Pyridoxine/pyridoxamine 5′‐phosphate oxidase (Sgll/PNPO) is important for DNA integrity and glucose homeostasis maintenance in Drosophila

Abstract

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. K E Y W O R D S chromosome aberrations, diabetes, Drosophila, sgll/PNPO, vitamin B6

Vitamin B6 and Diabetes: Relationship and Molecular Mechanisms

“…Moreover, the finding that insulin signaling is reduced in the dPdxk mutant larvae, suggested that dPdxk mutants might represent a new model of T2D [45]. In agreement with these results, the silencing of sgll by RNA interference produced diabetic hallmarks, such as hyperglycemia, reduced body size, and altered lipid metabolism [46]. Moreover, vitamin B6 administration rescues diabetic phenotypes in both Pdxk and Sgll depleted individuals, whereas the treatment with the PLP inhibitor 4-deoxypyridoxine (4-DP) causes hyperglycemia in wild type individuals [45,46,51].…”

“…By considering that PLP is both an antioxidant molecule and a cofactor for enzymes involved in DNA metabolism, it is expected that its reduced availability can contribute to increase DNA damage associated with diabetes. Studies in Drosophila and human cell cultures helped to gain evidence in support of this hypothesis, demonstrating that PLP deficiency can cause DNA damage throughout the formation of AGEs [45,46]. We demonstrated in fact that PLP deficiency in Drosophila and human cultured cells, trigger the formation of chromosome aberrations (CABs).…”

“…The most direct evidence indicating that vitamin B6 deficiency could cause diabetes was provided by data from studies in Drosophila, showing that mutations in genes involved in vitamin B6 metabolism cause diabetes [45,46].…”

The multifaceted role of vitamin B 6 in cancer: Drosophila as a model system to investigate DNA damage

“…Another study [131] showed that folate supplementation was able to alleviate mitochondrial dysfunction in a Parkinson fly model. However, to our knowledge, only vitamin B 6 has been studied in detail in a Drosophila model with the aim to understand cellular and molecular mechanisms at the basis of its beneficial effect on human diseases [132][133][134][135]. royalsocietypublishing.org/journal/rsob Open Biol.…”

“…AGEs have been associated with diabetic complications and are quenched by PLP and PM [51,52]. Interestingly, α-lipoic acid, a compound able to decrease AGE formation, rescues not only AGEs but also CABs in brains from dPdxk 1 mutants, Sgll-depleted individuals and 4-DP-fed larvae [132,135]. Taken together, these findings suggested that in low PLP conditions, CABs are mostly produced by hyperglycaemia, which in turn promotes AGE accumulation that causes DNA damage [132,135] (figure 4).…”