N5-CAIR synthetase is involved in the conversion of 5-amino-imidazole ribonucleotide (AIR), Mg2ATP and bicarbonate to N5-CAIR, Mg2ADP, and inorganic phosphate. In the first step of the mechanism, carboxyphosphate is formed from nucleophilic attack of bicarbonate on the ?-phosphate of ATP. This reaction has been modeled in the presence of two Mg2+ ions, two glutamate residues, and two water molecules using both second-order Moller-Plesset theory and the M06-2x density function with the Dunning aug-cc-pvtz basis set. The studied mechanism involves an SN2 type transition state that is facilitated by an Arg271 residue in the active site of N5-CAIR synthetase. Carboxyphosphate is formed in the dianionic state by this mechanism and is converted into the monoanionic state by Lys353. In the next step of the N5-CAIR synthetase mechanism, carboxyphosphate decomposes to carboxylate AIR and form N5-CAIR. This conversion was modeled using ONIOM QM/MM in which the high level QM layer consists of the molecules present in the model of the first step and the low level MM layer consists of the remaining residues of N5-CAIR synthetase. The computed activation energy for the carboxylation of AIR in the N5-CAIR synthetase active site is 2.8 kcal/mol.

Investigation of the role of carboxyphosphate in the mechanism of N<sup>5</sup>-CAIR synthetase

248th National Meeting (2014)

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Investigation of the role of carboxyphosphate in the mechanism of N5-CAIR synthetase

Investigation of the role of carboxyphosphate in the mechanism of N⁵-CAIR synthetase