Properties of the highly unstable carboxyphosphate intermediate (t1/2  < 70ms) and the catalytic mechanism of N5-CAIR synthetase are presented from ab initio, DFT and ONIOM-QM/MM studies. N5-carboxyaminoimidazole ribonucleotide (N5-CAIR) synthetase catalyzes the conversion of 5-aminoimidazole ribonucleotide (AIR), Mg2ATP, and bicarbonate into N5-CAIR, Mg2ADP, and inorganic phosphate, an important step in the de novo purine biosynthesis in microbes. First step in the reaction mechanism of N5-CAIR synthetase involves the formation of dianionic carboxyphosphate (CP) from the attack of bicarbonate on the ?-phosphate of Mg2ATP, through an SN2 type transition structure. Lys353 then donates a proton to dianionic CP for the formation of a specific monanionic �pseudo-cyclic� conformation that promotes proton transfer from the acid to phosphate side of CP, which in turn triggers decomposition to generate �activated CO2�. Asp153 then deprotonate the amine of AIR, thus promoting the attack of AIR onto CO2. Results are consistent with the site-directed mutagenesis studies.

Catalytic mechanism of N<sup>5</sup>-carboxyaminoimidazole ribonucleotide synthetase: A computational study

243rd National Meeting (2012)

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Catalytic mechanism of N5-carboxyaminoimidazole ribonucleotide synthetase: A computational study

Catalytic mechanism of N⁵-carboxyaminoimidazole ribonucleotide synthetase: A computational study