The Miracle of Vitamin B12 Biochemistry

Abstract

For decades, the comparison of experimental data with theoretical results in studying the biochemistry of vitamin B12 has been very confusing. While the methylcobalamin cofactor-dependent Methionine Synthase process can undergo unlimited turnovers, and some of the adenosylcobalamin-dependent processes run with close-to-unity equilibrium constants (e.g., with close-to-zero energy barriers), the DFT and QM/MM based on density functional theory, the most used and appreciated methods for calculating the electronic structure of molecules, have been showing a much shorter than experimental-determined Co-N distances in the vitamin B12 cofactors of Co+2 and the inadequate large energetic barriers of their enzymology bioprocesses. The confusion was even larger since some in vitro experimental data showed large barriers to the vitamin B12 cofactor reactions (which in fact play a destructive role in the Methionine Synthase process and which barriers were caused mostly by the influence of the solvents in which the reaction took place). It reached the point where solid contributions to the study of the biochemical processes of vitamin B12 were almost officially questioning the correctness of the experimental determination of the Co-N chemical bond distances in the cobalt(II) cofactors of vitamin B12. Unexpectedly, all the theoretical biochemistry of the vitamin B12 cofactors began to agree with all in vivo experimental data only when they were treated with the MCSCF method, the method that considers the orbital mixing, or in other words, the Pseudo-Jahn–Teller Effect. MCSCF data establish unknown mechanistic details of the methyl radical and hydrogen transfers, the origin of the electronic transfers between bioreagents, and the nature and the relationship between the bioreactions. The Pseudo-Jahn–Teller Effect, e.g., orbital mixing, governs vitamin B12 chemistry in general and provides insight into particular details of vitamin B12-dependent reactions in the human body. It turns out that the DFT or QM/MM based on DFT method theoretical data are incongruent with the experimental data due to their limitations, e.g., the unaccounted-for effects of orbital mixing.