Are oxidative stress and one-carbon metabolism mechanistically linked through methionine-cycle and transsulfuration pathways?

Oxidative stress and one-carbon metabolism are mechanistically linked through the methionine–homocysteine–transsulfuration axis. This relationship is biologically well established: sulfur from methionine-cycle intermediates can be directed toward cysteine production, supporting the glutathione system that buffers oxidant stress.

Mechanistic and experimental evidence

• Homocysteine from the methionine cycle enters transsulfuration through cystathionine β-synthase (CBS), forming cystathionine; cystathionine γ-lyase (CTH/CGL) then generates cysteine.
• Cysteine is a direct and potentially rate-limiting precursor for glutathione synthesis. Thus, transsulfuration provides a biochemical route by which one-carbon/methionine metabolism can contribute to cellular redox capacity.
• In human hepatoma-cell tracing experiments, approximately half of intracellular glutathione was attributed to homocysteine-derived sulfur. Peroxide exposure increased transsulfuration flux and cystathionine production, consistent with redox-responsive diversion of sulfur toward glutathione support.
• In cultured astrocytes, oxidizing conditions increased incorporation of methionine-derived label into glutathione. Inhibition of CTH/CGL depleted glutathione and impaired survival under oxidant challenge.
• Oxidative-stress-associated S-glutathionylation increased human CBS activity in vitro, providing a plausible molecular mechanism through which redox signaling can enhance flux toward cysteine production.

Context and implications

• The quantitative importance of this pathway is not fixed. It differs by tissue, degree of oxidative stress, and competing uses of transsulfuration intermediates, including hydrogen sulfide production.
• Direct evidence is strongest in cellular systems; these findings establish mechanism rather than a universal estimate of whole-body human glutathione production during oxidative stress.

Bottom line

• The claim is well supported: methionine-cycle and transsulfuration pathways can supply cysteine for glutathione synthesis, creating a functionally important, stress-responsive connection between one-carbon metabolism and oxidative defense.