Phenylalanine - -, - and -phenylalanine

and -phenylalanine

The stereoisomer -phenylalanine (DPA) can be produced by conventional organic synthesis, either as a single enantiomer or as a component of the racemic mixture. It does not participate in protein biosynthesis although it is found in proteins in small amounts - particularly aged proteins and food proteins that have been processed. The biological functions of -amino acids remain unclear although some, such as -phenylalanine, may have pharmacological activity. -phenylalanine, in particular, has been postulated to inhibit the enzymes that breakdown endorphins, giving it a potential analgesic profile.

-Phenylalanine (DLPA) is marketed as a nutritional supplement for its supposed analgesic and antidepressant activities. -Phenylalanine is a mixture of -phenylalanine and -phenylalanine. The reputed analgesic activity of -phenylalanine may be explained by the possible blockage by -phenylalanine of enkephalin (endorphin) degradation by the enzyme carboxypeptidase A. The mechanism of -phenylalanine's supposed antidepressant activity may be accounted for by the precursor role of -phenylalanine in the synthesis of the neurotransmitters norepinephrine and dopamine. Elevated brain levels of norepinephrine and dopamine are thought to have an antidepressant effect. Also, as -phenylalanine inhibits endorphin degradation, this leads to an inhibition of GABA release in the ventral tegmental neurons (in the midbrain), which results in greater dopamine release. This can explain the analgesic effects following ingestion. -Phenylalanine is absorbed from the small intestine and transported to the liver via the portal circulation. A small amount of -phenylalanine appears to be converted to -phenylalanine. -Phenylalanine is distributed to the various tissues of the body via the systemic circulation. It appears to cross the blood–brain barrier less efficiently than -phenylalanine, and so a small amount of an ingested dose of -phenylalanine is excreted in the urine without penetrating the central nervous system.

-Phenylalanine is an antagonist at α2δ Ca2+ calcium channels with a K_i of 980 nM. At higher doses, this may play a role in its analgesic and antidepressant properties.

In the brain, -phenylalanine is a competitive antagonist at the glycine binding site of NMDA receptor and at the glutamate binding site of AMPA receptor. At the glycine binding site of NMDA receptor -phenylalanine has an apparent equilibrium dissociation constant (K_B) of 573 µM estimated by Schild regression which is considerably lower than brain -phenylalanine concentration observed in untreated human phenylketonuria. -Phenylalanine also inhibits neurotransmitter release at glutamatergic synapses in hippocampus and cortex with IC₅₀ of 980 µM, a brain concentration seen in classical phenylketonuria, whereas -phenylalanine has a significantly smaller effect.