Homocysteine and redox signaling

Homocysteine is a thiol-containing amino acid that has gained notoriety because its elevation in the plasma is correlated with complex and multifactorial diseases, including cardiovascular diseases, neurodegenerative diseases, and neural tube defects. Homocysteine is redox-active, and its toxic effects have been frequently attributed to direct or indirect perturbation of redox homeostasis. Although the literature on the pathophysiology of elevated homocysteine is rather extensive, a very wide range of concentrations of this amino acid has been used in these studies ranging from normal to pathophysiological to unphysiological. It is clear that homocysteine induces varied responses that are specific to cell type and that cells, depending on their origin, display a wide range of sensitivity to homocysteine. In this review, we focus on the redox signaling pathways that have been connected to homocysteine in vascular (endothelial and smooth muscle) cells and in neuronal cells. We also discuss redox regulation of the key enzymes involved in homocysteine clearance: methionine synthase, betaine-homocysteine methyltranferase, and cystathionine beta-synthase.