The AtlasAmino acidsAromatic

PhenylalaninePhe · F

The amino acid with a benzene ring, the start of the road to dopamine and thyroid hormone, and the reason every newborn has a heel-prick test.

Status Reference · not yet an episodeSources 29Reviewed October 2026

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Skeletal formula — every corner and every line end is a carbon, and the hydrogens on carbon are left implied.

Molecule · Phe · 12 heavy atoms

Phenylalanine

C₉H₁₁NO₂165.19 g/mol

The amino acid with a benzene ring, the start of the road to dopamine and thyroid hormone, and the reason every newborn has a heel-prick test.

Built fromthe charted ones open their own entry

C9CarbonH11Hydrogen N Nitrogen O2Oxygen

Codes: Phe · F
Formula: C₉H₁₁NO₂
Molar mass: 165.19 g/mol
Systematic name: (2S)-2-amino-3-phenylpropanoic acid
Side chain: Benzyl: one carbon and a benzene ring; aromatic and nonpolar.
Class: Aromatic
In the diet: Essential
Carbon skeleton: Glucogenic and ketogenic
pKa: α-COOH 1.83 · α-NH₃⁺ 9.13
Isoelectric point: pH 5.48
Hydropathy: +2.8 (Kyte–Doolittle)
Codons: UUU UUC
Main transporters: SLC7A5 (LAT1, with CD98), SLC6A19 (B0AT1)

pKa and isoelectric point: Nelson and Cox, Lehninger Principles of Biochemistry, table of amino acid properties (free amino acid, 25 °C). Hydropathy: Kyte and Doolittle, J Mol Biol 1982. Essentiality: Reeds, J Nutr 2000. Formula and mass computed from the structure.

In brief

What it is

An essential amino acid whose side chain is a benzene ring on a single carbon: flat, rigid and water-avoiding. The body cannot make it, so it comes from protein in food ¹.

Why it matters

Its main fate is to become tyrosine, by phenylalanine hydroxylase, the first step on the road to dopamine, noradrenaline, thyroid hormone and melanin ^2,3. When that enzyme fails the result is phenylketonuria, the first inherited disease found by screening whole populations ⁴.

Where it runs short

Phenylalanine is essential, so a diet without it cannot sustain protein synthesis; the adult requirement, shared with tyrosine, is 25 mg per kilogram a day, and tyrosine can supply part of it ^1,5.

Where it turns

In untreated phenylketonuria blood phenylalanine runs above 1,200 µmol/L and damages the developing brain; current guidelines aim to hold it at or below 360 for life ^6,7.

The danger is not phenylalanine itself but phenylalanine with nowhere to go.

The molecule

Phenylalanine is alanine with a benzene ring attached: a benzyl side chain of seven carbons, six of them in a flat aromatic ring. It is among the most hydrophobic of the amino acids, so in proteins it sits buried in the core, stacking against other rings.

The ring has no hydroxyl group. Adding one, at the far end, is the single change that turns phenylalanine into tyrosine, and the enzyme that does it, phenylalanine hydroxylase, is one of a family of three related hydroxylases that also make the precursors of dopamine and serotonin ².

Charge · pHPhenylalanine carries almost no net charge at the pH of blood.

Move across the chart to read the charge at any pH.

Computed from its pKa values (α-carboxyl 1.83, α-amino 9.13) by the Henderson–Hasselbalch equation, for the free amino acid in water at 25 °C. Inside a folded protein the same groups can shift by a unit or more. The faint lines are the other amino acids.

HydropathyPhenylalanine scores +2.8: the 4th most water-avoiding of the twenty.

Kyte–Doolittle hydropathy index: positive values avoid water and tend to be buried inside a folded protein, negative values sit on its surface. Each letter is an amino acid; choose one to open it.

The genetic codePhenylalanine has 2 codons. The code is redundant, so most single-letter changes at the third position still write phenylalanine.

The 64 codons of the standard genetic code. Codons for phenylalanine are marked.
1st ↓ 2nd →	U	C	A	G	3rd
U	UUUPhe	UCUSer	UAUTyr	UGUCys	U
	UUCPhe	UCCSer	UACTyr	UGCCys	C
	UUALeu	UCASer	UAAStop	UGAStop	A
	UUGLeu	UCGSer	UAGStop	UGGTrp	G
C	CUULeu	CCUPro	CAUHis	CGUArg	U
	CUCLeu	CCCPro	CACHis	CGCArg	C
	CUALeu	CCAPro	CAAGln	CGAArg	A
	CUGLeu	CCGPro	CAGGln	CGGArg	G
A	AUUIle	ACUThr	AAUAsn	AGUSer	U
	AUCIle	ACCThr	AACAsn	AGCSer	C
	AUAIle	ACAThr	AAALys	AGAArg	A
	AUGMet	ACGThr	AAGLys	AGGArg	G
G	GUUVal	GCUAla	GAUAsp	GGUGly	U
	GUCVal	GCCAla	GACAsp	GGCGly	C
	GUAVal	GCAAla	GAAGlu	GGAGly	A
	GUGVal	GCGAla	GAGGlu	GGGGly	G

Where it comes from

The body cannot make the benzene ring, so phenylalanine is essential. Plants and bacteria build it from sugar by the shikimate pathway, which animals lack ⁸.

Requirements are set for phenylalanine and tyrosine together, because tyrosine is made from phenylalanine and spares it: 25 mg per kilogram a day for adults ¹. When phenylalanine intake was fixed at 9 mg/kg, adult men needed about 6 mg/kg of tyrosine on average, and the authors put the total aromatic amino acid need at 21 mg/kg ⁵.

EssentialMust come from food. The adult requirement for phenylalanine and tyrosine together is 25 mg per kilogram a day ¹; with phenylalanine held at 9 mg/kg, adult men needed about 6 to 7 mg/kg of tyrosine on top ⁵.

How much

With tyrosine, 25 mg per kilogram a day for adults ¹.

Where it is in food

Any protein: meat, fish, eggs, dairy, legumes, soy and grains all contain it, which is why the PKU diet restricts natural protein as a whole and supplies the rest as phenylalanine-free formula ⁹.
Aspartame, which is broken down in the gut to release phenylalanine ¹⁰.

In the bottle · fermentedIndustrial phenylalanine is made by fermentation in engineered Escherichia coli or Corynebacterium glutamicum, which build it from glucose through the shikimate pathway ⁸. It is the same molecule as in food.

What the body does with it

Most phenylalanine that is not built into protein is converted to tyrosine in the liver. Phenylalanine hydroxylase is a 452-amino-acid enzyme that assembles into a tetramer and switches between a resting and an activated shape; phenylalanine binding to its regulatory domain is what activates it, so the enzyme speeds up when phenylalanine is plentiful ^2,11.

From tyrosine come the catecholamines, dopamine, noradrenaline and adrenaline; the thyroid hormones, built on tyrosines of thyroglobulin; and melanin ^2,3. A phenylalanine that cannot be hydroxylated therefore causes two problems at once: an excess of phenylalanine and a shortage of what lies downstream ⁹.

The cofactor of the hydroxylation, tetrahydrobiopterin, is recycled and partly salvaged by the cell, and it serves the tyrosine and tryptophan hydroxylases and nitric oxide synthase as well ¹².

In three sentences each

Hydroxylated, not burned

Phenylalanine hydroxylase adds one oxygen atom to the ring to make tyrosine, with tetrahydrobiopterin (BH4) as its cofactor; phenylalanine itself switches the enzyme on by binding a regulatory domain ^2,12.

A crowded gate into the brain

Phenylalanine enters the brain on the same carrier as the other large neutral amino acids. In PKU it crowds them out, and giving patients extra competing amino acids blocked its entry into brain tissue completely ^13,14.

The cofactor’s other jobs

BH4 is also the cofactor for the enzymes that make dopamine and serotonin, so most of the six BH4 deficiencies raise phenylalanine and starve the brain of both transmitters ¹⁵.

How it is made, moved and broken down

When phenylalanine hydroxylase is missing, phenylalanine builds up in blood and is diverted into minor pathways, including transamination to phenylpyruvic acid, the compound Asbjørn Følling found in the urine of affected people in 1934 and that gave the disease its first name, imbecillitas phenylpyrouvica ¹⁶.

Carbon skeleton · glucogenic and ketogenicThrough tyrosine, its carbons end as fumarate, which can make glucose, and acetoacetate, a ketone body ¹⁷.

From phenylalanine to tyrosineThe step that fails in phenylketonuria ^2,12.

Phenylalanine
Phenylalanine hydroxylasePAH · BH4, O₂, iron
Tyrosine

When the main road is closedExcess phenylalanine is transaminated to the ketoacid that names the disease ¹⁶.

Phenylalanine
Transaminationvitamin B6
Phenylpyruvic acid

How it crosses membranes

SLC7A5 · LAT1, with CD98blood–brain barrier and placenta — the large neutral amino acid carrier phenylalanine competes for ^13,14
SLC6A19 · B0AT1small intestine and kidney — absorbs neutral amino acids from the gut and reclaims them from urine ¹⁸

Where it matters most

Liver: The main site of phenylalanine hydroxylase, and so where phenylalanine becomes tyrosine ⁹.
Brain: Where PKU does its damage. With plasma phenylalanine near 1,000 µmol/L, brain levels were about 250 and rose further after a load ¹³.
Placenta and fetus: Phenylalanine crosses the placenta on LAT1, so a mother’s high level reaches the fetus and injures a baby who does not itself have PKU ^14,19.

When it goes wrong

Inherited

Phenylketonuria (PAH deficiency)

PAH · autosomal recessive

About 0.45 million people worldwide; one birth in 23,930 on average, from one in 4,500 in Italy to one in 125,000 in Japan, with 758 known PAH variants ²⁰. Untreated, it causes severe intellectual disability, epilepsy and behavioural problems. Treated early and for life, intelligence is within normal limits ⁹, though a 2025 meta-analysis still found cognition about half a standard deviation below peers in children and adults alike ²¹.

How it is foundNewborn blood spot, then plasma phenylalanine and tyrosine and PAH genotyping ⁷.

Drug

Drugs for PKU

PAH

Sapropterin, a synthetic BH4, helps the minority whose enzyme still responds ⁹. Pegvaliase, an injected bacterial enzyme that breaks phenylalanine down, lowered mean levels from 1,233 to 311 µmol/L over two years, with joint pain in 70% and anaphylaxis-type reactions in 12 of 261 patients ⁶. Sepiapterin, a BH4 precursor, lowered phenylalanine by 63%, against a 1% rise on placebo, in patients who responded to it and was approved in 2025 ^22,23.

How it is foundResponse is defined by a fall in blood phenylalanine on a trial of the drug ²².

Acquired

Maternal PKU

High maternal phenylalanine in pregnancy causes microcephaly, intellectual disability and heart defects in the child ¹⁹. Guidelines ask women with PKU to reach 360 µmol/L or lower before conception ⁷.

How it is foundBlood phenylalanine before and throughout pregnancy ⁷.

Inherited

BH4 deficiencies

GCH1, PTS, QDPR, SPR, PCBD1 · mostly recessive

Six disorders of the cofactor’s synthesis or recycling. Most raise phenylalanine and all can deprive the brain of dopamine and serotonin, so they are treated with neurotransmitter precursors, not diet alone ¹⁵.

How it is foundPterins and neurotransmitter metabolites, after a raised phenylalanine on screening ¹⁵.

How it is measured

Phenylalanine is measured in plasma or in dried blood spots, newborn screening uses tandem mass spectrometry on the heel-prick card, and every PKU guideline sets its targets in micromoles per litre of blood ^7,24. The two sample types are not interchangeable without a correction ^25,26.

Newborn blood-spot phenylalaninePhenylalanine and tyrosine measured in a dried heel-prick blood spot by tandem mass spectrometry, the method that succeeded Guthrie’s 1963 blood-spot test ^24,27.Measuring tyrosine alongside phenylalanine separated true cases from many false positives flagged by the older fluorometric method ²⁴.A raised level is a starting point: the cause may be a PAH variant, a BH4 disorder or a transient rise, and guidelines now recommend genetic testing at diagnosis ^7,15.
Monitoring phenylalaninePeople with PKU track their levels with dried blood spots taken at home and posted to the laboratory ²⁵.Capillary spots track venous plasma phenylalanine closely enough for monitoring ²⁵.Spots read lower than plasma, by about 13% in one comparison, so each laboratory needs its own correction factor ^25,26.

Food, supplements and the evidence

Establishedreplicated in people, for a named outcome

For PKU, a lifelong low-phenylalanine diet started in the newborn period, with targets of 120 to 360 µmol/L ^4,7.
For PKU in pregnancy, tight control before conception and throughout ^7,19.

Uncertainsmall, short, mixed, surrogate or preclinical

Large neutral amino acid supplements for adults with PKU, which block phenylalanine’s entry to the brain; the mechanism is shown, the long-term benefit less so ¹³.

Sold asthe claim on the label, against the evidence

“DL-phenylalanine for pain and mood.” A crossover trial of D-phenylalanine in 30 people with chronic pain found no effect over placebo, and the depression trial comparing DL-phenylalanine with imipramine had no placebo arm ^28,29.

What is strange about it

Diet soft drinks carry the warning “contains a source of phenylalanine” because aspartame is a methyl ester of a dipeptide of aspartate and phenylalanine; the warning is for people with PKU ¹⁰.

In 1980, a survey of 524 pregnancies in 155 women with PKU found that among mothers whose phenylalanine was 20 mg/dL or higher, 95% had at least one child with intellectual disability, although the children did not have PKU ¹⁹.

One treatment for PKU is an enzyme taken from a cyanobacterium, Anabaena variabilis, which splits phenylalanine into trans-cinnamic acid and ammonia instead of making tyrosine. It is coated in polyethylene glycol to shield it from the immune system and injected daily, and immune reactions are still its main problem ^6,9.

Where it connects

In the Atlas

TyrTyrosineAromatic TrpTryptophanAromatic LeuLeucineNonpolar, aliphatic AspAspartateNegatively charged

Topics on the map

On the map

A star in The essential amino acids, one of 14. Upstream of tyrosine, dopamine and adrenaline. The reason every can of diet soda carries a warning is a single enzyme some people are born without.

Find it on the map

Sources

29 sources, numbered as they are cited. Every one was checked against PubMed or its publisher before it was cited here; the note under each says what it shows and what it does not.

1
Joint WHO/FAO/UNU Expert Consultation. Protein and amino acid requirements in human nutrition.World Health Organ Tech Rep Ser · 2007 · (935):1–265PMID 18330140
Adult requirements, including phenylalanine plus tyrosine at 25 mg/kg/day.
2
Fitzpatrick PF. Structural insights into the regulation of aromatic amino acid hydroxylation.Curr Opin Struct Biol · 2015 · 35:1–6doi:10.1016/j.sbi.2015.07.004 · PMID 26241318
PAH, TH and TPH; PAH activated by phenylalanine at its regulatory domain.
3
Citterio CE, Targovnik HM, Arvan P. The role of thyroglobulin in thyroid hormonogenesis.Nat Rev Endocrinol · 2019 · 15(6):323–338doi:10.1038/s41574-019-0184-8 · PMID 30886364
Thyroid hormones are built on iodinated tyrosines of thyroglobulin.
4
Vockley J, Andersson HC, Antshel KM, et al. Phenylalanine hydroxylase deficiency: diagnosis and management guideline.Genet Med · 2014 · 16(2):188–200doi:10.1038/gim.2013.157 · PMID 24385074
The first inborn error found by population screening; lifelong treatment, 120–360 µmol/L.
5
Roberts SA, Thorpe JM, Ball RO, Pencharz PB. Tyrosine requirement of healthy men receiving a fixed phenylalanine intake determined by using indicator amino acid oxidation.Am J Clin Nutr · 2001 · 73(2):276–282doi:10.1093/ajcn/73.2.276 · PMID 11157324
Six men; tyrosine need 6.0 mg/kg/day on top of 9 mg/kg phenylalanine.
6
Thomas J, Levy H, Amato S, et al. Pegvaliase for the treatment of phenylketonuria: results of a long-term phase 3 clinical trial program (PRISM).Mol Genet Metab · 2018 · 124(1):27–38doi:10.1016/j.ymgme.2018.03.006 · PMID 29653686
261 patients; mean phenylalanine 1,233 to 311 µmol/L at 24 months; frequent adverse events. Manufacturer-funded.
7
Smith WE, Berry SA, Bloom K, et al. Phenylalanine hydroxylase deficiency diagnosis and management: a 2023 evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG).Genet Med · 2025 · 27(1):101289doi:10.1016/j.gim.2024.101289 · PMID 39630157
Current US guideline: lifelong control at or below 360 µmol/L, including before conception; genetic testing at diagnosis.
8
Hirasawa T, Satoh Y, Koma D. Production of aromatic amino acids and their derivatives by Escherichia coli and Corynebacterium glutamicum.World J Microbiol Biotechnol · 2025 · 41(2):65doi:10.1007/s11274-025-04264-3 · PMID 39915353
Industrial fermentation through the shikimate pathway.
9
van Spronsen FJ, Blau N, Harding C, et al. Phenylketonuria.Nat Rev Dis Primers · 2021 · 7(1):36doi:10.1038/s41572-021-00267-0 · PMID 34017006
Review of the disease, its diet and its drugs.
10
Shaher SAA, Mihailescu DF, Amuzescu B. Aspartame safety as a food sweetener and related health hazards.Nutrients · 2023 · 15(16):3627doi:10.3390/nu15163627 · PMID 37630817
Aspartame’s structure; the warning for PKU.
11
Jaffe EK. New protein structures provide an updated understanding of phenylketonuria.Mol Genet Metab · 2017 · 121(4):289–296doi:10.1016/j.ymgme.2017.06.005 · PMID 28645531
The 452-residue enzyme’s resting and activated forms.
12
Blau N. Sepiapterin: from sapropterin to next-generation therapy.Mol Genet Metab · 2026 · 148(3):110110doi:10.1016/j.ymgme.2026.110110 · PMID 42119485
BH4 as cofactor of the aromatic hydroxylases and nitric oxide synthase; its salvage.
13
Pietz J, Kreis R, Rupp A, et al. Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria.J Clin Invest · 1999 · 103(8):1169–1178doi:10.1172/JCI5017 · PMID 10207169
Brain phenylalanine measured by spectroscopy; a large neutral amino acid load blocked its entry.
14
Scalise M, Galluccio M, Console L, et al. The human SLC7A5 (LAT1): the intriguing histidine/large neutral amino acid transporter and its relevance to human health.Front Chem · 2018 · 6:243doi:10.3389/fchem.2018.00243 · PMID 29988369
LAT1 with CD98 carries essential amino acids across the placenta and blood–brain barrier.
15
Opladen T, López-Laso E, Cortès-Saladelafont E, et al. Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies.Orphanet J Rare Dis · 2020 · 15(1):126doi:10.1186/s13023-020-01379-8 · PMID 32456656
Six disorders; hyperphenylalaninaemia in most; dopamine and serotonin deficiency.
16
Christ SE. Asbjørn Følling and the discovery of phenylketonuria.J Hist Neurosci · 2003 · 12(1):44–54doi:10.1076/jhin.12.1.44.13788 · PMID 12785112
1934: phenylpyruvic acid in the urine.
17
Han C, Ren C, Zhi T, et al. Disruption of fumarylacetoacetate hydrolase causes spontaneous cell death under short-day conditions in Arabidopsis.Plant Physiol · 2013 · 162(4):1956–1964doi:10.1104/pp.113.216804 · PMID 23743712
Cited for the end of tyrosine breakdown: fumarylacetoacetate to fumarate and acetoacetate.
18
Kleta R, Romeo E, Ristic Z, et al. Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder.Nat Genet · 2004 · 36(9):999–1002doi:10.1038/ng1405 · PMID 15286787
The neutral amino acid transporter of gut and kidney.
19
Lenke RR, Levy HL. Maternal phenylketonuria and hyperphenylalaninemia: an international survey of the outcome of untreated and treated pregnancies.N Engl J Med · 1980 · 303(21):1202–1208doi:10.1056/NEJM198011203032104 · PMID 7421947
524 pregnancies in 155 women.
20
Hillert A, Anikster Y, Belanger-Quintana A, et al. The genetic landscape and epidemiology of phenylketonuria.Am J Hum Genet · 2020 · 107(2):234–250doi:10.1016/j.ajhg.2020.06.006 · PMID 32668217
Global prevalence and variant spectrum.
21
Romani C, Huijbregts S, van Spronsen FJ, et al. Meta-analysis of cognitive outcomes in children and adults with early treated phenylketonuria: results across functions.Mol Genet Metab · 2025 · 146(1–2):109210doi:10.1016/j.ymgme.2025.109210 · PMID 40753692
About 0.5 SD below controls across functions, in children and adults.
22
Muntau AC, Longo N, Ezgu F, et al. Effects of oral sepiapterin on blood Phe concentration in a broad range of patients with phenylketonuria (APHENITY): results of an international, phase 3, randomised, double-blind, placebo-controlled trial.Lancet · 2024 · 404(10460):1333–1345doi:10.1016/S0140-6736(24)01556-3 · PMID 39368841
157 enrolled, 114 responsive; −63% against +1%. Manufacturer-funded.
23
Lah M, Kopesky J, Vucko E. Sepiapterin: a distinct, dual mechanism of action that leads to potential treatment benefits across the spectrum of phenylketonuria disease severities.Adv Ther · 2026doi:10.1007/s12325-026-03607-2 · PMID 42250073
Approval in 2025 in several countries including the US.
24
Chace DH, Millington DS, Terada N, et al. Rapid diagnosis of phenylketonuria by quantitative analysis for phenylalanine and tyrosine in neonatal blood spots by tandem mass spectrometry.Clin Chem · 1993 · 39(1):66–71PMID 8419060
The tandem mass spectrometry method; tyrosine separated false positives.
25
van Vliet K, van Ginkel WG, van Dam E, et al. Dried blood spot versus venous blood sampling for phenylalanine and tyrosine.Orphanet J Rare Dis · 2020 · 15(1):82doi:10.1186/s13023-020-1343-7 · PMID 32245393
45 patients; spots track plasma phenylalanine; laboratory-specific correction needed.
26
Carling RS, Barclay Z, Cantley N, et al. Investigation of the relationship between phenylalanine in venous plasma and capillary blood using volumetric blood collection devices.JIMD Rep · 2023 · 64(6):468–476doi:10.1002/jmd2.12398 · PMID 37927487
51 patients; capillary blood read on average 13% below plasma.
27
Guthrie R, Susi A. A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants.Pediatrics · 1963 · 32:338–343PMID 14063511
The original blood-spot screening test.
28
Walsh NE, Ramamurthy S, Schoenfeld L, Hoffman J. Analgesic effectiveness of D-phenylalanine in chronic pain patients.Arch Phys Med Rehabil · 1986 · 67(7):436–439PMID 3524509
30 patients, crossover: no difference from placebo.
29
Beckmann H, Athen D, Olteanu M, Zimmer R. DL-phenylalanine versus imipramine: a double-blind controlled study.Arch Psychiatr Nervenkr · 1979 · 227(1):49–58doi:10.1007/BF00585677 · PMID 387000
27 completers; no placebo arm.

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