ABSTRACT
INTRODUCTION: Depending in part on the glutathione:glutathione disulfide ratio, reversible protein glutathionylation to a mixed disulfide may occur. Reversible glutathionylation is important in protecting proteins against oxidative stress, guiding correct protein folding, regulating protein activity and modulating proteins critical to redox signaling. The potential also exists for irreversible protein glutathionylation via Michael addition of an -SH group to a dehydroalanyl residue, resulting in formation of a stable, non-reducible thioether linkage. AREAS COVERED: This article reviews factors contributing to reversible and irreversible protein glutathionylation and their biomedical implications. It also examines the possibility that certain drugs such as busulfan may be toxic by promoting irreversible glutathionylation. The reader will gain an appreciation of the protective nature and control of function resulting from reversible protein glutathionylation. The reader is also introduced to the recently identified phenomenon of irreversible protein glutathionylation and its possible deleterious effects. EXPERT OPINION: The process of reversible protein glutathionylation is now well established but these findings need to be substantiated at the tissue and organ levels, and also with disease state. That being said, irreversible protein glutathionylation can also occur and this has implications in disease and aging. Toxicologists should consider this when evaluating the possible side effects of certain drugs such as busulfan that may generate a glutathionylating species in vivo.
Subject(s)
Glutathione/chemistry , Oxidative Stress , Proteins/chemistry , Alanine/analogs & derivatives , Alanine/metabolism , Alanine/pharmacokinetics , Aldehydes/pharmacokinetics , Alzheimer Disease/therapy , Apoptosis , Busulfan/adverse effects , Busulfan/pharmacokinetics , Cataract/therapy , Cell Cycle , Cystic Fibrosis/therapy , Diabetes Mellitus, Type 2/therapy , Glutathione Disulfide/chemistry , Glutathione Transferase/antagonists & inhibitors , Neoplasms/therapy , Oxidation-Reduction , Protein Folding/drug effects , Signal Transduction , Sulfides/pharmacokineticsABSTRACT
The following review examines the role of calcium in promoting the in vitro and in vivo activation of transglutaminases in neurodegenerative disorders. Diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease exhibit increased transglutaminase activity and rises in intracellular calcium concentrations, which may be related. The aberrant activation of transglutaminase by calcium is thought to give rise to a variety of pathological moieties in these diseases, and the inhibition has been shown to have therapeutic benefit in animal and cellular models of neurodegeneration. Given the potential clinical relevance of transglutaminase inhibitors, we have also reviewed the recent development of such compounds.
