维生素 B12 的生化奇迹

Reactions Pub Date : 2024-01-05 DOI:10.3390/reactions5010002
Tudor Spataru
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引用次数: 0

摘要

几十年来,在研究维生素 B12 的生物化学过程中,实验数据与理论结果之间的比较一直非常混乱。虽然依赖甲基钴胺素辅助因子的蛋氨酸合成酶过程可以进行无限制的翻转,一些依赖腺苷钴胺素的过程以接近统一的平衡常数运行(如而基于密度泛函理论的 DFT 和 QM/MM(最常用和最受欢迎的分子电子结构计算方法)却显示,维生素 B12 辅因子中 Co+2 的 Co-N 间距比实验确定的要短得多,而且它们的酶学生物过程的能量障碍也不够大。由于一些体外实验数据显示维生素 B12 辅助因子反应存在巨大障碍(事实上,这些障碍在蛋氨酸合成酶过程中起着破坏作用,而这些障碍主要是由于发生反应的溶剂的影响造成的),因此造成了更大的混乱。对维生素 B12 的生化过程研究做出了坚实贡献的人,几乎都在正式质疑维生素 B12 的钴(II)辅助因子中 Co-N 化学键距离的实验测定的正确性。意想不到的是,维生素 B12 辅因子的所有理论生物化学数据只有在使用 MCSCF 方法(一种考虑轨道混合的方法,或者换句话说,伪雅恩-泰勒效应)处理时,才开始与所有体内实验数据相吻合。MCSCF 数据确定了甲基自由基和氢转移的未知机理细节、生物试剂之间电子转移的起源以及生物反应的性质和关系。伪贾恩-泰勒效应(如轨道混合)在总体上制约着维生素 B12 化学,并为了解人体中维生素 B12 依赖性反应的具体细节提供了启示。事实证明,DFT 或基于 DFT 方法的 QM/MM 理论数据与实验数据不一致,原因在于它们的局限性,如未考虑轨道混合效应。
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The Miracle of Vitamin B12 Biochemistry
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.
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