Target for diverse chemical modifications.

The chapter begins with an historical perspective of GAPDH isozymes that is juxtaposed to the fact that there is only one somatic functional gene in humans that is virtually identical among the mammalian species. Over the many years of GAPDH research, dozens of labs have reported the existence of multiple forms of GAPDH, which mostly vary as a function of charge with an occasional report of truncated forms. These observations are in part due to GAPDH being a substrate for many enzymatically-controlled post-translational modifications. While target residues have been identified and predictive algorithms have implicated certain residues, this area of research appears to be in its infancy regarding GAPDH. Equally fascinating, the uniquely susceptible nature of GAPDH to non-enzymatic reactions, that typically are associated with cell stress, such as oxidation and nitration, is also discussed. Two metabolic gases, nitric oxide and hydrogen sulfide, which are enzymatically produced, appear to exert their signaling properties through non-enzymatic reaction with GAPDH. Models of cellular decline are also proposed, including the compelling hypothesis that states cell compromise occurs by the physically blocking the function of chaperonins (i.e. dual-ring multiple-subunit molecular chaperones) by the attachment of misfolded GAPDH.