Molecular Insight into the Effect of a Single-Nucleotide Polymorphic Variation on the Structure and Dynamics of Methionine Synthase Reductase and Its Association with Neural Tube Defects.

ABSTRACT

Neural tube defects (NTDs) are among the common and severe congenital malformations in neonates. According to a WHO report, nearly three lakh babies are affected per year worldwide by NTDs. Most studies revealed that folate deficiency is the key element to promote NTD with other oligogenic and multifactorial elements. This folate is metabolized by the FOCM (folate one-carbon metabolism) pathway. The most important step in the FOCM pathway is the conversion of methionine to homocysteine, which is guided by the enzyme MTRR. Several single-nucleotide polymorphisms (SNPs) in the MTRR gene are strongly associated with the progression of NTD. A nonsynonymous allelic variant (rs1532268) of the protein leads to a missense mutation at the 202nd position from serine to leucine (S202L) and is associated with a higher disease prevalence in different populations. In our study, this SNP indicates a 2-fold increase in the risk of disease progression (p-value of 0.03; OR 2.76; 95% CI 1.08-7.11). Here, extensive molecular dynamics simulations and interaction network analysis reveal that the change of 202nd serine to leucine alters the structures of the FAD and NAD binding domains, which restricts the ligand binding. The S202L variation alters the functional dynamics that might impede the electron transport chain along the NADP(H)→ FAD→ FMN pathway and hamper phosphorylation by kinases like GSK-3 and CaM-II during the posttranscriptional modification of the protein. The present study provides functional insights into the effect of the genetic variations of the MTRR gene on the NTD disease pathogenesis.