General Information of MET (ID: META00062)
Name Phenylalanine
Synonyms   Click to Show/Hide Synonyms of This Metabolite
(-)-beta-Phenylalanine; (6S)-THFA; (6S)-Tetrahydrofolate; (6S)-Tetrahydrofolic acid; (L)-Phenylalanine; (S)-(-)-Phenylalanine; (S)-2-Amino-3-phenylpropanoate; (S)-2-Amino-3-phenylpropanoic acid; (S)-2-Amino-3-phenylpropionate; (S)-2-Amino-3-phenylpropionic acid; (S)-Phenylalanine; (S)-a-Amino-b-phenylpropionate; (S)-a-Amino-b-phenylpropionic acid; (S)-alpha-Amino-benzenepropanoate; (S)-alpha-Amino-benzenepropanoic acid; (S)-alpha-Amino-beta-phenylpropionic acid; (S)-alpha-Aminobenzenepropanoate; (S)-alpha-Aminobenzenepropanoic acid; (S)-alpha-Aminohydrocinnamate; (S)-alpha-Aminohydrocinnamic acid; 3-Phenyl-L-alanine; 5,6,7,8-Tetrahydrofolate; 5,6,7,8-Tetrahydrofolic acid; Endorphenyl; F; L-2-Amino-3-phenylpropionate; L-2-Amino-3-phenylpropionic acid; L-Isomer phenylalanine; PHENYLALANINE; Phe; Phenyl-alanine; Phenylalamine; Phenylalanine, L isomer; Phenylalanine, L-isomer; THF; Tetrahydrofolate; alpha-Aminohydrocinnamate; alpha-Aminohydrocinnamic acid; beta-Phenyl-L-alanine; beta-Phenyl-alpha-alanine; beta-Phenylalanine
Source Aromatic homomonocyclic compounds
Structure Type   Amino acids, peptides, and analogues  (Click to Show/Hide the Complete Structure Type Hierarchy)
Organic acids and derivatives
Carboxylic acids and derivatives
Amino acids, peptides, and analogues
PubChem CID
6140
HMDB ID
HMDB0000159
Formula
C9H11NO2
Structure
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3D MOL 2D MOL
  Click to Show/Hide the Molecular/Functional Data (External Links/Property/Function) of This Metabolite
KEGG ID
C00079
DrugBank ID
DB00120
ChEBI ID
17295
FooDB ID
FDB004940
ChemSpider ID
5910
METLIN ID
28
Physicochemical Properties Molecular Weight 165.19 Topological Polar Surface Area 63.3
XlogP -1.5 Complexity 153
Heavy Atom Count 12 Rotatable Bond Count 3
Hydrogen Bond Donor Count 2 Hydrogen Bond Acceptor Count 3
Function
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. As a general rule, aspartame should be avoided by phenylketonurics and pregnant women. When present in sufficiently high levels, 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. 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. 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).
Regulatory Network
Full List of Protein(s) Regulated by This Metabolite
      GPCR rhodopsin (GPCR-1)
            G-protein-coupled receptor PGR3 (GPR139) Click to Show/Hide the Full List of Regulating Pair(s):   1 Pair(s)
               Detailed Information Protein   Info click to show the details of this protein
               Regulating Pair Experim Info click to show the details of experiment for validating this pair [1]
                      Introduced Variation Phenylalanine addition (48 hours)
                      Induced Change GPR139 protein activity levels: increase
                      Summary Introduced Variation         Induced Change 
                      Disease Status Healthy individual
                      Details It is reported that phenylalanine addition causes the increase of GPR139 protein activity compared with control group.
      Transferases (EC 2)
            Signal-regulated kinase 1 (ERK1) Click to Show/Hide the Full List of Regulating Pair(s):   1 Pair(s)
               Detailed Information Protein   Info click to show the details of this protein
               Regulating Pair Experim Info click to show the details of experiment for validating this pair [2]
                      Introduced Variation Phenylalanine addition (0.08 hours)
                      Induced Change MAPK3 protein phosphorylation levels: increase
                      Summary Introduced Variation         Induced Change 
                      Disease Status Diabetes mellitus [ICD-11: 5A14]
                      Details It is reported that phenylalanine addition causes the increase of MAPK3 protein phosphorylation compared with control group.
            Signal-regulated kinase 2 (ERK2) Click to Show/Hide the Full List of Regulating Pair(s):   1 Pair(s)
               Detailed Information Protein   Info click to show the details of this protein
               Regulating Pair Experim Info click to show the details of experiment for validating this pair [2]
                      Introduced Variation Phenylalanine addition (0.08 hours)
                      Induced Change MAPK1 protein phosphorylation levels: increase
                      Summary Introduced Variation         Induced Change 
                      Disease Status Diabetes mellitus [ICD-11: 5A14]
                      Details It is reported that phenylalanine addition causes the increase of MAPK1 protein phosphorylation compared with control group.
Full List of Protein(s) Regulating This Metabolite
      Amino acid/auxin permease (AAAP)
            Sodium-coupled neutral amino acid transporter 9 (SLC38A9) Click to Show/Hide the Full List of Regulating Pair(s):   2 Pair(s)
               Detailed Information Protein   Info click to show the details of this protein
               Regulating Pair (1) Experim Info click to show the details of experiment for validating this pair [3]
                      Introduced Variation Truncation of SLC38A9
                      Induced Change Phenylalanine concentration: increase
                      Summary Introduced Variation         Induced Change 
                      Disease Status Healthy individual
                      Details It is reported that truncation of SLC38A9 leads to the increase of phenylalanine levels compared with control group.
               Regulating Pair (2) Experim Info click to show the details of experiment for validating this pair [3]
                      Introduced Variation Overexpression of SLC38A9
                      Induced Change Phenylalanine concentration: decrease
                      Summary Introduced Variation         Induced Change 
                      Disease Status Healthy individual
                      Details It is reported that overexpression of SLC38A9 leads to the decrease of phenylalanine levels compared with control group.
            Solute carrier family 38 member 2 (SLC38A2) Click to Show/Hide the Full List of Regulating Pair(s):   1 Pair(s)
               Detailed Information Protein   Info click to show the details of this protein
               Regulating Pair Experim Info click to show the details of experiment for validating this pair [4]
                      Introduced Variation Knockdown (siRNA) of SLC38A2
                      Induced Change Phenylalanine concentration: increase (FC = 1.65)
                      Summary Introduced Variation         Induced Change 
                      Disease Status Healthy individual
                      Details It is reported that knockdown of SLC38A2 leads to the increase of phenylalanine levels compared with control group.
            Solute carrier family 38 member 3 (SLC38A3) Click to Show/Hide the Full List of Regulating Pair(s):   2 Pair(s)
               Detailed Information Protein   Info click to show the details of this protein
               Regulating Pair (1) Experim Info click to show the details of experiment for validating this pair [5]
                      Introduced Variation Knockout of Slc38a3
                      Induced Change Phenylalanine concentration: decrease
                      Summary Introduced Variation         Induced Change 
                      Disease Status Healthy individual
                      Details It is reported that knockout of Slc38a3 leads to the decrease of phenylalanine levels compared with control group.
               Regulating Pair (2) Experim Info click to show the details of experiment for validating this pair [5]
                      Introduced Variation Knockout of SLC38A3
                      Induced Change Phenylalanine concentration: decrease
                      Summary Introduced Variation         Induced Change 
                      Disease Status Healthy individual
                      Details It is reported that knockout of SLC38A3 leads to the decrease of phenylalanine levels compared with control group.
      Amino acid/polyamine transporter (AAPT)
            Integral membrane E16 (SLC7A5) Click to Show/Hide the Full List of Regulating Pair(s):   1 Pair(s)
               Detailed Information Protein   Info click to show the details of this protein
               Regulating Pair Experim Info click to show the details of experiment for validating this pair [6]
                      Introduced Variation Overexperisson of SLC7A5
                      Induced Change Phenylalanine concentration: decrease
                      Summary Introduced Variation         Induced Change 
                      Disease Status Healthy individual
                      Details It is reported that co-overexperisson of SLC7A5 and SLC7A8 leads to the decrease of phenylalanine levels compared with control group.
            L-type amino acid transporter 2 (LAT2) Click to Show/Hide the Full List of Regulating Pair(s):   1 Pair(s)
               Detailed Information Protein   Info click to show the details of this protein
               Regulating Pair Experim Info click to show the details of experiment for validating this pair [6]
                      Introduced Variation Overexperisson of SLC7A8
                      Induced Change Phenylalanine concentration: decrease
                      Summary Introduced Variation         Induced Change 
                      Disease Status Healthy individual
                      Details It is reported that co-overexperisson of SLC7A5 and SLC7A8 leads to the decrease of phenylalanine levels compared with control group.
      GPCR rhodopsin (GPCR-1)
            Adrenergic receptor beta-3 (ADRB3) Click to Show/Hide the Full List of Regulating Pair(s):   1 Pair(s)
               Detailed Information Protein   Info click to show the details of this protein
               Regulating Pair Experim Info click to show the details of experiment for validating this pair [7]
                      Introduced Variation Agonist (CL-316,243) of Adrb3
                      Induced Change Phenylalanine concentration: increase
                      Summary Introduced Variation         Induced Change 
                      Disease Status Healthy individual
                      Details It is reported that agonist of ADRB3 leads to the increase of phenylalanine levels compared with control group.
      Hydrolases (EC 3)
            Alpha-N-acetylglucosaminidase (NAGLU) Click to Show/Hide the Full List of Regulating Pair(s):   1 Pair(s)
               Detailed Information Protein   Info click to show the details of this protein
               Regulating Pair Experim Info click to show the details of experiment for validating this pair [8]
                      Introduced Variation Knockout of Naglu
                      Induced Change Phenylalanine concentration: decrease
                      Summary Introduced Variation         Induced Change 
                      Disease Status Lysosomal storage diseases [ICD-11: 5C56]
                      Details It is reported that knockout of Naglu leads to the decrease of phenylalanine levels compared with control group.
            GTPase KRas (KRAS) Click to Show/Hide the Full List of Regulating Pair(s):   2 Pair(s)
               Detailed Information Protein   Info click to show the details of this protein
               Regulating Pair (1) Experim Info click to show the details of experiment for validating this pair [9]
                      Introduced Variation Overexpression of KRAS
                      Induced Change Phenylalanine concentration: decrease (FC = 0.76)
                      Summary Introduced Variation         Induced Change 
                      Disease Status Lung cancer [ICD-11: 2C25]
                      Details It is reported that overexpression of KRAS leads to the decrease of phenylalanine levels compared with control group.
               Regulating Pair (2) Experim Info click to show the details of experiment for validating this pair [9]
                      Introduced Variation Overexpression of KRAS
                      Induced Change Phenylalanine concentration: increase (FC = 1.31)
                      Summary Introduced Variation         Induced Change 
                      Disease Status Lung cancer [ICD-11: 2C25]
                      Details It is reported that overexpression of KRAS leads to the increase of phenylalanine levels compared with control group.
            Leukotriene-C4 hydrolase (GGT1) Click to Show/Hide the Full List of Regulating Pair(s):   1 Pair(s)
               Detailed Information Protein   Info click to show the details of this protein
               Regulating Pair Experim Info click to show the details of experiment for validating this pair [10]
                      Introduced Variation Knockdown (siRNA) of GGT1
                      Induced Change Phenylalanine concentration: increase
                      Summary Introduced Variation         Induced Change 
                      Disease Status Renal cell carcinoma [ICD-11: 2C90]
                      Details It is reported that knockdown of GGT1 leads to the increase of phenylalanine levels compared with control group.
            Sulfatase sulf-1 (SULF1) Click to Show/Hide the Full List of Regulating Pair(s):   1 Pair(s)
               Detailed Information Protein   Info click to show the details of this protein
               Regulating Pair Experim Info click to show the details of experiment for validating this pair [11]
                      Introduced Variation Knockdown (shRNA) of SULF1
                      Induced Change Phenylalanine concentration: decrease (FC = 0.52 / 0.53)
                      Summary Introduced Variation         Induced Change 
                      Disease Status Ovarian cancer [ICD-11: 2C73]
                      Details It is reported that knockdown of SULF1 leads to the decrease of phenylalanine levels compared with control group.
      Monocarboxylate porter (MNP)
            Monocarboxylate transporter 10 (SLC16A10) Click to Show/Hide the Full List of Regulating Pair(s):   1 Pair(s)
               Detailed Information Protein   Info click to show the details of this protein
               Regulating Pair Experim Info click to show the details of experiment for validating this pair [12]
                      Introduced Variation Overexpression of SLC16A10
                      Induced Change Phenylalanine concentration: increase
                      Summary Introduced Variation         Induced Change 
                      Disease Status Healthy individual
                      Details It is reported that overexpression of SLC16A10 leads to the increase of phenylalanine levels compared with control group.
      Oxidoreductases (EC 1)
            L-2-hydroxyglutarate dehydrogenase (L2HGDH) Click to Show/Hide the Full List of Regulating Pair(s):   1 Pair(s)
               Detailed Information Protein   Info click to show the details of this protein
               Regulating Pair Experim Info click to show the details of experiment for validating this pair [13]
                      Introduced Variation Mutation (Nonsense mutations or missense mutations) of L2hgdh
                      Induced Change Phenylalanine concentration: increase
                      Summary Introduced Variation         Induced Change 
                      Disease Status Melanoma [ICD-11: 2C30]
                      Details It is reported that mutation (nonsense mutations or missense mutations leading to KMT2D loss) of L2hgdh leads to the increase of phenylalanine levels compared with control group.
      Pore-forming PNC peptide (PNC)
            Cellular tumor antigen p53 (TP53) Click to Show/Hide the Full List of Regulating Pair(s):   1 Pair(s)
               Detailed Information Protein   Info click to show the details of this protein
               Regulating Pair Experim Info click to show the details of experiment for validating this pair [14]
                      Introduced Variation Knockout of TP53
                      Induced Change Phenylalanine concentration: decrease (Log2 FC=0.8)
                      Summary Introduced Variation         Induced Change 
                      Disease Status Colon cancer [ICD-11: 2B90]
                      Details It is reported that knockout of TP53 leads to the decrease of phenylalanine levels compared with control group.
      Transcription factor (TF)
            Forkhead box protein O1 (FOXO1) Click to Show/Hide the Full List of Regulating Pair(s):   1 Pair(s)
               Detailed Information Protein   Info click to show the details of this protein
               Regulating Pair Experim Info click to show the details of experiment for validating this pair [15]
                      Introduced Variation Overexpression of Foxo1
                      Induced Change Phenylalanine concentration: decrease (FC = 0.50)
                      Summary Introduced Variation         Induced Change 
                      Disease Status Healthy individual
                      Details It is reported that overexpression of Foxo1 leads to the decrease of phenylalanine levels compared with control group.
            Myc proto-oncogene protein (MYC) Click to Show/Hide the Full List of Regulating Pair(s):   1 Pair(s)
               Detailed Information Protein   Info click to show the details of this protein
               Regulating Pair Experim Info click to show the details of experiment for validating this pair [16]
                      Introduced Variation Knockdown (siRNA) of MYC
                      Induced Change Phenylalanine concentration: decrease
                      Summary Introduced Variation         Induced Change 
                      Disease Status Colorectal cancer [ICD-11: 2B91]
                      Details It is reported that knockdown of MYC leads to the decrease of phenylalanine levels compared with control group.
References
1 GPR139, an Orphan Receptor Highly Enriched in the Habenula and Septum, Is Activated by the Essential Amino Acids L-Tryptophan and L-Phenylalanine. Mol Pharmacol. 2015 Nov;88(5):911-25.
2 Computer-aided discovery of aromatic l--amino acids as agonists of the orphan G protein-coupled receptor GPR139. J Chem Inf Model. 2014 Jun 23;54(6):1553-7.
3 mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient. Cell. 2017 Oct 19;171(3):642-654.e12.
4 SNAT2 silencing prevents the osmotic induction of transport system A and hinders cell recovery from hypertonic stress. FEBS Lett. 2005 Jun 20;579(16):3376-80.
5 Loss of function mutation of the Slc38a3 glutamine transporter reveals its critical role for amino acid metabolism in the liver, brain, and kidney. Pflugers Arch. 2016 Feb;468(2):213-27.
6 Identification of a membrane protein, LAT-2, that Co-expresses with 4F2 heavy chain, an L-type amino acid transport activity with broad specificity for small and large zwitterionic amino acids. J Biol Chem. 1999 Jul 9;274(28):19738-44.
7 Metabolic changes in adipose tissues in response to 3 -adrenergic receptor activation in mice. J Cell Biochem. 2019 Jan;120(1):821-835.
8 Near-Complete Correction of Profound Metabolomic Impairments Corresponding to Functional Benefit in MPS IIIB Mice after IV rAAV9-hNAGLU Gene Delivery. Mol Ther. 2017 Mar 1;25(3):792-802.
9 Capturing the metabolomic diversity of KRAS mutants in non-small-cell lung cancer cells. Oncotarget. 2014 Jul 15;5(13):4722-31.
10 Impairment of gamma-glutamyl transferase 1 activity in the metabolic pathogenesis of chromophobe renal cell carcinoma. Proc Natl Acad Sci U S A. 2018 Jul 3;115(27):E6274-E6282.
11 Erratum to: Loss of HSulf-1 promotes altered lipid metabolism in ovarian cancer. Cancer Metab. 2014 Nov 4;2:24.
12 The human T-type amino acid transporter-1: characterization, gene organization, and chromosomal location. Genomics. 2002 Jan;79(1):95-103.
13 Enhancer Reprogramming Confers Dependence on Glycolysis and IGF Signaling in KMT2D Mutant Melanoma. Cell Rep. 2020 Oct 20;33(3):108293.
14 Integrative omics analysis of p53-dependent regulation of metabolism. FEBS Lett. 2018 Feb;592(3):380-393.
15 Metabolomic analysis of C2C12 myoblasts induced by the transcription factor FOXO1. FEBS Lett. 2019 Jun;593(12):1303-1312.
16 Global metabolic reprogramming of colorectal cancer occurs at adenoma stage and is induced by MYC. Proc Natl Acad Sci U S A. 2017 Sep 12;114(37):E7697-E7706.

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