Category: biosynthesis
The "right turn" off the methionine cycle. Where methionine_sam_cycle covers the methylation arm (SAM → SAH → homocysteine → re-methylation), this pathway covers the *transsulfuration* arm: homocysteine → cystathionine → cysteine → downstream sulfur metabolism (taurine, H₂S, glutathione). Step 1: cystathionine β-synthase (CBS, B6-dependent) condenses homocysteine + serine → cystathionine — the committed step away from re-methylation toward sulfur excretion / antioxidant pool. CBS deficiency causes classic homocystinuria. Step 2: cystathionine γ-lyase (CSE / CTH, B6-dependent) cleaves cystathionine → cysteine + α-ketobutyrate + NH3. Step 3: cysteine has three fates — (a) γ-glutamylcysteine synthetase (γ-GCS, rate-limiting for GSH; feedback-inhibited by GSH) → GSH (via γ-GC + glycine by GSS); (b) cysteine dioxygenase (CDO) → cysteine sulfinate → hypotaurine → taurine; (c) CBS/CSE catalyzed H₂S production (gasotransmitter; vasorelaxant). Step 4: GSH redox cycling — GSH → GSSG by GPx (selenoenzyme) consuming peroxide; GSSG → GSH by GR + NADPH. The transsulfuration arm is the primary path for converting dietary methionine into the antioxidant + xenobiotic-conjugating GSH pool. Therapeutic relevance: NAC bypasses CBS/CSE by directly providing cysteine; SAMe supplementation pushes methionine cycle flux that ultimately replenishes GSH precursor; B6 is the obligate CBS/CSE cofactor (deficiency mimics CBS deficiency biochemically). Cross-links: [[methionine_sam_cycle]], [[glutathione_metabolism]], [[ros_oxidative_stress]], [[conjugation_phase2_overview]] (GST-driven xenobiotic conjugation depends on GSH availability).