| Autor: |
Dash R; Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Korea., Mitra S; Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Korea., Munni YA; Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Korea., Choi HJ; Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Korea., Ali MC; Department of Biotechnology & Genetic Engineering, Faculty of Biological Sciences, Islamic University, Kushtia 7003, Bangladesh., Barua L; Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh., Jang TJ; Department of Pathology, Dongguk University College of Medicine, Gyeongju 38066, Korea., Moon IS; Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Korea. |
| Abstrakt: |
An enzyme of the mammalian amino-sugar metabolism pathway, N -acetylglucosamine kinase (NAGK), that synthesizes N -acetylglucosamine (GlcNAc)-6-phosphate, is reported to promote dynein functions during mitosis, axonal and dendritic growth, cell migration, and selective autophagy, which all are unrelated to its enzyme activity. As non-enzymatic structural functions can be altered by genetic variation, we made an effort in this study aimed at deciphering the pathological effect of nonsynonymous single-nucleotide polymorphisms (nsSNPs) in NAGK gene. An integrated computational approach, including molecular dynamics (MD) simulation and protein-protein docking simulation, was used to identify the damaging nsSNPs and their detailed structural and functional consequences. The analysis revealed the four most damaging variants (G11R, G32R, G120E, and A156D), which are highly conserved and functional, positioned in both small (G11R and G32R) and large (G120E and A156D) domains of NAGK. G11R is located in the ATP binding region, while variants present in the large domain (G120E and A156D) were found to induce substantial alterations in the structural organizations of both domains, including the ATP and substrate binding sites. Furthermore, all variants were found to reduce binding energy between NAGK and dynein subunit DYNLRB1, as revealed by protein-protein docking and MM-GBSA binding energy calculation supporting their deleteriousness on non-canonical function. We hope these findings will direct future studies to gain more insight into the role of these variants in the loss of NAGK function and their role in neurodevelopmental disorders. |
