Computational Study on Mechanistic Details of the Aminoethanol Rearrangement Catalyzed by the Vitamin B12-Dependent Ethanolamine Ammonia Lyase: His and Asp/Glu Acting Simultaneously as Catalytic Auxiliaries

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Abstract
The rearrangement of aminoethanol catalyzed by ethanolamine ammonia lyase is investigated by computational means employing DFT (B3LYP/6-31G*) and ab initio molecular orbital theory (QCISD/cc-pVDZ). The study aims at providing a detailed account on various crucial aspects, in particular a distinction between a direct intramolecular migration of the partially protonated NH2 group vs elimination of NH4+. Three mechanistic scenarios were explored: (i) According to the calculations, irrespective of the nature of the protonating species, intramolecular migration of the NH3 group is energetically less demanding than elimination of NH4+. However, all computed activation enthalpies exceed the experimentally derived activation enthalpy (15 kcal/mol) associated with the rate-determining step, i.e., the hydrogen abstraction from the 5‘-deoxyadenosine by the product radical. For example, when imidazole is used as a model system for His interacting with the NH3 group of the substrate, the activation enthalpy for the migration process amounts to 27.4 kcal/mol. If acetic acid is employed to mimic Asp or Glu, the activation enthalpy is somewhat lower, being equal to 24.2 kcal/mol. (ii) For a partial deprotonation of the substrate 2 at the OH group, the rearrangement mechanism consists of the dissociation of an NH2 radical from C(2) and its association at C(1) atom. For all investigated proton acceptors (i.e., OH-, HCOO-, CH3COO-, CH2NH, imidazole), the activation enthalpy for the dissociation step also exceeds 15 kcal/mol. Typical data are 20.2 kcal/mol for Ac- and 23.8 kcal/mol for imidazole. (iii) However, in a synergistic action of partial protonation of the NH2 group and partial deprotonation of the OH group by the two conceivable catalytic auxiliaries Asp/Glu and His, the activation enthalpy computed is compatible with the experimental data. For imidazole and acetate as model systems, the activation enthalpy is equal to 13.7 kcal/mol. This synergistic action of the two catalytic groups is expected to take place in a physiologically realistic pH range of 6−9.5, and the present computational findings may help to further characterize the yet unknown structural details of the ethanolamine ammonia lyase's active site.

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