Homocystinuria due to cystathionine beta-synthase (CBS) deficiency is pyridoxine-responsive in approximately 50% of cases. What is the biochemical rationale for this responsiveness?

• A Pyridoxine activates the alternative methionine salvage pathway via adenosylmethionine, bypassing CBS
• B Pyridoxal phosphate (PLP) is an essential cofactor for CBS; in some missense mutations, high-dose PLP supplementation overcomes the reduced affinity of mutant CBS for its cofactor, partially restoring enzyme activity ✓
• C Pyridoxine is converted to pyridoxamine, which non-enzymatically reduces homocysteine to methionine in plasma
• D Pyridoxine supplementation increases folate absorption in the gut, providing more 5-MTHF for the methionine synthase pathway to remethylate homocysteine

Explanation

CBS requires pyridoxal phosphate (PLP) as a cofactor for the condensation of homocysteine and serine to form cystathionine. In certain mild/moderate missense mutations, the mutant CBS enzyme has a reduced binding affinity for PLP. Pharmacological doses of pyridoxine (vitamin B6) increase intracellular PLP concentrations sufficiently to saturate the mutant enzyme and partially restore catalytic activity — pyridoxine-responsive CBS deficiency. Non-responsive forms have null mutations. Clinically, pyridoxine-responsive homocystinuria has a milder phenotype and responds to B6 + folate + methionine restriction.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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