A 6-month-old presents with tyrosinaemia type I (fumarylacetoacetase deficiency). Succinylacetone is a diagnostic marker found in urine. It inhibits which enzyme, causing a secondary complication?
- A Homogentisate dioxygenase, causing alkaptonuria-like pigmentation
- B 4-Hydroxyphenylpyruvate dioxygenase, blocking tyrosine catabolism further upstream
- C ALA dehydratase (porphobilinogen synthase), causing secondary porphyria-like crisis ✓
- D Fumarylacetoacetate hydrolase in a substrate-product feedback loop
Explanation
In tyrosinaemia type I, fumarylacetoacetase (FAH) deficiency causes accumulation of fumarylacetoacetate and maleylacetoacetate, which non-enzymatically form succinylacetone (and succinylacetoacetate). Succinylacetone is a potent inhibitor of ALA dehydratase (porphobilinogen synthase), the second enzyme in heme synthesis. This inhibition blocks heme synthesis, leading to accumulation of delta-aminolevulinic acid (ALA) and causing porphyria-like neurological crises (peripheral neuropathy, painful episodes). This explains the neurological complications of tyrosinaemia type I beyond the hepatorenal disease from direct toxin accumulation. NTBC (nitisinone), an inhibitor of 4-HPPD, is used to treat tyrosinaemia type I by blocking production of the toxic downstream metabolites.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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