For over 40 years, carboxyphosphate has been postulated as a key intermediate in several carboxylase enzymes. Unfortunately, this compound is extremely unstable (t1/2 of 70 ms), thus precluding direct experimental studies. Therefore, we have utilized high level ab inito (MP2 and CCSD(T)), DFT (B3LYP, BB1K, M05-2X, M06-2X and MPW1K) and ONIOM(DFT:AMBER) methods to investigate the  structure and energetics of carboxyphoshpate in vacuum, in a PCM continuum solvation model and in the active site of N5-CAIR synthetase, an enzyme shown to proceed via the formation of carboxyphosphate. We report here, for the first time, that carboxyphosphate adopts a �pseudo-chair� conformation and calculations reveal that this conformation is found to be the most stable in vacuum, solvent and the active site. This study has implications in the development of the carboxyphosphate analogs as potential inhibitors, in understanding the instability of the compound, and in elucidating the mechanisms of enzymes utilizing this compound.

Pseudo-chair conformation of carboxyphosphate

240th National Meeting (2010)

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