Phenylalnine Synthesis

Q1: What is the deficient enzyme in classical PKU? Give full name and abbreviation.

A1: Phenylalanine hydroxylase (PAH).

Q2: Write the complete reaction catalyzed by phenylalanine hydroxylase (PAH).

A2: L-Phenylalanine + Tetrahydrobiopterin (BH₄) + O₂ → L-Tyrosine + Dihydrobiopterin (BH₂) + H₂O.

Q3: Name all cofactors/coenzymes required for PAH activity.

A3: Tetrahydrobiopterin (BH₄ – electron donor), molecular oxygen (O₂), and iron (Fe²⁺).

Q4: What is the pattern of inheritance for PKU?

A4: Autosomal recessive.

Q5: What is the normal blood phenylalanine level, and what is the level in untreated PKU?

A5: Normal = 1.4–1.9 mg/dL. Untreated PKU = ~25 mg/dL (or higher).

Q6: Why does phenylalanine accumulate in PKU?

A6: PAH is blocked, so phenylalanine cannot be converted to tyrosine. It enters blood from protein catabolism and alternative transamination pathways become overloaded.

Q7: What is the alternative pathway for phenylalanine when PAH is blocked, and what are the main products?

A7: Transamination via phenylalanine aminotransferase (PLP-dependent) produces phenylpyruvate, phenylacetate, and phenyllactate.

Q8: Write the transamination reaction of phenylalanine to phenylpyruvate.

A8: L-Phenylalanine + α-Ketoglutarate ⇌ Phenylpyruvate + L-Glutamate. Enzyme: Phenylalanine aminotransferase. Coenzyme: PLP (vitamin B₆).

Q9: What causes the characteristic "mousy" or "musty" odor in PKU urine and sweat?

A9: Phenylpyruvate, phenylacetate, and phenyllactate (alternative metabolites of phenylalanine).

Q10: Why does tyrosine become an essential amino acid in PKU?

A10: Because the conversion of phenylalanine → tyrosine is blocked, tyrosine cannot be synthesized and must be supplied in the diet.

Q11: List three clinical consequences of tyrosine deficiency in PKU.

A11: 1) Impaired protein synthesis. 2) Neurotransmitter deficiency (dopamine, NE, epi). 3) Reduced melanin synthesis (fair skin/hair).

Q12: How does elevated phenylalanine inhibit tyrosine hydroxylase?

A12: Phenylalanine acts as a competitive inhibitor of tyrosine hydroxylase, competing with tyrosine for the active site.

Q13: What is the first enzyme in catecholamine synthesis, and what does it convert?

A13: Tyrosine hydroxylase (TH). It converts L-tyrosine to L-DOPA. Cofactors: BH₄, O₂, Fe²⁺.

Q14: Why do PKU patients often have fair skin, light hair, and blue eyes?

A14: Low tyrosine reduces melanin synthesis, and high phenylalanine competitively inhibits tyrosinase (the melanin-producing enzyme).

Q15: Write the reaction for the transamination of alanine to pyruvate.

A15: L-Alanine + α-Ketoglutarate ⇌ Pyruvate + L-Glutamate. Enzyme: Alanine aminotransferase (ALT). Coenzyme: PLP.

Q16: What is the glucose-alanine cycle, and why is it important?

A16: It transports nitrogen and carbon from muscle to liver. Muscle makes alanine from pyruvate; liver converts alanine to pyruvate → glucose (gluconeogenesis) and urea (nitrogen excretion).

Q17: What is the role of PLP (vitamin B₆) in phenylalanine and alanine metabolism?

A17: PLP is the coenzyme for transaminases: phenylalanine aminotransferase (phenylalanine → phenylpyruvate) and ALT (alanine → pyruvate).

Q18: Write the complete pathway from tyrosine to epinephrine, naming all enzymes.

A18: Tyrosine → (tyrosine hydroxylase) → L-DOPA → (DOPA decarboxylase) → Dopamine → (dopamine β-hydroxylase) → Norepinephrine → (PNMT) → Epinephrine.

Q19: Name the four enzymes in catecholamine synthesis and their cofactors.

A19: 1) Tyrosine hydroxylase (BH₄, O₂, Fe²⁺). 2) DOPA decarboxylase (PLP). 3) Dopamine β-hydroxylase (Cu²⁺, ascorbate, O₂). 4) PNMT (SAM as methyl donor).

Q20: Why do PKU patients have reduced dopamine, norepinephrine, and epinephrine?

A20: Low tyrosine (substrate deficiency) and high phenylalanine (competitive inhibition of tyrosine hydroxylase) → reduced catecholamine synthesis.

Q21: List four mechanisms of neurological damage in untreated PKU.

A21: 1) Tyrosine deficiency → ↓ catecholamines. 2) Competitive inhibition of TH by phenylalanine. 3) Impaired myelination. 4) Neurotransmitter imbalance and excitotoxicity.

Q22: What is the main dietary intervention for PKU?

A22: Restrict phenylalanine intake (low-protein diet, avoid aspartame) and provide a phenylalanine-free amino acid formula supplemented with tyrosine.

Q23: Why must tyrosine be supplemented in the PKU diet?

A23: Because tyrosine becomes essential in PKU (cannot be synthesized from phenylalanine).

Q24: What is the target blood phenylalanine range for treated PKU patients?

A24: 2–6 mg/dL (120–360 μmol/L).

Q25: List four clinical consequences of untreated PKU.

A25: 1) Mental retardation (IQ < 50). 2) Seizures and tremors. 3) Fair skin/hair/blue eyes. 4) "Mousy" urine/sweat odor.

Q26: Why is newborn screening for PKU essential?

A26: Because early treatment (within first 2–3 months) prevents irreversible neurological damage; screening is simple, cost-effective, and legally mandated.

Q27: What tests are used for newborn PKU screening?

A27: Guthrie test (bacterial inhibition assay) and tandem mass spectrometry (MS/MS) on a heel-prick blood spot.

Q28: What is the connection between phenylpyruvate, phenyllactate, and the odor in PKU?

A28: Phenylpyruvate (from transamination) is reduced to phenyllactate or decarboxylated to phenylacetate; these volatile compounds cause the mousy/musty odor.

Q29: How does the lack of PAH affect nitrogen disposal in PKU?

A29: Phenylalanine is transaminated to phenylpyruvate and glutamate, allowing some nitrogen removal, but this pathway is overloaded, leading to accumulation and urinary excretion of phenylpyruvate.

Q30: What is the role of BH₄ in phenylalanine metabolism, and what happens if BH₄ is deficient?

A30: BH₄ is the electron donor for PAH. BH₄ deficiency causes a form of hyperphenylalaninemia (malignant PKU) that also affects neurotransmitter synthesis (since TH also needs BH₄).

Q31: How does phenylalanine competitively inhibit tyrosine hydroxylase, and what is the clinical consequence?

A31: Phenylalanine competes with tyrosine at TH’s active site, reducing L-DOPA production. Consequence: ↓ dopamine, NE, epi → neurological and behavioral dysfunction.

Q32: What is the significance of phenylalanine aminotransferase in PKU?

A32: It becomes the major pathway for phenylalanine disposal when PAH is blocked, producing phenylpyruvate (excreted in urine) and glutamate.

Q33: Compare the metabolic fate of phenylalanine in a normal individual vs. a PKU patient.

A33: Normal: Phenylalanine → (PAH) → Tyrosine (major route). PKU: PAH blocked → phenylalanine accumulates → transaminated to phenylpyruvate, phenylacetate, phenyllactate (excreted). Tyrosine becomes essential.