Phenylalanine and Tyrosine Metabolism

Overview

• Biochemistry, 8th ed - Lippincott Illustrated Reviews, p. 742
• Harper's Illustrated Biochemistry, 32nd Ed, p. 289

1. Phenylalanine → Tyrosine (The Gateway Reaction)

• One atom of O₂ incorporates as the hydroxyl group on tyrosine
• The other atom is reduced to H₂O
• BH4 is oxidized to dihydrobiopterin (BH2), then regenerated by NADPH-requiring dihydropteridine reductase

• Biochemistry, 8th ed - Lippincott, p. 742

2. Tyrosine Catabolism → Fumarate + Acetoacetate

3. Biosynthetic Products of Tyrosine

A. Catecholamines (Neurons & Adrenal Medulla)

1. Tyrosine → L-DOPA
   Enzyme: Tyrosine hydroxylase (rate-limiting step)
   Cofactor: BH4 (same cofactor as PAH)
   Note: Tyrosine hydroxylase is usually saturated, so dietary tyrosine levels do not readily alter catecholamine synthesis rate
2. L-DOPA → Dopamine
   Enzyme: DOPA decarboxylase (aromatic L-amino acid decarboxylase, AADC)
   Cofactor: Pyridoxal phosphate (PLP/B6)
3. Dopamine → Norepinephrine (in neurons & adrenal medulla)
   Enzyme: Dopamine β-hydroxylase
   Cofactors: O₂, Cu²⁺, Vitamin C (ascorbate)
4. Norepinephrine → Epinephrine (in adrenal medulla only)
   Enzyme: Phenylethanolamine N-methyltransferase (PNMT)
   Methyl donor: S-adenosylmethionine (SAM)

• Basic Medical Biochemistry - A Clinical Approach 6e, p. 1632-1633
• Ganong's Review of Medical Physiology, p. 555-566

B. Melanin (Melanocytes)

C. Thyroid Hormones

4. Summary Metabolic Map

5. Disorders of Phenylalanine & Tyrosine Metabolism

A. Phenylketonuria (PKU)

• Defect: Loss-of-function mutations in PAH (100+ known mutations; autosomal recessive)
• Incidence: ~1:15,000 - the most common inborn error of amino acid metabolism
• Biochemistry: Hyperphenylalaninemia (10× normal); tyrosine becomes deficient; phenylalanine is shunted to phenylpyruvic acid and other metabolites excreted in urine
• Clinical: Severe intellectual disability, seizures, fair hair/skin/eyes (reduced melanin), musty urine odor
• Newborn screening: Blood phenylalanine measured after 24-48 hours of protein feeding (normal levels at birth because mother clears it via placenta)
• Treatment:
  • Phenylalanine-restricted diet (lifelong)
  • Tyrosine supplementation (becomes essential)
  • Avoid aspartame (contains phenylalanine)
  • Must start within first 7-10 days of life to prevent cognitive damage
  • Discontinuation even in adulthood leads to IQ deterioration
• BH4-deficient variant: Rare; hyperphenylalaninemia plus deficient neurotransmitter synthesis (BH4 also needed for tyrosine hydroxylase and tryptophan hydroxylase). Dietary restriction alone is insufficient - requires BH4 + L-DOPA + 5-hydroxytryptophan supplementation
• Maternal PKU: Women with PKU who become pregnant and resume normal diet expose the fetus to high phenylalanine - causes microcephaly, intellectual disability, and cardiac defects in the (often unaffected) offspring
• Lippincott Biochemistry, p. 759-766
• Emery's Elements of Medical Genetics and Genomics, p. 282

B. Tyrosinemia Type I (Hepatorenal Tyrosinemia)

• Defect: Fumarylacetoacetate hydrolase (FAH) - the last enzyme in tyrosine catabolism
• Key metabolite: Fumarylacetoacetate and its by-product succinylacetone accumulate; succinylacetone inhibits ALA dehydratase (heme synthesis)
• Clinical: Liver failure, renal tubular acidosis (Fanconi syndrome), characteristic cabbage-like urine odor
• Treatment: Dietary restriction of phenylalanine and tyrosine; nitisinone (NTBC) - inhibits 4-OH-phenylpyruvate dioxygenase to block production of toxic metabolites

C. Tyrosinemia Type II (Richner-Hanhart Syndrome)

• Defect: Tyrosine aminotransferase (first step of tyrosine catabolism, in the liver)
• Clinical: Corneal erosions (corneal crystals), painful palmoplantar keratosis, possible intellectual disability

D. Tyrosinemia Type III

• Defect: 4-OH-Phenylpyruvate dioxygenase
• Clinical: Mild - mainly neurological symptoms

E. Alkaptonuria

• Defect: Homogentisic acid oxidase - autosomal recessive; the first inborn error of metabolism ever described (Garrod, 1902)
• Clinical triad:
  1. Homogentisic aciduria - urine turns dark brown/black on standing (oxidation of HA)
  2. Ochronosis - black pigment deposits in cartilage, tendons, and collagenous tissue (ear cartilage, sclerae, intervertebral discs)
  3. Arthritis - severe degenerative arthritis of large joints (onset ~age 40)
• Dark diaper staining may be the first sign in infants, but symptoms are typically absent until mid-life
• Treatment: Dietary restriction of phenylalanine and tyrosine; nitisinone has also been explored
• Lippincott Biochemistry, p. 771

F. Albinism

• Defect: Tyrosinase (Cu²⁺-dependent) - absent or defective; autosomal recessive (most common)
• Result: Absent or severely reduced melanin in skin, hair, and eyes
• Clinical: Hypopigmentation, photophobia, vision defects, increased risk of skin cancer
• Lippincott Biochemistry, p. 769

Quick Reference Summary

Key concept: Both phenylalanine and tyrosine are glucogenic AND ketogenic because their degradation produces both fumarate (enters TCA → gluconeogenesis) and acetoacetate (a ketone body). - Lippincott Biochemistry, p. 742