296
chapter 15
Carbohydrate Metabolism II: Gluconeogenesis, Glycogen Synthesis and Breakdown, and Alternative Pathways
Chapters 11 and 16). Glucuronic acid is usually not a com-
ponent of glycoproteins or glycolipids.
Other metabolic routes available to UDP-glucuronic
acid are shown in Figure 15-15. Hydrolysis to free glu-
curonic acid and NADPH-dependent reduction together
lead to L-gulonic acid, which spontaneously cyclizes to
L-gulonolactone. In many animals and higher plants, this
can be converted to
2
-ketogulonolactone, a precursor of
ascorbic acid (vitamin C), by gulonolactone oxidase. In
humans and other primates and in guinea pigs, absence
of this enzyme makes ascorbic acid an essential dietary
ingredient (Chapter 38).
Gulonic acid is oxidized and decarboxylated to
L-
xylulose. Entry of this sugar into the pentose phosphate
pathway requires isomerization to D-xylulose. This is
accomplished by reduction (NADPH) to xylitol via
L-
xylulose reductase
and by oxidation to D-xylulose with
reduction of NAD+. D-Xylulose, after conversion of xy-
lulose 5-phosphate, is metabolized in the pentose phos-
phate pathway or converted to oxalate via formation of
xylulose-1-phosphate, glycoaldehyde, and glycolate. In
essential pentosuria
, a clinically benign inborn error of
metabolism, L-xylulose reductase (also known as
NADP-
linked xylitol dehydrogenase
) is abnormal or absent, and
large amounts (1-4 g/day) of L-xylulose appear in the
urine. Because L-xylulose is a reducing sugar, tests for
urinary reducing substances that are intended to detect
glucose may result in an erroneous diagnosis of diabetes
mellitus. A positive test for urinary reducing substances,
especially in the absence of clinical symptoms of diabetes
mellitus, should be verified by a method that is specific for
glucose.
Alimentary pentosuria may follow ingestion of large
quantities of fruit, with L-arabinose and L-xylose occur-
ring in high concentrations in urine. Ribosuria may occur
in some muscular dystrophy patients. In both conditions,
urine is positive for reducing substances.
Fructose and Sorbitol Metabolism
Fructose is a ketohexose found in honey and a wide vari-
ety of fruits and vegetables. Combined with glucose in an
a(
1 ->
2)P
linkage, it forms sucrose (Chapter 9). It makes
up one sixth to one third of the total carbohydrate intake
of most individuals in industrialized nations. Inulin, found
in some plants, is a polymer containing about 40 fruc-
tose residues connected in /
1 ( 2
—>•
1
) linkages with some
/6(2 —>•
6
) branch points. It cannot be hydrolyzed by any
human enzyme and has been used for measurement of
renal clearance.
Sorbitol, a sugar alcohol, is a minor dietary constituent.
It can be synthesized in the body from glucose by NADPH-
dependent aldose reductase (Figure 15-16). It is clinically
Glucose
NADP+- J
Aldose
reductase
NADH + H*-— 'j n
Sorbitol
NAD+H s o rb i.o l
NADH
+
^ - f ehydr0SenaSe
ATP
ADP
Fructose
Fructokinase
Fructose 1-phosphate
l______
Aldolase B
Dihydroxyacetone 3-phosphate
Glyceraldehyde
ATP-
ADP —^
Glyceraldehyde 3-phosphate
Fructose-1,6-
bisphosphate aldolase
Fructose 1,6-bisphosphate
Glycolysis -^-Gluconeogenesis
Pyruvate
Glucose
F I G U R E 1 5 -1 6
Metabolic pathway for sorbitol and fructose. Sorbitol dehydrogenase is
sometimes known as iditol dehydrogenase. Aldolase B is also called
fructose-1-phosphate aldolase, in contrast to fructose-1,6-bisphosphate
aldolase.
important because of its relationship to cataract formation
in diabetic patients. Fructose and sorbitol are catabolized
by a common pathway (Figure 15-16). Fructose transport
and metabolism are insulin-independent; only a few tis-
sues (e.g., liver, kidney, intestinal mucosa, and adipose tis-
sue, but not brain) can metabolize it. Fructose metabolism,
which is much less tightly regulated, is more rapid than
glucose metabolism. The renal threshold for fructose is
very low, and fructose is more readily excreted in urine
than is glucose. Despite these differences, the metabolic
fates of glucose and fructose are closely related because
most fructose is ultimately converted to glucose. Fructose
metabolism (Figure 15-16) starts with phosphorylation
and formation of fructose
- 1
-phosphate, and this reaction is
the rate-limiting step. The
Km
of hexokinase for fructose
is several orders of magnitude higher than that for glucose,
and at the concentrations of glucose found in most tissues,
fructose phosphorylation by hexokinase is competitively
inhibited. In tissues that contain fructokinase, such as liver,
the rate of fructose phosphorylation depends primarily on
fructose concentration, and an increase in fructose concen-
tration depletes intracellular ATR
Essential fructosuria
is caused by absence of hepatic fructokinase activity. The
condition is asymptomatic but, as with pentosuria, may be
misdiagnosed as diabetes mellitus.
The next step in fructose metabolism is catalyzed by al-
dolase B (fructose-1-phosphate aldolase), which cleaves
fructose-
1
-phosphate to the trioses dihydroxyacetone
