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CHAPTER 2 METABOILISM OF
CARBOHYDRATE
Metabolic pathways of glucose
1. Coversion into Glycogen and degradation
i) Glycogenesis in which the excess glucose is converted into
glycogen as a cellular storage compound.
ii) Glycogenolysis involves the breakdown of glycogen into
glucose, which provides a glucose supply for glucosedependent tissues.
2. Oxidative degradation to CO2
i)Glycolysis is the pathway in which the oxidation metabolism
of glucose molecules forms ATP and pyruvate.
ii) Citric acid cycle in which pyruvate from glycolysis enters
the citric acid cycle or Krebs cycle in aerobic organism or to
lactate or alcohol in anaerobic condition and in anaerobic
organisms.
3. Gluconeogenesis which is involved in the synthesis of glucose
molecules from simple other compounds such as fatty acid or
amino acid.
(I) COVERSION INTO GLYCOGEN AND
DEGRADATION
(i) GLYCOGENESIS
• Glycogenesis is the process of biosynthesis of glycogen
from glucose and occurs mainly in muscle and liver.
• The following steps are involved
1. Formation of glucose 6-phosphate
Glucose is phosphorylated to glucose 6-phosphate, a
reaction that is common to the first reaction in the
pathway of glycolysis from glucose.
This reaction is catalyzed by hexokinase in muscle and
glucokinase in liver.
Hexokinase
Glucose + ATP → Glucose 6-phosphate + ADP
2. Conversion of Glucose 6- phosphate to
glucose 1- phosphate
Glucose 6- phosphate is converted to glucose 1phosphate in a reaction catalyzed by the enzyme
phosphoglucomutase.
Phosphoglucomutase
Glucose 6- phosphate ↔ glucose 1- phosphate
3. Formation of UDPG
Next, glucose 1- phosphate reacts with uridine
triphosphate (UTP) to form the active nucleotide
diphosphate glucose (UDPGIc) (Fig.2.1)
The reaction between glucose 1- phosphate and uridine
triphoaphate is catalyzed by the enzyme UDPGlc
pyrophosphorylase.
UDPGlc pyrophosphorylase
UTP + Glucose 1- phosphate ↔ UDPGlc + PPi
4. Action of glycogen synthase
• By the action of the enzyme glycogen synthase, the C1
of the activated glucose of UDPGlc forms a glycosidic
bond with the C4 of a terminal glucose residue of
glycogen, liberating uridine diphosphate (UDP).
• Glycogen synthase
• UDPGlc + Glycogen primer( n ) → Glycogen(n+1) +
UDP
• A preexisting glycogen molecule, or “glycogen primer”,
must be present to initiate this reaction. Further glucose
residues are attached in the 1-4 position to make a short
chain that is acted upon by glycogen synthase.
• The addition of a glucose residue to a preexisting
glycogen chain, or “primer,” occurs at the nonreducing,
outer end of the molecule so that the “branches” of the
glycogen “tree” become elongated as successive a 1-4
linkages are formed.
5. Action of Branching enzyme
• When the chain has been lengthened to a minimum of
11 glucose residues, a second enzyme, the branching
enzyme (amylo[α 1-4 ] [α 1-6] -transglucosidase),
transfers a part of the α 1-4 chain (minimum length 6
glucose residues) to a neighboring chain to form a α 1-6
linkage, thus establishing a branch point in the molecule.
The branches grow by further additions of a 1-4 glucosy1
units and further branching (Fig.2.2). As the number of
nonreducing terminal residues increases, the total
number of reactive sites in the molecule increases,
speeding up both glycogenesis and glycogenolysis.
•
• (ii) GLYCOGENOLYSIS
•
Glycogenolysis is the breakdown of glycogen into glucose.
It is not the reverse of glycogenesis but is a separate pathway.
Degradation involves a debranching mechanism.
• 1.Action of phosphorylase
• First step is catalyzed by phosphorylase
•
Phosphorylase
•
(C6)n + Pi ↔ (C6)n -1 + Glucose 1- phosphate
•
glycogen
glycogen
•
This enzyme is specific for the phosphorlytic breaking
(phosphorolysis; of hydrolysis) or the 1-4 linkages of glycogen to
yield glucose 1-phosphate. The terminal glucosyl residues from the
outermost chains of the glycogen molecule are removed
sequentially until approximately four glucose residues remain on
either side of a 1-6 branch.
• 2. Action of transferase
• Another enzyme (a -[1-4 ] a -[1-4 ] glucan
transferase) transfers a trisaccharide unit from
one branch to the other, exposing the 1-6 branch
point. The hydrolytic splitting of the branch,
further action by phosphorylase can proceed.
The combined action of phosphorylase and
these other enzymes leads to the complete
breakdown of glycogen (Fig.2.3).
• The reaction catalyzed by
phosphoglucomutase is reversible, so that
glucose 6-phophate can be formed from
glucose 1- phosphate. In liver and kidney,
glucose-6- phosphatase, from glucose 6phosphate, enabling glucose to diffuse
from the cell into the blood. This is the final
step in hepatic glycogenolysis, which is
reflected by an increase in the blood
glucose.
• Regulation of glycogenesis and
glycogenolysis: Cyclic AMP (Fig.2.4.)
integrates the regulation of glycogenolysis and
glycogenesis. The principal enzymes controlling
glycogen metabolism glycogen phosphorylase
and glycogen synthase are regulated by a
complex series of reactions involving both
allosteric mechanisms and covalent
modifications due to reversible phosphorylation
and dephosphorylation of enzyme protein.
• Many covalent modifications are due to the action of cAMP (3’,5’ cyclic adenylic acid; cyclic AMP). cAMP is the intracellular
intermediate compound or second messenger through which many
hormones act. It is formed from ATP by an enzyme,
adenyly1cyclase, occurring in the inner surface of cell membranes.
Adenyly1 cyclase in activated by hormones such as epinephine and
norepinephrine acting through β - adrenergic receptors on the cell
membrane and additionally in liver by glucagon acting through an
independent glucagon receptor.
• cAMP is destroyed by a phosphodiesterase, and it is the activity of
this enzyme that maintains the normally low level of cAMP. Insulin
has been reported to increase its activity in liver, thereby lowering
the concentration of cAMP.
•
• Phosphorylase differs between liver and muscle.
In liver the enzyme exists in both an active and
an inactive form. Active phosphorylase
(phosphorylase a) has one of its serine
hydroxy1 groups phosphorylated in an ester
linkage. By the action of a specific phosphatase,
protein phosphatase-1, the enzyme is in
activated to phosphorylase b in a reaction that
involves hydrolytic removal of the phosphate
from the serine residue. Reactivation requires
rephosphorylation with ATP and a specific
enzyme, phosphorylase kinase