Schematic representations of mammalian homocysteine metabolism. Homocysteine metabolism is at the intersection of two main pathways: remethylation and transsulfuration pathway. Intracellular folate cycling is tightly connected to the remethylation pathway, in which methionine is activated by condensation with adenosine triphosphate (ATP) to yield the ubiquitous methyl donor, SAM, which is transformed into SAH by donating its methyl group to the substrates of methylation reactions. Subsequently, SAH gives rise to homocysteine in a reversible reaction that favors SAH over homocysteine production. The transsulfuration process is catalyzed by two vitamin B6-dependent enzymes: CBS and CSE. Hcy can be sequentially converted into cystathionine and then cysteine by CBS and CSE and subsequently results in the generation of H2S and other by-products including homoserine, pyruvate, GSH, taurine, and serine as well. MS, methionine synthase; THF, tetrahydrofolate; MTHFR, methylene tetrahydrofolatereductase; BHMT, betaine-homocysteine S-methyltransferase; DMG, dimethylglycine; SAM, S-adenosyl methionine; SAH, S-adenosylhomocysteine; CBS, cystathionine β-synthase; CSE, cystathionine γ-lyase; GSH, glutathione.