A computational study of 1-formyl 1,2-ethanediol aminolysis predicts a stepwise mechanism involving syn-2-OH-assisted proton transfer. The syn-oriented 2-OH takes over the catalytic role of the external water or amine molecule previously observed in 2-deoxy ester aminolysis. It provides more favorable, that is, more linear, proton transfer geometry for the rate-limiting transition state resulting in an almost billion-fold rate acceleration of the overall reaction. These findings provide structural basis for explanation of the efficiency of the proton shuttling mechanism and imply double proton transfer catalysis by peptidyl tRNA A76 2'-OH as a possible catalytic strategy used by ribosome.

The hydrolysis of H-phosphonodiesters bearing a vicinal hydroxyl group is found to be subject to two competing reaction pathways in aprotic organic media. An observation of the increased proportion of cis-1,2-diol leaving with decrease of the water content is interpreted in terms of a change of the hydrolytic mechanism on changing the reaction medium from aqueous to nonaqueous. The hydroxyl group in cis-1,2diol monoanions hydrogen bonds strongly to the adjacent oxyanion, implying a low-energy route closely related to reactions, catalyzed by large ribozymes.

ABSTRACT:This work reports a density functional study of the mechanism of acyl migration between vicinal OH groups in monoformylated cis-tetrahydrofuran-3,4-diol as a model system for the acyl migration in amino-acylated tRNA. In addition, migration toward the ionized hydroxyl group was modeled, which simulates the process in the presence of basic reagents. The polarized continuum model (PCM) for four solvents evaluated the solvent effect on the reaction energetics. The computational results suggest that the stepwise mechanism via an orthoester intermediate is preferred by 45-48 kJ/mol over the concerted mechanism where migration of the formyl group, and the proton from the vicinal OH group occurs simultaneously via a four-atom transition state. The conformational constrains of the THF ring could increase the energy of the transition states by ϳ24 and 37 kJ/mol for the stepwise and concerted reaction paths, respectively. The calculated lowest activation energy of the reaction both in vacuum and in solvents is rather high, at 188 and 172-182 kJ/mol, respectively. These results suggest that in real systems, the process is most likely catalyzed by preliminary deprotonation of the vicinal OH group. In this case, the formyl group migration proceeds spontaneously, and the intermediate formed is 15-30 kJ/mol more stable than the initial anion of the monoformylated diol.

The possible catalytic effect of the vicinal hydroxyl group during the ammonolysis of acetylcatechol has been studied by first principle calculations. A very efficient intramolecular catalysis was found to occur when the catechol ester o-OH group is deprotonated: the activation energy of the ammonolysis decreases by 24 kcal mol(-1) as compared to that of acetylphenol ammonolysis. Using this value, the o-oxyanion-catalysed intramolecular ammonolysis was estimated to be orders of magnitude faster than the ammonolysis of acetylphenol or nonionised acetylcatechol. The analogy with the aminolysis of peptidyl-tRNA that occurs during protein biosynthesis implies several orders of magnitude acceleration due to complete or partial deprotonation of its 3'-terminal adenosine 2'-OH providing a mechanistic possibility for general acid-base catalysis by the ribosome.

A physical organic study reveals general base catalysis by the 2′‐oxyanion of the peptidyl adenosine ethanolysis; this implies a proton‐shuttle role for the 2′‐OH of peptidyl tRNA A76 in the ribosome substrate‐assisted catalytic mechanism.