Mammalian sulfur amino acid metabolism: a nexus between redox regulation, nutrition, epigenetics and detoxification

Abstract

SIGNIFICANCE:Transsulfuration allows conversion of methionine into cysteine using homocysteine as an intermediate. This pathway produces S-adenosylmethionine, a key metabolite for cell function, and provides 50% of the cysteine needed for hepatic glutathione synthesis. The route requires the intake of essential nutrients (e.g. methionine, vitamins) and is regulated by their availability. Transsulfuration presents multiple interconnections with epigenetics, ATP and glutathione synthesis, polyol and pentose phosphate pathways and detoxification that rely mostly in the exchange of substrates or products. Major hepatic diseases, rare diseases and sensorineural disorders, among others that concur with oxidative stress, present impaired transsulfuration. Recent advances. In contrast to the classical view, a nuclear branch of the pathway, potentiated under oxidative stress, is emerging. Several transsulfuration proteins regulate gene expression, suggesting moonlighting activities. Additionally, abnormalities in homocysteine metabolism link nutrition and hearing loss.

CRITICAL ISSUES:Knowledge about the cross-regulation between pathways is mostly limited to the hepatic availability/removal of substrates and inhibitors. However, advances regarding protein-protein interactions involving oncogenes, identification of several post-translational modifications and putative moonlighting activities expand the potential impact of transsulfuration beyond methylations and homocysteine.

FUTURE DIRECTIONS:Increasing the knowledge on transsulfuration outside the liver, understanding the protein-protein interaction networks involving these enzymes, the functional role of their post-translational modifications or the mechanisms controlling their nucleocytoplasmic shuttling may provide further insights into the pathophysiological implications of this pathway, allowing design of new therapeutic interventions.