Drosophila carrying epilepsy-associated variants in the vitamin B6 metabolism gene PNPO display allele- and diet-dependent phenotypes was written by Chi, Wanhao;Iyengar, Atulya S. R.;Fu, Wenqin;Liu, Wei;Berg, Abigayle E.;Wu, Chun-Fang;Zhuang, Xiaoxi. And the article was included in Proceedings of the National Academy of Sciences of the United States of America in 2022.Synthetic Route of C8H10NO6P The following contents are mentioned in the article:
Pyridox(am)ine 5′-phosphate oxidase (PNPO) catalyzes the rate-limiting step in the synthesis of pyridoxal 5′-phosphate (PLP), the active form of vitamin B6 required for the synthesis of neurotransmitters gamma-aminobutyric acid (GABA) and the monoamines. Pathogenic variants in PNPO have been increasingly identified in patients with neonatal epileptic encephalopathy and early-onset epilepsy. These patients often exhibit different types of seizures and variable comorbidities. Recently, the PNPO gene has also been implicated in epilepsy in adults. It is unclear how these phenotypic variations are linked to specific PNPO alleles and to what degree diet can modify their expression. Using CRISPR-Cas9, we generated four knock-in Drosophila alleles, hWT, hR116Q, hD33V, and hR95H, in which the endogenous Drosophila PNPO was replaced by wild-type human PNPO complementary DNA (cDNA) and three epilepsy-associated variants. We found that these knock-in flies exhibited a wide range of phenotypes, including developmental impairments, abnormal locomotor activities, spontaneous seizures, and shortened life span. These phenotypes are allele dependent, varying with the known biochem. severity of these mutations and our characterized mol. defects. We also showed that diet treatments further diversified the phenotypes among alleles, and PLP supplementation at larval and adult stages prevented developmental impairments and seizures in adult flies, resp. Furthermore, we found that hR95H had a significant dominant-neg. effect, rendering heterozygous flies susceptible to seizures and premature death. Together, these results provide biol. bases for the various phenotypes resulting from multifunction of PNPO, specific mol. and/or genetic properties of each PNPO variant, and differential allele-diet interactions. This study involved multiple reactions and reactants, such as (4-Formyl-5-hydroxy-6-methylpyridin-3-yl)methyl dihydrogen phosphate (cas: 54-47-7Synthetic Route of C8H10NO6P).
(4-Formyl-5-hydroxy-6-methylpyridin-3-yl)methyl dihydrogen phosphate (cas: 54-47-7) belongs to pyridine derivatives. Pyridines are an important class of heterocycles and occur in polysubstituted forms in many naturally occurring biologically active compounds, drug molecules and chiral ligands. Pyridine groups exist in countless molecules, and their applications include catalysis, drug design, molecular recognition, and natural product synthesis.Synthetic Route of C8H10NO6P