Phenylalanine

The first description of phenylalanine was made in 1879, when Schulze and Barbieri identified a compound with the empirical formula, C₉H₁₁NO₂, in yellow lupine (Lupinus luteus) seedlings. In 1882, Erlenmeyer and Lipp first synthesized phenylalanine from phenylacetaldehyde, hydrogen cyanide, and ammonia.{{ cite book | vauthors = Thorpe TE | author-link = Thomas Edward Thorpe | title = A Dictionary of Applied Chemistry | url = https://archive.org/details/bub_gb_6uVYAAAAYAAJ | access-date = 2012-06-04 | year = 1913 | publisher = Longmans, Green, and Co. | pages = [https://archive.org/details/bub_gb_6uVYAAAAYAAJ/page/n202 191]–193 }}{{ cite book | vauthors = Plimmer RH |author-link=R. H. A. Plimmer| veditors = Plimmer RH, Hopkins FG | title = The Chemical Composition of the Proteins | url = https://books.google.com/books?id=7JM8AAAAIAAJ&pg=PA93 | access-date = 2012-06-04 | edition = 2nd | series = Monographs on Biochemistry | volume = Part I. Analysis | orig-year = 1908 | year = 1912 | publisher = Longmans, Green and Co. | location = London | pages = 93–97 }}

The genetic codon for phenylalanine was first discovered by J. Heinrich Matthaei and Marshall W. Nirenberg in 1961. They showed that by using mRNA to insert multiple uracil repeats into the genome of the bacterium E. coli, they could cause the bacterium to produce a polypeptide consisting solely of repeated phenylalanine amino acids. This discovery helped to establish the nature of the coding relationship that links information stored in genomic nucleic acid with protein expression in the living cell.

Good sources of phenylalanine are eggs, chicken, liver, beef, milk, and soybeans.{{cite book | first1 = Harvey M. | last1 = Ross | first2 = June | last2 = Roth | title = The Mood Control Diet: 21 Days to Conquering Depression and Fatigue | url = https://books.google.com/books?id=hHWQCZvGUMEC | date = 1 April 1991 | publisher = Simon & Schuster | isbn = 978-0-13-590449-7 | page = 59 }} Another common source of phenylalanine is anything sweetened with the artificial sweetener aspartame, such as diet drinks, diet foods and medication; the metabolism of aspartame produces phenylalanine as one of the compound's metabolites.{{cite web |last1=Zeratsky |first1=Katherine |title=Phenylalanine in diet soda: Is it harmful? |url=https://www.mayoclinic.org/healthy-lifestyle/nutrition-and-healthy-eating/expert-answers/phenylalanine/faq-20058361 |website=Mayo Clinic |access-date=30 April 2019}}

The Food and Nutrition Board (FNB) of the U.S. Institute of Medicine set Recommended Dietary Allowances (RDAs) for essential amino acids in 2002. For phenylalanine plus tyrosine, for adults 19 years and older, 33 mg/kg body weight/day.{{cite book | last1 = Institute of Medicine | title = Dietary Reference Intakes for Energy, Carbohydrates, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids | chapter = Protein and Amino Acids | publisher = The National Academies Press | year = 2002 | location = Washington, DC | pages = 589–768 | doi = 10.17226/10490 | isbn = 978-0-309-08525-0 | chapter-url = https://www.nap.edu/read/10490/chapter/12| author1-link = Institute of Medicine }} In 2005 the DRI is set to 27 mg/kg per day (with no tyrosine), the FAO/WHO/UNU recommendation of 2007 is 25 mg/kg per day (with no tyrosine).{{Cite journal |last1=Elango |first1=Rajavel |last2=Ball |first2=Ronald O. |last3=Pencharz |first3=Paul B. |date=August 2012 |title=Recent advances in determining protein and amino acid requirements in humans |journal=British Journal of Nutrition |language=en |volume=108 |issue=S2 |pages=S22–S30 |doi=10.1017/S0007114512002504 |pmid=23107531 |issn=0007-1145|doi-access=free }}

L-Phenylalanine is biologically converted into L-tyrosine, another one of the DNA-encoded amino acids. L-tyrosine in turn is converted into L-DOPA, which is further converted into dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline). The latter three are known as the catecholamines.

Phenylalanine uses the same active transport channel as tryptophan to cross the blood–brain barrier. In excessive quantities, supplementation can interfere with the production of serotonin and other aromatic amino acids{{Cite journal |last1=Eriksson |first1=Johan G |last2=Guzzardi |first2=Maria-Angela |last3=Iozzo |first3=Patricia |last4=Kajantie |first4=Eero |last5=Kautiainen |first5=Hannu |last6=Salonen |first6=Minna K |date=2017-01-01 |title=Higher serum phenylalanine concentration is associated with more rapid telomere shortening in men |journal=The American Journal of Clinical Nutrition |volume=105 |issue=1 |pages=144–150 |doi=10.3945/ajcn.116.130468 |pmid=27881392 |issn=0002-9165|doi-access=free }} as well as nitric oxide due to the overuse (eventually, limited availability) of the associated cofactors, iron or tetrahydrobiopterin. {{citation needed|date=December 2018}} The corresponding enzymes for those compounds are the aromatic amino acid hydroxylase family and nitric oxide synthase.{{Phenylalanine biosynthesis|caption=Phenylalanine in humans may ultimately be metabolized into a range of different substances.}}

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.{{cite book | vauthors = Nelson DL, Cox MM | title = Lehninger, Principles of Biochemistry | edition = 3rd | publisher = Worth Publishing | location = New York | year = 2000 | isbn = 1-57259-153-6 | url-access = registration | url = https://archive.org/details/lehningerprincip01lehn }}

Phenylalanine is biosynthesized via the shikimate pathway.

{{main|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.{{medcn|date=April 2016}}

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"{{cite web | url = http://www.food.gov.uk/safereating/chemsafe/additivesbranch/sweeteners/55174#h_4 | title = Aspartame | publisher = Food Standards Agency | location = UK | access-date = 2007-06-19 | archive-date = 2012-02-21 | archive-url = https://web.archive.org/web/20120221223646/http://www.food.gov.uk/safereating/chemsafe/additivesbranch/sweeteners/55174#h_4 | url-status = dead }} 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.

{{See also|D-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.{{cite web|title=D-Phenylalanine: Biological activity |url=http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=5797|website=The IUPHAR/BPS Guide to PHARMACOLOGY|access-date=27 December 2018}}

DL-Phenylalanine (DLPA) is marketed as a nutritional supplement for its purported analgesic and antidepressant activities, which have been supported by clinical trials.{{cite journal | last1=Wood | first1=David R. | last2=Reimherr | first2=Fred W. | last3=Wender | first3=Paul H. | title=Treatment of attention deficit disorder with DL-phenylalanine | journal=Psychiatry Research | publisher=Elsevier BV | volume=16 | issue=1 | year=1985 | issn=0165-1781 | doi=10.1016/0165-1781(85)90024-1 | pages=21–26| pmid=3903813 | s2cid=3077060 }}{{cite journal | last1=Beckmann | first1=H. | last2=Strauss | first2=M. A. | last3=Ludolph | first3=E. | title=DL-Phenylalanine in depressed patients: An open study | journal=Journal of Neural Transmission | publisher=Springer Science and Business Media LLC | volume=41 | issue=2–3 | year=1977 | issn=0300-9564 | doi=10.1007/bf01670277 | pages=123–134| pmid=335027 | s2cid=5849451 }}{{cite journal | last1=Beckmann | first1=Helmut | last2=Athen | first2=Dieter | last3=Olteanu | first3=Margit | last4=Zimmer | first4=Reinhild | title=DL-Phenylalanine versus imipramine: A double-blind controlled study | journal=Archiv für Psychiatrie und Nervenkrankheiten | publisher=Springer Science and Business Media LLC | volume=227 | issue=1 | year=1979 | issn=0003-9373 | doi=10.1007/bf00585677 | pages=49–58| pmid=387000 | s2cid=23531579 }} 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.{{cite web|title=D-Phenylalanine: Clinical data|url=http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=clinical&ligandId=5797|website=The IUPHAR/BPS Guide to PHARMACOLOGY|access-date=27 December 2018}}{{cite journal |author1-link=David W. Christianson | vauthors = Christianson DW, Mangani S, Shoham G, Lipscomb WN | title = Binding of D-phenylalanine and D-tyrosine to carboxypeptidase A | journal = The Journal of Biological Chemistry | volume = 264 | issue = 22 | pages = 12849–12853 | date = August 1989 | doi = 10.1016/S0021-9258(18)51564-7 | pmid = 2568989 | url = http://www.jbc.org/content/264/22/12849.full.pdf | doi-access = free }} Enkephalins act as agonists of the mu and delta opioid receptors, and agonists of these receptors are known to produce antidepressant effects.{{cite journal | last1=Jelen | first1=Luke A. | last2=Stone | first2=James M. | last3=Young | first3=Allan H. | last4=Mehta | first4=Mitul A. | title=The opioid system in depression | journal=Neuroscience & Biobehavioral Reviews | publisher=Elsevier BV | volume=140 | year=2022 | issn=0149-7634 | doi=10.1016/j.neubiorev.2022.104800 | page=104800| pmid=35914624 | pmc=10166717 | s2cid=251163234 | doi-access=free }} The mechanism of DL-phenylalanine's supposed antidepressant activity may also be accounted for in part by the precursor role of L-phenylalanine in the synthesis of the neurotransmitters norepinephrine and dopamine, though clinical trials have not found an antidepressant effect from L-phenylalanine alone. 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.{{Cite journal|last1=Lehmann|first1=W. D.|last2=Theobald|first2=N.|last3=Fischer|first3=R.|last4=Heinrich|first4=H. C.|date=1983-03-14|title=Stereospecificity of phenylalanine plasma kinetics and hydroxylation in man following oral application of a stable isotope-labelled pseudo-racemic mixture of L- and D-phenylalanine|journal=Clinica Chimica Acta; International Journal of Clinical Chemistry|volume=128|issue=2–3|pages=181–198|issn=0009-8981|pmid=6851137|doi=10.1016/0009-8981(83)90319-4}}

L-Phenylalanine is an antagonist at α₂δ Ca²⁺ calcium channels with a K_i of 980 nM.{{cite journal | vauthors = Mortell KH, Anderson DJ, Lynch JJ, Nelson SL, Sarris K, McDonald H, Sabet R, Baker S, Honore P, Lee CH, Jarvis MF, Gopalakrishnan M | title = Structure-activity relationships of alpha-amino acid ligands for the alpha2delta subunit of voltage-gated calcium channels | journal = Bioorganic & Medicinal Chemistry Letters | volume = 16 | issue = 5 | pages = 1138–4111 | date = March 2006 | pmid = 16380257 | doi = 10.1016/j.bmcl.2005.11.108 }}

In the brain, L-phenylalanine is a competitive antagonist at the glycine binding site of NMDA receptor{{cite journal | vauthors = Glushakov AV, Dennis DM, Morey TE, Sumners C, Cucchiara RF, Seubert CN, Martynyuk AE | title = Specific inhibition of N-methyl-D-aspartate receptor function in rat hippocampal neurons by L-phenylalanine at concentrations observed during phenylketonuria | journal = Molecular Psychiatry | volume = 7 | issue = 4 | pages = 359–367 | year = 2002 | pmid = 11986979 | doi = 10.1038/sj.mp.4000976 | doi-access = free }} and at the glutamate binding site of AMPA receptor.{{cite journal | vauthors = Glushakov AV, Dennis DM, Sumners C, Seubert CN, Martynyuk AE | title = L-Phenylalanine selectively depresses currents at glutamatergic excitatory synapses | journal = Journal of Neuroscience Research | volume = 72 | issue = 1 | pages = 116–124 | date = April 2003 | pmid = 12645085 | doi = 10.1002/jnr.10569 | s2cid = 42087834 }} At the glycine binding site of NMDA receptor L-phenylalanine has an apparent equilibrium dissociation constant (K_B) of 573 μM estimated by Schild regression{{cite journal | vauthors = Glushakov AV, Glushakova O, Varshney M, Bajpai LK, Sumners C, Laipis PJ, Embury JE, Baker SP, Otero DH, Dennis DM, Seubert CN, Martynyuk AE | title = Long-term changes in glutamatergic synaptic transmission in phenylketonuria | journal = Brain | volume = 128 | issue = Pt 2 | pages = 300–307 | date = February 2005 | pmid = 15634735 | doi = 10.1093/brain/awh354 | doi-access = free }} which is considerably lower than brain L-phenylalanine concentration observed in untreated human phenylketonuria.{{cite journal | vauthors = Möller HE, Weglage J, Bick U, Wiedermann D, Feldmann R, Ullrich K | title = Brain imaging and proton magnetic resonance spectroscopy in patients with phenylketonuria | journal = Pediatrics | volume = 112 | issue = 6 Pt 2 | pages = 1580–1583 | date = December 2003 | doi = 10.1542/peds.112.S4.1580 | pmid = 14654669 | hdl = 11858/00-001M-0000-0010-A24A-C | s2cid = 2198040 | hdl-access = free }}

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.

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.{{ cite book | last = Sprenger | first = G. A. | title = Amino Acid Biosynthesis: Pathways, Regulation and Metabolic Engineering | publisher = Springer | year = 2007 | edition = 1st | chapter = Aromatic Amino Acids | pages = 106–113 | isbn = 978-3-540-48595-7 }}

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.

• Phenylalaninol

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{{Commons category|L-Phenylalanine}}

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

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