Editing Phenylalanine (section)

==<small>D</small>-, <small>L</small>- and <small>DL</small>-phenylalanine==
{{See also|D-Phenylalanine}}

The [[stereoisomer]] [[D-phenylalanine|<small>D</small>-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 [[food processing|processed]]. The biological functions of <small>D</small>-amino acids remain unclear, although <small>D</small>-phenylalanine has [[pharmacological activity]] at [[niacin receptor 2]].<ref name="IUPHAR/BPS-bio">{{cite web|title=D-Phenylalanine: Biological activity |url=http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=5797|website=The IUPHAR/BPS Guide to PHARMACOLOGY|access-date=27 December 2018}}</ref>

<small>DL</small>-Phenylalanine (DLPA) is marketed as a nutritional supplement for its purported [[analgesic]] and [[antidepressant]] activities, which have been supported by clinical trials.<ref name="Wood Reimherr Wender 1985 pp. 21–26">{{cite journal | last1=Wood | first1=David R. | last2=Reimherr | first2=Fred W. | last3=Wender | first3=Paul H. | title=Treatment of attention deficit disorder with DL-phenylalanine | journal=Psychiatry Research | publisher=Elsevier BV | volume=16 | issue=1 | year=1985 | issn=0165-1781 | doi=10.1016/0165-1781(85)90024-1 | pages=21–26| pmid=3903813 | s2cid=3077060 }}</ref><ref name="Beckmann Strauss Ludolph 1977 pp. 123–134">{{cite journal | last1=Beckmann | first1=H. | last2=Strauss | first2=M. A. | last3=Ludolph | first3=E. | title=DL-Phenylalanine in depressed patients: An open study | journal=Journal of Neural Transmission | publisher=Springer Science and Business Media LLC | volume=41 | issue=2–3 | year=1977 | issn=0300-9564 | doi=10.1007/bf01670277 | pages=123–134| pmid=335027 | s2cid=5849451 }}</ref><ref name="Beckmann Athen Olteanu Zimmer 1979 pp. 49–58">{{cite journal | last1=Beckmann | first1=Helmut | last2=Athen | first2=Dieter | last3=Olteanu | first3=Margit | last4=Zimmer | first4=Reinhild | title=DL-Phenylalanine versus imipramine: A double-blind controlled study | journal=Archiv für Psychiatrie und Nervenkrankheiten | publisher=Springer Science and Business Media LLC | volume=227 | issue=1 | year=1979 | issn=0003-9373 | doi=10.1007/bf00585677 | pages=49–58| pmid=387000 | s2cid=23531579 }}</ref>  <small>DL</small>-Phenylalanine is a mixture of <small>D</small>-phenylalanine and <small>L</small>-phenylalanine. The reputed analgesic activity of <small>DL</small>-phenylalanine may be explained by the possible blockage by <small>D</small>-phenylalanine of [[enkephalin]]  [[Chemical decomposition|degradation]] by the [[enzyme]] [[carboxypeptidase A]].<ref name="IUPHAR/BPS-clinical">{{cite web|title=D-Phenylalanine: Clinical data|url=http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=clinical&ligandId=5797|website=The IUPHAR/BPS Guide to PHARMACOLOGY|access-date=27 December 2018}}</ref><ref>{{cite journal |author1-link=David W. Christianson | vauthors = Christianson DW, Mangani S, Shoham G, Lipscomb WN | title = Binding of D-phenylalanine and D-tyrosine to carboxypeptidase A | journal = The Journal of Biological Chemistry | volume = 264 | issue = 22 | pages = 12849–12853 | date = August 1989 | doi = 10.1016/S0021-9258(18)51564-7 | pmid = 2568989 | url = http://www.jbc.org/content/264/22/12849.full.pdf | doi-access = free }}</ref> Enkephalins act as agonists of the [[mu opioid receptor|mu]] and [[delta opioid receptor]]s, and agonists of these receptors are known to produce antidepressant effects.<ref name="Jelen Stone Young Mehta 2022 p=104800">{{cite journal | last1=Jelen | first1=Luke A. | last2=Stone | first2=James M. | last3=Young | first3=Allan H. | last4=Mehta | first4=Mitul A. | title=The opioid system in depression | journal=Neuroscience & Biobehavioral Reviews | publisher=Elsevier BV | volume=140 | year=2022 | issn=0149-7634 | doi=10.1016/j.neubiorev.2022.104800 | page=104800| pmid=35914624 | pmc=10166717 | s2cid=251163234 | doi-access=free }}</ref> The mechanism of <small>DL</small>-phenylalanine's supposed antidepressant activity may also be accounted for in part by the [[protein precursor|precursor]] role of <small>L</small>-phenylalanine in the synthesis of the [[neurotransmitter]]s [[norepinephrine]] and [[dopamine]], though clinical trials have not found an antidepressant effect from <small>L</small>-phenylalanine alone.<ref name="Wood Reimherr Wender 1985 pp. 21–26"/> Elevated brain levels of norepinephrine and dopamine are thought to have an antidepressant effect.  <small>D</small>-Phenylalanine is absorbed from the [[small intestine]] and transported to the liver via the [[portal circulation]]. A small amount of <small>D</small>-phenylalanine appears to be converted to <small>L</small>-phenylalanine. <small>D</small>-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 <small>L</small>-phenylalanine, and so a small amount of an ingested dose of <small>D</small>-phenylalanine is excreted in the [[urine]] without penetrating the central nervous system.<ref>{{Cite journal|last1=Lehmann|first1=W. D.|last2=Theobald|first2=N.|last3=Fischer|first3=R.|last4=Heinrich|first4=H. C.|date=1983-03-14|title=Stereospecificity of phenylalanine plasma kinetics and hydroxylation in man following oral application of a stable isotope-labelled pseudo-racemic mixture of L- and D-phenylalanine|journal=Clinica Chimica Acta; International Journal of Clinical Chemistry|volume=128|issue=2–3|pages=181–198|issn=0009-8981|pmid=6851137|doi=10.1016/0009-8981(83)90319-4}}</ref>

<small>L</small>-Phenylalanine is an antagonist at [[Voltage-gated calcium channel|α<sub>2</sub>δ Ca<sup>2+</sup> calcium channels]] with a K<sub>i</sub> of 980 nM.<ref name="pmid16380257">{{cite journal | vauthors = Mortell KH, Anderson DJ, Lynch JJ, Nelson SL, Sarris K, McDonald H, Sabet R, Baker S, Honore P, Lee CH, Jarvis MF, Gopalakrishnan M | title = Structure-activity relationships of alpha-amino acid ligands for the alpha2delta subunit of voltage-gated calcium channels | journal = Bioorganic & Medicinal Chemistry Letters | volume = 16 | issue = 5 | pages = 1138–4111 | date = March 2006 | pmid = 16380257 | doi = 10.1016/j.bmcl.2005.11.108 }}</ref>

In the brain, <small>L</small>-phenylalanine is a [[competitive antagonist]] at the [[glycine]] binding site of [[NMDA receptor]]<ref>{{cite journal | vauthors = Glushakov AV, Dennis DM, Morey TE, Sumners C, Cucchiara RF, Seubert CN, Martynyuk AE | title = Specific inhibition of ''N''-methyl-D-aspartate receptor function in rat hippocampal neurons by L-phenylalanine at concentrations observed during phenylketonuria | journal = Molecular Psychiatry | volume = 7 | issue = 4 | pages = 359–367 | year = 2002 | pmid = 11986979 | doi = 10.1038/sj.mp.4000976 | doi-access = free }}</ref>  and at the [[glutamate]] binding site of [[AMPA receptor]].<ref name="Glushakov 116–24">{{cite journal | vauthors = Glushakov AV, Dennis DM, Sumners C, Seubert CN, Martynyuk AE | title = L-Phenylalanine selectively depresses currents at glutamatergic excitatory synapses | journal = Journal of Neuroscience Research | volume = 72 | issue = 1 | pages = 116–124 | date = April 2003 | pmid = 12645085 | doi = 10.1002/jnr.10569 | s2cid = 42087834 }}</ref>  At the [[glycine]] binding site of [[NMDA receptor]] <small>L</small>-phenylalanine has an apparent equilibrium dissociation constant (K<sub>B</sub>) of 573 μM estimated by [[Schild regression]]<ref>{{cite journal | vauthors = Glushakov AV, Glushakova O, Varshney M, Bajpai LK, Sumners C, Laipis PJ, Embury JE, Baker SP, Otero DH, Dennis DM, Seubert CN, Martynyuk AE | title = Long-term changes in glutamatergic synaptic transmission in phenylketonuria | journal = Brain | volume = 128 | issue = Pt 2 | pages = 300–307 | date = February 2005 | pmid = 15634735 | doi = 10.1093/brain/awh354 | doi-access = free }}</ref> which is considerably lower than brain <small>L</small>-phenylalanine concentration observed in untreated human [[phenylketonuria]].<ref>{{cite journal | vauthors = Möller HE, Weglage J, Bick U, Wiedermann D, Feldmann R, Ullrich K | title = Brain imaging and proton magnetic resonance spectroscopy in patients with phenylketonuria | journal = Pediatrics | volume = 112 | issue = 6 Pt 2 | pages = 1580–1583 | date = December 2003 | doi = 10.1542/peds.112.S4.1580 | pmid = 14654669 | hdl = 11858/00-001M-0000-0010-A24A-C | s2cid = 2198040 | hdl-access = free }}</ref>
<small>L</small>-Phenylalanine also inhibits [[neurotransmitter]] release at [[glutamatergic]] [[synapses]] in [[hippocampus]] and [[Cerebral cortex|cortex]] with [[IC50|IC<sub>50</sub>]] of 980 μM, a brain concentration seen in classical [[phenylketonuria]], whereas <small>D</small>-phenylalanine has a significantly smaller effect.<ref name="Glushakov 116–24"/>