title: Reversible and irreversible protein glutathionylation: biological and clinical aspects.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biochemistry and Molecular Biology, New York Medical College, 15 Dana Road, Valhalla, NY 10595, USA. arthur_cooper@nymc.edu
authors.forename: Arthur Jl
authors.initials: AJ
authors.lastname: Cooper
authors.forename: John T
authors.initials: JT
authors.lastname: Pinto
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Callery
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D000447:Aldehydes / Q000493:pharmacokinetics; D000544:Alzheimer Disease / Q000628:therapy; D017209:Apoptosis; D002066:Busulfan / Q000009:adverse effects / Q000493:pharmacokinetics; D002386:Cataract / Q000628:therapy; D002453:Cell Cycle; D003550:Cystic Fibrosis / Q000628:therapy; D003924:Diabetes Mellitus, Type 2 / Q000628:therapy; D005978:Glutathione / Q000737:chemistry*; D019803:Glutathione Disulfide / Q000737:chemistry; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000628:therapy; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017510:Protein Folding / Q000187:drug effects; D011506:Proteins / Q000737:chemistry*; D015398:Signal Transduction; D013440:Sulfides / Q000493:pharmacokinetics
chemical_list: C403894:4-oxo-2-nonenal; D000447:Aldehydes; D011506:Proteins; D013440:Sulfides; C015102:dehydroalanine; D005982:Glutathione Transferase; D002066:Busulfan; D005978:Glutathione; C001520:lanthionine; D000409:Alanine; D019803:Glutathione Disulfide