Phenylalanine Amino Acids: Properties, Function, Benefits, and Sources

What is phenylalanine?

Phenylalanine (Phe) is an important amino acid that possesses both glucogenic and ketogenic properties and is metabolized to tyrosine by phenylalanine hydroxylase. Plasma levels of phenylalanine and glutamine were elevated in centenarians relative to other old adults. A longitudinal study revealed that aging affects the metabolism of phenylalanine/tyrosine, tryptophan, and methionine in the plasma of marmosets, a primate model for aging. Phenylalanine levels diminished with advancing age. Phenylalanine binds to hydroxyl radicals and inhibits hydroxyl radical-mediated suppression of acetylcholinesterase activity in brain homogenates.

Phenylalanine structure

Phenylalanine's structure has the typical amino acid backbone accompanied by a unique aromatic side chain. The core carbon atom is covalently connected to the amino group, carboxyl group, a hydrogen atom, and the benzyl side chain. The side chain comprises a benzene ring (C₆H₅) linked to a single carbon (CH₂), rendering it an aromatic, nonpolar group.

Chemical structures of phenylalanine, tyrosine, and tryptophan. (Kang C., et al., 2014)

Phenylalanine sources

The amino acid phenylalanine can be found in breast milk and a variety of other foods such as chicken, fish, cottage cheese, peanuts, seeds from sesame plants, and meat. An essential amino acid, phenylalanine can be ineffectively metabolized by some people due to a genetic disorder called phenylketonuria (PKU). If left untreated, this condition can lead to seizures, brain damage, and mental retardation as the body stores phenylalanine for later use.

Phenylalanine amino acids at Creative Peptides

Phenylalanine metabolism

Chorismate is the beginning point for the bacterial production of tyrosine and phenylalanine. The isomerase enzyme that catalyzes the conversion of phenylalanine and tyrosine into prephenate is called chorismate mutase, hydroxyphenylpyruvate synthase, or chorismate pyruvatemutase. The enzyme pheA, which is typically encoded by the chorismate mutase (EC 5.4.99.5)/prephenate dehydratase (EC 4.2.1.51), is involved in the phenylalanine anabolic pathway and is responsible for converting prephenate to phenylpyruvate by rearranging chorismate to it. During tyrosine biosynthesis, the enzyme EC 5.4.99.5, which is encoded by the tyrA gene, converts chorismate into 4-hydroxyphenylpyruvate instead of phenylpyruvate.

The tyrosine aminotransferase (TAT) (EC 2.6.1.5) is the last enzyme in the biosynthesis of both phenylalanine and tyrosine. It is encoded by the tyrB gene and is dependent on pyridoxal-5-phosphate (PLP). Glutamate is the amino group donor in this enzyme. Genes involved in the production of other amino acids may serve as aminotransferases in the biosynthesis of phenylalanine and tyrosine in numerous bacteria, even though aromatic aminotransferases are required for AAA biosynthesis according to the Integrated Microbial Genomes (IMG) database. Because of their promiscuous substrate specificity, which permits an overlap with TyrB activity, it is known that other aminotransferases, like the branched chain aminotransferase IlvE (EC 2.6.1.42) and the aspartate aminotransferase AspC (EC 2.6.1.1), are involved in tyrosine and phenylalanine anabolism. Therefore, it appears that bacteria have evolved a mechanism to provide nutritional flexibility under different growth conditions. This strategy involves numerous aminotransferases with overlapping substrates. Enzymes that serve both tasks probably evolved from the same ancestor, since controlled evolution of aspartate aminotransferase to TAT in bacteria was successful without compromising the original aspartate aminotransferase function. Additionally, there have been instances where genes that are listed as aromatic aminotransferases in genome databases actually encode enzymes that have different activities. As an example, it was demonstrated that the Candida glabrata fungus's putative aromatic aminotransferase CgAro8p is involved in histidine degradation.

While chorismate is an integral part of both the bacterial and fungal phenylalanine and tyrosine biosynthesis pathways, the plant-based process is unique. at contrast, an aminotransferase reaction occurs at the penultimate stage of the plant route, not the last. This is the most notable distinction. Chorismate mutase (EC 5.4.99.5) converts chorismate to prephenate. Producing arogenate from prephenate is the subsequent step in a glutamate-dependent aminotransferase process facilitated by prephenate aminotransferase (EC 2.6.1.79). The enzymes arogenate dehydratase (EC 4.2.1.91) and tyrosine (EC 1.3.1.43) convert arogenate to phenylalanine (EC 4.2.1.91) by oxidation and decarboxylation, respectively, at the branching point arogenate. In plants, the plastid is where all the AAA are biosynthesized. It is debatable whether or not subsequent enzymes in the pathway are present, however chorismate mutases have been identified in the cytosol of various plant species. Recent studies have shown that the two essential Arabidopsis enzymes, arogenate dehydrogenase (tyrosine biosynthesis) and arogenate dehydratase (phenylalanine biosynthesis), are localized to the plastids.

Secondary metabolites derived from the three amino acids. (Pascual M B., et al., 2016)

Pathway of phenylalanine and tyrosine metabolism. (Kim S Z., et al., 2000)

Phenylalanine sources

Phenylalanine is ingested by dietary sources or supplementation, including lentils, chickpeas, pecans, soybeans, whole grains, sesame seeds, pumpkin seeds, peanuts, nuts, lima beans, cheese, cottage cheese, corn, brewer's yeast, bananas, almonds, dairy products, and eggs.

Phenylalanine function

(1) Regulate the immune responses

Modulating inhibition of T-cell immunological responses is clearly impacted by phenylalanine metabolism. When IL-4 induced gene 1 (IL4I1) encodes a phenylalanine oxidase, it reduces Phe and increases hydrogen peroxide (H₂O₂) through oxidative deamination. This process can suppress T-cell proliferation and cause signaling deficiencies. In both humans and mice, APCs have the ability to express IL4I1. There is evidence that IL4I1 plays a role in the negative feedback regulation of T-cell activation, as microarray data have shown a notable rise of IL4I1 mRNA levels in tumor-induced mouse MDSCs. By inhibiting CD3ζ chain expression and T-cell proliferation through H₂O₂ generation, it is extremely probable that IL4I1 functions as an immunomodulatory factor. phenylalanine and its metabolism are thought to play a regulatory function in T cell proliferation, activation, and immune response regulation, according to these findings taken together.

(2) Protein Synthesis

When building proteins, the body makes use of twenty different amino acids, one of which is phenylalanine. During translation, it is integrated into proteins and helps them work. An enzyme called phenylalanine hydroxylase converts phenylalanine to tyrosine. Although it is not required for survival, tyrosine plays a pivotal role in the synthesis of numerous vital compounds.

What is phenylalanine used for?

(1) As a disease marker

There has long been evidence that phenylalanine can be used as a measure of severity. Prior to the COVID-19 pandemic, a study examined patients with various serious infections (SOFA ≥ 2) between 2017 and 2018. The individuals were tested for levels of plasma phenylalanine, leucine, C-reactive protein (CRP), and nutritional indices (albumin, pre-albumin, and transferrin), and the results were tracked for three months. Compared to pre-albumin, transferrin, and leucine levels, phenylalanine was linked to increased mortality and intensive care unit admission rates, SOFA scores, bacteremia events, CRP levels, and CRP levels. Patients were categorized based on their phenylalanine levels; those with greater levels exhibited higher rates of ICU admission, higher CRP and leucine levels, and higher SOFA scores. Nevertheless, a multivariate model incorporating potential confounding variables was not used to examine the correlation between phenylalanine levels and inflammatory markers in this investigation. In comparison to the moderate and severe disease groups, the mild disease group had much lower levels of phenylalanine and tyrosine. After controlling for possible confounders and analyzing phenylalanine in relation to the cytokines of interest, linear regression models demonstrated a positive and independent association with illness severity. Also, for the first 10 days after illness start until hospital admission, mild cases consistently had decreased serum phenylalanine levels. A measure of the severity of illness is phenylalanine. This correlation holds true regardless of the severity of the inflammatory condition or the duration between the beginning of symptoms.

Levels of phenylalanine according to the time from illness onset and disease severity. (Luporini R L., et al., 2021)

(2) Treatment of vitiligo

With 68.5% of patients attaining a 75% or greater improvement, 90.9% of participants shown improvement. The face achieved this 75% improvement rate 87.9% of the time, the trunk 60.4% of the time, and the limbs 54.6% of the time. On the other hand, patients suffering from focal and segmental vitiligo showed a moderate improvement after receiving the medication. Patients that were exposed to UVA lamp light showed a little extra improvement. No patients were found to have any biochemical abnormalities. For youngsters or areas prone to evolutive vitiligo, a combination of L-phenylalanine and 0.025% clobetasol propionate, together with exposure to sunshine or UVA lamps during winter, seems to be an effective and safe treatment option.

(3) Mitigate depressed disease

Twenty patients suffering from depression were managed with phenylalanine in a clinical study. There was a 20-day treatment period. A daily dosage of 75-200 mg of phenylalanine was measured. Twelve patients were attended to near the end of treatment, and their care was deemed unnecessary. Four patients exhibited a subdued response to direct stimulation. In four cases, phenylalanine had no discernible effect. In patients suffering from depression, this analysis reveals that phenylalanine plays a substantial role.

(4) As the fungicide

The majority of the fruit that is gathered goes to waste because it rots. At the same time, there is a need for environmentally friendly substitutes due to limitations on postharvest fungicides. The primary components of fruit's inherent resistance, the antioxidant and antifungal flavonoids and anthocyanins, are produced from the phenylpropanoid pathway, which begins with phenylalanine. One study postulated that phenylalanine might stimulate the immune system and increase fruit tolerance to fungal infections. Phenylalanine was found to decrease anthracnose in mango fruits and stem-end rot in avocado fruits caused by Colletotrichum gloeosporioides and Lasiodiplodia theobromae, respectively, when applied postharvest. Phenylalanine, when applied to citrus fruits after harvest, decreased Penicillium digitatum green mold. After harvest, apply 6 mM of phenylalanine to citrus fruits and 8 mM to mangoes and avocados for the best results. Citrus fruits, strawberries, and mangoes were all treated with phenylalanine before harvest to stave down spoilage. Curiously, inoculation done two days after phenylalanine treatment triggered the defense response, but inoculation done just after phenylalanine administration had no effect on citrus fruit resistance to P. digitatum. Rapid phenylalanine metabolism likely explains why no traces of the medication remained on or in the fruit five hours following treatment. The inhibition of conidial germination by phenylalanine was also not demonstrated in vitro. Ultimately, we defined phenylalanine as a novel fruit defense response inducer that, when applied to fruit either before or after harvest, inhibited fungal pathogen-induced postharvest decay, implying that phenylalanine could be a safe and environmentally friendly substitute for fungicides.

Phenylalanine induces fruit resistance to postharvest pathogens. (Kumar Patel M., et al., 2020)

FAQ

Is Phenylalanine polar or nonpolar?

Phenylalanine is categorized as a nonpolar amino acid because of its hydrophobic benzyl side chain. The side chain of phenylalanine is –CH₂–C₆H₅, comprising a benzene ring (aromatic hydrocarbon). Benzene is nonpolar, and the entire side chain is devoid of electronegative atoms or polar functional groups.

References

1. Akram M., et al., Role of phenylalanine and its metabolites in health and neurological disorders[M]//Synucleins-Biochemistry and Role in Diseases. IntechOpen, 2020.
2. Kang C., et al., Simultaneous determination of aromatic amino acids in different systems using three-way calibration based on the PARAFAC-ALS algorithm coupled with EEM fluorescence: exploration of second-order advantages, Analytical Methods, 2014, 6(16): 6358-6368.
3. Pascual M B., et al., Biosynthesis and metabolic fate of phenylalanine in conifers, Frontiers in plant science, 2016, 7: 1030.
4. Matthews D E. An overview of phenylalanine and tyrosine kinetics in humans, The Journal of nutrition, 2007, 137(6): 1549S-1555S.
5. Kim S Z., et al., Hepatocellular carcinoma despite long‐term survival in chronic tyrosinaemia I, Journal of inherited metabolic disease, 2000, 23(8): 791-804.
6. Sikalidis A K. Amino acids and immune response: a role for cysteine, glutamine, phenylalanine, tryptophan and arginine in T-cell function and cancer?, Pathology & Oncology Research, 2015, 21(1): 9-17.
7. Luporini R L., et al., Phenylalanine and COVID-19: Tracking disease severity markers, International Immunopharmacology, 2021, 101: 108313.
8. Camacho F., et al., Oral and topical L-phenylalanine, clobetasol propionate, and UVA/sunlight--a new study for the treatment of vitiligo, Journal of Drugs in Dermatology: JDD, 2002, 1(2): 127-131.
9. Kumar Patel M., et al., Phenylalanine: A promising inducer of fruit resistance to postharvest pathogens, Foods, 2020, 9(5): 646.