Pathways and regulation of homocysteine metabolism in mammals

Two intersecting pathways, the methionine cycle and the transsulfuration se quence, compose the mechanisms for homocysteine metabolism in mammals. The methionine cycle occurs in all tissues and provides for the remethylation o f homocysteine, which conserves methionine. In addition, the cycle is essen tial for the recycling of methyltetrahydrofolate. The synthesis of cystathi onine is the first reaction in the irreversible pathway for the catabolism of homocysteine by means of the sequential conversion to cysteine and sulfa te. This pathway has a limited distribution and is found primarily in the l iver, kidney, small intestine and pancreas. Regulation of homocysteine meta bolism is achieved by changes in the quantity of homocysteine distributed b etween the two competing pathways. Two mechanisms are basic to the regulato ry process. Changes in tissue content of the relevant enzymes are the respo nse to sustained perturbations. The inherent kinetic properties of the enzy mes provide an immediate response to alterations in the tissue concentratio ns of substrates and other metabolic effecters. S-adenosylmethionine, S-ade nosylhomocysteine, and methyltetrahydrofolate are of particular importance in that context.