Glucokinase: from allosteric glucose sensing to disease variants
2025年1月2日 · Glucokinase (GCK) functions as a glucose sensor in the pancreas and liver. Appropriate GCK activity relies on enzyme conformational dynamics. Variants that perturb GCK function are linked to three diseases: GCK maturity-onset diabetes of the young, permanent neonatal diabetes mellitus, and hyperinsulinemic hypoglycemia.
Glucokinase (GCK) in diabetes: from molecular mechanisms to …
2024年9月8日 · Glucokinase (GCK) is a member of the hexokinase family, also known as hexokinase IV. It plays an essential role in glucose metabolism, crucial for sustaining blood glucose levels within normal ranges. It is a pivotal metabolic enzyme that catalyzes the first rate-limiting step of glycolysis in the pancreas and liver.
Characterizing glucokinase variant mechanisms using a …
2024年4月16日 · In this study, we identify residues important for GCK metabolic stability and conformational dynamics. These residues could be targeted to modulate GCK activity, and thereby affect glucose homeostasis. Protein function is crucial for cellular and organismal homeostasis, but can be perturbed by missense variants through various mechanisms.
A comprehensive map of human glucokinase variant activity
2023年4月26日 · Glucokinase (GCK) regulates insulin secretion to maintain appropriate blood glucose levels. Sequence variants can alter GCK activity to cause hyperinsulinemic hypoglycemia or hyperglycemia associated with GCK-maturity-onset diabetes of the young (GCK-MODY), collectively affecting up to 10 million people worldwide.
Assessing the potential of glucokinase activators in diabetes
2009年4月17日 · Glucokinase activators (GKAs) have been discovered recently that stimulate the enzyme allosterically by lowering its glucose S 0.5 (the concentration of glucose that allows half-maximal activity...
Insights into Mechanism of Glucokinase Activation - PubMed …
The small domain is composed of residues 66–202 and helix C, which consists of residues 442–465 (the C terminus). The large domain accounts for the rest of the protein (see Fig. 1 ). In most structures of GK complexes, the enzyme adopts an active closed conformation in which glucose is completely buried at a binding site formed by residues ...
Molecular basis for the role of glucokinase regulatory protein as …
The residues and secondary structures of the wedge in xGKRP (red) are shown to interact with the residues in the allosteric cleft of xGK (blue and cyan). The hydrophobic interface in the cleft of xGK is presented as a transparent surface.
Determinants of Human Glucokinase Activation and Implications …
Ser 64 residue is shown in red (Residues 1–13, 462–465 were missing from PDB:1V4S). In the current study, focusing on the clinically significant mutant GK-S64Y, we determine that the GK hyperactive mutant has distinct structural and thermodynamic characteristics during substrate recognition using small angle X-ray scattering (SAXS) and ...
Catalytic activation of human glucokinase by substrate binding: residue …
In the present study, we combined functional mutagenesis with structural dynamic analyses to identify residue contacts involved in the initial binding of alpha-d-glucose and conformational transitions.
Human β-Cell Glucokinase - Journal of Biological Chemistry
Glucokinase is distinguished from yeast hexokinase and low Kmmammalian hexokinases by its low affinity for glucose and its cooperative behavior, even though glucose binding residues and catalytic residues are highly conserved in all of these forms of hexokinase.