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chapter 13
Carbohydrate Metabolism I: Glycolysis and TCA Cycle
TABLE 13-1
P ro p erties o f H u m an G lu co se T ran sporters (G L U T )
Transporters
Major Tissue Distribution
Properties
GLUT 1
Brain, microvessels, red blood cells, placenta,
kidney, and many other cells
Low Km (about ImM), ubiquitous basal
transporter
GLUT 2
Liver, pancreatic /3—cell, small intestine
High Km (15-20mM)
GLUT 3
Brain, placenta, fetal muscle
Low Km, provide glucose for tissue cells
metabolically dependent on glucose
GLUT 4
Skeletal and heart muscle, fat tissue (adipocytes)
Km (5mM), insulin responsive transporter
GLUT 5
Small intestine, testes
Exhibits high affinity for fructose
(Table 13-1). The tranporters combine with glucose and
facilitate its transport across the intervening membrane for
entry into the cells. The GLUT has features characteris-
tic of Michaelis-Menten kinetics, namely, bidirectional-
ity and competitive inhibition. GLUT proteins belong to a
family of homologous proteins coded by multiple genes.
They vary from 492-524 amino acids and share 39-65%
identity among primary sequences. All GLUT proteins are
single-polypeptide chains and contain
1 2
transmembrane
a-helical domains with both amino and carboxytermini
extending into the cytoplasm.
Insulin-stimulated glucose uptake in muscle and adi-
pose tissue cells is mediated by GLUT4. Insulin’s role in
recruiting GLUT4 proteins from intracellular vessels to
the plasma membrane consists of trafficking through mul-
tiple intracellular membrane compartments (Chapter 22).
Defects in GLUT4 can result in insulin resistance. GLUT5
is located both at the luminal and basolateral sides of the
intestinal epithelial cells. At the luminal side, it functions
in tandem with Na+ glucose symporter and at the baso-
lateral site it is involved in the transport of glucose from
the absorptive epithelial cells into portal blood circula-
tion.
G L U T 2
is located in the liver and pancreatic
/3
-cell
membranes. It has a high
Km
for glucose and, therefore,
the entry of glucose is proportional to blood glucose lev-
els. In the liver, glucose can be stored as glycogen or
converted to lipids when the plasma glucose levels are
high (
h yp erg lycem ia
), and during low levels of plasma
glucose (
h y p o g ly c e m ia
) the liver becomes a provider of
glucose to extrahepatic tissues by glycogenolysis, gluco-
neogenesis, or both (Chapter 15). In pancreatic
f
cells,
plasma membrane GLUT2 participates in insulin secretion
(Chapter 22). GLUT1 and 3 are present in many cell mem-
branes and are basal transporters of glucose at a constant
rate into tissues which are metabolically dependent on glu-
cose (e.g., brain and red blood cells). These transporters
have lower
Km
for glucose than GLUT2 and, therefore,
transport glucose preferentially.
The importance or GLUT1 in brain metabolism is
illustrated in a report of two infants with a syndrome of
poorly controlled seizures and delayed development and
who have a genetic defect in GLUT1 protein. Glucose is
an essential fuel for the brain and is transported by GLUT1
across the plasma membranes of the brain endothelial
cells of the blood-brain barrier system. In these patients
despite normal blood glucose levels, low levels of glucose
in cerebrospinal fluid (CSF)
(h yp o g lyco rrh a ch ia )
as well
as low levels of CSF lactate were observed. Since GLUT1
is present in both red blood cells and brain endothelial
cells, the more accessible GLUT1 in red blood cells is
used in clinical studies of disorders of brain glucose
transport. Two patients with a primary defect of glucose
transport into the brain were treated with a ketogenic diet.
The metabolism of ketogenic substrates does not depend
on the glucose transporter and thus can provide a large
fraction of the brain’s energy requirement.
Reactions of Glycolysis
The overall pathway is shown in Figure 13-1, and some
properties of these reactions and the enzymes involved
are listed in Table 13-2. Glycolytic enzymes can be clas-
sified into six groups according to the type of reaction cat-
alyzed: kinase, mutase, dehydrogenase, cleaving enzyme,
isomerase, and enolase.
P h o sp h o ryla tio n o f G lu co se
Glucose is phosphorylated by hexokinase (in extrahep-
atic tissues) or glucokinase (in the liver).
Mg2+
a-D-Glucose + ATP
4
— ►
a-D-glucose —
6
-phosphate2_ + ADP3~ + H+
The Mg2+ is complexed with ATP4- and is present
as Mg ATP
2
\ This reaction, essentially an irreversible
