Acetaldehyde and microtubules.
Acetaldehyde covalently binds to tubulin to form stable and unstable adducts. Although tubulin has numerous lysine residues available to react with acetaldehyde, a key highly reactive lysine (HRL) on the alpha chain appears to be a preferential target for stable binding. The HRL residue is available for selective binding when tubulin is in the free (dimer) state but not when it is in the polymerized (microtubule) state. Stable binding of acetaldehyde to the HRL residue markedly inhibits tubulin assembly into microtubules, whereas stable binding to other residues (bulk adducts) has little influence on assembly. Substoichiometric stable binding of acetaldehyde to the HRL is sufficient to inhibit polymerization, via direct interference of tubulin dimer-dimer interactions, and an HRL adduct on only one out of 20 tubulin molecules can totally inhibit polymerization. These findings, along with our previous studies demonstrating impaired microtubule-dependent protein trafficking pathways in livers of ethanol-fed animals, indicate that low acetaldehyde concentrations, formed during ethanol oxidation in vivo, could generate sufficient amounts of HRL adducts on the alpha chain of tubulin in cellular systems to alter microtubule formation and function. In addition to alpha-tubulin, calmodulin and actin have also been found to have enhanced reactivity toward acetaldehyde. Thus, a general hypothesis to describe cellular injury induced by acetaldehyde adducts can be formulated: during ethanol oxidation, acetaldehyde forms stable adducts via binding to reactive lysine residues of preferential target proteins, resulting in selective functional impairment of these proteins and ultimately leading to cellular injury.
Tuma
D J
DJ
Liver Study Unit, Department of Veterans Affairs Medical Center, Omaha, Nebraska 68105.
Smith
S L
SL
Sorrell
M F
MF
D000079:Acetaldehyde / Q000378:metabolism*; D000431:Ethanol / Q000378:metabolism*; D066298:In Vitro Techniques; D008870:Microtubules / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding; D014404:Tubulin / Q000378:metabolism*
D014404:Tubulin; D000431:Ethanol; D000079:Acetaldehyde