Dipartimento di Biologia e Biotecnologie "C. Darwin,", Sapienza Università di Roma, Rome, Italy.
School of Biological Science, Institute of Structural Biology, Nanyang Technological University, Singapore.
J Cell Physiol. 2020 Jan;235(1):504-512. doi: 10.1002/jcp.28990. Epub 2019 Jul 10.
Pyridoxine/pyridoxamine 5'-phosphate oxidase (PNPO) and pyridoxal kinase (PDXK) cooperate to produce pyridoxal 5'-phosphate (PLP), the active form of vitamin B6. PDXK phosphorylates pyridoxine, pyridoxamine, and pyridoxal by producing PNP, PMP, and PLP, whereas PNPO oxidizes PNP, PMP, into PLP. We previously demonstrated that PDXK depletion in Drosophila and human cells impacts on glucose metabolism and DNA integrity. Here we characterized sgll, the Drosophila ortholog of PNPO gene, showing that its silencing by RNA interference elicits chromosome aberrations (CABs) in brains and induces diabetic hallmarks such as hyperglycemia and small body size. We showed that in sgll neuroblasts CABs are largely produced by the genotoxic effect of the advanced glycation end products triggered by high glucose. As in sgll cells, part of PLP is still produced by PDXK activity, these data suggest that PLP dosage need to be tightly regulated to guarantee glucose homeostasis and DNA integrity.
吡哆醇/吡哆醛 5'-磷酸氧化酶 (PNPO) 和吡哆醇激酶 (PDXK) 合作产生吡哆醛 5'-磷酸 (PLP)，这是维生素 B6 的活性形式。PDXK 通过产生 PNP、PMP 和 PLP 来磷酸化吡哆醇、吡哆醛和吡哆醛，而 PNPO 将 PNP、PMP 氧化成 PLP。我们之前证明，果蝇和人类细胞中 PDXK 的耗竭会影响葡萄糖代谢和 DNA 完整性。在这里，我们对果蝇的 PNPO 基因的同源物 sgll 进行了表征，表明其 RNA 干扰沉默会在大脑中引起染色体畸变 (CABs)，并诱导高血糖和小体型等糖尿病特征。我们表明，在 sgll 神经母细胞瘤中，CABs 主要是由高葡萄糖引发的糖基化终产物的遗传毒性作用产生的。由于 sgll 细胞中仍有部分 PLP 是由 PDXK 活性产生的，这些数据表明需要严格调节 PLP 剂量以保证葡萄糖稳态和 DNA 完整性。
