Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 3 Carbohydrate Metabolism and Its Diseases
The G-6-P formed as a result of the GK (HK-IV) catalyzed
reaction is central to glucose catabolism. There are
at least five different pathways that G-6-P can follow: free
glucose, glycogenesis, glycolysis, hexose monophosphate,
and glucuronate pathway.
a . Free Glucose
The simplest direction for G-6-P is a reversal of phosphorylation
by a separate enzyme catalyzed reaction in
which G-6-P is hydrolyzed to form free glucose and inorganic
phosphate. This reaction is catalyzed by the enzyme
G-6-Pase:
G-6-Pase
glucose-6-PO4 → glucose P i
This is an irreversible reaction that opposes the previously
described unidirectional GK (HK-IV) reaction.
These two opposing and independently catalyzed enzyme
reactions are the site of metabolic control for glucose
because the balance of these enzyme activities regulates
the net direction of the reaction. Significant amounts of
G-6-Pase are found only in liver and to a lesser extent in the
kidney. This is in accord with the well-known function of
the liver as the principal source of supply of glucose for the
maintenance of blood glucose concentration. The G-6-Pase
activity is generally higher than the GK activity for most
of a 24-hour day except for a few hours after each meal.
This means that for most of the day, the liver is supplying
glucose rather than using glucose.
Muscle G-6-P, however, because of the absence of
G-6-Pase, does not contribute glucose from its glycogen
to blood directly. Muscle G-6-P does, however, contribute
glucose to blood indirectly via the lactate or Cori cycle.
Lactate formed in muscle by glycolysis is transported to the
liver, where it is resynthesized to glucose and its precursors
as outlined in Figure 3-4 .
b . Glycogenesis
This pathway for G-6-Pase leading to the synthesis of
glycogen is discussed in Section IV.C.1.
c . Anaerobic Glycolysis
One of the three oxidative pathways of G-6-P is the classic
anaerobic glycolytic or Embden-Meyerhof pathway
(EMP). The intermediate steps involved in this pathway
of breakdown of G-6-P into two three-carbon compounds
are summarized in Figure 3-5 . A mole of ATP is used to
phosphorylate fructose-6-phosphate (F-6-P) to form fructose-1,6-diphosphate
(F-1,6-P). This phosphorylation reaction
is also irreversible and catalyzed by a specific kinase,
phosphofructokinase (PFK). The opposing unidirectional
reaction is catalyzed by a specific phosphatase, fructose-
1,6-diphosphatase (F-1,6-Pase). These opposing PFK and
FIGURE 3-4 The lactate or Cori cycle. Muscle cells are devoid of
glucose-6-phosphatase, therefore muscle glycogen contributes indirectly
to blood glucose by this pathway.
F-1,6-Pase catalyzed reactions are a second site of metabolic
control regulated by the activities of these two highly
specific enzymes. At this point in the process, starting from
glucose, a total of two high-energy phosphates from ATP
have been donated to form a mole of F-1,6-P.
F-1,6-P is next cleaved to form two three carbon compounds
as shown in Figure 3-5 . The next step is an oxidative
step catalyzed by the enzyme glyceraldehyde-3-phosphate
dehydrogenase (GA-3-PD) with oxidized nicotinamide
adenine dinucleotide (NAD ) as the hydrogen acceptor.
During the process, the molecule is phosphorylated. In
the succeeding steps, the molecule is dephosphorylated
at the points indicated, and a mole of ATP is generated at
each point.
A third site of control of glycolysis is the irreversible
formation of pyruvate catalyzed by the enzyme pyruvate
kinase (PK). In the reverse direction, two enzymatic
reactions operate. Pyruvate carboxylase (PC) first catalyzes
the carboxylation of pyruvate to oxaloacetate (OAA),
and the OAA is then converted to phospho-enol-pyruvate
(PEP) by the enzyme PEP carboxykinase (PEP-CK)
( Figs. 3-5 and 3-8 ).
Thus, the overall conversion of a mole of glucose to 2
moles of pyruvate requires 2 moles of ATP for the initial
phosphorylations and a total of 4 moles of ATP are generated
in the subsequent dephosphorylations. This net gain
of 2 moles of ATP represents the useful energy of anaerobic
glycolysis.
For repeated function of the glycolytic pathway, a supply
of NAD must be available for use in the oxidative
(GA-3-PD) step. Normally in the presence of molecular O 2