The novel reductase, MenJ, which selectively reduces the double bond of the β-isoprene unit of menaquinone (MK), represents a novel virulence factor due to the fact that it is contextually essential for Mycobacterium tuberculosis survival in host macrophages. We are currently synthesizing and characterizing the physical properties such as solution structure and redox potential of MK substrate analogs. Specifically, MK-1 and the corresponding saturated analog, MK-1(H2). These analogs were chosen because a better understanding of the simplest truncated analogs is essential for understanding the natural substrate with nine isoprene units, denoted as MK-9. We used 2D NOESY NMR spectroscopy to elucidate the solution structure of MK-1 and MK-1 (H2) and are attempting to determine the redox potential using cyclic voltammetry. We have observed that the solution conformation of MK-1 and MK-1 (II-H2) does indeed change based on the solvent environment as evidenced by chemical shift changes and information gleaned from 2D NOESY experiments. We are also investigating how MK-1 and MK-1 (H2) interacts at an interface using reverse micelles as a model membrane system using 1D and 2D NMR techniques. Gaining access to these compounds is vital for understanding the structure-activity relationships of MenJ and the relationship of MK-structure with the phenotype of the bacterium.

Synthesis of menaquinone (MK) analogs and investigation into the solution structure of MK-1 and MK-1 (H2)

253rd National Meeting (2017)

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