Alkaptonuria (homogentisate 1,2-dioxygenase deficiency) is a rare autosomal recessive disorder of tyrosine catabolism. A 45-year-old presents with ochronosis (dark pigmentation of cartilage) and arthropathy. Which biochemical mechanism causes the connective tissue damage?
- A Homogentisic acid auto-oxidizes to benzoquinoneacetic acid, which covalently binds collagen fibers, making them rigid and brittle ✓
- B Homogentisic acid chelates calcium, causing dystrophic calcification of tendons
- C Fumarylacetoacetate accumulation activates matrix metalloproteinases in cartilage
- D Excess tyrosine deposits in cartilage as crystal aggregates triggering inflammatory arthritis
Correct answer: A. Homogentisic acid auto-oxidizes to benzoquinoneacetic acid, which covalently binds collagen fibers, making them rigid and brittle
Explanation
In alkaptonuria, homogentisic acid (HGA) accumulates and is excreted in urine (turns black on standing — oxidation). HGA that deposits in connective tissues spontaneously oxidizes to benzoquinoneacetic acid (BQA), which then polymerizes and covalently cross-links collagen fibers, turning them dark (ochronosis). This makes cartilage rigid and brittle, leading to ochronotic arthropathy resembling osteoarthritis. Nitisinone (NTBC — inhibits 4-hydroxyphenylpyruvate dioxygenase, an earlier step) reduces HGA production and is now used therapeutically.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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