Redox regulation and trapping sulfenic Acid in the peroxide-sensitive human mitochondrial branched chain aminotransferase.
ABSTRACT The human branched chain aminotransferase enzymes are key regulators of glutamate metabolism in the brain and are among a growing number of redox-sensitive proteins. Studies that use thiol-specific reagents and electrospray ionization mass spectrometry demonstrate that the mitochondrial BCAT enzyme has a redox-active CXXC center, which on oxidation forms a disulfide bond (RSSR), via a cysteine sulfenic acid intermediate. Mechanistic details of this redox regulation were revealed by the use of mass spectrometry and dimedone modification. We discovered that the thiol group at position C315 of the CXXC motif acts a redox sensor, whereas the thiol group at position C318 permits reversible regulation by forming an intrasubunit disulphide bond. Because of their roles in redox regulation and catalysis, there is a growing interest in cysteine sulphenic acids. Therefore, development of chemical tags/methods to trap these transient intermediates is of immense importance.
SourceAvailable from: William Willmore[Show abstract] [Hide abstract]
ABSTRACT: Mitochondria have a myriad of essential functions including metabolism and apoptosis. These chief functions are reliant on electron transfer reactions and the production of ATP and reactive oxygen species (ROS). The production of ATP and ROS are intimately linked to the electron transport chain (ETC). Electrons from nutrients are passed through the ETC via a series of acceptor and donor molecules to the terminal electron acceptor molecular oxygen (O2) which ultimately drives the synthesis of ATP. Electron transfer through the respiratory chain and nutrient oxidation also produces ROS. At high enough concentrations ROS can activate mitochondrial apoptotic machinery which ultimately leads to cell death. However, if maintained at low enough concentrations ROS can serve as important signaling molecules. Various regulatory mechanisms converge upon mitochondria to modulate ATP synthesis and ROS production. Given that mitochondrial function depends on redox reactions, it is important to consider how redox signals modulate mitochondrial processes. Here, we provide the first comprehensive review on how redox signals mediated through cysteine oxidation, namely S-oxidation (sulfenylation, sulfinylation), S-glutathionylation, and S-nitrosylation, regulate key mitochondrial functions including nutrient oxidation, oxidative phosphorylation, ROS production, mitochondrial permeability transition (MPT), apoptosis, and mitochondrial fission and fusion. We also consider the chemistry behind these reactions and how they are modulated in mitochondria. In addition, we also discuss emerging knowledge on disorders and disease states that are associated with deregulated redox signaling in mitochondria and how mitochondria-targeted medicines can be utilized to restore mitochondrial redox signaling.01/2013; 2. DOI:10.1016/j.redox.2013.12.011
[Show abstract] [Hide abstract]
ABSTRACT: Protein sulfenic acid formation has long been regarded as unwanted damage caused by reactive oxygen species (ROS). However, over the past 10 years, accumulating evidence has shown that the reversible oxidation of cysteine thiol groups to sulfenic acid functions as a redox-based signal transduction mechanism. Here, we review the mechanisms of sulfenic acid formation by ROS. We present some of the most important roles played by sulfenic acids in living cells as well as the pathways that regulate sulfenic acid formation. We highlight the experimental tools that have been developed to study the cellular sulfenome and show how computational approaches might help to better understand the mechanisms of sulfenic acid formation.Free Radical Biology and Medicine 07/2011; 51(2):314-26. DOI:10.1016/j.freeradbiomed.2011.04.031 · 5.71 Impact Factor
Chemical Reviews 11/2012; 113(1). DOI:10.1021/cr300073p · 45.66 Impact Factor