Abstract
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.
Highlights
N-acetylglucosamine kinase (GlcNAc kinase or NAGK; E.C. 2.7.1.59) is a major enzyme from the sugar-kinase/Hsp70/actin superfamily, which is involved in the conversion of GlcNAc (N-acetylglucosamine) to GlcNAc-6-phosphate, a catalytic event present in amino sugar metabolism [1]
Concerning the vital role of missense variants on in vivo protein functions in various complex diseases [20,21], the present study only considered the missense SNPs to study their effects on NAGK structural dynamics
Sci. 2021, 22, 8048 diseases [20,21], the present study only considered the missense SNPs to study their effects on NAGK structural dynamics
Summary
N-acetylglucosamine kinase (GlcNAc kinase or NAGK; E.C. 2.7.1.59) is a major enzyme from the sugar-kinase/Hsp70/actin superfamily, which is involved in the conversion of GlcNAc (N-acetylglucosamine) to GlcNAc-6-phosphate, a catalytic event present in amino sugar metabolism [1]. This metabolic pathway produces UDP-GlcNAc, which is the major substrate for the enzymes involved in protein N- and O-glycosylation and a substrate for sialic acid biosynthesis [2].
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