TY - JOUR
T1 - Glucokinase
T2 - from allosteric glucose sensing to disease variants
AU - Gersing, Sarah
AU - Hansen, Torben
AU - Lindorff-Larsen, Kresten
AU - Hartmann-Petersen, Rasmus
N1 - Publisher Copyright:
© 2024 Elsevier Ltd
PY - 2025
Y1 - 2025
N2 - Human glucokinase (GCK) functions as a glucose sensor in the pancreas and liver, where GCK activity regulates insulin secretion and glycogen synthesis, respectively. GCK's low affinity for glucose and the sigmoidal substrate dependency of enzymatic turnover enables it to act as a sensor that makes cells responsive to changes in circulating glucose levels. Its unusual kinetic properties are intrinsically linked to the enzyme's conformational dynamics. Accordingly, genetic variants that alter the dynamics or other aspects of GCK function are linked to three glucose homeostasis diseases. In this review, we describe the enzyme GCK, focusing on its role as a glucose sensor, its unusual kinetic properties, and recent large-scale efforts to assess GCK variant effects.
AB - Human glucokinase (GCK) functions as a glucose sensor in the pancreas and liver, where GCK activity regulates insulin secretion and glycogen synthesis, respectively. GCK's low affinity for glucose and the sigmoidal substrate dependency of enzymatic turnover enables it to act as a sensor that makes cells responsive to changes in circulating glucose levels. Its unusual kinetic properties are intrinsically linked to the enzyme's conformational dynamics. Accordingly, genetic variants that alter the dynamics or other aspects of GCK function are linked to three glucose homeostasis diseases. In this review, we describe the enzyme GCK, focusing on its role as a glucose sensor, its unusual kinetic properties, and recent large-scale efforts to assess GCK variant effects.
KW - conformational dynamics
KW - cooperativity
KW - deep mutational scanning
KW - GCK-MODY
KW - glucose homeostasis
KW - variant effects
U2 - 10.1016/j.tibs.2024.12.007
DO - 10.1016/j.tibs.2024.12.007
M3 - Review
C2 - 39753435
AN - SCOPUS:85214007836
JO - Trends in Biochemical Sciences
JF - Trends in Biochemical Sciences
SN - 0968-0004
ER -