Ricerc@Sapienza

Maturity-onset diabetes of the young (MODY) type 2 is caused by heterozygous inactivating
mutations in the gene encoding glucokinase (GCK), a pivotal enzyme for glucose homeostasis. In
the pancreas GCK regulates insulin secretion, while in the liver it promotes glucose utilization
and storage. We showed that silencing the Drosophila GCK orthologs Hex-A and Hex-C results in
a MODY-2-like hyperglycemia. Targeted knock-down revealed that Hex-A is expressed in insulin

In eukaryotes, pyridoxal kinase (PDXK) acts in vitamin B-6 salvage pathway to produce pyridoxal 5'-phosphate (PLP), the active form of the vitamin, which is implicated in numerous crucial metabolic reactions. In Drosophila, mutations in the dPdxk gene cause chromosome aberrations (CABs) and increase glucose content in larval hemolymph. Both phenotypes are rescued by the expression of the wild type human PDXK counterpart.

Pyridoxal 5′-phosphate (PLP), the active form of vitamin B6, works as cofactor in numerous enzymatic reactions and it behaves as antioxidant molecule. PLP deficiency has been associated to many human pathologies including cancer and diabetes and the mechanism behind this connection is now becoming clearer. Inadequate intake of this vitamin increases the risk of many cancers; furthermore, PLP deprivation impairs insulin secretion in rats, whereas PLP supplementation prevents diabetic complications and improves gestational diabetes.

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

Vitamin B6 is a cofactor for approximately 150 reactions that regulate the metabolism of glucose, lipids, amino acids, DNA, and neurotransmitters. In addition, it plays the role of antioxidant by counteracting the formation of reactive oxygen species (ROS) and advanced glycation end-products (AGEs). Epidemiological and experimental studies indicated an evident inverse association between vitamin B6 levels and diabetes, as well as a clear protective effect of vitamin B6 on diabetic complications.

A combined IRMPD and DFT study of the isomeric forms of protonated pyridoxine, pyridoxamine and pyridoxal has allowed to establish the spectroscopic and some peculiar structural features of these basic components of the vitamin B6 group in the gas phase, with the aim to offer a standpoint free from the environmental effects, which could help in understanding their behavior in the condensed phase typical of biological systems. The imine-enamine and the neutral-zwitterion tautomerism have been considered.