298
chapter 15
Carbohydrate Metabolism II: Gluconeogenesis, Glycogen Synthesis and Breakdown, and Alternative Pathways
G a la c to s e
A T P -
G alacto k in ase*
Mg*,
ADP-^
G a la c to s e 1-p h o sp h a te
—U D P -g lu co se
G lu c o se 1-p h o sp h a te
P h o sp h o -
gluco-
m u ta se
G lu c o se
6
-p h o sp h a te
G alacto se-1 -p h o s p h a te
uridylyitransferase*
G lu c o se
U D P
^ 2
H20
R-^
G lu c o se
G lu co se-
6
-p h o s-
p h a ta s e
U D P -g a a c to s e Lacto s S S y n th ase* L acto se
U ridine
d ip h o sp h o g alac to se-
4 -e p im e ra se (NAD+)
U D P -g lu co se
G ly co g en sy n th esis
G ly co g en
| G ly co g en b reak d o w n
l
G lu c o se
F I G U R E 1 5 -1 7
Metabolic pathway of galactose. ‘Inherited defects that lead to
galactosemia.
reversible, converts UDP-glucose to UDP-galactose for
the synthesis of lactose, glycoproteins, and glycolipids.
The epimerase requires NAD+ and is inhibited by NADH.
It may also be regulated by the concentrations of UDP-
glucose and other uridine nucleotides. Because of this
epimerase, preformed galactose is not normally required
in the diet. However, infants with deficiency of epimerase
in hepatic and extrahepatic tissues require small quantities
of dietary galactose for normal development and growth.
An isolated deficiency of epimerase in erythrocytes, which
is clinically benign, has been described.
Genetically determined deficiencies of galactokinase
and galactose 1-phosphate uridylyitransferase cause clin-
ically significant galactosemia. Galactokinase deficiency
is a rare, autosomal recessive trait in which high concen-
trations of galactose are found in the blood, particularly
after a meal that includes lactose-rich foods, such as milk
and nonfermented milk products.
Patients frequently
develop cataracts before 1 year of age because of accumu-
lation of galactitol in the lens. Galactose diffuses freely
into the lens, where it is reduced by aldose reductase,
the enzyme that converts glucose to sorbitol. Galactitol
may cause lens opacity by the same mechanisms as does
sorbitol. Galactose in the urine is detected by nonspe-
cific tests for reducing substances, as are fructose and
glucose.
Deficiency of the transferase causes a more severe form
of galactosemia. Symptoms include cataracts, vomiting,
diarrhea, jaundice, hepatosplenomegaly, failure to thrive,
and mental retardation. If galactosuria is severe, nephro-
toxicity with albuminuria and aminoaciduria may occur.
The more severe clinical course may be due to accumu-
lation of galactose-1-phosphate in cells. Measurement of
transferase activity in red blood cells is the definitive test
for this disorder.
In about 70% of transferase alleles in the white popu-
lation, the DNA in cells of transferase-deficient patients
possesses an A-to-G transition that leads to the Q186R
mutation.
Both forms of galactosemia are treated by rigorous ex-
clusion of galactose from the diet. In pregnancies for which
the family history suggests that the infant may be af-
fected, the best outcomes have been reported when the
mother was maintained on a galactose-free diet during
gestation.
Condensation of glucose with UDP-galactose, cat-
alyzed by lactose synthase (Figure 15-17), forms lactose,
the only disaccharide made in large quantities by mam-
mals. This enzyme is a complex of galactosyltransférase, a
membrane-bound enzyme that participates in glycoprotein
synthesis (Chapter 16), and a-lactalbumin, a soluble pro-
tein secreted by the lactating mammary gland. Binding of
a-lactalbumin to galactosyltransférase changes the
Km
of
the transferase for glucose from 1-2 mol/L to 10-3 mol/L.
Synthesis of a-lactalbumin by the mammary gland is ini-
tiated late in pregnancy or at parturition by the sudden
decrease in progesterone level that occurs at that time.
Prolactin promotes the rate of synthesis of galactosyltrans-
férase and a-lactalbumin.
Metabolism of Amino Sugars
In amino sugars, one hydroxyl group, usually at C
2
, is
replaced by an amino group. Amino sugars are important
constituents of many complex polysaccharides, including
glycoproteins and glycolipids (Chapters 10 and 16), and
of glycosaminoglycans (Chapters 11 and 16).
De novo
synthesis of amino sugars starts from glucose-
6-phosphate, but salvage pathways can also operate. Some
reactions involved are shown in Figure 15-18. Incorpora-
tion of amino sugars into biological macromolecules is
described in Chapter 16.
Pentose Phosphate Pathway
The series of cytoplasmic reactions known as the pentose
phosphate pathway is also called the hexose monophos-
phate (HMP) shunt (or cycle) or the phosphogluconate
pathway. The qualitative interconversions that take place
