A representative model of GAPDH-dependent metabolic modulation in stored RBCs. For simplicity, GAPDH monomers are shown. The oxidative lesion may affect oxygen-dependent metabolic modulation, promoting GAPDH binding to the N-term or other residues of band 3, promoting a metabolic shift from Embden-Meyerhof to the PPP as to generate reducing equivalents (NADPH) and attempt to restore the redox poise. As RBCs approach the end of the storage period, oxidative stress becomes overwhelming and irreversible oxidative lesions accumulate in GAPDH, and as previously reported, Hb.²⁶  Irreversibly oxidized proteins are thus selectively vesiculated in RBC supernatants, a potential protective mechanism.⁴⁰  ROS, reactive oxygen species.