Phenylalanine · What Is It, Function, Phenylketonuria, and More

Phenylalanine is one of the body’s essential amino acids. Amino acids are the basic building blocks for proteins. Although there are hundreds of amino acids in nature, humans only use 20 amino acids to make every protein in the body. These amino acids can be classified as non-essential or essential, depending on whether the body can synthesize them or acquire them through protein in the diet. 

Phenylalanine plays a vital role in the biosynthesis of other amino acids and is essential in the structure and function of many proteins and enzymes. Most dietary phenylalanine is converted into another amino acid, tyrosine, by the enzyme phenylalanine hydroxylase (PAH) with the help of a cofactor called tetrahydrobiopterin (BH4). Tyrosine is then converted into several other products, including dopamine, a neurotransmitter involved in coordination, movement, as well as pleasure and reward; serotonin, a neurotransmitter that helps to regulate mood, appetite, and cognitive function; norepinephrine and epinephrine, which are also neurotransmitters and hormones used by the sympathetic nervous system; as well as the pigment melanin, which gives color to the skin, hair, and eyes.

Supplementation with phenylalanine has been recommended for decades due to its supposed health benefits, although few randomized controlled trials exist to support its effectiveness. Current research suggests phenylalanine supplements and ultraviolet (UV) light treatment may improve skin repigmentation in individuals with vitiligo, a skin condition that causes patches of skin discoloration. Phenylalanine is also commonly used as a dietary supplement for its mood stabilizer and antidepressant effects, though the evidence is still inconclusive. To this day, the use of phenylalanine to treat other conditions (e.g., chronic pain, ADHD, Parkinson disease) is not recommended due to a lack of evidence. 

The recommended daily intake of phenylalanine for healthy individuals needs to be better established due to differences in measurement methods between studies. According to a 2007 report published by the World Health Organization (WHO) and the Food and Agriculture Organization of the United Nations (FAO), daily phenylalanine requirements are estimated to be 25 mg/kg of body weight per day. However, other studies suggest daily requirements may be as high as 48 mg/kg of body weight per day. 

Phenylalanine deficiency is rare in healthy individuals since a balanced diet containing high-protein foods and fruits, vegetables, beans, and whole grains is likely to provide the minimum daily requirements of phenylalanine. However, sporadic case reports indicate that low phenylalanine levels may be associated with eczematous rashes, hair loss, visual problems, prolonged diarrhea, and failure to thrive in infants.

The amount of phenylalanine found in natural protein is generally safe and does not pose any risks for healthy individuals when consumed as part of a balanced diet. 

Side effects of phenylalanine usually arise in individuals with phenylketonuria (PKU), a genetic disorder that causes phenylalanine to build up in the body, damaging the central nervous system. Some evidence suggests phenylalanine may worsen tardive dyskinesia (i.e., a condition characterized by constant involuntary, rhythmic movements) in individuals with schizophrenia and in those taking neuroleptic medications (e.g., monoamine oxidase inhibitors, or MAOIs, anticonvulsants, and levodopa). 

Phenylketonuria (PKU) is a genetic disorder caused by a deficiency in phenylalanine hydroxylase (PAH), an enzyme that helps break down the amino acid phenylalanine into tyrosine. In individuals with PKU, phenylalanine builds up in the body and is converted into phenylketones such as phenylpyruvate, phenylacetate, and phenylacetate, which are excreted in the urine. The build-up of phenylalanine and phenylketones may lead to problems in brain development, leading to symptoms like intellectual disability, psychiatric disorders, and seizures.

The severity of phenylketonuria depends on the degree of enzyme activity, which can vary from a complete absence of enzyme to a milder form with some enzyme capability but still unusually high phenylalanine levels.

Because of widespread testing for PKU as part of neonatal screening, clinical manifestations of PKU are rare. Newborn infants are typically asymptomatic until they begin feeding with breast milk or standard infant formula, which contain high levels of phenylalanine. If PKU is not detected during the newborn period, the onset of PKU is insidious and may not cause symptoms until early infancy. In untreated individuals, clinical manifestations include developmental delays, intellectual disability, behavioral problems, seizures, and skin disorders.

Treatment of PKU is focused on dietary restriction of natural protein to prevent excessive accumulation of phenylalanine in the body. This usually requires eliminating all high-protein foods from the diet, including meat, fish, eggs, dairy products, nuts, seeds, quinoa, whole grains (e.g., wheat, oats, rye, barley), beans, gelatin, and plant algae such as spirulina. Diet drinks and foods containing the artificial sweetener aspartame may also be eliminated from the diet, as they are important dietary sources of phenylalanine. Most fruit and vegetables can be eaten without limit, and small amounts of cereal and grains may be allowed depending on phenylalanine tolerance. 

The phenylketonuria diet usually requires supplementation with medical foods containing phenylalanine-free protein substitutes (i.e., amino acid mixtures) that provide most of the body’s protein requirements. In mild cases of PKU, pharmacological treatment with a synthetic form of BH4 called sapropterin can help make the diet less restrictive and better manage blood phenylalanine levels. Alternatively, pegvaliase, a recombinant enzyme that converts phenylalanine to non-toxic metabolites, can be used as an adjuvant treatment of PKU in adults with very high levels of phenylalanine. 

Phenylalanine is naturally present in high-protein foods, such as meat, fish, eggs, dairy products, cereals, beans, nuts, and tofu. It is also present in some non-protein foods, such as carbonated drinks and foods containing artificial sweeteners aspartame. 

Phenylalanine is an essential amino acid to make proteins and other vital molecules such as neurotransmitters and hormones. As a crucial amino-acid, phenylalanine must be acquired through protein in the diet, though it can also be consumed as a dietary supplement. Phenylalanine can pose severe health risks for individuals with phenylketonuria (PKU), a genetic disorder that causes phenylalanine and its metabolites to build up in the body. If not treated, phenylketonuria can damage the central nervous system, resulting in developmental delays, intellectual disability, and seizures. A dietary therapy with the restriction of phenylalanine intake is the mainstay of therapy for PKU.