Engelhardt Institute of Molecular Biology, Russian Academy of Science, 119991 Moscow, Russia.
Int J Mol Sci. 2023 Nov 8;24(22):16070. doi: 10.3390/ijms242216070.
Inactivation of enzymes responsible for biosynthesis of the cell wall component of ADP-glycero-manno-heptose causes the development of oxidative stress and sensitivity of bacteria to antibiotics of a hydrophobic nature. The metabolic precursor of ADP-heptose is sedoheptulose-7-phosphate (S7P), an intermediate of the non-oxidative branch of the pentose phosphate pathway (PPP), in which ribose-5-phosphate and NADPH are generated. Inactivation of the first stage of ADP-heptose synthesis () prevents the outflow of S7P from the PPP, and this mutant is characterized by a reduced biosynthesis of NADPH and of the Glu-Cys-Gly tripeptide, glutathione, molecules known to be involved in the resistance to oxidative stress. We found that the derepression of purine biosynthesis () normalizes the metabolic equilibrium in PPP in mutants, suppressing the negative effects of mutation likely via the over-expression of the glycine-serine pathway that is under the negative control of PurR and might be responsible for the enhanced synthesis of NADPH and glutathione. Consistently, the activity of the system, as well as the level of glutathionylation and oxidation of proteins, indicative of oxidative stress, were reduced in the double mutant compared to the mutant.
使负责合成 ADP-甘油基-D-甘露庚糖细胞壁成分的酶失活会导致细菌产生氧化应激并对疏水性抗生素敏感。ADP-庚糖的代谢前体是 sedoheptulose-7-phosphate (S7P)，它是戊糖磷酸途径（PPP）非氧化分支的中间产物，在此过程中会产生核糖-5-磷酸和 NADPH。阻断 ADP-庚糖合成的第一阶段（）会阻止 S7P 从 PPP 中流出，这种突变体的特点是 NADPH 和 Glu-Cys-Gly 三肽（谷胱甘肽）的生物合成减少，而谷胱甘肽是已知参与抵抗氧化应激的分子。我们发现嘌呤生物合成的去阻遏（）可以使 PPP 中的代谢平衡在突变体中正常化，通过过度表达受 PurR 负调控的甘氨酸-丝氨酸途径来抑制突变体的负面影响，这可能是 NADPH 和谷胱甘肽合成增强的原因。一致地，双突变体（）中，与单突变体（）相比，系统的活性以及谷胱甘肽化和蛋白质氧化的水平（指示氧化应激）降低。
