GCK

Official Full Name

GDP dissociation inhibitor 2

Organism

Homo sapiens

GeneID

2665

Background

GDP dissociation inhibitors are proteins that regulate the GDP-GTP exchange reaction of members of the rab family, small GTP-binding proteins of the ras superfamily, that are involved in vesicular trafficking of molecules between cellular organelles. GDIs slow the rate of dissociation of GDP from rab proteins and release GDP from membrane-bound rabs. GDI2 is ubiquitously expressed. The GDI2 gene contains many repetitive elements indicating that it may be prone to inversion/deletion rearrangements. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

Synonyms

RABGDIB; HEL-S-46e;

Bio Chemical Class

Kinase

Protein Sequence

MLDDRARMEAAKKEKVEQILAEFQLQEEDLKKVMRRMQKEMDRGLRLETHEEASVKMLPTYVRSTPEGSEVGDFLSLDLGGTNFRVMLVKVGEGEEGQWSVKTKHQMYSIPEDAMTGTAEMLFDYISECISDFLDKHQMKHKKLPLGFTFSFPVRHEDIDKGILLNWTKGFKASGAEGNNVVGLLRDAIKRRGDFEMDVVAMVNDTVATMISCYYEDHQCEVGMIVGTGCNACYMEEMQNVELVEGDEGRMCVNTEWGAFGDSGELDEFLLEYDRLVDESSANPGQQLYEKLIGGKYMGELVRLVLLRLVDENLLFHGEASEQLRTRGAFETRFVSQVESDTGDRKQIYNILSTLGLRPSTTDCDIVRRACESVSTRAAHMCSAGLAGVINRMRESRSEDVMRITVGVDGSVYKLHPSFKERFHASVRRLTPSCEITFIESEEGSGRGAALVSAVACKKACMLGQ

Open

Disease

Acute diabete complication, Diabetes mellitus, Obesity, Type 2 diabetes mellitus

Approved Drug

Clinical Trial Drug

16 +

Discontinued Drug

3 +

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Detailed Information

Glucokinase (GCK) is a remarkable 52-kDa enzyme made up of 465 amino acids that play a vital role in glucose metabolism. Unlike other hexokinases, GCK has distinct features that make it an ideal glucose sensor. The enzyme consists of two main domains - a large domain and a small domain - connected by flexible loops that form a hinge. Between these domains lies a deep cleft where glucose binds.

GCK can exist in multiple conformational states that affect its function. In its super-open state, the enzyme shows low glucose affinity and remains inactive. When glucose binds, GCK shifts to a closed conformation, becoming catalytically active. This structural flexibility allows GCK to respond to varying glucose levels, making it an effective glucose sensor in the body.

Figure 1 illustrates the surface representation of the GCK/GKRP complex, highlighting different structural components. Figure 1. Surface representation of the overall structure of GCK/GKRP complex. (Abu Aqel Y, et al., 2024)

The gene encoding GCK is found on chromosome 7 and contains two distinct promoters. One promoter controls GCK expression in pancreatic islet cells, while the other regulates expression in the liver. This dual-promoter system allows for tissue-specific regulation of GCK, enabling it to serve different roles in different organs.

GCK's Central Role in Pancreatic β-cells

In pancreatic β-cells, GCK serves as a glucose sensor and plays a crucial role in insulin secretion. When glucose enters β-cells through glucose transporters, GCK phosphorylates it to glucose-6-phosphate, initiating the glucose metabolism pathway. This process leads to increased ATP production, which triggers a cascade of events resulting in insulin release.

GCK exists in two forms within β-cells: a free-diffusing form with high activity and a bound form with lower activity. The bound form is typically associated with mitochondria and insulin secretory granules. This interaction with mitochondria helps protect β-cells from apoptosis under high glucose conditions. The binding to insulin granules, regulated by nitric oxide synthase, serves as a storage mechanism that allows for rapid mobilization when needed.

Figure 2 describes the biochemical process where glucose uptake in pancreatic Beta-cells through low-affinity glucose transporters leads to insulin secretion. Figure 2. GCK role in pancreatic β-cells. (Abu Aqel Y, et al., 2024)

Several proteins interact with and regulate GCK in β-cells. The BAD protein, typically known for its role in apoptosis, can bind to GCK and influence its activity. When phosphorylated, BAD helps activate GCK and stimulate insulin release, improving β-cell function and survival. Additionally, the enzyme PFK-2/FBPase-2 can bind to GCK and enhance its activity, helping regulate glucose metabolism.

GCK's Impact on Cell Function and Disease

GCK's function goes beyond basic glucose metabolism. Higher glucose levels in β-cells cause more GCK expression, which activates cell proliferation-related genes such as IRS-2 and cyclin D2. IRS-2 is very vital for preserving β-cell mass and avoiding cell death, so it is critical for diabetes prevention.

Different systems, notably the ubiquitin-proteasome system, help to precisely control the action of the enzyme. The SUMO-1 protein may attach to GCK, hence boosting its stability and activity. Though this control seems complicated and might include other elements, the PDX1 protein can control GCK expression in beta-cells at the transcriptional level.

Alterations in GCK activity could cause many illnesses. Changes in enzyme activity brought on by mutations have been connected to several kinds of diabetes as well as other metabolic diseases. Knowing these links has helped GCK to be a key target for therapeutic therapies in metabolic illnesses.

Research on GCK mutations highlights even more its essential function in glucose regulation. Compromised GCK activity may interfere with proper glucose sensing and insulin release, hence causing problems in glucose metabolism. This emphasizes the need to maintain appropriate GCK activity for metabolic health.

GCK modulates insulin release in response to glucose levels in pancreatic beta cells; in the liver, it helps manage glucose intake and glycogen production. GCK is a key factor in preserving whole-body glucose homeostasis and energy balance because of its dual function.

References:

Abu Aqel Y, Alnesf A, Aigha II, et al. Glucokinase (GCK) in diabetes: from molecular mechanisms to disease pathogenesis. Cell Mol Biol Lett. 2024;29(1):120.
Dai T, Yang Y, Zhang J, et al. GCK exonic mutations induce abnormal biochemical activities and result in GCK-MODY. Front Genet. 2023 Apr 4;14:1120153.

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