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

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Chapter | 3 Carbohydrate Metabolism and Its Diseases
The initial unidirectional phosphorylation reaction permits
the accumulation of glucose in the liver cells because
phosphorylated sugars do not pass freely into and out of
the cell in contrast to the readily transported free sugars.
The glucose-6-phosphate (G-6-P) accumulated in the cell
next undergoes a mutation in which the phosphate group
is transferred to the C-1 position of the glucose molecule.
This reaction is catalyzed by the enzyme, phosphoglucomutase
(PGM) and involves glucose-1–6-diphosphate as
an intermediate:
gluocse-6-P
→ glucose-1-P (II)
Glycogen is synthesized from this glucose-1-phosphate
(G-1-P) through a series of reactions involving the formation
of uridine derivatives. Uridine-di-phosphoglucose (UDP-G)
is synthesized by the transfer of glucose from G-1-P to
uridine triphosphate (UTP). This reaction is catalyzed by
the enzyme UDP-G-pyrophosphorylase (UDP-G-PPase):
UTP G-1-P → UDP-G PP (III)
In the presence of a polysaccharide primer and the
enzyme glycogen synthase (glucosyl transferase), the glucose
moiety of UDP-G is linked to the polysaccharide
chain by an α -1–4 link:
glycogen
UDP-G (glucose 14 – ) n → (glucose1–
4) n + 1
UDP(IV)
synthase
Through repeated transfers of glucose, the polysaccharide
chain is lengthened. When the chain length of the
polysaccharide reaches a critical level between 11 and 16
glucosyl units, the brancher enzyme, α -glucan glycosyl 4:6
transferase, transfers the terminal 7 residue portion from an
α -1–4 linkage to an α -1–6 linkage. The newly established
1–6 linkage thus becomes a branch point in the expanding
glycogen molecule. The remaining stub can again be lengthened
by the action of glycogen synthase. Approximately 7%
of the glucose units of the glycogen molecule are involved
in these branch points.
2 . Glycogenolysis
The breakdown of liver glycogen to glucose (glycogenolysis)
takes place via a separate pathway. The key initiating
and regulating factor in glycogenolysis is the action
of epinephrine on liver and muscle glycogen and of glucagon
on liver glycogen only. The mechanism of action
of glucagon and epinephrine is through a series of reactions
that culminate in the phosphorolytic cleavage of the
1–4 glucosyl links of glycogen. In the liver cell, glucagon
and epinephrine stimulate the enzyme adenylate cyclase to
form 3 –5 cyclic adenosine monophosphate (cAMP) from
ATP. cAMP in turn activates a protein kinase, which in its
turn activates liver phosphorylase (LP), the phosphorolytic
enzyme. As with many enzymes, LP is present in an inactive
form, dephospho-liver phosphorylase (dLP), which is
converted to its active form, LP ( Cherrington and Exton,
1976 ) by the protein kinase, phosphorylase kinase.
The action of the LP is to cleave the 1–4 glucosyl links
of glycogen by the addition of orthophosphate in a manner
analogous to a hydrolytic cleavage with water, hence the
analogous term “ phosphorolysis. ” Phosphate is added to
the C-1 position of the glucose moiety while H is added
to the C-4 position of the other.
cAMP is also a key regulating factor in cellular processes
in addition to LP activation. It is required for the
conversio n of inactive muscle phosphorylase b to active
muscle phosphorylase a, again via phosphorylase b kinase.
The actions of other hormones known to be mediated by
activating adenylate cyclase and cAMP include ACTH,
LH, TSH, MSH, T3, and insulin. From these findings, a
general concept of hormone action has evolved in which
the hormone elaborated by the endocrine organ is described
as the first messenger and cAMP within the target cell is
the second messenger.
Glucagon acts only on liver glycogen whereas epinephrine
acts on both liver and muscle glycogen. In liver, glucagon
promotes the formation and release of glucose by
increasing glycogenolysis and decreasing glycogenesis. In
liver, the hydrolysis of G-6-P is catalyzed by the enzyme
glucose-6-phosphatase (G-6-Pase) to release free glucose,
thus promoting hyperglycemia. Additionally, glucagon promotes
hyperglycemia by stimulation of hepatic gluconeogenesis
and thus glucagon is a potent hyperglycemic factor.
With muscle glycogen, however, because the enzyme G-6-
Pase is absent from muscle, glycogen breakdown in muscle
results in the production and release of pyruvate and lactate
rather than glucose. Mainly lactate and some pyruvate are
transported to the liver where glucose is resynthesized via
reverse glycolysis (Cori cycle; Section IV.D).
The continued action of LP on the 1–4 linkages results
in the sequential release of glucose-1-P (G-1-P) units until
a branch point in the glycogen molecule is reached. The
residue is a limit dextrin. The debrancher enzyme, amylo-
1-6-glucosidase, then cleaves the 1–6 linkage, releasing
free glucose. The remaining 1–4 linked chain of the molecule
is again open to attack by LP until another limit dextrin
is formed. Thus, by the combined action of LP and the
debrancher enzyme, the glycogen molecule is successively
reduced to G-1-P and free glucose units.
G-1-P is converted to G-6-P by the reversible reaction
catalyzed by phosphoglucomutase (PGM, Section IV.C.1,
Reaction II). The G-6-P is then irreversibly cleaved to free
glucose and phosphate by the enzyme G-6-Pase, which is
found in liver and kidney. The free glucose formed can,
unlike its phosphorylated intermediates, be transported