Biotin-dependent carboxylases catalyze key reactions in fatty acid biosynthesis, gluconeogenesis, and amino acid degradation. Their roles in these biological processes have attracted great interest as therapeutic targets.  Although these enzymes have been studied for decades, their mechanism is poorly understood. It is widely accepted that the reaction proceeds through a carboxyphosphate intermediate; however, this intermediate's half-life (70 ms) is too short for it to be measured experimentally. Thus, the reaction of bicarbonate to carboxybiotin has been modeled using ONIOM QM/MM methods. The residues lysine 238, glutamate 296 and arginines 292 and 338 have been implicated as being critical to this mechanism and were therefore included in the QM region along with bicarbonate, biotin, and MgATP and treated with B3LYP/6-31G*, while the rest of the enzyme was treated with the AMBER force field. Elucidation of this mechanism could lead to new strategies to combat a variety of human diseases.

Mechanistic investigation of biotin carboxylase

243rd National Meeting (2012)

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