Homocystinuria due to cystathionine beta-synthase (CBS) deficiency causes elevated plasma homocysteine and methionine. Which pyridoxal phosphate (PLP)-dependent step is defective, and what is the rationale for pyridoxine treatment in CBS-responsive patients?

• A PLP is the cofactor for methionine synthase (homocysteine → methionine); pyridoxine increases methionine synthase activity
• B PLP is the cofactor for CBS (homocysteine + serine → cystathionine); pyridoxine supplementation increases residual CBS enzyme activity in responsive mutations ✓
• C PLP activates MTHFR to regenerate 5-methyltetrahydrofolate required for remethylation
• D PLP is the cofactor for cystathionase (cystathionine → cysteine + alpha-ketobutyrate), bypassing the defective CBS

Explanation

CBS catalyses the condensation of homocysteine + serine → cystathionine (transsulfuration pathway), with PLP (derived from pyridoxine/B6) as its essential cofactor. In CBS-deficient patients, approximately 50% have mutations that destabilise the enzyme but do not destroy catalytic activity; in these B6-responsive cases, supraphysiological PLP concentrations increase the properly folded, PLP-saturated enzyme fraction, enhancing residual enzyme activity sufficiently to lower homocysteine. B6-non-responsive patients have null mutations or severely truncated protein; they are treated with methionine-restricted diet, betaine (remethylation), and folate/B12. Methionine synthase uses methylcobalamin, not PLP. MTHFR uses FAD. Cystathionase is a downstream enzyme.

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

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