Mechanism of pyridoxine 5'-phosphate accumulation in pyridoxal 5'-phosohate-binding protein-deficiency
Mechanism of pyridoxine 5'-phosphate accumulation in pyridoxal 5'-phosohate-binding protein-deficiency
复制标题
吡哆醛 5-磷酸结合蛋白缺陷中吡哆醇 5-磷酸积累的机制
DOI：
10.1128/jb.00521-21
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
T.
中科院分区：
文献类型：
--
作者：
Ito;T.;Ogawa;H.;Hemmi;H.;Downs;D. M.;& Yoshimura;T.
吡哆醛5′-磷酸（PLP）结合蛋白（PLPBP）在维生素B6体内平衡中起重要作用。在大肠杆菌和人类等生物体中，这种蛋白质的缺失会破坏维生素B6库，并诱导5′-磷酸吡哆醇（PNP）的细胞内积累，而这在野生型细胞中通常是检测不到的。这种积累的PNP可以通过抑制一些PLP依赖性酶来影响多种代谢系统。在这项研究中，我们研究了由于yggSin E编码的PLPBP蛋白的丢失而导致PNP在细胞内积累的尚不清楚的机制。杆菌利用几种PLPBP缺陷型大肠杆菌菌株进行遗传研究。大肠杆菌缺乏维生素B6的新途径或补救途径中的已知酶，包括吡哆醇（胺）5′-磷酸氧化酶（PNPO）、PNP合酶、吡哆醛激酶和吡哆醛还原酶，表明新途径或补救途径的通量都不是PLPBP突变引起的PNP积累的唯一原因。对缺乏PLPBP和PNPO的菌株的研究表明PNP与PMP共享相同的池，并且表明PNP水平受PMP水平的影响，反之亦然。在这里，我们表明，PLPBP的破坏扰乱PMP的稳态，这可能会导致PNP积累在PLPBP缺陷strains.IMPORTANCEA PLP-binding蛋白（PLPBP）从保守的COG 0325家族最近被认为是一个关键的球员在维生素B6的稳态在各种生物体。PLPBP的缺失破坏了维生素B6的体内平衡，扰乱了多种代谢，包括氨基酸和α-酮酸代谢。PNP的积累是PLPBP缺乏症的特征性表型，并被认为是多效性效应的潜在原因，但这种积累的机制知之甚少。在这项研究中，我们表明，PNP的合成/代谢通量是不负责的PNP的积累。我们的研究结果表明，PLPBP参与了吡哆胺5′-磷酸的稳态，它的破坏可能导致在PLPBP缺乏时PNP的积累。
The pyridoxal 5′-phosphate (PLP)-binding protein (PLPBP) plays an important role in vitamin B6homeostasis. Loss of this protein in organisms such as Escherichia coli and humans disrupts the vitamin B6pool and induces intracellular accumulation of pyridoxine 5′-phosphate (PNP), which is normally undetectable in wild-type cells. This accumulated PNP could affect diverse metabolic systems through the inhibition of some PLP-dependent enzymes. In this study, we investigated the as-yet-unclear mechanism of intracellular accumulation of PNP due to the loss of PLPBP protein encoded byyggSin E. coli. Genetic studies using several PLPBP-deficient strains of E. coli lacking a known enzyme(s) in thede novoor salvage pathways of vitamin B6, including pyridoxine (amine) 5′-phosphate oxidase (PNPO), PNP synthase, pyridoxal kinase, and pyridoxal reductase, demonstrated that neither the flux from thede novopathway nor the salvage pathway solely contributed to the PNP accumulation caused by the PLPBP mutation. Studies of the strains lacking both PLPBP and PNPO suggested that PNP shares the same pool with PMP, and showed that PNP levels are impacted by PMP levels and vice versa. Here, we show that disruption of PLPBP perturbs PMP homeostasis, which may result in PNP accumulation in the PLPBP-deficient strains.IMPORTANCEA PLP-binding protein (PLPBP) from the conserved COG0325 family has recently been recognized as a key player in vitamin B6homeostasis in various organisms. Loss of PLPBP disrupts vitamin B6homeostasis and perturbs diverse metabolisms, including amino acid and α-keto acid metabolism. Accumulation of PNP is a characteristic phenotype of PLPBP deficiency and is suggested to be a potential cause of the pleiotropic effects, but the mechanism of this accumulation has been poorly understood. In this study, we show that fluxes for PNP synthesis/metabolism are not responsible for the accumulation of PNP. Our results indicate that PLPBP is involved in the homeostasis of pyridoxamine 5′-phosphate, and that its disruption may lead to the accumulation of PNP in PLPBP deficiency.