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Phenylalanine is an electrically neutral amino acid with the chemical formula C9H11NO2. This essential amino acid is one of 20 building blocks of proteins in humans. Due to its benzyl group, phenylalanine is hydrophobic. Since its discovery in 1879, phenylalanine has been studied for its antidepressant and analgesic effects. The synthesis of phenylalanine is complex and does not occur in mammals. The metabolism of phenylalanine produces various hormones and neurotransmitters. Genetic mutations can result in several disorders relating to the metabolism of phenylalanine. This report will identify the biological importance of the amino acid phenylalanine by examining its history, uses, metabolic pathways and disorders, and biological synthesis.
Discovery and History
Schulze and Barbieri discovered phenylalanine in plant sprouts in 1879. The researchers extracted phenylalanine copper salts from Lupinus Zuteus seedlings, which were refined to isolate phenylalanine ("L-Phenylalanine," n.d.). Before 1940, research on phenylalanine did not describe its biological metabolism during the formation of tyrosine. Womack and Rose showed the essentiality and dependence on phenylalanine in the diet of rats. Dietary intake of tyrosine in the rats was deemed nonessential. Evidence from the trials proved that phenylalanine is the precursor of tyrosine, but phenylalanine cannot be synthesized from tyrosine (Matthews, 2007).
The discovery of the codon of phenylalanine was a significant breakthrough in determining the relationship between messenger ribonucleic acid and protein production. In 1961, Matthaei and Nirenberg repeatedly inserted uracil nucleotides into E. coli bacteria, producing long phenylalanine peptide chains. The researchers deduced that the codons for phenylalanine include UUU and UUC ("Phenylalanine," 2009).
In the 1960s, a more efficient method of phenylalanine production resulted in the large-scale fermentation of phenylalanine. This method was incorporated into the nutritional supplement and drug industries ("L-Phenylalanine," n.d.). Phenylalanine supplements are currently used to treat depression, chronic pain, Parkinson's disease, and vitiligo ("Supplements with Similar," n.d.).
Since 1981, aspartame has been used as a food additive in Canada. Aspartame degrades through metabolism and digestion to form phenylalanine. Phenylalanine has recently been under intense scrutiny due to its elevated levels in aspartame, and the occurrence of phenylketonuria ("Aspartame," 2005).
Importance and Uses
Phenylalanine is an essential amino acid in the diet of humans. Mammals cannot form benzene rings, therefore limiting the biosynthesis of phenylalanine in humans (Kretchmer & Etzwiler, 1958). Phenylalanine is important in amino acid metabolism and the synthesis of structural proteins in tissue. The concentrations of phenylalanine control the amounts of other electrically neutral amino acids in the brain (Humphries, Pretorius, & Naude, 2007). Phenylalanine is an essential building block for many hormones and neurotransmitters. Phenylalanine is converted into DOPA, dopamine, epinephrine, norepinephrine, phenylethylamine, and phenylacetate (Humphries et al., 2007).
Depression can be treated with phenylalanine medication. Treatment of oral and intravenous application of deprenyl plus phenylalanine has significant antidepressant action (Birkmayer, Linauer, Riederer, & Knoll, 1984). While many natural health and nutritional companies claim D-phenylalanine is effective in chronic pain reduction, clinical studies have determined no significant analgesic results (Walsh, Ramamurthy, Schoenfeld, & Hoffman, 1986).
L-DOPA, a molecule composed of a phenylalanine base, has been used as a symptom repressor in Parkinson's disease for over fifty years. In 1967, Cortzias showed in his report on Parkinson's disease, that L-DOPA has a noteworthy rehabilitative quality in reducing rigidity and akinesia (McDowell & Lee, 1970). The major problem of Parkinson's disease is lowered levels of dopamine in the brain due to trauma or dysfunction of dopaminergic cells. Administered L-DOPA is able to cross the blood-brain barrier for conversion into dopamine, thus increasing dopamine levels ("Oxidation of L-dopa," 2002). Current research suggests that phenylalanine administration along with ultraviolet radiation aids in vitiligo patients. The phenylalanine absorbs the radiation resulting in slight pigmentation changes in the skin ("Supplements with Similar," n.d.).
Several disorders arise from the deficiency of enzymes required in phenylalanine metabolism. Phenylketonuria is the most common, resulting from the inability to convert phenylalanine into tyrosine. Alkaptonuria is characterized by darkened urine, and is the result of a mutation to the gene involved with the catabolism of aromatic ring structures (Gross, Hartz, Kniffin, & McKusick, 1986).
Phenylketonuria (PKU) is a recessive inborn genetic error characterized by lowered levels of the enzyme phenylalanine hydroxylase. This enzyme metabolizes phenylalanine into tyrosine, a molecule involved primarily in the production of neurotransmitters. Since PKU is a recessive trait, heterozygous persons are considered 'carriers' of the genetic condition. Heterozygous parents have a 25 percent chance of conceiving a child with PKU (Gross et al., 1986). Figure 1 shows the genetic mapping of two heterozygous parents with PKU alleles ("Phenylketonuria," 2009).
PKU is a substitution point mutation occurring on chromosome twelve. Fifty different mutations have been linked with phenylalanine hydroxylase deficiency. These mutations affect the PAH gene, which regulates the production of phenylalanine hydroxylase. Not all of the mutations cause PKU. Milder versions of the disorder appear in the population. Named non-PKU hyperphenylalaninemia is characterized by elevated phenylalanine levels, but has a lowered risk of brain damage. This variant disorder does not require additional treatment other than a specialized diet restricting high protein foods ("Phenylketonuria," 2008).
Left untreated, phenylalanine accumulates in high concentrations in the brain. Normal adults have a phenylalanine blood concentration of 1 mg/dL. Untreated PKU patients have blood levels ranging from six to 80 mg/dL ("Phenylalanine Definition," n.d.). Phenylalanine levels saturate the brain capillary transport system, resulting in the deficiency of other essential amino acids. This leads to impaired cognitive development, and mental retardation. Other symptoms include a 'mousy' odour, eczema, difficulty walking and epilepsy (Gross et al., 1986).
Since PKU is a genetic disorder, genetic mapping of family history can help determine the probability of the disorder arising in a child. PKU is diagnosed through routine blood testing, although placental biopsy is equally effective. An abnormally elevated level of phenylalanine hydroxylase is seen in the placenta of PKU patients (Gross et al., 1986). All babies are required to have a PKU blood test done around 24 hours following birth. Blood is taken from the heel using a small needle to collect blood (Golonka, 2008).
Dietary restrictions on phenylalanine implemented during childhood prevent intellectual defects in individuals with PKU (Gross et al., 1986). High protein foods must be avoided to limit exposure to phenylalanine. Most medical clinics suggest lifelong dietary restriction to promote physical and mental development ("Phenylalanine Definition," n.d.).
The distribution of PKU is geographically unequal. Incidence levels in Ireland are one per 4500, whereas in Switzerland levels are one per 16,000. Currently the incidence in United States Caucasians is one per 8,000 (Gross et al., 1986).
Alkaptonuria is an autosomal recessive genetic disorder resulting from an inborn genetic error to the HGD gene, responsible for producing the enzyme homogentisate oxidase. This enzyme is used in the metabolism of phenylalanine and tyrosine. The deficiency of this enzyme results in phenylalanine and tyrosine being converted into homogentisic acid. Alkaptonuria is a rare disease, characterized by progressive spinal arthritis, and darkened pigment on ears, sclera, and cornea. Individuals with alkaptonuria excrete urine that darkens to a brown colour in the presence of air. Clinical trials have suggested that high dosage vitamin C treatments reduce pigment levels, and slow the process of arthritis (Kirmse, 2007).
The synthesis of phenylalanine involves a notable formation of an aromatic ring from aliphatic molecules. Since phenylalanine contains a benzyl ring, humans are unable to synthesize this amino acid. In plants, the biosynthesis of phenylalanine begins with a four-carbon sugar phosphate, D-erythrose 4-phosphate. This sugar reacts with phosphoenolpyruvate, producing a phosphorylated 7-carbon keto sugar. The sugar produces an aliphatic hexagonal ring structure. Next, the hexagonal sugar is dehydroxylated to form shikimic acid. Shikimic acid is the basis of tyrosine and phenylalanine. During the biosynthesis of phenylalanine, shikimic acid converts to prephenic acid, which is later aromatized through the simultaneous dehydration and decarboxylation, yielding phenylpyruvic acid. Phenylpyruvic acid is aminated to form phenylalanine. This process does not occur in mammals. Aromatic amino acids are produced in higher plants and bacteria, such as E. coli (Lehinger, 1981).
Phenylalanine is converted along a metabolic pathway to produce various hormones and neurotransmitters. Phenylalanine is transported along the Large neutral Amino acid Transporter in brain capillaries. Using this protein transporter, phenylalanine is able to cross the blood-brain barrier ("Phenylalanine," 2009).
The first step of metabolism is the hydroxylation of phenylalanine to form tyrosine, a non-essential amino acid. Tyrosine is the precursor to pigments, hormones, neurotransmitters, and alkaloids ("Tyrosine," 2009). Tyrosine is hydroxylated to form L-DOPA via the enzyme tyrosine hydroxylase. L-DOPA is decarboxylated in the synthesis of dopamine, an important neurotransmitter of the brain. This is followed by the Î²-oxidation into norepinephrine, a stress hormone. Lastly, the final step adds a methyl group to produce epinephrine ("Phenylalanine," 2009). Figure 2 outlines the metabolic pathway of phenylalanine as it produces tyrosine, L-DOPA, norepinephrine, and epinephrine ("Phenylalanine," 2009).