Chemistry Reference
In-Depth Information
OPO
3
2-
OH
H
H
H
H
O
O
Glucokinase
HO
H
+
HO
MgATP
2-
MgADP +
+
+
H
HO
H
HO
H
H
OH
OH
H
OH
H
OH
Glucose-6-phosphate
Glucose
Figure 3.1
Glucokinase enzymatic reaction.
glucose homeostasis and initiated a drug discovery program to identify small
molecules to increase its enzymatic activity.
2
Glucokinase is primarily expressed
in pancreatic b-cells and liver. In pancreatic b-cells, GK has a control strength
approaching unity, allowing for a tight coupling of GK enzymatic activity and
pathway changes that lead to glucose-stimulated insulin release. Glucokinase,
also known as hexokinase IV or D, is one of four hexokinase isozymes that
metabolize glucose. It utilizes ATP for the phosphorylation of glucose to glu-
cose-6-phosphate (G-6-P), and plays an important role in regulating glucose-
stimulated insulin release in b-cells, and in hepatic glucose utilization as dis-
cussed below (Figure 3.1).
Matschinsky and Ellerman
3
first proposed the ''gluco-stat'' concept, today
known as the GK glucose-sensor concept,
in which the GK rate sets the
threshold concentration of glucose (
5mM) required to initiate the signaling
cascade leading to insulin release. A key feature of this concept is the enzyme's
low anity (S
0.5
¼
7mM, glucose concentration at half-maximal enzyme
velocity) for glucose and positive cooperativity (nH
¼
1.7). This translates into
a sigmoidal velocity versus [glucose] curve whereby GK is essentially inactive at
low glucose concentrations (i.e. during a fasting period). As glucose levels
approach and exceed its S
0.5
(i.e. during a post-prandial state), GK enzymatic
activity rapidly increases. Thus glucose metabolism is tightly coupled to glucose
levels. Following b-cell GK-mediated phosphorylation of glucose, glycolysis
occurs leading to an increase in the ATP : ADP ratio. This in turn results in the
closing of ATP-sensitive K
1
channels, membrane depolarization, opening of
the voltage-gated Ca
21
channel, and an influx of Ca
21
ions which then triggers
insulin release (Figure 3.2).
Sulfonylureas, which are a popular class of oral antidiabetic drugs, cause
release of insulin via their direct action on ATP-sensitive K
1
channels, but act
independently of plasma glucose levels. This mechanism is uncoupled from
glucose levels and can lead to episodes of hypoglycemia. In contrast, insulin
release via GK activation is coupled to plasma glucose levels and thus should be
safer as it is a natural physiological mechanism. The decreased stress on the b-
cells by coupling insulin release with demand could also lead to improved
preservation of b-cell mass and a decrease in the rate of progression of T2D.
Thus GK plays a critical role in the regulation of insulin secretion and has been
termed a pancreatic b-cell glucose sensor on account of its kinetics which allow
b-cells to change the glucose phosphorylation rate over a range of physiological
glucose concentrations.
B
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