SECTION 13.1
Glycolysis
229
Plasma Glucose Concentration
F IG U R E 1 3 -2
The role of tissue-specific glucokinases of liver and pancreatic
ß
cells.
During the periods of abundant supply of glucose (e.g., postprandial
conditions), the plasma levels of glucose are increased. This induces
glucokinase expression in pancreatic islet
ß
cells with eventual insulin
secretion. In the hepatocytes, insulin induces the glucokinase expression
with accompanying increased metabolism. Insulin also enhances glucose
utilization by recruiting glucose transporters, GLUT-4 in insulin-sensitive
tissues, f = Increased; © = positive effect.
channels. The increased cytosolic Ca2+ triggers the secre-
tion of insulin (Chapter 22).
Tissue-specific glucokinases expressed in liver and pan-
creatic islet /3 cells are differentially regulated. The glu-
cokinase gene consists of two different transcription con-
trol regions. Other examples of genes that contain different
transcription control regions (promoters) yet produce
mRNAs that code for identical proteins, are a-amylase
and
a i-antitrypsin
genes.
In
the
hepatocytes,
in-
sulin
promotes
glucokinase
expression,
whereas
in
/3 cells insulin has no effect but glucose promotes
enzyme expression. In the hepatocytes, cAMP (and
thus glucagon) and insulin have opposing effects on
the expression of glucokinase (Chapter 22). Tissue-
specific
glucose
transporters
and
glucokinases
play
critical roles
in glucose homeostasis
(Figure
13-2).
Mutations that alter these proteins may lead to inherited
forms of diabetes mellitus (Chapter 22).
Phosphorylation of Fructose-6-Phosphate to
Fructose-1,6-Bisphosphate
This second phosphorylation reaction is catalyzed by
6
-phosphofructokinase (PFK-1).
D-Fructose-
6
-phosphate
2
+ ATP
4
Mg2+
D-fructose-l,6-bisphosphate4
+ ADP3+ + H+
The reaction is essentially irreversible under physiolog-
ical conditions and is a major regulatory step of gly-
colysis. PFK-1 is an inducible, highly regulated, al-
losteric enzyme. In its active form, muscle PFK-1 is
a homotetramer (M.W. 320,000) that requires K+ or
N H j, the latter of which lowers
Km
for both sub-
strates. When adenosine triphosphate (ATP) levels are
low during very active muscle contraction, PFK activ-
ity is modulated positively despite low concentration
of fructose-
6
-phosphate. Allosteric activators of muscle
PFK-1 include adenosine monophosphate (AMP), adeno-
sine diphosphate (ADP), fructose-
6
-phosphate, and inor-
ganic phosphate (P;); inactivators are citrate, fatty acids,
and ATP.
The most potent regulator of liver PFK-1 is fructose-
2
,
6
-bisphosphate,
which
relieves
the
inhibition
of
PFK-1
by ATP and lowers the
Km
for fructose-
6
-
phosphate. Fructose-2,
6
-bisphosphate is a potent inhibitor
of fructose-
1
,
6
-bisphosphatase (which is important in
gluconeogenesis) and thus ensures the continuation of
glycolysis. Metabolism of fructose-2,
6
-bisphosphate, its
role as activator of PFK-1 and inhibitor of fructose-1,6-
bisphosphatase, and its allosteric and hormonal regulation
are discussed in Chapter 15.
Cleavage of Fructose-1,6-Bisphosphate into
Two Triose Phosphates
In this reversible reaction, aldolase (or fructose-1,6-
bisphosphate aldolase) cleaves fructose-
1
,
6
-bisphosphate
into two isomers:
D-Fructose-1,
6
-bisphosphate4- ^ D-Glyceraldehyde
3-phosphate
2
+ dihydroxyacetone phosphate2-
Isomerization of Glucose-6-Phosphate to
Fructose-6-Phosphate
This freely reversible reaction requires Mg2+ and is spe-
cific for glucose-
6
-phosphate and fructose-
6
-phosphate.
It is catalyzed by glucose-phosphate isomerase.
a-D-glucose-6-phosphate — a-D-fructose-6-phosphate
Isomerization of Dihydroxyacetone Phosphate to
Glyceraldehyde 3-Phosphate
In this reversible reaction, triose-phosphate isomerase
converts dihydroxyacetone phosphate to D-glyceralde-
hyde 3-phosphate, which is the substrate for the next reac-
tion. Thus, the net effect of the aldolase reaction is to yield
