PENTOSE PHOSPHATE PATHWAY AND OTHER PATHWAYS

Learning Objectives

3. Identify the uronic acid pathway and its importance for synthesis of glucunoric acid for conjugation
reactions and (in animals for which it is not a vitamin) vitamin C.

 The uronic acid pathway is an alternative pathway for the oxidation of glucose that does not
provide a means of producing ATP, but is utilized for the generation of the activated form of
glucuronate, a UDP-glucunorate which is mainly used for detoxification of foreign chemicals and
for the synthesis of Mucopolysaccharides. This pathway also produces Ascorbic acid in certain
animals.

Steps of Uronic acid pathway

i. Formation of UDP glucose

Glucose 6-phosphate is isomerized to glucose 1-phosphate in a reaction catalyzed by
Phosphoglucomutase, which then reacts with uridine triphosphate (UTP) to form uridine
diphosphate glucose (UDPGIc) in a reaction catalyzed by UDPGIc Pyro phosphorylase, as
occurs in glycogen synthesis.

ii. Formation of D-Glucuronic acid

UDPGIc is oxidized at carbon 6 by NAD =-dependent UDPGIc dehydrogenase in a two-step
reaction to yield UDP-glucuronate.

UDP-glucuronate is the source of glucuronate for reactions involving its incorporation into
proteoglycans or for reactions of substrates such as steroid hormones, bilirubin, and a number of
drugs that are excreted in urine or bile as glucoronide conjugates. UDP-G is hydrolyzed to form D-
glucuronic acid.

iii. Formation of L-Gulonic acid

Glucuronate is first reduced by the NADPH dependent enzyme.
Glucuronate reductase to form L-gulonate.

iv. Fate of L-Gulonate in human beings

The Uronic acid pathway is connected to Pentose phosphate pathway through L-gulonate,
since the latter can be converted to an intermediate of the Pentose phosphate pathway.

v. Fate of L-Xylulose
L-Xylulose is converted to the D isomer by an NADPH-dependent reduction to Xylitol,
catalyzed by Xylitol dehydrogenase enzymes. The deficiency of Xylitol dehydrogenase causes
Essential pentosuria, a clinical state of excess excretion of L-Xylulose in urine.

 In humans and other primates, as well as guinea pigs, bats, and some birds and fishes, ascorbic
acid cannot be synthesized because of the absence of L-gluconolactone oxidase. It is due to a
genetic deficiency of this enzyme. It appears that the capacity to synthesize ascorbic acid was lost
in these species due to a mutation which was not lethal. These species require vitamin C in the
diet. Thus a single enzyme defect in the Uronic acid pathway is responsible for the inefficiency to
synthesize ascorbic acid in primates.
4. Describe Fructose Metabolism

 Fructose, either free or derived from the digestion of sucrose, is phosphorylated to fructose-1-
phosphate (F1P) by fructokinases (KHK-A or KHK-C). Aldolase B hydrolyzes F1P to
glyceraldehyde and dihydroxyacetone phosphate (DHAP). The glyceraldehyde is metabolized with
the predominantl pathway involving phosphorylation by triokinase (also called glyceraldehyde
kinase) allowing both DHAP and glyceraldehyde from fructose to be utilized for ATP production in
the glycolytic pathway.

4.1 Describe and explain the consequences of large intakes of fructose

− Consumption of fructose has been shown to be highly correlated with the development
of diabetes, obesity and the metabolic syndrome. Consumption of soft drinks (high in HFCS) is
associated with an increased risk for obesity in adolescents and for type 2 diabetes in young and
middle-aged women. Excess fruit juice (also rich in fructose) is associated with the development of
obesity in children. One distinction between fructose and glucose metabolism is that the
metabolism of fructose results in increases in serum uric acid concentration. Elevated serum uric
acid is a good predictor for the development of obesity and hypertension.

5. Identify the metabolism of galactose and its physiological significance

Step 1 Formation of galactose-1-P - Galactokinase catalyses the phophorylation of galactose,

using ATP as phosphate donor

Step 2 Epimerization of galactose-1-phosphate to Glucose 1-P (G1P) requires the transfer of

UDP from uridine diphosphoglucose (UDP-glucose) catalyzed by galactose-1-phosphate uridyl
transferase. This generates UDP-galactose and G1P.

Step 3 Epimerization of UDP galactose to UDP Glucose. The UDP-galactose is epimerized

to UDP-glucose by UDP-galactose-4 epimerase. The reaction involves oxidation, then reduction, at
carbon 4, with NAD= as coenzyme.

 Deficiencies in galactose pathway enzymes produce a disease called galactosemia, since they

lead to an elevation in blood galactose concentration.
 Classic galactosemia results from a deficiency in Gal1P uridyl-transferase. It is characterized by an
accumulation of both galactose and Gal1P in blood and tissues. Gal1P is cytotoxic and produces
liver and neural damage. Galactose is also converted to galactitol by aldose reductase.
Accumulation of galactitol in the lens causes osmotic and oxidative stress, leading to cataracts as
a result of denaturation and precipitation of lens crystallin (see Fig. 9-6).