Pyridoxine/pyridoxamine 5′-phosphate oxidase (Sgll/PNPO) is important for DNA integrity and glucose homeostasis maintenance in Drosophila
Pyridoxine/pyridoxamine 5′-phosphate oxidase (Sgll/PNPO) is important for DNA integrity and glucose homeostasis maintenance in Drosophila
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DOI：
10.1002/jcp.28990
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发表时间：
2019-07-10
影响因子：
5.6
通讯作者：
Verni, Fiammetta
中科院分区：
文献类型：
--
作者：
Mascolo, Elisa;Amoroso, Noemi;Verni, Fiammetta
吡哆醇/吡哆胺5 '-磷酸氧化酶（PNPO）和吡哆醛激酶（PDXK）协同产生维生素B6的活性形式吡哆醛5 '-磷酸（PLP）。PDXK通过产生PNP、PMP和PLP磷酸化吡哆醇、吡哆胺和吡哆醛，而PNPO将PNP、PMP氧化成PLP。我们先前证明了果蝇和人类细胞中PDXK的缺失会影响葡萄糖代谢和DNA完整性。在这里，我们表征了果蝇PNPO基因的直系同源物sgll，表明其通过RNA干扰沉默导致大脑中的染色体畸变（CAB），并诱导糖尿病特征，如高血糖和小体型。我们发现，在sgll（RNAi）成神经细胞中，CAB主要是由高糖引发的晚期糖基化终产物的遗传毒性作用产生的。如在sgII（RNAi）细胞中，部分PLP仍然由PDXK活性产生，这些数据表明PLP剂量需要严格调节以保证葡萄糖稳态和DNA完整性。
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(RNAi) neuroblasts CABs are largely produced by the genotoxic effect of the advanced glycation end products triggered by high glucose. As in sgll(RNAi) 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.