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).
Organ Systems
digestive
immune-hematologic
Pathway Steps
homocysteine + serine → cystathionine — via CBS (cystathionine β-synthase, P5P cofactor) — RATE-LIMITING, deficiency = homocystinuria. Cystathionine β-synthase commits homocysteine to disposal (transsulfuration) rather than remethylation; it needs P5P (B6) and is activated by SAM, so a high methyl state routes homocysteine to catabolism. CBS deficiency causes classic homocystinuria.
cystathionine → cysteine + α-ketobutyrate — via CSE / CTH (cystathionine γ-lyase, P5P cofactor). Cystathionine γ-lyase (also P5P-dependent) releases cysteine — making cysteine only conditionally non-essential, dependent on adequate methionine/homocysteine. This is how dietary methionine ultimately yields cysteine, taurine, and glutathione.
cysteine → γ-glutamylcysteine — via γ-GCS / GCLC — rate-limiting for GSH; feedback-inhibited by GSH. γ-glutamylcysteine ligase is the rate-limiting step of glutathione synthesis, feedback-inhibited by GSH; the cysteine supplied by transsulfuration is usually the limiting substrate, tying methionine/B6 status to antioxidant capacity.
γ-glutamylcysteine + glycine → glutathione (GSH) — via glutathione synthetase (GSS). Glutathione synthetase adds glycine to complete the tripeptide. Transsulfuration thus feeds the body’s main thiol antioxidant, and oxidative demand for GSH pulls homocysteine toward this route and away from remethylation.
cysteine → hypotaurine → taurine — via CDO + CSAD — taurine biosynthesis branch. An alternative cysteine fate: cysteine dioxygenase then CSAD make hypotaurine → taurine, among the most abundant free amino acids (bile-salt conjugation, osmoregulation, membrane stabilization) and conditionally essential in infants.
cysteine → H₂S (gasotransmitter) — via CBS / CSE / 3-MST — vasorelaxant + neuromodulator. The same CBS/CSE enzymes (with 3-MST) also generate hydrogen sulfide, a gasotransmitter causing vasorelaxation and neuromodulation — placing the transsulfuration enzymes at the heart of H₂S signaling alongside their metabolic role.
GSH → GSSG (consumed) — via glutathione peroxidase (selenoenzyme; reduces H₂O₂ + lipid peroxides). Glutathione peroxidase (a selenoenzyme) spends two GSH to reduce H₂O₂ and lipid peroxides to water — the antioxidant payoff of the cysteine supplied by transsulfuration.
GSSG → GSH (regenerated) — via glutathione reductase + NADPH. Glutathione reductase regenerates GSH from GSSG using NADPH (from the pentose-phosphate pathway), closing the redox cycle; the GSH:GSSG ratio reports cellular oxidative state.
Known Modulators
nac (substrate) — cysteine direct precursor — bypasses CBS/CSE. N-acetylcysteine; canonical Rx for acetaminophen toxicity (replenishes hepatic GSH)
n acetylcysteine amide (substrate) — cysteine precursor — improved BBB penetration vs NAC