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首页> 外文期刊>Biochemistry >Investigating Substrate Analogues for Mycobacterial MenJ: Truncated and Partially Saturated Menaquinones
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Investigating Substrate Analogues for Mycobacterial MenJ: Truncated and Partially Saturated Menaquinones

机译：调查分枝杆菌MENJ的底物类似物：截短和部分饱和的母牛

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Menaquinones (MKs) are essential for electron transport in prokaryotes, and importantly, partially saturated MKs represent a novel virulence factor. However, little is known regarding how the degree of saturation in the isoprenyl side chain influences conformation or quinone redox potential. MenJ is an enzyme that selectively reduces the second isoprene unit on MK-9 and is contextually essential for the survival of Mycobacterium tuberculosis in J774A.1 macrophage-like cells, suggesting that MenJ may be a conditional drug target for pathogenic mycobacteria. Therefore, fundamental information about the properties of this system is important, and we synthesized the simplest MKs, unsaturated MK-1 and the saturated analogue, MK-1(H-2). Using two-dimensional nuclear magnetic resonance spectroscopy, we established that MK-1 and MK-1(H-2) adopted similar folded-extended conformations (i.e., the isoprenyl side chain folds upward) in each solvent examined but the folded-extended conformations differed slightly between organic solvents. Saturation of the isoprenyl side chain slightly altered the MK-1 analogue conformation in each solvent. We used molecular mechanics to illustrate the MK-1 analogue conformations. The measured quinone redox potentials of MK-1 and MK-1(H-2) differed between organic solvents (presumably due to differences in dielectric constants), and remarkably, an similar to 20 mV semiquinone redox potential difference was observed between MK-1 and MK-1(H-2) in pyridine, acetonitrile, and dimethyl sulfoxide, demonstrating that the degree of saturation in the isoprenyl side chain of MK-1 influences the quinone redox potential. Finally, MK-1 and MK-1(H-2) interacted with Langmuir phospholipid monolayers and Aerosol-OT reverse micelle (RM) model membrane interfaces, where MK-1 adopted a slightly different folded conformation within the RM model membrane interface.
机译：menaquinons（MKS）对于原核生物中的电子传输是必不可少的，重要的是，部分饱和的MKS表示新颖的毒力因子。然而，关于异戊二烯基侧链的饱和程度如何影响构象或醌氧化还原潜力。 MENJ是一种选择性地减少MK-9上的第二异戊二烯单元的酶，并且对于J774A.1巨噬细胞的细胞核分子分枝杆菌的存活，表明MENJ可能是致病性分枝杆菌的条件药物靶标。因此，关于该系统性质的基本信息很重要，并且我们合成了最简单的MKS，不饱和MK-1和饱和的类似物，MK-1（H-2）。使用二维核磁共振光谱，我们建立了MK-1和MK-1（H-2）采用了类似的折叠延伸的构象（即，异戊二烯基侧链向上折叠）在检查的每个溶剂中，但折叠延伸的构象有机溶剂之间略微不同。异戊二烯基侧链的饱和略微改变了每种溶剂中的MK-1类似物构象。我们使用了分子机制来说明MK-1模拟构象。 MK-1和MK-1（H-2）的测量醌氧化还原电位不同于有机溶剂（可能是由于介电常数的差异），并且显着地，在MK-1之间观察到类似于20mV的半醌氧化还原电位差异和MK-1（H-2）在吡啶，乙腈和二甲基亚砜中，表明MK-1等异戊二烯链中的饱和度影响了醌氧化还原潜力。最后，MK-1和MK-1（H-2）与Langmuir磷脂单层和气溶胶 - OT反向胶束（RM）模型膜界面相互作用，其中MK-1在RM模型膜界面内采用略微不同的折叠构象。

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