Novel mutation in hexokinase 2 confers resistance to 2-deoxyglucose by altering protein dynamics

Abstract

Glucose is central to many biological processes, serving as an energy source and a building block for biosynthesis. After glucose enters the cell, hexokinases convert it to glucose-6-phosphate (Glc-6P) for use in anaerobic fermentation, aerobic oxidative phosphorylation, and the pentose-phosphate pathway. We here describe a genetic screen in Saccharomyces cerevisiae that generated a novel spontaneous mutation in hexokinase-2, hxk2G238V, that confers resistance to the toxic glucose analog 2-deoxyglucose (2DG). Wild-type hexokinases convert 2DG to 2-deoxyglucose-6-phosphate (2DG-6P), but 2DG-6P cannot support downstream glycolysis, resulting in a cellular starvation-like response. Curiously, though the hxk2G238V mutation encodes a loss-of-function allele, the affected amino acid does not interact directly with bound glucose, 2DG, or ATP. Molecular dynamics simulations suggest that Hxk2G238V impedes sugar binding by altering the protein dynamics of the glucose-binding cleft, as well as the large-scale domain-closure motions required for catalysis. These findings shed new light on Hxk2 dynamics and highlight how allosteric changes can influence catalysis, providing new structural insights into this critical regulator of carbohydrate metabolism. Given that hexokinases are upregulated in some cancers and that 2DG and its derivatives have been studied in anti-cancer trials, the present work also provides insights that may apply to cancer biology and drug resistance.

Prot2Prot: a deep learning model for rapid, photorealistic macromolecular visualization

“…To demonstrate these animation styles, we first used UCSF Chimera [ 2 ] to generate a multi-frame PDB file of S. cerevisiae hexokinase 2 ( Sc Hxk2). Specifically, we used Chimera’s “Morph Conformations” tool to capture the transition between open and closed Sc Hxk2 structures extracted from a recent molecular dynamics simulation [ 29 ]. We created video animations of this transition from image sequences of 48 Prot2Prot-rendered trajectory frames (Online Resource 1).…”

Prot2Prot: A Deep Learning Model for Rapid, Photorealistic Macromolecular Visualization

“…To demonstrate these animation styles, we first used UCSF Chimera [3] to generate a multi-frame PDB file of S. cerevisiae hexokinase 2 ( Sc Hxk2). Specifically, we used Chimera’s “Morph Conformations” tool to capture the transition between open and closed Sc Hxk2 structures extracted from a recent molecular dynamics simulation [19]. We created video animations of this transition from image sequences of 48 Prot2Prot-rendered trajectory frames (Video S1).…”

“…Conformations" tool to capture the transition between open and closed ScHxk2 structures extracted from a recent molecular dynamics simulation [19]. We created video animations of this transition from image sequences of 48 Prot2Prot-rendered trajectory frames (Video S1).…”

Various Biomimetics as Antifungals

“…The use of the created biomimetics is aimed at their competition with the substituted molecules, which affects the metabolic activity and growth of fungal cells [105]. The well-known metabolomics of fungi enable developing of approaches to the decrease in fungal resistance and adaptation to various stress conditions (ionizing radiation, pH change, hypoxic stress, solar ultraviolet radiation, presence of toxic compounds, nutrient stress, oxidative stress, cold-heat stress) (Table 5) [17,89,[106][107][108][109][110][111][112][113].…”