Density functional theory calculation of cyclic carboxylic phosphorus mixed anhydrides as possible intermediates in biochemical reactions: implications for the Pro-Tide approach.
Cyclic acyl phosphoramidates (CAPAs) are important components in several fundamental biological reactions such as protein synthesis and phosphorylation. These structures are particularly interesting in the nucleotide pro-drug approach, Pro-Tide, since they are putative intermediates in one of the hydrolysis steps required for activation. The central role played by the amino acid carboxylate function suggests first the formation of a cyclic mixed phosphorus anhydride, rapidly followed by water attack. To investigate such speculations, we performed quantum mechanical calculations using the B3LYP/6-311+G** level of theory for the plausible mechanisms of action considered. In the five-membered ring case, transition state theory demonstrated how the overall, gas-phase, mechanism of action could be split into two in-line addition-elimination (A-E) steps separated by a penta-coordinate phosphorane intermediate. The difference between five-membered and six-membered ring first A-E was also explored, revealing a single step, unimolecular reaction for the six-membered ring A-E profile. Implicit solvent contribution further confirmed the importance of CAPAs as reactive intermediates in such kind of reactions. Lastly, the second A-E pathway was analyzed to understand the complete pathway of the reaction. This analysis is the first attempt to clarify the putative mechanism of action involved in the activation of Pro-Tides and casts light also on the possible mechanism of action involved in primordial protein syntheses, strengthening the hypothesis of a common cyclic mixed phosphorus anhydride species as a common intermediate.
The Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, United Kingdom. riccia@cf.ac.uk
Antonio
A
Ricci
Andrea
A
Brancale
D000577:Amides / Q000737:chemistry*; D000812:Anhydrides / Q000737:chemistry*; D003500:Cyclization; D008958:Models, Molecular; D010753:Phosphoranes / Q000737:chemistry; D010756:Phosphoric Acids / Q000737:chemistry*; D010758:Phosphorus / Q000737:chemistry; D011789:Quantum Theory; D014867:Water / Q000737:chemistry
D000577:Amides; D000812:Anhydrides; D010753:Phosphoranes; D010756:Phosphoric Acids; D014867:Water; D010758:Phosphorus; C011067:phosphoramidic acid