3. Definition: Synthesis of glucose from non-
carbohydrate compounds is called
“gluconeogenesis”.
Essential for maintaining blood glucose.
Site: mitochondrial and cytosolic fraction.
Mainly occurs in liver(90%) & kidney(10%).
Supply glucose after liver glycogen is depleted.
Gluconeogenesis
5. Comparison of Glycolysis and
Gluconeogenesis
Not a simple reversal of glycolysis.
In gluconeogenesis, key enzymes bypass
irreversible reactions of glycolysis.
Key enzymes:
1. Pyruvate carboxylase
2. Phosphoenolpyruvate carboxykinase
3. Fructose-1, 6-bisphosphatase
4. Glucose-6-phosphatase
6. Gluconeogenic precursors are molecules that can
give rise to a net synthesis of glucose.
Includes all the intermediates of glycolysis and the
citric acid cycle.
Major precursor is pyruvate.
Glycerol—hydrolysis of triacylglycerols in adipose
tissue
Lactate—exercising skeletal muscle and RBCs
Glucogenic amino acids—hydrolysis of tissue
proteins
Substrates for Gluconeogenesis
7. Requires biotin as coenzyme.
Occurs in mitochondria of liver and kidney cells.
Provides OAA for gluconeogenesis and the TCA
cycle (replenish).
Bypass1: Carboxylation of Pyruvate
Biotin
Allosterically activated
by acetyl CoA; ADP
inhibits it.
8. Biotin(Vitamin B7) is
coenzyme in many
carboxylases.
It functions as a CO2
carrier by acquiring a
carboxyl group.
Biotin
9. No transport for OAA to across the inner mitochondrial
membrane.
OAA must be reduced to malate which can be transported.
In cytosol, malate is reoxidized to OAA for further reactions.
Transport of OAA to Cytosol
Malate Dehydrogenase(MD)
11. Decarboxylation and
phosphorylation.
In cytosol (and
mitochondria).
Mg2+- dependent reaction
requires GTP asthe
phosphoryl groupdonor.
Bypass1: Decarboxylation of OAA
12. Important regulatory step.
Bypass2: Dephosphorylation
ATP activates it; AMP,
fructose 2,6-bisphosphate
inhibit it.
Fructose 2,6-bisphophate, an allosteric
effector whose cont is influenced by
insulin/glucagon.
13. Liver and kidney are the only organs to release
glucose from G6P.
Occurs in lumen of the endoplasmic reticulum.
Bypass3: Dephosphorylation
Pi
H2O
Glucose 6 phosphate, acetyl
CoA activate it; glucose
inhibits it.
14. For per molecule of
glucose synthesis:
Requires 6ATP;
2NADH.
4 ATP needed to
overcome the barrier
of production of 2 PEP.
Energetics
15. Substrate availability
Acetyl CoA: diverts pyruvate
away from oxidation and towards
gluconeogenesis.
Hormone
Regulation of Gluconeogenesis
Kinase
(active)
PFK-2
16. Gluconeogenesis and Glycolysis
are reciprocally regulated .
When glycolysis is on,
gluconeogenesis is turned off
especially in the fed state,
whereas under starvation,
gluconeogenesis is fully on and
glycolysis is off.
Both the cycles are never active
at the same pace at the same
time.
Reciprocal Regulation of Gluconeogenesis
and Glycolysis in the Liver
17. Entry of Glycerol
It happens in starvation where fat becomes the
primary fuel.
Fat stored in adipose tissue is mobilized to fatty
acids and glycerol.
Substrates of Gluconeogenesis
19. Entry of Propionate
Propionate arises from
the beta - oxidation of
fatty acids and some
amino acids.
Major precursor in
ruminants, relatively
minor in human.
20. In active skeletal muscle the rate of glycolysis
exceeds the rate of oxidative metabolism which
leads to anaerobic glycolysis (lactate) in skeletal
muscle.
Lactate can be converted to pyruvate in liver.
Entry of Lactate
21. Lactate is released from muscle to blood and travels to the
liver for conversion to pyruvate, ultimately to glucose.
Glucose is then returned to the blood for muscle as an
energy source-- Cori cycle.
Lactate is efficiently reutilized by the body by Cori cycle.
It counteracts lactic acidosis.
Cori Cycle
22. Gluconeogenesis meets the needs of the body for glucose
when sufficient carbohydrate is not available from the diet or
glycogen reserves --- essential for the survival.
Regulate blood glucose level to keep it in a narrow range.
Brain, erythrocytes, testes & kidney medulla are dependent
on glucose for continuous supply ofenergy.
Glucose is the only source to skeletal muscle in anaerobic
conditions.
Effectively prevent the accumulation of certain metabolites in
blood. E.g. lactate, glycerol, propionate etc.
Biomedical Importance
23. 53
Summary Chart : Regulation
Enzyme Effect of
substrate
concentration
Allosteric Induction/ Clinical
modification/ Repression
Significance
Feed back
Inhibition
Pyruvate
carboxylase
Inhibited by high
carbohydrate diet
Stimulated during
fasting
Activator-Acetyl Induced by Activity
CoA Glucocorticoids, increases in
glucagon, Diabetes
Inhibitor epinephrine Mellitus
ADP Repressed by
Insulin
Fructose 1,6
bisphosphata
se
Inhibited by high
carbohydrate diet
Stimulated during
fasting
Activator-Citrate Induced by Activity
Glucocorticoids, increases in
Inhibitor glucagon, Diabetes AMP,
Fr 2,6 epinephrine Mellitus
bisphosphate Repressed by
Insulin
25. Glucose is energy source for brain, RBC, and
exercising muscle.
Blood glucose can be obtained from three primary
sources: the diet, degradation of glycogen, and
gluconeogenesis.
Glycogen, the storage form of glucose can
undergo metabolism rapidly comparing to
gluconeogenesis.
Polymer held by glycosidic linkages, stored as
granules in cytoplasm.
Glycogen Metabolism
26. Glycogen in skeletal muscle can yield ATP.
Glycogen in liver is to maintain the blood glucose
cont, particularly during the early stages of a
fast.(10–18 hrs)
Structure of glycogen: α(1→4) linkage in linear
chain, branch containing an α(1→6) linkage on
average of eight to ten glucosyl residues.
Glycogen Metabolism
27. Synthesis of glycogen
It occurs immediately after meal.
In the cytosol.
Requires energy supplied by ATP (for the
phosphorylation of glucose) and uridine
triphosphate (UTP).
α-D-glucose is source for glycogenesis.
Glycogenesis
29. Glycogen synthase makes α(1→4) linkages, but it
can only elongate already existing chains of
glucose.
It requires a primer:
A fragment of glycogen
Glycogenin (protein)
by providing the site to get attach to the first glucose
residue.(catalyzed by itself)
O Glycogenin stays associated with and forms the
core of a glycogen granule.
Initiation
31. Branches (eight residues) make glycogen highly
branched, tree-like and more soluble.
Branches also create more terminal residues to
increase the rate of glycogen synthesis and
degradation.
Branching enzyme: amylo-α(1→4)→α(1→6)-
transglucosidase
Formation of Branches
32.
33. Degradation of glycogen
Not a reversal of glycogenesis.
Require a separate set of enzymes.
Occurs in the cytosol.
Glycogenolysis
34. Glycogen phosphorylase cleaves the α(1→4)
glycosidic bonds, producing glucose 1-phosphate
until four glucosyl units remain on each chain
before a branch point.
Pyridoxal phosphate(PLP) as coenzyme.
Shortening of Chains
Inhibited by G6P,
ATP; activated by
Ca2+
In liver inhibited by glucose; in
muscle activated by AMP
35. Debranching enzyme: bifunctional
Transfers the outer three of the four glucosyl
residues
Break an α(1→6) linkage at branch(release
glucose)
Removal of Branches
36. Glucose 1-phosphate is converted to G6P
by phosphoglucomutase.
In liver, gluconeogenesis to glucose
In muscle, anaerobic glycolysis to ATP
Removal of Branches
Glucose1-P
37.
38. A small amount is continuously degraded(1%–3%)
α(1→4)-glucosidase (acid maltase)
The purpose is unknown.
Deficiency: accumulation of glycogen in vacuoles in
the lysosomes
Glycogen storage disease (GSD)
Type II: Pompe disease
The only GSD that is a lysosomal storage disease.
Lysosomal Degradation
39. Glycogenesis consumes 2ATP(1 in form of GTP).
The energy yield from breakdown of glycogen is
highly efficient.
About 90% of the residues are cleaved to G1P,
which is converted at no cost into G6P.
The other 10% are branch residues, hydrolyzed to
glucose.
Conversion of glucose to G6P requires 1ATP.
Energetics
40. The synthesis and degradation of glycogen are
reciprocally regulated.
The body state and organs:
In the liver, when well fed, glycogenesis; during fasting
glycogenolysis.
In skeletal muscle, during active exercise
glycogenolysis; but at rest, glycogenesis.
Two levels of regulation:
Allosterical effector
Hormonal: glucagon or epinephrine activate
phosphorylase; inhibit synthase.
Regulation
42. For maintenance of blood glucose mainly
between meals.
Liver glycogen largely concerned with transport
& storage of hexose units.
Muscle glycogen is a readily available source of
glucose in the muscle contraction.
Biomedical Importance
43. Clinical Aspects:
Glycogen Storage Diseases
GSDs: a group of genetic diseases.
Caused by defects in enzymes required for
glycogen metabolism.
Result: abnormal structure or accumulation of
glycogen.
Liver (resulting in hypoglycemia) or muscle
(causing muscle weakness), or generalized
The severity of the GSDs varies.
47. Also called hexose monophosphate shunt. (HMP
shunt)
Occurs in the cytosol.
No ATP directly consumed or produced.
Provides NADPH (biochemical reductant); ribose 5-
phosphate for biosynthesis of nucleotides.
It’s a metabolism for five carbon sugars.
Begins with glucose 6-phosphate (glycolytic
intermediate), alternative route for metabolism of
glucose.
Pentose Phosphate Pathway
52. Dehydrogenation of glucose 6-phosphate (G6PD).
Irreversible, rate limiting step.
NADP+ as the coenzyme.
Irreversible Oxidative Reactions
NADPH is
competitive
inhibitor; induced by
insulin
53. Formation of ribulose 5-phosphate
Not rate limiting.
Irreversible Oxidative Reactions
54. This entails extensive carbon atom rearrangement.
Transketolase(2C) requires the coenzyme thiamine
pyrophosphate (TPP), the transaldolase(3C) does not.
Reversible Nonoxidative Reactions
3C5 2C6 + C3
55. G6PD is the regulatory enzyme.
Metabolic needs of a particular cell or tissue:
Rapidly dividing cells require more ribose 5-
phosphate than NADPH.
More NADPH is needed than ribose 5-phosphate
in fatty acid synthesis in adipose cells.
Regulation
56. Reductive biosynthesis
Maintain reduced
glutathione (GSH)
(cellular antioxidant)
especially in RBC
Cytochrome P450
Phagocytosis by WBC
Synthesis of NO
NADPH
57.
58. Pentose is useful in synthesis of DNA & RNA.
NADPH is required for reductive biosynthesis of
fatty acids & steroids.
Microsomal cytochrome P450 monooxygenase
system brings detoxification of drugs & foreign
compounds.
Integrity of RBC membrane.
Biomedical Importance
59. Glucose 6-phosphate Dehydrogenase
Deficiency
It is a hereditary disease characterized by
hemolytic anemia caused by the inability to
detoxify oxidizing agents.
Most common disease---enzyme abnormality.
May have neonatal jaundice, black color urine.
Precipitating factors: oxidant drugs, favism (fava
bean), infection.
Clinical Aspects: G6PD Deficiency
60.
61. Membranes damaged by the Heinz bodies & ROS
become deformed & the cell undergoes LYSIS ----
Hemolytic anemia.
62.
63. Dzugaj A: Localization and regulation of muscle fructose 1,6-
bisphosphatase, the key enzyme of glyconeogenesis. Adv Enzyme Regul
2006;46:51.
Victor W, David L. Harper's Illustrated Biochemistry, 30th edition (2015)
Philp A, Hargreaves M: More than a store: regulatory roles for glycogen
in skeletal muscle adaptation to exercise. Am J Physiol Endocrinol Metab
2012;302:E1343
David L. Nelson, Michael M. Cox: Lehninger Principles of Biochemistry,
4th Edition
https://www.slideshare.net/YESANNA/hmp-shunt-pathway.
Cappellini MD, Fiorelli G: Glucose 6-phosphate dehydrogenase
deficiency. Lancet 2008;371:64.
https://www.slideshare.net/ArunViswanathan3/gluconeogenesis-the-
pathway-and-regulation.
References