| Description | Phenylalanine (Phe), also known as L-phenylalanine is an alpha-amino acid. These are amino acids in which the amino group is attached to the carbon atom immediately adjacent to the carboxylate group (alpha carbon). Amino acids are organic compounds that contain amino (-NH2) and carboxyl (-COOH) functional groups, along with a side chain (R group) specific to each amino acid. L-phenylalanine is one of 20 proteinogenic amino acids, i.e., the amino acids used in the biosynthesis of proteins. Phenylalanine is found in all organisms ranging from bacteria to plants to animals. It is classified as an aromatic, non-polar amino acid. In humans, phenylalanine is an essential amino acid and the precursor of the amino acid tyrosine. Like tyrosine, phenylalanine is also a precursor for catecholamines including tyramine, dopamine, epinephrine, and norepinephrine. Catecholamines are neurotransmitters that act as adrenalin-like substances. Interestingly, several psychotropic drugs (mescaline, morphine, codeine, and papaverine) also have phenylalanine as a constituent. Phenylalanine is highly concentrated in the human brain and plasma. Normal metabolism of phenylalanine requires biopterin, iron, niacin, vitamin B6, copper, and vitamin C. An average adult ingests 5 g of phenylalanine per day and may optimally need up to 8 g daily. Phenylalanine is highly concentrated in a number of high protein foods, such as meat, cottage cheese, and wheat germ. An additional dietary source of phenylalanine is artificial sweeteners containing aspartame (a methyl ester of the aspartic acid/phenylalanine dipeptide). As a general rule, aspartame should be avoided by phenylketonurics and pregnant women. When present in sufficiently high levels (>500 uM), phenylalanine can act as a neurotoxin and a metabotoxin. A neurotoxin is a compound that disrupts or attacks neural cells and neural tissue. A metabotoxin is an endogenously produced metabolite that causes adverse health effects at chronically high levels. Chronically high levels of phenylalanine are associated with at least five inborn errors of metabolism, including Hartnup disorder, hyperphenylalaninemia due to guanosine triphosphate cyclohydrolase deficiency, phenylketonuria (PKU), tyrosinemia type 2 (or Richner-Hanhart syndrome), and tyrosinemia type III (TYRO3). Phenylketonurics have elevated serum plasma levels of phenylalanine up to 400 times normal. High plasma concentrations of phenylalanine influence the blood-brain barrier transport of large neutral amino acids. The high plasma phenylalanine concentrations increase phenylalanine entry into the brain and restrict the entry of other large neutral amino acids (PMID: 19191004 ). Phenylalanine has been found to interfere with different cerebral enzyme systems. Untreated phenylketonuria (PKU) can lead to intellectual disability, seizures, behavioural problems, and mental disorders. It may also result in a musty smell and lighter skin. Classic PKU dramatically affects myelination and white matter tracts in untreated infants; this may be one major cause of neurological disorders associated with phenylketonuria. Mild phenylketonuria can act as an unsuspected cause of hyperactivity, learning problems, and other developmental problems in children. It has been recently suggested that PKU may resemble amyloid diseases, such as Alzheimer's disease and Parkinson's disease, due to the formation of toxic amyloid-like assemblies of phenylalanine (PMID: 22706200 ). Higher serum/plasma levels (>75 µmol/L) of phenylalanine are commonly seen in people suffering from heart failure, chronic inflammation or infections, as well those suffering from sepsis or septic shock (PMID: 31170548 ; PMID: 32618142 ). Normally most amino acid levels drop during inflammation or infection, so a rise in phenylalanine levels is considered unusual. While normal levels of phenylalanine are between 40-75 µmol/L, those in intensive care units with phenylalanine levels >110 µmol/L are at much greater risk of dying (PMID: 32618142 ). These moderately high levels of phenylalanine are not necessarily toxic, they are simply secondary indicators of something else that is seriously wrong. The metabolism of phenylalanine and its level in blood directly relates to the activity of the enzyme phenylalanine hydroxylase, which is functionally attenuated by high levels of inflammation. The attenuation of phenylalanine hydroxylase appears to be associated with insufficient tetrahydrobiopterin (BH4), the co‐factor for phenylalanine hydroxylase. In particular, inflammation‐induced production of reactive oxygen species (ROS) may consume a significant portion of BH4, thereby leaving phenylalanine unmetabolized. Pro‐inflammatory cytokine‐mediated inflammation also increases the production of neopterin at the expense of the production of BH4. Insufficient bioavailability of BH4 also leads to dysfunction in multiple systems, including nitric oxide synthase, tryptophan/kynurenine metabolism, the catecholamine pathway, the neural system, and thyroid hormone production (PMID: 32618142 ). High phenylalanine concentrations in septic patients may also reflect the breakdown of muscle tissues (leading to amino acid release) and the body’s differential metabolic capacity for different amino acids. Muscle tissue is easily able to oxidize branched chain amino acids to support its own energy requirements. Muscle tissue is also able to metabolize alanine, glycine, proline, aspartate, glutamate, histidine, glutamine and serine for gluconeogenesis, but aromatic amino acids such as phenylalanine and tyrosine as well as many cysteine-containing amino acids are not as easily metabolized. This may also account for the increase in the levels of phenylalanine and tyrosine seen during sepsis (PMID: 99098 ). Phenylalanine also has some potential benefits. Phenylalanine can act as an effective pain reliever. Its use in premenstrual syndrome and Parkinson's may enhance the effects of acupuncture and electric transcutaneous nerve stimulation (TENS). Phenylalanine and tyrosine, like L-DOPA, produce a catecholamine-like effect. Phenylalanine is better absorbed than tyrosine and may cause fewer headaches. Low phenylalanine diets have been prescribed for certain cancers with mixed results. For instance, some tumours use more phenylalanine than others (particularly melatonin-producing tumours called melanomas).Phenylalanine is elevated by a factor of two or more in the urine of patients with diet-controlled PKU or phenylketonuria (PMID: 37446577 ). |
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