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Role of Phenylalanine and Its Metabolites in Health and Neurological Disorders

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Chapter
Role of Phenylalanine and
Its Metabolites in Health and
Neurological Disorders
MuhammadAkram, MuhammadDaniyal, AatiqaAli,
RidaZainab, Syed MuhammadAli Shah, NaveedMunir
and Imtiaz MahmoodTahir
Abstract
Phenylalanine, an amino acid, is a “building block” of protein. Phenylalanine is
a component of food sources and also derived through supplementation. In current
treatment, phenylalanine is prescribed as anti-depressant agent. The present study
reviewed the possible antidepressant potential of phenylalanine. We reviewed data
using the major databases, namely, Web of Science, SciFinder, Google Scholar, and
PubMed. This manuscript provides a brief overview of the role of phenylalanine in
depressive disorders. Phenylalanine possesses anti-depressant potential. Significant
anti-depressant activities have been studied both in-vitro and in-vivo models. Based on
current data, phenylalanine could be recommended as a potential candidate for clinical
anti-depressant trials. Phenylalanine hydroxylase (PAH) deficiency results in intoler-
ance to the dietetic consumption of the phenylalanine and a variety of syndromes such
as deep and permanent logical disability, impaired cognitive development.
Keywords: depression, phenylalanine, tyrosine, metabolic product of phenylalanine,
diseases related to phenylalanine
1. Background
Phenylalanine is consumed either through food sources or through supplemen-
tation including wheat germ, oats, milk products, and meats. Phenylalanine is a
fundamental amino corrosive and is convertible into tyrosine, however not the
other way around. Transformation of phenylalanine to tyrosine is catalyzed by
phenylalanine hydroxylase which is a blended capacity oxygenase [1]. Adrenaline,
noradrenaline, and dopamine are subordinates of tyrosine. The transformation of
tyrosine in dihydroxyphenylalanine (DOPA) is catalyzed by tyrosine hydroxylase.
Decarboxylation of DOPA to dopamine is catalyzed by DOPA decarboxylase
conversion of neither dopamine to nor epinephrine catalyzed by dopamine—beta-
hydroxylase. Transformation of neither dopamine to nor epinephrine by trans-
methylation is catalyzed by phenylethanolamine-N-methyl transferase. The protein
phenylethanolamine N-methyltransferase is prompted by glucocorticoids in the
adrenal medulla, which acquires glucocorticoids from the adrenal cortex through
entryway course in gigantic amounts. With the goal, that the adrenal medulla has
Synucleins - Biochemistry and Role in Diseases
2
100 times a greater number of glucocorticoids than the plasma. α-Methy I—DOPA
is a drug, which aggressively hinders the chemical DOPA decarboxylase, in this
manner restrains the arrangement of catecholamine and is utilized as a part of the
administration of hypertension. Adrenaline and noradrenaline are the hormones of
the adrenal medulla and have a place with the gathering of mixes called catechol-
amine [2]. They are likewise discharged at postganglionic thoughtful nerve endings
and go about as neurotransmitters [3]. Dopamine has imperative physiological
properties, e.g., incitement of the myocardial contractility (inotropic activity). It
is additionally a neurotransmitter in the focal sensory system and its inadequacy in
the basal ganglia delivers additional pyramidal illness known as Parkinsonism [4].
Dopamine of the hypothalamic starting point additionally goes about as prolactin
discharge restraining factor in the front pituitary organ.
1.1 Food sources
Food sources are lentils, chickpeas, pecans, soybeans, whole grains, sesame
seeds, pumpkin seeds, peanuts, nuts, lima beans, cheese, cottage, corn, brewer’s
yeast, bananas, almonds, dairy products, and eggs [5].
1.2 Role of phenylalanine in the body
This supplement is necessary to the usual working of the central nervous
system; particularly regarding manifestations like chronic pain and depression
along with numerous other disorders that have been associated with the nervous
system malfunction. It is involved in formation of neurotransmitters such as nor-
epinephrine, epinephrine, and dopamine. Nervous system requires all these chemi-
cals for proper functioning. As a nootropic, phenylalanine has numerous valuable
properties improved motivation, increased concentration and focus, anxiety relief
and mood enhancement [6].
1.3 Role in vitiligo
L-phenylalanine in combination with UVA exposure or application of
L-phenylalanine in combination with UVA exposure to the skin appears to be useful
in the treatment of vitiligo in children and adults [7].
1.4 Weight loss benefits
Phenylalanine regulates the discharge of the hormone cholecystokinin (CCK).
Phenylalanine conveys signals to the brain that person is satisfied after eating. If some-
one is attempting to reduce some weight, incorporate supplementary diets that possess
this essential amino acid into food. A person may feel more pleased after eating less.
1.5 Parkinsons disease
Restricted study recommends that administration of D-phenylalanine might
reduce manifestations of Parkinsons disease [8].
1.6 Metabolic role of tyrosine
Metabolic products of tyrosine are tyrosine-O-sulfate, cresol, phenol, tyramine,
melanin pigment, catecholamine, tri-iodotyrosine and thyroxine [9, 10].
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Role of Phenylalanine and Its Metabolites in Health and Neurological Disorders
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1.7 Tyrosine becomes essential
Because the tyrosine can no longer be formed in phenylketonuria, it becomes an
essential amino acid.
1.8 Development of melanin
It is the main color of the skin and is additionally present in the eye, even in the
cerebrum (e.g., substantia nigra). In the skin, it is delivered by particular cells called
melanocytes, which are located in the limit between the epidermis and dermis and in
hair globules. Melanin is a co-polymer of dopa-quinine, indole 5, 6 quinone, and indole
quinine 2—carboxylic corrosive in the proportion 3:2:1. It is delivered on the surface
of intracellular granules called melanosomes, which are rich in the catalyst tyrosinase.
It is exceedingly insoluble substance. Zinc particles are important for the melanin
development. Arrangement of melanin is animated by light (e.g., tanning), ACTH and
MSH.Nonappearance of Cu-containing protein tyrosinase (tyrosine hydroxylase)
produces tyrosinase-negative oculocutaneous albinism. Human skin is presented to
bright light that can harm the skin. Melanin keeps harm of skin from bright light [11].
1.9 Homogentisic acid
Homogentisic acid is a metabolite in the breakdown process of amino acids such as
tyrosine and phenylalanine. In normal condition, it is not detected in urine and blood.
1.10 Homogentisic acid accumulation
In deficiency of homogentisic acid dioxygenase, homogentisic acid builds up in
the blood and excretes in urine. When come in contact with air, homogentisic acid
reacts with oxygen and cause the urine to become black. This is because of black
pigment knows as alkapton and termed as alkaptonuria. This same black pigment in
a procedure known as ochronosis causes bone and tissue to darken and degenerate.
This causes disabling and painful joint disease called as osteoarthritis [12].
1.11 Alkaptonuria
It is an inborn error of metabolism, a genetic disorder caused by a deficiency of
enzyme homogenetic acid dioxygenase. Without this enzyme, persons cannot break
down the amino acids such as tyrosine and phenylalanine, which cause accumula-
tion of homogentisic acid in urine, cartilage, and bone. The characteristics of
Alkaptonuria are black urine, ochronosis (black cartilage and bone), and degenera-
tive arthritis of the joint [13].
1.12 Homogentisic acid dioxygenase deficiency
The deficiency of homogentisic acid dioxygenase occurs due to the mutation in the
homogentisic acid dioxygenase gene. It occurs in children when both father and mother
are the carriers of mutated gene. This is known as autosomal recessive disease [14].
1.13 Hypopigmentation
Pigmentation loss is usually seen in patients with phenylketonuria due to reduc-
tion in amino acid tyrosine which is utilized by melanocytes to form melanin [15].
Synucleins - Biochemistry and Role in Diseases
4
1.14 Catabolism of phenylalanine and tyrosine
Phenylalanine is changed over to numerous subsidiaries, which are discharged
in pee. These incorporate phenyls lactic corrosive, phenyl acidic corrosive, ortho-
hydroxyphenylpyruvic corrosive and ortho-hydroxyphenylacetic corrosive. In
any case, this is ordinarily a minor pathway of phenylalanine and it turns out to be
quantitatively more critical just when phenylalanine is not changed over to tyrosine,
which is the real pathway of phenylalanine catabolism. The catabolic results of tyro-
sine incorporate homogentisic corrosive which is additionally separated to fumaric
corrosive and acetoacetic corrosive [16].
1.15 Diseases associated with an abnormal metabolism of phenylalanine
and tyrosine
.. Phenylketonuria
It is likewise called phenylpyruvic oligophrenia. It is because of absence of the
chemical phenylalanine hydroxylase, which changes over phenylalanine to tyrosine.
Phenylalanine is redirected to its ordinarily minor metabolic pathway framing
para-hydroxy phenylpyruvic corrosive, para-hydroxy phenyl lactic corrosive, para-
hydroxy phenyl acidic corrosive, and phenyl acetylglutamine all of which gather in
the body alongside phenylalanine. These are discharged in pee in vast sums, which
causes mental hindrance. The infection ought to be determined early because to have
appropriate treatment (low phenylalanine abstains from food) the impediment of
mental improvement can be halted. The best test is finding a raised blood level of
phenylalanine. Nonetheless, it can likewise be analyzed prenatally (before birth)
by DNA ponders as the quality for phenylalanine hydroxylase has been cloned. The
name of the illness phenylketonuria is because of the discharge of parahydroxyphe-
nyl pyruvic corrosive, which is a keto corrosive. This infection is currently gathered
under the term hyperphenylalanemia of which there are numerous assortments [17].
.. Manifestation
Manifestations include psychiatric disorders, behavioral problems, delayed develop-
ment, seizures, and intellectual disability, lighter hair, skin, musty, or mouse-like odor,
microcephaly. Studies propose that untreated phenylketonuria in pregnancy is linked to
attention-deficit hyperactivity disorder, intellectual disability, and microcephaly.
.. Musty or mousy body odor
Aromatic amino group is present in phenylketones, which is responsible for
musty or mousy odor in patients which is feature for phenylketonuria [18].
.. Maternal PKU
Maternal PKU is developed when there is increased concentration of phenylala-
nine in a females blood during gestation. This goes to the developing fetus. These
high levels significantly enhance the danger for a baby to be born with behavioral
problems, characteristic facial features, heart defects, growth retardation, and a
small head size (microcephaly). For female with phenylketonuria, it is significant
that they follow a low phenylalanine diet if they plan to develop expectant or are
expectant. The bad effects of high levels of phenylalanine can be stopped if this diet
is followed before conception and during the pregnancy [19].
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Role of Phenylalanine and Its Metabolites in Health and Neurological Disorders
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.. Adults with PKU
Adults with PKU carry on taking care throughout whole life. Older adults with
phenylketonuria who may have stopped the PKU food in their teens may advantage
from an appointment with their physicians. Returning to the food may increase
intellectual working and performance and gentle impairment to the central nervous
system in adults with increased levels of phenylalanine [20].
.. Calcium homeostasis
Calcium homeostasis is vital for brain activity and its dysregulation in phenylke-
tonuria was recommended by numerous studies. In this background, dehydrocho-
lecalciferol, osteocalcin and parathyroid hormone were found enhanced in blood
of infants with phenylketonuria, but level of calcitonin was low. These changes
were not returned by Phenylalanine restricted food. In additional work, Yu and
colleagues proved that Phenylalanine modifies intracellular free calcium levels by
altering plasma membrane Ca2+-ATPase in cortical neurons [21].
.. Diagnosis
Phenylketonuria is analyzed by examining the amino acids in the plasma.
Screening programs have been introduced in numerous countries that permit
identifying the illness in neonates within the first few days of birth. The objec-
tive of these recognition programs is to manage the babies prior to the initiation
of exhibiting manifestations of the illness. Once identified, the children will be
referred to a reference hospital for differential diagnosis with other less frequent
forms of diseases, which can cause a rise of blood phenylalanine levels and
initiate the management. The analysis of the PAH gene mutations approves the
diagnosis [22].
.. Tracking pH levels
Children and young kids with phenylketonuria require having consistent blood
tests for measurement of phenylalanine levels. If there is too much or too little
phenylalanine in the blood, the formula and diet may require to be attuned [23].
.. Molecular testing
It is usually unnecessary for a diagnosis of phenylketonuria. However, restricted
genotype-phenotype association has been designated. In addition, molecular testing
is necessary for prenatal diagnosis [24].
.. Screening
Blood is taken from a 2-week-old infant to test for phenylketonuria [25].
Phenylketonuria is generally incorporated into the infant screening board of vari-
ous nations, with various identification systems. Most infants in created nations are
screened for phenylketonuria not long after birth. Screening for phenylketonuria
is finished with bacterial hindrance test (Guthrie test), immunoassays utilizing
fluorometric or photometric location, or amino corrosive estimation utilizing pair
mass spectrometry (MS/MS) [26]. Estimations done utilizing MS/MS decide the
grouping of phenylalanine and the proportion of phenylalanine to tyrosine, the
proportion will be hoisted in phenylketonuria.
Synucleins - Biochemistry and Role in Diseases
6
.. PKU carriers
Sisters and brothers who do not have phenylketonuria still have a chance to be
carriers like their parents. Except in special cases, the carrier testing should be done
merely in persons older than 18. Each of the parents’ sisters and brothers has a 50%
chance to be a carrier. It is significant for other family members to be said that they
could be carriers. There is a minor chance they are also at danger to have offspring
with phenylketonuria. When both parents are carriers, newborn screening out-
comes are not adequate to rule out the disorder in a neonatal baby. In this situation,
special investigative testing should be done in addition to newborn screening [27].
.. Foods to be avoided in phenylketonuria
Nuts, beans, eggs, dairy, meats, chocolate, ice cream, cheese, yogurt, regular
bread, birthday cake, and pizza.
.. Management of phenylketonuria
Treatment ought to be begun as right on time as conceivable after birth.
Phenylalanine is a basic amino corrosive and, in this manner, cannot be completely
barred from the eating routine. Eating routine containing low phenylalanine with
included tyrosine is suggested. Phenylalanine levels ought to be kept up between 6
and 9mg%. Extremely serious limitation of phenylalanine prompts tissue break-
down. Strict limitation is suggested until eighth year of life. After this, confinement
may not be so unbending [28].
.. Medical formula
Even though they require less phenylalanine, children with phenylalanine still
require a definite quantity of protein. The medical formula gives children and the
babies with phenylketonuria the protein and nutrients they require while keeping their
phenylalanine amount within a nontoxic array. The dietician and metabolic physicians
will tell you what kind of formula is greatest and how much to use. Administering a
phenylketonuria formula for life is to make sure patient gets sufficient essential protein
(without phenylalanine) and nutrients that are vital for general health and growth.
.. Foods that are allowed (excessive use is not allowed)
Fruits allowed include strawberries, apples, grapefruit, oranges, grapes, melons,
bananas, and peaches. Vegetables allowed include tomatoes, radishes, lettuce,
cucumber, celery, cauliflowers, carrots, and French beans.
.. Food not allowed
All meats including fish, fish products, chicken, bacon, pork, lamb, organ meats
(liver, heart, kidney) and all dairy products including pudding, ice cream, yogurt,
milk, cheese, cottage cheese, seeds, nuts, legumes, biscuits and flour cakes.
1.16 Prevention
.. Follow a low-phenylalanine diet
Female with phenylketonuria can inhibit birth defects by sticking to (or return-
ing to) a low-phenylalanine diet prior to the becoming pregnant. Female with PKU
should consult to physician prior to conception.
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Role of Phenylalanine and Its Metabolites in Health and Neurological Disorders
DOI: http://dx.doi.org/10.5772/intechopen.83648
.. Prognosis
The consequence is predictable to be very good if the food is carefully
monitored, beginning soon after the birth of child. If management is late or the
disorder remains untreated, damage of brain will occur. School working may be
slightly reduced. If proteins comprising phenylalanine are not evaded, phenyl-
ketonuria can lead to intellectual incapacity by the completion of the first year
of life.
.. Hypertyrosinemia
It is because of the shortage of tyrosine aminotransferase [29].
.. Hereditary tyrosinemia
It occurs due to deficiency of fumarylacetoacetate hydrolase [30].
.. Alkaptonuria
This results from the lack of the enzyme homogentisate 1,2-dioxygenase. This
leads to buildup in the body of homogenetisic acid, which is expelled in urine.
Oxidation of homogentisic acid occurs that causes the urine to become dark.
Patients with alkaptonuria are also affected with arthritis. This disease was discov-
ered by Archibald Garrod in early 1900s. This was the major disorder in which an
association between an enzyme and inheritable trait was established [31].
.. Attention deficit disorder
In the solitary double-blind, crossover study available in this part, quantities of
up to DL-phenylalanine (1200mg) were prescribed in 19 patients with attention
deficit disorder. After 2weeks, a substantial alteration in mood lability and mood
was detected in the treatment cluster. After 2–4months, however, patients who had
improved with the use of DL-phenylalanine developed tolerant and did not respond
to higher quantities [32].
.. Dopamine history
Dopamine was first made in 1910 by James Ewens and George Barger and at
Wellcome Laboratories in London, England. In 1958, Nils-Åke Hillarp and Arvid
Carlsson at the Laboratory for Chemical Pharmacology of the National Heart
Institute of Sweden, found the dopamine work as a neurotransmitter. Arvid
Carlsson was introduced the 2000 Nobel Prize in Medicine or Physiology for
demonstrating that dopamine is not only an antecedent of epinephrine and norepi-
nephrine however a neurotransmitter, too [33].
.. Role of dopamine in pain
Dopamine has an impact in handling of agony in various levels of the focal
sensory system, for example, cingulate cortex, basal ganglia, thalamus, periaq-
ueductal dark, and the spinal line. Diminished centralization of dopamine has
been connected to excruciating signs that regularly saw in Parkinson’s infection.
Distortions in dopaminergic neurotransmission likewise occurs in various difficult
clinical issue, for example, fretful legs disorder, fibromyalgia and consuming mouth
disorder [34].
Synucleins - Biochemistry and Role in Diseases
8
.. Drug-nutrient interactions
Phenylalanine has been revealed to contest with levodopa for passage through
the blood-brain barrier [35]. Tyramine, dopamine, norepinephrine, epinephrine is
derived from phenylalanine. Supposedly, attention is necessary with the concomi-
tant use of phenylalanine and monoamine-oxidase inhibitors.
.. Side effects and toxicity
LD-50 of D-phenylalanine in rats is higher than 10g/kg. No tissue toxicity
was observed in murine studies at dose of 1mg/kg daily for 6months. Short time
adverse effects are insomnia, aggressiveness, irritability, headache, and increase of
blood pressure [32].
.. Dosage
Dosages differs with the disorder; 1–4g daily for pain treatment and 1–14g daily
for depression.
.. Warnings and contraindications
Phenylalanine supplementation should be avoided in phenylketonuria [36].
Phenylalanine can affect efficacy and absorption of levodopa [37]. Phenylalanine
use is contraindicated in patients with schizophrenia [38].
2. Research study
2.1 Impact of co-trimoxazole on phenylalanine metabolism in man
An investigation was completed to assess impact of co-trimoxazole on phenyl-
alanine digestion. It was discovered that phenylalanine level stays high in the wake
of taking co-trimoxazole. Proportion between serum-phenylalanine and tyrosine
was likewise high. In a few patients, serum phenylalanine levels were marginally
brought up in fasting conditions. As a conclusion, it was proposed that the trim-
ethoprim/sulfamethoxazole blend has a synergistic activity in offending phenylala-
nine resistance [39].
2.2 An open study on phenylalanine in depressed patients
In a clinical trial, phenylalanine was regulated to 20 patients with gloom. Length
of treatment was 20days. Measurement of phenylalanine was 75–200mg/day.
Toward the finish of treatment, 12 patients were dealt with and there was no further
need of treatment for these patients. Mellow to direct reaction was seen in 4 patients.
Four patients did not react at all to phenylalanine. This examination shows that
phenylalanine is significant in depressive patients [40].
2.3 Schizophrenia and blockage of dopaminergic neurotransmission
Phenylalanine is hydroxylated to tyrosine and tyrosine to dopa and dopa to
dopamine. Dopamine has been embroiled for a long time in the pathophysiol-
ogy of schizophrenia, and the run of the mill antipsychotics, by means of bar of
dopaminergic neurotransmission, have furnished help for patients with positive
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Role of Phenylalanine and Its Metabolites in Health and Neurological Disorders
DOI: http://dx.doi.org/10.5772/intechopen.83648
manifestations [41]. In any case, just dopamine blockage is not sufficient to ease
manifestations of schizophrenia in the way it is viewed as those different neu-
rotransmitters are additionally associated with pathophysiology of schizophrenia.
Dopamine partiality for dopamine receptor is diminished by expanding adenosiner-
gic transmission. Adenosine level might be expanded by presentation of allopurinol
that is xanthine oxidase inhibitor, at last prompting antipsychotic and anxiolytic
impacts. Confirmation for this treatment has been accounted for in both case
reports and little clinical trials. Different investigations demonstrate that allopu-
rinol is valuable in those patients who are ineffectively receptive to existing treat-
ment for schizophrenia. Nevertheless, additionally study ought to be completed to
discover its viability and wellbeing as a standard treatment for schizophrenia. In
any case, exhibits think about demonstrate that allopurinol at 300mgday by day is
sufficient to assuage side effects of schizophrenia [42].
2.4 Impact of loading measurements of phenylalanine in unipolar discouraged
patients with and without tardive dyskinesia (TD)
In a clinical trial, phenylalanine was managed to three distinct gatherings.
Dosage of medication was 100mg/kg phenylalanine. Eleven patients were in first
gathering (discouraged patients with tardive dyskinesia). Ten patients were in
second gathering (discouraged patient presented to neuroleptics yet without TD),
10 patients were in third gathering (patients never presented to NLs). There was no
critical factual contrast among three gatherings. A relationship was found between
automatic development and fasting, and phenylalanine stacking following 2 hours.
Three TD patients indicated surprisingly expansive increments in phenylalanine
level in plasma. This examination demonstrated that variations from the norm in
digestion of phenylalanine add to the improvement and seriousness of TD in some
NL-treated unipolar discouraged patients [43].
3. Conclusion
Phenylalanine hydroxylase (PAH) deficit consequences in intolerance to the
dietetic consumption of the important amino acid phenylalanine and produces a
variety of syndromes. The hazard of antagonistic consequence fluctuates based
on the grade of PAH deficit. Deprived of effective management, maximum
individuals with severe phenylalanine hydroxylase deficit, recognized as classic
phenylketonuria, develop deep and permanent logical disability. Affected patients
on an unrestricted food who have phenylalanine concentration above normal but
below 1200μmol/L (20mg/dL) are at much lower hazard for impaired cognitive
development in the lack of management. Phenylalanine is prescribed for alcohol
withdrawal symptoms, vitiligo, weight loss, depression, rheumatoid arthritis,
osteoarthritis, pain, multiple sclerosis, depression, Parkinsons disease and atten-
tion deficit-hyperactivity disorder.
Synucleins - Biochemistry and Role in Diseases
10
© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms
of the Creative Commons Attribution License (http://creativecommons.org/licenses/
by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.
Author details
MuhammadAkram1, MuhammadDaniyal2*, AatiqaAli3, RidaZainab1,
Syed MuhammadAli Shah1, NaveedMunir4 and Imtiaz MahmoodTahir5
1 Department of Eastern Medicine, Government College University, Faisalabad,
Pakistan
2 TCM and Ethnomedicine Innovation and Development International Laboratory,
School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
3 Department of Eastern Medicine, Jinnah University for Women, Karachi, Pakistan
4 Department of Biochemistry, University of Agriculture, Faisalabad, Pakistan
5 College of Allied Health Professionals, Directorate of Medical Sciences,
Government College University, Faisalabad, Pakistan
*Address all correspondence to: daniyaldani151@yahoo.com
11
Role of Phenylalanine and Its Metabolites in Health and Neurological Disorders
DOI: http://dx.doi.org/10.5772/intechopen.83648
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... Phenylalanine, an essential amino acid, serves as a fundamental constituent of proteins that is present in various food sources and can also be obtained through supplementation (Akram et al., 2020). Phenylalanine is obtained from either dietary sources or supplementation, encompassing items such as wheat germ, oats, dairy products and meat (Akram et al., 2020). ...
... Phenylalanine, an essential amino acid, serves as a fundamental constituent of proteins that is present in various food sources and can also be obtained through supplementation (Akram et al., 2020). Phenylalanine is obtained from either dietary sources or supplementation, encompassing items such as wheat germ, oats, dairy products and meat (Akram et al., 2020). It serves as a fundamental amino acid and can be converted into tyrosine (Gupta, 2008). ...
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