All proteins in living cells are composed almost entirely of an assortment of twenty amino acids. Like many vital, naturally occurring molecules, however, amino acids can be toxic if present in abnormal quantities or in individuals with various genetic disorders. One such amino acid, our Molecule of the Week, is phenylalanine.

Phenylalanine is an amino acid with the standard three-letter abbreviation Phe and the one-letter abbreviation F. Phenylalanine consists of a benzyl (or methylphenyl) group attached to a simple amino acid backbone. The benzyl group and phenylalanine are displayed as expanded structures in Figure 1.

The central carbon atom is tetrahedral, so there are two chemically-distinct mirror images of phenylalanine; such mirror images are called enantiomers. In humans (and, to the author's knowledge, all living organisms) the biologically-active enantiomer of phenylalanine is the so-called L species. Figure 2 shows an organic chemist's condensed line structures of both enantiomers. Note that in cells the -COOH (carboxylic acid group) loses a proton to the -NH₂ (amino group) to give an internal salt, or zwitterion. Ordinarily, bulky non-polar organic groups like benzyl cause molecules to be insoluble in water (hydrophobic, literally "water-fearing"). It is the formation of a highly polar zwitterion that makes amino acids water-soluble, and hence this phenomenon was crucial for life to evolve on Earth in an aqueous environment.

Phenylalanine reacts in a condensation reaction with other amino acids to give larger molecules called peptides (tiny proteins) that are connected by amides (sometimes referred to by biochemists and biologists as peptide bonds). Figure 3 illustrates such a reaction, in this case to give the peptide H₂N-Ala-Phe-COOH. A brief consideration of Figure 3 should make it clear that the bond could just as easily formed between the amino group of alanine and the carboxyl group of phenylalanine. In cells, enzymes catalyze condensation reactions and work to ensure that the amino acids are strung together in only one direction to form a growing chain of defined sequence.

Phenylalanine is frequently found in the interior regions of proteins where it is shielded from water. It thus probably serves an important structure-defining role in many proteins, causing them to "fold" into specific shapes.

Phenylalanine is used heavily in organic synthesis, especially as a chiral building block, that is, a molecule available as a pure enantiomer (note 1). It is available commercially at relatively low cost. At the time of writing, a major chemical company charged a little over $250/kg for pure L-phenylalanine, and a little over $2000/kg for the non-naturally-occurring D-phenylalanine; while these prices may seem high they are actually quite low for single-enantiomer commercial chemicals. Companies that use huge quantities of the compound for production purposes (e.g. pharmaceutical companies and, as discussed below, flavor manufacturers) undoubtedly receive substantial volume discounts off the catalog price. Phenylalanine comes as a crystalline solid, as shown in Figure 4.

Cells are very adept at interconverting amino acids. In humans, an enzyme called phenylalanine hydroxylase adds a hydroxyl group to the benzyl group of phenylalanine to give the related amino acid tyrosine (Tyr, Y), as shown in Figure 5. When a surfeit of phenylalanine is present the excess is metabolized and possibly excreted in a process that begins with conversion to tyrosine. A small percentage of people are born with a genetic defect that results in the absence of functional phenylalanine hydroxylase, a medical condition called phenylketonuria (PKU). Such individuals cannot break down phenylalanine through normal means and alternative degradation products (ketones) appear in the urine, hence the name of the disorder.

If left untreated (that is, no diet modification), phenylketonuria leads to mental retardation due to toxicity of high concentrations of phenylalanine and its alternative breakdown products (hence the "dirty little secret" in this week's subtitle). Whenever children in industrialized nations are born in a hospital nowadays one of a number of tests is performed that can diagnose PKU before it becomes debilitating.

If you have ever eaten foods sweetened with aspartame (often sold as NutraSweet or Equal brands, and found in diet soda pops) then you may have noticed a warning to the effect of the "Phenylketonuriacs: Contains phenylalanine." Aspartame is a slightly modified dimer of phenylalanine and aspartic acid, another amino acid. When metabolized by the body it releases free phenylalanine, which can be dangerous to phenylketonuriacs.