Aluminum interaction with glutamate and α-ketoglutarate: a computational study

Area of Science:

• Biochemistry
• Toxicology
• Computational Chemistry

Background:

• Aluminum is a nonessential element implicated in various human diseases.
• Aluminum (Al(III)) is known to interfere with metabolic pathways, including the tricarboxylic acid cycle.
• Alpha-ketoglutarate (α-KG) is a key intermediate in the tricarboxylic acid cycle, interconverted with glutamate by glutamate dehydrogenase (GDH).

Purpose of the Study:

• To investigate the interaction between aluminum (Al(III)) and both keto and enol tautomers of alpha-ketoglutarate (α-KG).
• To examine the complexation of glutamate with aluminum.
• To elucidate the role of citrate in modulating these interactions and explore potential biological complexation mechanisms.

Main Methods:

• Computational analysis of Al(III) interactions with α-KG tautomers.
• Investigation of Al(III) complexation with glutamate.
• Inclusion of citrate in the system to assess its effect on Al(III)-α-KG interactions.

Main Results:

• Al(III) significantly favors the enol tautomer of α-KG by 28 kcal/mol, suggesting a mechanism for glutamate dehydrogenase (GDH) inhibition.
• The presence of citrate substantially reduces the stabilization of the α-KG enol tautomer, making it only 1.5 kcal/mol more stable than the keto form.
• Ternary complexes involving Al(III), citrate, and either α-KG or glutamate are proposed as likely species in biological environments.

Conclusions:

• Aluminum's inhibition of GDH may be mediated by promoting α-KG tautomerization to its enol form.
• Citrate can mitigate aluminum's effect on α-KG tautomerization, potentially offering a protective mechanism.
• The formation of ternary Al(III)-citrate-α-KG/glutamate complexes is a plausible pathway for aluminum's biological activity.