Redox-Dependent Regulation of Sulfur Metabolism in Biomolecules: Implications for Cardiovascular Health

Abstract

Significance:

Sulfur-containing amino acids are integral to the molecular mechanisms that underlie many aspects of cellular function and homeostasis, facilitated by reversible changes in the oxidation states of sulfur atoms. Sulfur-containing amino acids are metabolically linked by interacting pathways that impact the one-carbon metabolic cycle and generation of methyl groups, the folate cycle, and maintenance of the major cellular redox buffer; glutathione. Dysregulation of these pathways is associated with diverse pathologies, notably of the cardiovascular (CV) system, which are typically characterized by inappropriate plasma levels of sulfur-containing amino acids.

Recent Advances:

Perhaps not surprisingly, the cellular redox state has emerged as a major regulator of many enzymatic processes within these metabolic cycles. The metabolism of cysteine can also result in the production of hydrogen sulfide (H₂S), a signaling molecule whose activity is potentially linked to intracellular levels of both reactive oxygen species (ROS) and molecular oxygen.

Critical Issues:

In most cases, the endogenous physiological sources of ROS that might mediate the interlinked metabolic pathways of sulfur-containing biomolecules remain unknown. However, the family of NADPH oxidases, and Nox4 in particular, is emerging as a likely candidate.

Future Directions:

This review focuses on the current knowledge of key aspects of sulfur metabolism, which are regulated by redox-based chemical reactions, and the likely intracellular oxidant sources that might mediate this regulation. This knowledge will be important to guide future targeted therapeutic interventions in diverse CV disorders.