Transsulfuration

Transsulfuration is a metabolic pathway that converts homocysteine, an intermediate in methionine metabolism, into cysteine. It links the methionine cycle to the biosynthesis of cysteine and downstream sulfur-containing compounds such as glutathione and taurine. In humans, the principal sequence begins with homocysteine reacting with serine to form cystathionine via cystathionine beta-synthase (CBS). Cystathionine is then cleaved by cystathionine gamma-lyase to produce cysteine, alpha-ketobutyrate, and ammonia. Under physiological conditions in humans, this route is effectively irreversible and is most active in the liver and kidney.

Enzymes and cofactors are central to transsulfuration. Both CBS and cystathionine gamma-lyase are pyridoxal phosphate (vitamin B6)–dependent enzymes. CBS is allosterically activated by S-adenosylmethionine (SAM), which helps couple methionine status to cysteine production. The pathway thus serves to detoxify homocysteine by channeling it toward cysteine when remethylation to methionine is not favored.

Clinical and nutritional relevance is notable. Defects in CBS cause classical homocystinuria, marked by elevated homocysteine and a risk of vascular, ocular, and skeletal problems. Less common deficiencies of cystathionine gamma-lyase also disrupt transsulfuration and raise homocysteine levels. Because cysteine is a key precursor for glutathione—the cellular antioxidant—impairment of transsulfuration can affect redox balance. Management considerations include B6 supplementation and dietary strategies to modulate methionine and cysteine availability, depending on the underlying condition.