Biochemistry · Metabolic pathway
Phenylalanine and tyrosine metabolism !
Phenylalanine becomes tyrosine, which is then broken down to fumarate and acetoacetate. Each blocked enzyme gives a classic disease.
Updated 2026-11-01
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Key facts
- Phenylalanine hydroxylase (liver) needs tetrahydrobiopterin (BH4), O₂ and Fe²⁺; its failure causes phenylketonuria.
- Phenylalanine is essential; tyrosine becomes essential when the hydroxylase does not work.
- Both are glucogenic and ketogenic at once: they give fumarate (glucose) and acetoacetate (ketone bodies).
- Blocks in order: PAH → phenylketonuria; TAT → tyrosinaemia II; HGD → alkaptonuria; FAH → tyrosinaemia I.
- Tyrosine also gives catecholamines, melanin and thyroid hormones.
Regulation
- Phenylalanine activates its own hydroxylase by binding the regulatory domain; phosphorylation by PKA (glucagon) also activates it.
- Glucocorticoids induce tyrosine aminotransferase in the liver.
The steps, one by one
- Step 1 · Phenylalanine hydroxylase (PAH) irreversible Phenylalanine + Tetrahydrobiopterin + o2 → Tyrosine + Dihydrobiopterin (BH₂) + H₂OAdds an OH to the ring of phenylalanine to make tyrosine; BH4 gives the electrons and is left as BH₂.If it fails: Phenylketonuria: phenylalanine builds up and harms the brain; BH4 deficiency gives a similar picture. Phenylketonuria (PKU) →
- Step 2 · Tyrosine aminotransferase (TAT) Tyrosine + α-ketoglutarate ⇌ p-Hydroxyphenylpyruvate + GlutamateMoves the amino group of tyrosine to α-ketoglutarate, leaving the keto acid p-hydroxyphenylpyruvate.If it fails: Tyrosinaemia II (oculocutaneous): corneal ulcers, palm and sole lesions and sometimes intellectual disability.
- Step 3 · 4-Hydroxyphenylpyruvate dioxygenase (HPPD) irreversible p-Hydroxyphenylpyruvate + o2 → Homogentisate + CO₂With oxygen it decarboxylates the keto acid and shifts the side chain on the ring, making homogentisate.If it fails: Its failure causes rare tyrosinaemia III; nitisinone blocks it on purpose in tyrosinaemia I. Tyrosinaemia type I (hepatorenal) →
- Step 4 · Homogentisate 1,2-dioxygenase (homogentisate oxidase, HGD) irreversible Homogentisate + o2 → MaleylacetoacetateOpens the aromatic ring of homogentisate with oxygen to make maleylacetoacetate.If it fails: Alkaptonuria: homogentisate builds up, darkens urine and stains cartilage and valves. Alkaptonuria →
- Step 5 · Maleylacetoacetate isomerase (GSTZ1) Maleylacetoacetate ⇌ FumarylacetoacetateFlips a double bond from cis to trans (maleyl → fumaryl) using glutathione.If it fails: Its deficiency is very rare and nearly silent, because a non-enzymatic bypass exists.
- Step 6 · Fumarylacetoacetate hydrolase (FAH) irreversible Fumarylacetoacetate + H₂O → fumarate + AcetoacetateSplits fumarylacetoacetate into fumarate (to the Krebs cycle and glucose) and acetoacetate (a ketone body).If it fails: Tyrosinaemia I: fumarylacetoacetate and succinylacetone build up and damage liver, kidney and nerves. Tyrosinaemia type I (hepatorenal) →
Clinical notes
- Newborn screening detects phenylketonuria; in Colombia, Law 1980 of 2019 created the newborn screening programme.
- Nitisinone blocks 4-hydroxyphenylpyruvate dioxygenase and prevents succinylacetone, the toxin of tyrosinaemia I, from forming.
- In alkaptonuria, homogentisic acid darkens urine on standing in air and deposits in cartilage (ochronosis).
- Oculocutaneous albinism hits a side branch: melanocyte tyrosinase, which makes melanin.
Pathways
Related conditions
Related
- Phenylalanine
- Tyrosine
- Tetrahydrobiopterin (BH4)
- Phenylalanine hydroxylase (PAH)
- Tyrosine hydroxylase
- Glutamate (glutamic acid)
- Glucogenic and ketogenic amino acids
- Krebs cycle (citric acid cycle)
Test yourself
Think of the answer, then tap the question to see it.
Which cofactors does phenylalanine hydroxylase need?
Tetrahydrobiopterin (BH4), oxygen and ferrous iron; that is why BH4 deficiency also raises phenylalanine.
Which enzyme is missing in alkaptonuria?
Homogentisate 1,2-dioxygenase: homogentisic acid builds up, darkens urine and stains cartilage.
Why does nitisinone help tyrosinaemia I if it blocks the same pathway?
It blocks an earlier step (HPPD), so fumarylacetoacetate and succinylacetone, the toxins, are not made; tyrosine stays high, which is less harmful.
Which products does tyrosine breakdown end in?
Fumarate, which is glucogenic, and acetoacetate, which is ketogenic.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: Phenylalanine and tyrosine metabolism (Reactome, 2026); Tyrosine catabolism (Reactome, 2026); Tyrosinemia: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).
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Representative model, for educational purposes only.