Describe the metabolism of phenylalanine and tyrosine. Discuss the disorders arising from blocks in this pathway.

Introduction

• Both are glucogenic and ketogenic

The Central Reaction

Phenylalanine → Phenylalanine hydroxylase — needs tetrahydrobiopterin (BH4) and O2 → tyrosine

• Irreversible — tyrosine cannot make phenylalanine
• BH4 is regenerated by dihydropteridine reductase
• The same cofactor is needed by tyrosine hydroxylase and tryptophan hydroxylase — which is why BH4 defects are so damaging

Fates of Tyrosine

Degradation Pathway

Tyrosine → Tyrosine transaminase → p-Hydroxyphenylpyruvate → p-Hydroxyphenylpyruvate dioxygenase → homogentisate → homogentisate oxidase → Maleylacetoacetate → Fumarylacetoacetate → fumarate (glucogenic) + acetoacetate (ketogenic)

Disorders — Where Each Block Lies

Phenylketonuria in Detail

Phenylalanine hydroxylase deficient → Phenylalanine accumulates (> 20 mg/dL; normal 1–2) → Diverted to transamination → Phenylpyruvate, phenyllactate, phenylacetate → Excreted in urine — phenylacetate gives the mousy odour → Phenylalanine competes for the amino acid transporter at the blood–brain barrier → Impaired brain development → mental retardation

• Fair skin and hair — excess phenylalanine inhibits tyrosinase, so melanin falls
• Incidence about 1 in 10,000; autosomal recessive
• Guthrie bacterial inhibition test or tandem mass spectrometry on a heel prick, taken after 48–72 hours of milk feeding
• Treatment — a low phenylalanine diet started within the first weeks of life, continued at least through childhood
• Aspartame must be avoided — it is a phenylalanine-containing dipeptide
• Malignant PKU — defect in BH4 synthesis or in dihydropteridine reductase; diet alone does not help because catecholamine and serotonin synthesis also fail. Needs BH4, L-dopa and 5-hydroxytryptophan

Catecholamine Synthesis and Degradation

Tyrosine → Tyrosine hydroxylase (BH4) — rate-limiting → dopa → dopa decarboxylase (PLP) → dopamine → Dopamine β-hydroxylase (vitamin C, copper) → noradrenaline → PNMT (SAM; induced by cortisol) → adrenaline

• Degraded by MAO and COMT → excreted as VMA and metanephrines
• Dopamine in the brain is degraded to homovanillic acid (HVA)
• Urinary VMA is the screening test for phaeochromocytoma; HVA and VMA for neuroblastoma

Melanin and Thyroid Hormone

• Melanin — tyrosine → dopa → dopaquinone → eumelanin (brown-black) or phaeomelanin (red-yellow, requires cysteine). Enzyme: tyrosinase, a copper enzyme
• Thyroid hormone — tyrosine residues on thyroglobulin are iodinated to MIT and DIT, then coupled to T3 and T4

Applied Aspects

• Maternal PKU — a treated woman who abandons the diet in pregnancy exposes the fetus to high phenylalanine → microcephaly, congenital heart disease and retardation even in a genetically normal baby. Strict dietary control must resume before conception
• Alkaptonuria is usually harmless in childhood; the ochronotic arthritis of the spine and large joints appears after 30. Urine darkens on standing or on adding alkali
• Albinism — the lack of melanin means no protection from ultraviolet light; skin cancer and visual defects are the real dangers
• Newborn screening for PKU is one of the great successes of preventive medicine — a cheap test that prevents irreversible retardation
• Tyrosinaemia type I — treated with nitisinone, which blocks the pathway higher up and prevents the toxic intermediate; a rare example of treating a metabolic block by creating another
• Parkinson disease — loss of nigral dopamine; treated with L-dopa, which crosses the blood–brain barrier whereas dopamine does not
• Carbidopa inhibits peripheral dopa decarboxylase, so more L-dopa reaches the brain and nausea is reduced
• α-Methyldopa produces a false neurotransmitter and was widely used as an antihypertensive in pregnancy
• Vitiligo — acquired autoimmune destruction of melanocytes; distinct from albinism, which is congenital and enzymatic
• Copper deficiency impairs tyrosinase and gives hypopigmented hair, as in Menkes disease
• Maple syrup urine disease — branched-chain α-keto acid dehydrogenase deficiency; sweet-smelling urine, ketoacidosis and neurological damage. It uses the same five coenzymes as the PDH complex
• Hartnup disease — defective tryptophan transport → a pellagra-like rash, since tryptophan is a precursor of niacin
• Carcinoid syndrome — the tumour diverts tryptophan to serotonin → may cause pellagra as well as flushing and diarrhoea
• Tandem mass spectrometry detects more than thirty inborn errors from a single dried blood spot — the modern basis of newborn screening
• Levodopa-induced dyskinesia limits long-term treatment of Parkinson disease and reflects pulsatile rather than continuous dopamine stimulation