Glycogenolysis

 The degradation of stored glycogen in liver and muscle constitutes glycogenolysis.

Control of Glycogen metabolism

Glycogen metabolism is controlled by the enzymes glycogen synthase and glycogen
phosphorylase. Regulation of these enzymes is accomplished by three mechanisms
1 .Allosteric regulation
2. Hormonal regulation
3. lnfluence of calcium.

l. Allosteric regulation of glycogen metabolism: There are certain metabolites that

allosterically regulate the activities of glycogen synthase and glycogen phosphorylase. The
control is carried out in such a way that glycogen synthesis is increased when substrate
availability and energy levels are high. On the other hand, glycogen breakdown is enhanced
when glucose concentration and energy levels are low. In a well-fed state, the availability of
glucose6 –phosphate is high which allosterically activates glycogen synthase for more
glycogen synthesis. On the other hand, glucose 6-phosphate and ATP allosterically inhibit
glycogen phosphorylase. Free glucose in liver also acts as an allosteric inhibitor of glycogen
phosphorylase.
2.Hormonal regulation of glycogen metabolism: The hormones, through a complex series
of reactions, bring about covalent modification, namely phosphorylation and
dephosphorylation of enzyme proteins which, ultimately control glycogen synthesis or its
degradation.
cAMP as second messenger for hormones : The hormones like epinephrine and
norepinephrine and glucagon( in liver) activate adenylate cyclase to increase the production
of cAMP. The enzyme phosphodiesterase breaks down cAMP. The hormone insulin
increases the phosphodiesterase activity in liver and lowers the cAMP levels.
Regulation of glycogen synthesis by cAMP: The glycogenesis is regulated by glycogen
synthase. This enzyme exists in two forms glycogen synthase 'a'-which is not phosphorylated
and most active, and secondly, glycogen synthase 'b' as phosphorylated inactive form.
Glycogen synthase 'a' can be converted to 'b' form (inactive) by phosphorylation. The degree
of phosphorylation is proportional to the inactive state of enzyme. The process of
phosphorylation is catalysed by a cAMP dependent protein kinase. The protein kinase
phosphorylates and inactivates glycogen synthase by converting 'a' form to 'b' form. The
glycogen synthase 'b' can be converted back to synthase' a' by protein phosphatase l.
Regulation of glycogen degradation by cAMP: The hormones like epinephrine and
glucagon bring about glycogenolysis by their action on glycogen phosphorylase through
cAMP. Glycogen phosphorylase exists in two forms, an active 'a' form and inactive form 'b'.
The cAMP-formed due to hormonal stimulus-activates cAMP dependent protein
kinase. This active protein kinase phosphorylates inactive form of glycogen phsophorylase
kinase to active form. The active phosphorylase kinase phosphorylates inactive glycogen
phosphorylase 'b ' to active glycogen phosphorylase 'a' which degrades glycogen. The
enzyme protein phosphatase 1 can dephosphorylate and convert active glycogen
phosphorylase 'a' to inactive 'b' form.

3. Effect of Ca2+ ions on glycogenolysis: When the muscle contracts, Ca2+ ions are
released from the sarcoplasmic reticulum. Ca2+ binds to calmodulin- calcium modulating
protein and directly activates phosphorylase kinase without the involvement of cAMP-
dependent protein kinase. The overall effect of hormones on glycogen metabolism is that an
elevated glucagon or epinephrine level increases glycogen degradation whereas elevated
insulin results in increased glycogen synthesis.

Pentose phosphate pathway:

 The pentose phosphate pathway (also called the phosphogluconate pathway and
the hexose monophosphate shunt) is a metabolic pathway parallel to glycolysis.
 It generates NADPH and pentoses (5-carbon sugars) as well as ribose 5-phosphate,
the last one a precursor for the synthesis of nucleotides.
 There are two distinct phases in the pathway. The first is the oxidative phase, in which
NADPH is generated, and the second is the non-oxidative synthesis of 5-carbon
sugars.
 For most organisms, the pentose phosphate pathway takes place in the cytosol; in
plants, most steps take place in plastids.

Reactions of the pathway:

The sequence of reactions of HMP shunt is divided into two phases-oxidative

and non-oxidative.

1.Oxidative phase :
Glucose 6-phosphate dehydrogenase(C 6PD) is an NADP-dependent enzyme that converts
glucose 6-phosphate to 6-phosphogluconolactone. The latter is then hydrolysed by the
gluconolactone hydrolase to 6-phosphogluconate. The next reaction involving the synthesis
of NADPH is catalysed by 6-phosphogluconate dehydrogenase to produce 3 keto 6-
phosphogluconate which then undergoes decarboxylation to give ribulose 6 -phosphate.

2. Non-oxidative phase:
The non-oxidative reactions are concerned with the interconversion of three, four, five and
seven carbon monosaccharides. Ribulose5 –phosphate is acted upon by an epimerase to
produce xylulose 5-phosphate while ribose5 –phosphate keto isomerase converts ribulose 5 –
phosphate to ribose 5-phosphate. The enzyme transketolase catalyses the transfer of two
carbon moiety from xylulose 5-phosphate to ribose 5-phosphate to give a 3-carbon
glyceraldehyde 3-phosphate and a 7-carbon sedoheptulose 7-phosphate. Transketolase is
dependent on the coenzyme thiamine pyrophosphate (TPP) and Mg2+ ions. Transaldolase
brings about the transfer of a 3-carbon fragment (active dihydroxyacetone) from
sedoheptulose 7-phosphate to glyceraldehydes 3-phosphate to give fructose 6-phosphate and
four carbon erythrose 4 phosphate. Transketolase acts on xylulose 5-phosphate and transfers
a 2-carbon fragment (glyceraldehyde) from it to erythrose 4-phosphate to generate fructose 6-
phosphate and glyceraldehydes 3-phosphate. Fructose 6-phosphate and glyceraldehydes 3-
phosphate can be further catabolized through glycolysis and citric acid cycle. Glucose may
also be synthesized from these two compounds.
The overall reaction may be represented as
6 Glucose6 -phosphate+ 12 NADP+ + 6H2O ----- 6CO2 +'12 NADPH + 12H+ + 5 Glucose
6-phosphate.
Figure: Pentose phosphate pathway
Significance of HMP shunt:

HMP shunt is unique in generating two important products-pentoses and NADPH needed for
the biosynthetic reactions and other functions.

1. Producing NADPH + H+ :
 Hexose MonoPhosphate Shunt producing Biochemical reductant NADPH + H +. This
reductant participating in reductive anabolic pathway. Especially in Fatty acid
Biosynthesis
 NADPH involves in Glutathione Reductase catalysis. This enzyme neutralizes the
superoxide and hydroxyl radicals from hydroxyl peroxide molecules.
 The NADPH is one of the important coenzyme for the microsomal for the liver
microsomal, Cytochrome-P450 Mono-Oxygenase system. This is the major pathway
for the hydroxylation of Aromatic and Aliphatic compounds such as Steroid alcohols
and many drugs.
 In Phagocytosis mechanism NADPH + H+ is very important in Respiratory Burst.
 Ribose-5-Phosphate is the precursor molecule for nucleotide synthesis. The
concentration of Ribose-5-Phosphate is optimized by the enzyme Glucose-6-Phopshate
dehydrogenase in HMP shunt.
2. Producing Ribose-5-Phosphate:
 Hexose MonoPhosphate shunt provides Ribose-5-Phosphate for the Purine biosynthesis
by the level of Ribose-5-Phosphate is regulated by Glucose-6-Phosphodehydrogenase.
3. Producing Glycolytic Intermediate:
 In the Hexose MonoPhosphate Shunt Pathway, few molecules of Glycolytic
intermediates are produced these are directly involves in Glycolysis. The molecules
are Glyceraldehyde-3-Phosphate and Fructose-6-Phosphate.

Glyoxylate pathway:
The glyoxylate cycle is regarded as an anabolic variant of citric acid cycle. Acetyl CoA
produced from fatty acid oxidation condenses with oxaloacetate to give citrate which is then
converted to isocitrate. At this stage, isocitrate bypasses the citric acid cycle and is cleaved by
isocitrate lyase to succinate and glyoxylate. Another molecule of acetyl CoA is now utilized
to combine with glyoxylate to form malate. This reaction is catalysed by malate synthase and
the malate so formed enters citric acid cycle. The glyoxylate cycle is a cyclic pathway that
results in the conversion of two 2-carbon fragments of acetyl CoA to 4-carbon compound,
succinate. The succinate is converted to oxaloacetate and then to glucose involving the
reactions of gluconeogenesis.
Figure: Glyoxylate cycle