Phenylalanine

Phenylalanine (symbol Phe or F)[2] is an essential α-amino acid

Phenylalanine
with the formula C9H11NO2. It can be viewed as a benzyl group
substituted for the methyl group of alanine, or a phenyl group in
place of a terminal hydrogen of alanine. This essential amino
acid is classified as neutral, and nonpolar because of the inert
and hydrophobic nature of the benzyl side chain. The L-isomer is
used to biochemically form proteins, coded for by DNA.
L-Phenylalanine
Phenylalanine is a precursor for tyrosine, the monoamine
neurotransmitters dopamine, norepinephrine (noradrenaline),
and epinephrine (adrenaline), and the skin pigment melanin. It is
encoded by the codons UUU and UUC.

Phenylalanine is found naturally in the breast milk of mammals.

L-Phenylalanine at physiological pH
It is used in the manufacture of food and drink products and sold
as a nutritional supplement for its reputed analgesic and
antidepressant effects. It is a direct precursor to the
neuromodulator phenethylamine, a commonly used dietary
supplement. As an essential amino acid, phenylalanine is not
synthesized de novo in humans and other animals, who must
ingest phenylalanine or phenylalanine-containing proteins.

3D phenylalanine model
Contents Names

History Pronunciation US: /ˌfɛnəlˈæləniːn/,

UK: /ˌfiːnaɪl-/
Dietary sources
IUPAC name
Dietary recommendations
(S)-2-Amino-3-phenylpropanoic
Other biological roles
acid
In plants
Identifiers
Phenylketonuria
CAS Number 150-30-1 (http://ww
D-, L- and DL-phenylalanine
w.commonchemistr
Commercial synthesis y.org/ChemicalDeta
Derivatives il.aspx?ref=150-30-
References 1) (DL)

External links 63-91-2 (http://ww

w.commonchemistr
y.org/ChemicalDeta

History il.aspx?ref=63-91-
2) (L)
3D model Interactive image
(JSmol)
The first description of phenylalanine was made in 1879, when (https://chemapps.
Schulze and Barbieri identified a compound with the empirical stolaf.edu/jmol/jmo
formula, C9H11NO2, in yellow lupine (Lupinus luteus) l.php?model=N%5
seedlings. In 1882, Erlenmeyer and Lipp first synthesized BC%40%40H%5
phenylalanine from phenylacetaldehyde, hydrogen cyanide, and D%28CC1%3DC
ammonia.[3][4] C%3DCC%3DC1%
29C%28O%29%3
The genetic codon for phenylalanine was first discovered by J. DO)
Heinrich Matthaei and Marshall W. Nirenberg in 1961. They Zwitterion:
showed that by using mRNA to insert multiple uracil repeats Interactive image
into the genome of the bacterium E. coli, they could cause the (https://chemapps.
bacterium to produce a polypeptide consisting solely of repeated stolaf.edu/jmol/jmo
phenylalanine amino acids. This discovery helped to establish l.php?model=%5B
the nature of the coding relationship that links information NH3%2B%5D%5B
stored in genomic nucleic acid with protein expression in the C%40%40H%5D%
living cell. 28CC1%3DCC%3
DCC%3DC1%29
Dietary sources C%28%5BO-%5
D%29%3DO)
Good sources of phenylalanine are eggs, chicken, liver, beef,
milk, and soybeans.[5] Another common source of phenylalanine ChEBI CHEBI:58095 (http
is anything sweetened with the artificial sweetener aspartame, s://www.ebi.ac.uk/c
such as diet drinks, diet foods and medication; the metabolism of hebi/searchId.do?c
aspartame produces phenylalanine as one of the compound's hebiId=58095)
metabolites.[6] ChEMBL ChEMBL301523 (h
ttps://www.ebi.ac.u
Dietary recommendations k/chembldb/index.p
hp/compound/insp
The Food and Nutrition Board (FNB) of the U.S. Institute of
ect/ChEMBL30152
Medicine set Recommended Dietary Allowances (RDAs) for
3)
essential amino acids in 2002. For phenylalanine plus tyrosine,
for adults 19 years and older, 33 mg/kg body weight/day.[7] ChemSpider 5910 (http://www.c
hemspider.com/Ch
emical-Structure.59
Other biological roles
10.html)
L-Phenylalanine is biologically converted into L-tyrosine,
DrugBank DB00120 (https://w
another one of the DNA-encoded amino acids. L-tyrosine in turn
ww.drugbank.ca/dr
is converted into L-DOPA, which is further converted into
ugs/DB00120)
dopamine, norepinephrine (noradrenaline), and epinephrine
(adrenaline). The latter three are known as the catecholamines. ECHA InfoCard 100.000.517 (http
s://echa.europa.eu/
Phenylalanine uses the same active transport channel as substance-informat
tryptophan to cross the blood–brain barrier. In excessive ion/-/substanceinfo/
quantities, supplementation can interfere with the production of 100.000.517)
serotonin and other aromatic amino acids as well as nitric oxide IUPHAR/BPS 3313 (http://www.g
due to the overuse (eventually, limited availability) of the uidetopharmacolog
associated cofactors, iron or tetrahydrobiopterin. The y.org/GRAC/Ligand
corresponding enzymes in for those compounds are the aromatic DisplayForward?ta
amino acid hydroxylase family and nitric oxide synthase. b=summary&ligand
Id=3313)
KEGG D00021 (https://ww
w.kegg.jp/entry/D0
0021)
PubChem CID 994 (https://pubche
m.ncbi.nlm.nih.gov/
compound/994)
UNII 8P946UF12S (http
s://fdasis.nlm.nih.g
ov/srs/srsdirect.js
p?regno=8P946UF
12S)
CompTox DTXSID4040763
Dashboard
(https://comptox.ep
(EPA)
a.gov/dashboard/D
TXSID4040763)

InChI
InChI=1S/C9H11NO2/c10-8(9(11)12)6-7-4-2-1
-3-5-7/h1-5,8H,6,10H2,(H,11,12)/t8-/m0/s1

Key: COLNVLDHVKWLRT-QMMMGPOBSA-N

InChI=1/C9H11NO2/c10-8(9(11)12)6-7-4-2-1-
3-5-7/h1-5,8H,6,10H2,(H,11,12)/t8-/m0/s1
Key: COLNVLDHVKWLRT-QMMMGPOBBC

SMILES
N[C@@H](CC1=CC=CC=C1)C(O)=O

Zwitterion: [NH3+][C@@H](CC1=CC=CC=C1)
C([O-])=O

Properties
Chemical C9H11NO2
formula
Molar mass 165.192 g·mol−1
Acidity (pKa) 1.83 (carboxyl),
9.13 (amino)[1]
Hazards
Safety data See: data page
sheet
NFPA 704
(fire diamond) 1
2 0

Supplementary data page

Structure and Refractive index
properties
 (n),
Dielectric constant
(εr), etc.
Thermodynamic Phase behaviour
data solid–liquid–gas
Spectral data UV, IR, NMR, MS
Except where otherwise noted, data
are given for materials in their
standard state (at 25 °C [77 °F],
100 kPa).
verify (what is ?)
Infobox references

Biosynthetic pathways for catecholamines and trace amines in the human brain[8][9][10]

AADC PNMT

L-Phenylalanine Phenethylamine N-Methylphenethylamine

AAAH
N-Methyltyramine
PNMT

AADC

L-Tyrosine p-Tyramine DBH

brain minor p-Octopamine

AAAH CYP2D6 pathway

PNMT
AADC
primary
pathway
L-DOPA Dopamine

Synephrine
DBH COMT

PNMT

Epinephrine Norepinephrine 3-Methoxytyramine

Phenylalanine in humans may ultimately be metabolized into a range of different substances.
In plants
Phenylalanine is the starting compound used in the synthesis of flavonoids. Lignan is derived from
phenylalanine and from tyrosine. Phenylalanine is converted to cinnamic acid by the enzyme
phenylalanine ammonia-lyase.[11]

Phenylketonuria
The genetic disorder phenylketonuria (PKU) is the inability to metabolize phenylalanine because of a
lack of the enzyme phenylalanine hydroxylase. Individuals with this disorder are known as
"phenylketonurics" and must regulate their intake of phenylalanine. Phenylketonurics often use blood
tests to monitor the amount of phenylalanine in their blood. Lab results may report phenylalanine levels
using either mg/dL and μmol/L. One mg/dL of phenylalanine is approximately equivalent to 60 μmol/L.

A (rare) "variant form" of phenylketonuria called hyperphenylalaninemia is caused by the inability to

synthesize a cofactor called tetrahydrobiopterin, which can be supplemented. Pregnant women with
hyperphenylalaninemia may show similar symptoms of the disorder (high levels of phenylalanine in
blood), but these indicators will usually disappear at the end of gestation. Pregnant women with PKU
must control their blood phenylalanine levels even if the fetus is heterozygous for the defective gene
because the fetus could be adversely affected due to hepatic immaturity.

A non-food source of phenylalanine is the artificial sweetener aspartame. This compound is metabolized
by the body into several chemical byproducts including phenylalanine. The breakdown problems
phenylketonurics have with the buildup of phenylalanine in the body also occurs with the ingestion of
aspartame, although to a lesser degree. Accordingly, all products in Australia, the U.S. and Canada that
contain aspartame must be labeled: "Phenylketonurics: Contains phenylalanine." In the UK, foods
containing aspartame must carry ingredient panels that refer to the presence of "aspartame or E951"[12]
and they must be labeled with a warning "Contains a source of phenylalanine." In Brazil, the label
"Contém Fenilalanina" (Portuguese for "Contains Phenylalanine") is also mandatory in products which
contain it. These warnings are placed to help individuals avoid such foods.

Geneticists sequenced the genome of macaques in 2007. Their investigations found "some instances
where the normal form of the macaque protein looked like the diseased human protein" including
markers for PKU.[13]

D-, L- and DL-phenylalanine

The stereoisomer D-phenylalanine (DPA) can be produced by conventional organic synthesis, either as a
single enantiomer or as a component of the racemic mixture. It does not participate in protein
biosynthesis although it is found in proteins in small amounts - particularly aged proteins and food
proteins that have been processed. The biological functions of D-amino acids remain unclear, although D-
phenylalanine has pharmacological activity at niacin receptor 2.[14]

DL-Phenylalanine (DLPA) is marketed as a nutritional supplement for its purported analgesic and
antidepressant activities. DL-Phenylalanine is a mixture of D-phenylalanine and L-phenylalanine. The
reputed analgesic activity of DL-phenylalanine may be explained by the possible blockage by D-
phenylalanine of enkephalin degradation by the enzyme carboxypeptidase A.[15][16] The mechanism of
DL-phenylalanine's supposed antidepressant activity may be accounted for by the precursor role of L-
phenylalanine in the synthesis of the neurotransmitters norepinephrine and dopamine. Elevated brain
levels of norepinephrine and dopamine are thought to have an antidepressant effect. D-Phenylalanine is
absorbed from the small intestine and transported to the liver via the portal circulation. A small amount
of D-phenylalanine appears to be converted to L-phenylalanine. D-Phenylalanine is distributed to the
various tissues of the body via the systemic circulation. It appears to cross the blood–brain barrier less
efficiently than L-phenylalanine, and so a small amount of an ingested dose of D-phenylalanine is
excreted in the urine without penetrating the central nervous system.[17]

L-Phenylalanine is an antagonist at α2δ Ca2+ calcium channels with a Ki of 980 nM.[18]

In the brain, L-phenylalanine is a competitive antagonist at the glycine binding site of NMDA
receptor[19] and at the glutamate binding site of AMPA receptor.[20] At the glycine binding site of
NMDA receptor L-phenylalanine has an apparent equilibrium dissociation constant (KB) of 573 μM
estimated by Schild regression[21] which is considerably lower than brain L-phenylalanine concentration
observed in untreated human phenylketonuria.[22] L-Phenylalanine also inhibits neurotransmitter release
at glutamatergic synapses in hippocampus and cortex with IC50 of 980 μM, a brain concentration seen in
classical phenylketonuria, whereas D-phenylalanine has a significantly smaller effect.[20]

Commercial synthesis
L-Phenylalanine is produced for medical, feed, and nutritional applications, such as aspartame, in large
quantities by utilizing the bacterium Escherichia coli, which naturally produces aromatic amino acids
like phenylalanine. The quantity of L-phenylalanine produced commercially has been increased by
genetically engineering E. coli, such as by altering the regulatory promoters or amplifying the number of
genes controlling enzymes responsible for the synthesis of the amino acid.[23]

Derivatives
Boronophenylalanine (BPA) is a dihydroxyboryl derivative of phenylalanine, used in neutron capture
therapy.

4-Azido-l-phenylalanine is a protein-incorporated unnatural amino acid used as a tool for

bioconjugation in the field of chemical biology.

References
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2. "Nomenclature and Symbolism for Amino Acids and Peptides" (http://www.chem.qmul.ac.u
k/iupac/AminoAcid/AA1n2.html). IUPAC-IUB Joint Commission on Biochemical
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the Proteins (https://books.google.com/?id=7JM8AAAAIAAJ&pg=PA93). Monographs on
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CYP2D". Eur. J. Pharmacol. 724: 211–218. doi:10.1016/j.ejphar.2013.12.025 (https://doi.or
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Worth Publishing. ISBN 1-57259-153-6.
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74#h_4). UK: Food Standards Agency.
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playForward?tab=biology&ligandId=5797). The IUPHAR/BPS Guide to PHARMACOLOGY.
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Retrieved 27 December 2018.
16. Christianson DW, Mangani S, Shoham G, Lipscomb WN (August 1989). "Binding of D-
phenylalanine and D-tyrosine to carboxypeptidase A" (http://www.jbc.org/content/264/22/12
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of phenylalanine plasma kinetics and hydroxylation in man following oral application of a
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18. Mortell KH, Anderson DJ, Lynch JJ, Nelson SL, Sarris K, McDonald H, Sabet R, Baker S,
Honore P, Lee CH, Jarvis MF, Gopalakrishnan M (March 2006). "Structure-activity
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AE (2002). "Specific inhibition of N-methyl-D-aspartate receptor function in rat hippocampal
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48595-7.

External links
Phenylalanine mass spectrum (http://gmd.mpimp-golm.mpg.de/Spectrums/53729aa2-297a-
4bc7-818b-be4515403113.aspx)
Phenylalanine at ChemSynthesis (http://www.chemsynthesis.com/base/chemical-structure-
453.html)

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