Phenylalanine

Phenylalanine (abbreviated as Phe or F) is an α-amino acid with the chemical formula C₉H₁₁NO₂. It belongs to a group of four aromatic amino acids and is one of the 21 proteinogenic amino acids found in all life forms. It is also one of the nine essential amino acids, meaning humans and other animals cannot produce it internally and must acquire it through diet—from foods like meat, dairy, eggs, and legumes. Naturally, it occurs in mammalian milk. Commercially, it is used in food and drink manufacturing and sold as a dietary supplement, as it serves as a direct precursor to the neuromodulator phenethylamine.

Structurally, phenylalanine can be seen as alanine with a benzyl group replacing its methyl group, or as alanine with a phenyl group substituted for a terminal hydrogen. It is classified as neutral and nonpolar due to the inert, hydrophobic nature of its benzyl side chain. The L-isomer is the form used by cells to build proteins as directed by DNA. Phenylalanine is a precursor to tyrosine, which in turn leads to the monoamine neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), as well as the pigment melanin. In messenger RNA, it is encoded by the codons UUU and UUC. The one-letter symbol F was chosen for its phonetic resemblance to the name.

**History** Phenylalanine was first described in 1879, when Schulze and Barbieri identified a compound with the empirical formula C₉H₁₁NO₂ in yellow lupine seedlings. In 1882, Erlenmeyer and Lipp synthesized it for the first time using phenylacetaldehyde, hydrogen cyanide, and ammonia. The genetic codon for phenylalanine was discovered in 1961 by J. Heinrich Matthaei and Marshall W. Nirenberg. They demonstrated that inserting multiple uracil repeats into the genome of *E. coli* caused the bacterium to produce a polypeptide made entirely of repeated phenylalanine units, helping to establish how genomic nucleic acid codes for protein expression.

**Dietary Sources** Good dietary sources include eggs, chicken, liver, beef, milk, and soybeans. Another common source is anything sweetened with the artificial sweetener aspartame—such as diet drinks, diet foods, and medications—since aspartame metabolism yields phenylalanine as one of its byproducts.

**Dietary Recommendations** In 2002, the U.S. Institute of Medicine’s Food and Nutrition Board set Recommended Dietary Allowances for essential amino acids. For adults 19 and older, the recommendation for phenylalanine plus tyrosine was 33 mg per kg of body weight per day. In 2005, the DRI was adjusted to 27 mg/kg per day (without tyrosine), and the 2007 FAO/WHO/UNU recommendation is 25 mg/kg per day (without tyrosine).

**Metabolism** As an essential amino acid, phenylalanine is not made by animals; they must obtain it from diet. Bacteria, archaea, fungi, algae, some protozoans, and plants produce it via the shikimate pathway. Although animals cannot synthesize it, they can break it down. The liver enzyme phenylalanine hydroxylase (PAH) irreversibly converts phenylalanine into tyrosine. L-Phenylalanine is biologically converted into L-tyrosine, another DNA-encoded amino acid. L-Tyrosine then becomes L-DOPA, which is further converted into dopamine, norepinephrine, and epinephrine—collectively known as catecholamines. Phenylalanine crosses the blood–brain barrier using the same active transport channel as tryptophan. In excessive amounts, supplementation can interfere with serotonin production and other aromatic amino acids, as well as nitric oxide, due to overuse of cofactors like iron or tetrahydrobiopterin. The relevant enzymes belong to the aromatic amino acid hydroxylase family and nitric oxide synthase.

**In Plants** In plants, phenylalanine is the starting compound for flavonoid synthesis. Lignan is derived from both phenylalanine and tyrosine. Phenylalanine is also converted into cinnamic acid by the enzyme phenylalanine ammonia-lyase.

**Phenylketonuria** The genetic disorder phenylketonuria (PKU) results from an inability to metabolize phenylalanine due to a lack of the enzyme phenylalanine hydroxylase. Individuals with this disorder, called phenylketonurics, must regulate their phenylalanine intake, often using blood tests to monitor levels. Lab results may report phenylalanine in mg/dL or μmol/L; 1 mg/dL is roughly equivalent to 60 μmol/L. A rare variant form, hyperphenylalaninemia, is caused by an inability to synthesize the cofactor tetrahydrobiopterin, which can be supplemented. Pregnant women with hyperphenylalaninemia may show similar high blood phenylalanine levels, but these usually resolve after pregnancy. Pregnant women with PKU must control their blood phenylalanine levels even if the fetus is heterozygous for the defective gene, because the fetus’s immature liver could be harmed. A non-food source of phenylalanine is aspartame, which the body breaks down into several byproducts, including phenylalanine. Phenylketonurics experience the same buildup problems with aspartame ingestion, though to a lesser degree. Consequently, in Australia, the U.S., and Canada, all products containing aspartame must be labeled: "Phenylketonurics: Contains phenylalanine." In the UK, foods with aspartame must list it as "aspartame or E951" on ingredient panels.