diet. The biosynthetic pathway
however does not produce sufficient Arg, and
some must still be consumed through diet.
Legumes, seeds and nuts are usually rich in
arginine. The richest source by dry weight is
sunflower seeds, followed by carob and butternut
squash. Other rich sources are pumpkin seeds,
sesame seeds, soybeans, watercress, peanuts,
fenugreek, mustard seeds, almonds and Indian
figs (Watson and Zibadi, 2012). But the research
on Arg refers to supplementation with the free
amino acid, which is different from how arginine
appears in sunflower seeds and other foods. In
food, amino acids are linked together by the
hundreds or even thousands and must be broken
down to be used by the body. In other words, the
arginine present in sunflower seeds, nuts, and
legumes within the structure of the proteins, so
it cannot be replaced by the synthesized free
arginine used for scientific trials (Leigh, 1998).
Arginine methylation
Arg i nine me t h ylatio n is a common p ost
translational modification. It occurs on both
cy to plasmic and nucl ear proteins, and is
particularly abundant on shuttling proteins. Arg
methylation of the interior histone tails plays
various roles in regulating chromatin function.
Arginine methyltransferases, a family of protein,
is a su bset ta rget histones that catalyze
methylation reactions (Lorenzo and Bedford,
2011). Protein arginin e methyltran sferase 6
(PRMT6) is a member of the protein arginine
meth y ltrans ferase (RMT) family, whi ch
comprises 45 enzymes, nine of which are known
to catalyze protein arginine N-methylation
reactions. These post-translational modifications
are important regulators of RNA processing,
transcriptional regulation, signal transduction,
and other cellular processes (Figure 2) (Mitchell
et al., 2015)
Arginine metabolism
Arginine is metabolized through a complex and
highly regulated set of pathways that remain
incompletely understood at both the whole body
and the cellular levels. The partial reactions of the
urea cycle, th e L-arginine-NO pathway , a
citrulline-NO cycle, and a branch point leading
to the formation of guanidino compounds in Arg
metabolism occurs in the conifers in eastern
Canada (Durzan, 2009). Adding to the metabolic
comple xity is the fact that limited arginine
availability can selectively affect the expression
of specific genes, most of which are involved in
some aspect of Arg metabolism (Morris, 2006).
Arginine has numerous metabolic fates and
thus is one of the most multipurpose amino acids.
It is metabolically inter convertible with the
Figure 1: Chemical structure of the two isoforms of arginine:
D-Arginine and L-Arginine
Figure 2: Ribbon representation of the crystal structure of
human protein arginine methyltransferase PRMT6 bound to
SAH and an aryl pyraz ole inhibitor (PDB ID: 4Y2H)

Diverse prospectives of arginine 239
amino acids proline and glutamate, and also
serves as a precursor for urea, protein synthesis,
nitric oxide, agmatine, creatine and polyamines
(Figure 3, 4). These processes do not all occur
within each cell but are differentially expressed
according to age, cell type, diet, developmental
stage and state of health or disease. Currently the
picture of Arg metabolism is imperfect and
incomplete for any mammalian species. Complete
understanding of arginine metabolism will
require integration of information obtained from
multiple ap proaches, including genomics,
proteomics, and metabolomics (Morris, 2007).
Ar ginine me thylation con tributes t o
tumourigenesis
In the field of infectious diseases the multifaceted
amino acid Arg has reached special attention as
subs t rate for th e ho st prod uction of t he
antimicrobial agent nitric oxide. A variety of
infectious organisms interfere with this part of the
ho s t im m une response by reducin g the
availability of Arg (Blackwell and Ceman, 2012).
E2F transcription factors are implicated in
diverse cellular functions. The founding member,
E2F-1, is endowed with contradictory activities,
being able to promote cell-cycle progression and
induce apoptosis. However, the mechanisms that
unde rlie the opposing outcomes of E2F-1
activation remain largely unknown. E2F-1 is
directly methylated by protein argini ne
methyltransferase 5 and arginine methylation is
responsible for regulating its biochemical and
functional properties, which impacts on E2F-1-
dependent growth control. Arginine methylation
in fluen ces E2F-1 protein sta bility and the
en h a n ced transcr iption of a variety of
downstream target genes reflect increased E2F-1
DNA-binding activity. Importantly, E2F-1 is
methylated in tumour cells, and a reduced level
of methylation is evident under DNA damage
conditions that allow E2F-1 stabilization and give
rise to apoptosis. Arg methylation regulates the
biological activity of E2F-1 activity, and raise the
possibility that arginine methylation contributes
Figure 3: Pictorial representation of arginine as a precursor
for various compounds such as urea, protein, nitric oxide,
agmatine, creatine and polyamines
Figure 4: Biosynthetic pathway for the metabolism of arginine
Pharmacological applications
Arginine contributes in various pharmacological
app lica tions like tumourigenesis, obe s ity,
asthama, melanoma, gastric environment, erectile
dys f u nctio n, progra mm ed cell d eath and
congestive heart failure (Figure 5). Arginine’s NO-
stimulating effects can be utilized in therapeutic
regimens for angina pectoris, congestive heart
failure, hypertension, coronary heart disease,
preeclampsia, intermittent claudication, and
erectile dysfunction. In addition, Arg has been
studied in the treatment of HIV/AIDS, athletic
performance, burns and trauma, cancer, diabetes
and syndrome X, gastrointestinal diseases, male
and fem a le infertility , int erstitial cystitis ,
im m u n omodulat ion, a n d s enile dementia
(Appleton, 2002).
Fi g ur e 5: Pi ctor i al rep r esen tatio n for t he d i ffer ent
pharmacological applications of arginine

240 Journal of Proteins and Proteomics
to tumourigen esis by influencing the E2F
pathway (Cho et al., 2012).
Nitric oxide- link between obesity and asthama
via arginine
Obesity adversely affects asthma severity and
control by mech anisms that are not fully
understood. Nitric oxide plays a role as a potential
mechanistic link between obesity and late onset
asthma (>12 years). There is an inverse association
between increasing body mass index and reduced
exhaled nitric oxide. This is related to nitric oxide
synthase uncoupling, which occurs due to an
imbalance between L- Arg and its endogenous
in hibito r, asymmetr i c dimethyl arginine
(Holguin, 2013).
Arginine and melanoma
Des p ite recent dev elopment of promis ing
im m u n othera peutic a n d targete d drugs,
prognosis in patients with advanced melanoma
remains poor, and a cure for this disease remains
elusive in most patients. The success of melanoma
therapy depends on a better understanding of the
biology of melanoma and development of drugs
that effectively target the relevant genes or
proteins ess e ntial for tu m or cell su rvival.
Melanoma cells frequently lack argininosuccinate
synthetase, an essential enzyme for Arg synthesis,
and as a result they become dependent on the
availability of exogenous Arg. Accordingly, a
therapeutic approach involving depletion of
available arginine has been shown to be effective
in preclinical studies. Early clinical studies have
demonstrated sufficient antitumor activity to give
rise to cautious optimism (Yoon et al., 2012).
Arginine in programmed cell death
Programmed Cell Death 4 (PDCD4) has been
described as a tumor suppressor, with high
expression correlating with better outcomes in a
number of cancer types. Yet a substantial number
of cancer patients with high PDCD4 in tumors
have poor survival, signifying that oncogenic
pathways may inhibit or change PDCD4 function.
PDCD4 has significance in breast cancer and
Protein Arginine Methyltransferase 5 (PRMT5)
acts as a cofactor that radically alters PDCD4
function. Co-expression of PDCD4 and PRMT5
in an orthotopic model of breast cancer causes
accelerated tumor growth and that this growth
phenotype is dependent on both the catalytic
activity of PRMT5 and a site of methylation
within the N-terminal region of PDCD4. These
results reveal a new cofactor for PDCD4 that alters
its tumor suppressor functions and point to the
utility of PDCD4/PRM T5 stat us as both a
prognostic biomarker and a potential target for
chemotherapy (Powers et al., 2011).
Arginine in gastric environment
The Arg-dependent extreme acid resistance
system helps enteric bacteria survive the harsh
gastric environment. At the center of this multi-
protein system is an arginine-agmatine antiporter,
AdiC. To maintain cytoplasmic pH, AdiC imports
arginine and exports its decarboxylated product
agmatine, resulting in a net extrusion of one
“virtual proton” in each turnover. The random
orientation of AdiC in reconstituted liposomes
throws up an obstacle to quantifying its transport
mechanism (Tsai et al., 2012).
Erectile dysfunction and arginine
Th ere are only very few reports on the
improvement of erectile function by L- Arg
administration. A study by Chen et al. (1999)
revealed a significant subjective improvement in
sexual function in men with organic erectile
dysfunction (31% of cases) after oral intake of 5 g
l-arginine for 6 weeks, but only if they had
decreased NOx excretion or production. Other
stu d ies h ave shown that long ter m oral
administration of pharmacological doses of L-
Arg improves the erectile response in the aging
rat (1997) as well as in patients with erectile
dysfunction (Melman, 1997; Zorgniotti and Lizza,
1994). However, Klotz et al. (1999) reported in a
controlled crossover study that oral L- Arg at
3×500 mg/day was not better than a placebo as a
first line treatme nt for th e mixe d ty pe of
impotence.
Arginine in congestive heart failure
L- Arginine may improve cardiac performance in
people with congestive heart failure, according
to a 2000 study published in Clinical Cardiology.
L- Arg exerted a negative chronotropic effect and

Diverse prospectives of arginine 241
improved systemic hemodynamic condition
without affecting contractility. Nitric oxide
inhalation increased pulmonary capillary wedge
pressure and did not change systolic and diastolic
cardiac function in severe cardiomyopathy. Our
results should encourage further investigations
to determine whether endothelial dysfunction in
heart failure can be attenuate d or partially
reversed by L- Arg for a new therapeutic option
(Bocchi et al., 2000).
Role of L-Arginine in other phy siological
response
Arginine as a good source of pharmacological
activities also plays a vital role in other biological
process (Figure 6).
Role of arginine as a precursor to other molecules
Arginine is the immediate precursor of nitic
oxide, urea, ornithine and agmatine; is necessary
for the synthesis of creatine; and can also be used
for the synthesis of polyamines (mainly through
or nithine an d to a lesser degree t hr ough
agmatine), citrulline, and glutamate. For being a
precursor of nitric oxide, (relaxes blood vessels),
Arg is used in many conditions where
vasodilation is required (Tapiero et al., 2002).
Arginine in nervous system
Arginine may be useful for the treatment of
Alzheimer’s disease (due to its ability to repair
damaged Axons by increasing polyamines levels)
(Tarkowski et al., 2000). Arg has also been reported
to present a hydrophobic environment and exist
in a supramolecular assemblies and binds to
Alziemer’s amyloid beta 1-42 (A�1-4 2) which
modulates the hydrophobicity of A�1-42 molecule
and suppress fibrillar suppression (Das et al., 2007).
Arg (combined with Lysine) may reduce stress
induced anxiety (Samriga et al., 2007). Arg may be
essential for the regeneration of damaged axons
of neurons (its role appears to be as an agent for
degrading proteins that have been damaged
through axon injury) (Cestaro, 1994). It may
facilitate the potency of long term memory (by
stimulating the production of nitric oxide, a
Neurotransmitter responsible for the potentiation
(storage) of long term memory (Pautler, 1994). Arg
improves memory and cognitive functions.
(Pandhi and Balakrishnan, 1999). Arginine
improves pituitary responsiveness and modulates
hormonal control (di Luigi et al., 1999).
Cytotoxic role of arginine
Other reported effects of L- Arg include increased
quantity and cytotoxic capability of lymphokine-
activated and natural killer T-cells in breast cancer
(Brittenden et al., 1994). Specifically, patients with
cancer have reduced levels of L- Arg due to the
increased production of arginase I, causing a
decrease in T-cell proliferation and impaired T-
cell function. One study found a reduction in
stimulated T-cell proliferation when cultured
without L- Arg. However, the addition of L- Arg
or citrulline allowed for recovery of T-cell
proliferation. The investigators concluded that
Arginine helps to prevent hair loss
The vasodilatory effect of Arg promotes hair
growth as the nitrogen oxide generated from Arg
opens the potassium channels of the cells. The
blood supply to the hair root is then improves,
which in turn stimulates hair growth (Watson and
Zibadi, 2013). Arg helps to produce keratin and
helps to minimize disease-related hair loss by
enhancing immune function. It also protects the
hair from the damaging effects of hair colouring
and bleaching (Ohimura and Ino, 2004).
Arginine inhibits ageing
Arg i nine may inhibit one of the primary
mechanisms of the aging process cross-linking
(Radner et al., 1994). Arg increases the release of
the human growth hormone (HGH) (also known
as the anti-aging hormone) from the pituitary
gland (Gianotti et al., 2000).
Role of arginine in cell division
Arginine plays an important role in cell division,
the healing of wounds, removing ammonia from
the body, immune function, and the release of
hormones (Bishop et al., 2013).
Figure 6: Role of L-Arginine in physiological response

242 Journal of Proteins and Proteomics
tumor cell regulation of amino acid availability
is possibly what allows these cells to escape the
immune response (Rodriguez et al., 2007).
Ergogenic response
Ergogenic response of arginine has also been
reported by Chromiak and Antonio (2002). The
role of arginine supplementation on healthy and
diseas e d popula tions has to be concluded
(Campbell, 2004).
Side effects of L-arginine
Oral administration of L- Arg (up to 30 g/day) in
humans does not appear to cause any major
adverse reactions, with only infrequent reports
of nausea and diarrhea (Shah and Shah 2004;
Battaglia et al., 2002). In a trial of malnourished
patients with head and neck cancer, the incidence
of diarrhea was higher compared with standard
therapy (de Luis, 2004). No adverse reactions
were reported with L- Arg 9 g/day over 6 months
(Ceremuzyñski et al., 1997). Higher doses may be
associated with a bitter taste and may affect
patient compliance (Chagan et al., 2002).
Conclusion
Various symptoms can be reduced with the help
of arginine, which is a semi-essential amino acid
for good reason and has a decisive impact on
numerous vital processes. Pharmacological use of
arginine in demand today to reduce various
symptoms and it is no longer possible to imagine
orthomolecular medicine without this vital
substance.
Acknowledgement
The authors are thankful to Prof. Aditya Shastri, Hon. Vice
Chancellor, Bana stha li University, for his suppor t and
encouragement. We also thank the authorities of Banasthali
University for providing necessary facilities to conduct this
study.
Abbreviations
Arginine: Arg, NO: Nitric Oxide, PDCD4: Programmed Cell
Death 4, PRMT5: Protein Arginine Methyltransferase 5,
LDL: Low Density Lipoprotein
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