B12 derivatives as potential antivitamins

B12 derivatives are organometallic compounds that are essential for humans and many other organisms. Its physically active forms play important roles as cofactors and coenzymes in the process of red blood cell formation as well as synthesis and regulation of DNA. Almost all higher evolved organisms are not capable of B12 biosynthesis and need to intake these so-called cobalamins in the form of physiologically inactive vitamin B12. The functioning of the B12 metabolism thus depends on the successful uptake, binding, and activation of B12. The inability to digest this vitamin results in pernicious anemia, a life-threatening disease. Being able to understand the B12 metabolism in all detail on a molecular level may provide a permanent cure of this and other diseases associated with B12 deficiency. Although crystal structures of the most prominent B12 derivatives, vitamin B12 and coenzyme B12, have been discovered more than 50 years ago, their role in the B12 metabolism is still not fully understood. A promising route to elucidate their functioning is a selective deactivation of key steps of the B12 metabolism. This may be achieved by modification of the axial cyano ligand in vitamin B12. Two interesting B12 derivatives have recently been reported and represent a new class of B12 derivatives. They cannot be transformed into a physiologically active from by processing protein homocystinuria type C (CblC). Instead, they block the B12 metabolism and function as vitamin B12 antagonists or B12 antivitamins. Their molecular properties and their binding to the protein CblC are scarcely understood and shall be explored in this study. The objective of this project is to understand the functioning of the two novel B 12 compounds as antivitamins by quantum chemical and molecular mechanical investigations and suggest improved antivitamins, which block the B12 metabolism more efficiently. Computational studies provide time- and spatially resolved analyses resulting in information not accessible in experiment. Molecular properties of the cobalamins for example, molecular structures and bond dissociation energies, are studied as well as how these properties are affected by an explicit interaction with the processing protein CblC. Thus, we are able to identify characteristics, which could be intrinsic properties of the antivitamins or substrate-protein interaction, that induce an inhibition of the B12 metabolism, and ultimately propose improved antivitamins. Findings of this investigation may contribute to a more complete understanding of the functioning of cobalamins in human metabolism and may shed light on their role in nerve diseases.

B12 derivatives as potential antivitamins B12 derivatives are organometallic compounds that are essential for humans and many other organisms. Their physically active forms play important roles as cofactors and coenzymes in the process of red blood cell formation as well as synthesis and regulation of DNA. Almost all higher evolved organisms are not capable of B12 biosynthesis and need to intake these so-called cobalamins in the form of physiologically inactive vitamin B12. The functioning of the B12 metabolism thus depends on the successful uptake, binding, and activation of B12. The inability to digest this vitamin results in pernicious anemia, a life-threatening disease. Being able to understand the B12 metabolism in all detail on a molecular level may provide a permanent cure of this and other diseases associated with B12 deficiency. Although crystal structures of vitamin B12 and coenzyme B12, have been discovered more than 50 years ago, their role in the B12 metabolism is still not fully understood. A promising route to elucidate their functioning is a selective deactivation of key metabolic steps. Thus, the concept of antivitamins as structural mimics of vitamin B12 and coenzyme B12 has been developed experimentally. These antimetabolites are recognized by the organism and bind at the same position but cannot be transformed into a physically active form. Hence, they block further B12 absorption. One strategy to yield such B12 antivitamins was to modify the ligand at the upper side of the corrin ring. This project focused on exploring their scarcely understood chemical properties as well as their interaction with the processing enzyme at an atomistic level. Extensive quantum chemical studies determined the bond dissociation energies of two B12 antivitamin derivatives. Opposed to our initial hypothesis the Co-ligand bond strength was not found to be the determining factor for the functioning as antimetabolite. With the experimental availability of a "naked" metal-free corrin ligand, that is hydrogenobyric acid, the central metal could be replaced - opening access to another type of B12 antivitamins. Consequently, we shifted our focus to studying the chemical nature of this ligand and explored the effects of replacement of Co as central metal on the potential functioning as antimetabolites. Working on these questions, it became evident that (explicit) solvation effects must be included in the computational treatment to yield robust models. Hence, we developed a concept for quantum chemical microsolvation, where explicit solvent molecules are automatically placed based on calculated physical properties - opening a new research branch by studying complex solvation effects of large bioinorganic complexes at low cost.