Glucokinase: from allosteric glucose sensing to disease variants

Sarah Gersing*, Torben Hansen, Kresten Lindorff-Larsen, Rasmus Hartmann-Petersen

*Corresponding author for this work

Research output: Contribution to journalReviewResearchpeer-review

Abstract

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.

Original languageEnglish
JournalTrends in Biochemical Sciences
ISSN0968-0004
DOIs
Publication statusAccepted/In press - 2025

Bibliographical note

Publisher Copyright:
© 2024 Elsevier Ltd

Keywords

  • conformational dynamics
  • cooperativity
  • deep mutational scanning
  • GCK-MODY
  • glucose homeostasis
  • variant effects

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