Unit 2 carbohydrate Biochemistry, II semester First Year

1. CARBOHYDRATE METABOLISM
Mrs. Kulkarni Dipali M.
Assistant Professor,
Yash Institute of Pharmacy,
Aurangabad.

2. Glycogen metabolism Pathways and glycogen storage diseases
(GSD)
Gluconeogenesis- Pathway and its significance
Hormonal regulation of blood glucose level and Diabetes mellitus

3. • Glycogen is a chain of glucose subunits held
together by( α 1,4 glycosidic bonds),
glycogen is a branched structure. At the
branch points, subunits are joined by ( α1,6
glycosidic bonds).
• Branches occur every 8-10 residues.

4. Glycogenesis is the process of
Glycogen synthesis
• Glycogen is synthesized when blood
glucose levels are high .
• Glucose is converted into glucose-6-
phosphate by the action of :
Hexokinase catalyses this reaction in most
tissues.
In the liver and pancreas there is an extra
enzyme; Glucokinase exhibiting different
kinetic properties.

5. • This state is reflected inside liver cells by the
presence of high levels of glucose-6-
phosphate. G6P is converted to G1P by
phosphoglucomutase.
• This reaction is analogous to the reaction
catalyzed by phosphoglycerate mutase in of
glycolysis, and proceeds by a similar mechanism,
with a bisphosphate intermediate.
glucokinase

6. • Conversion of G1P into glycogen is energetically
unfavorable, so another source of energy input is
required.
• This comes in the form of hydrolysis of UTP
(uridine triphosphate). The high- energy
phosphoanhydride bonds in UTP are equivalent to
those in ATP. First, UTP is combined with G1P by
UDP-glucose pyrophosphorylase.

7. :::Next, glycogen synthase catalyzes the addition of this
activated glucose subunit to the C4-hydroxyl group at the
end of a glycogen chain (the non-reducing end).

8. • After the chain is more than four residues long, glycogen
synthase takes over. Glycogenin remains bound to the
reducing end of glycogen (the C1 hydroxyl group at the
right side of the pictures). Glycogen synthase works
efficiently only when it is bound to glycogenin.
• Thus the number of glycogen granules in a cell is
determined by the number of glycogenin molecules
available, and the size of the granules is limited by the
need for physical association between glycogenin and
glycogen synthase. When the granule grows too large, the
synthase stops working.

9. • Formation of branches is catalyzed by
"branching enzyme",( amylo (α-1,4‫ـــ‬α1,6)
transglycosylase).
• This enzyme breaks off a chain of about 5 to 8
glucose residues from the growing end of
glycogen by hydrolyzing an( α 1,4 glycosidic
linkage), and transfers the short chain to another
residue in the same glycogen molecule that is at
least four residues away from the cleavage point,
forming an( α 1,6 glycosidic linkage)

10. ➢ After the transfer, both the old C4 end and the newly exposed C4 end
can be elongated by glycogen synthase.
As soon as the new ends are long enough, they can again be
branched. A mature glycogen granule may have seven layers of
branches.

11. • Branching gives glycogen two advantages
over starch as a storage form of glucose.
• First, it is more soluble than its unbranched
cousin.
• Second, the exposure of more C4
(nonreducing) ends means that glycogen
can be both sythesized and degraded more
quickly than a single starch chain with the
same number of residues.

12. ❖Epinephrine (Adrenaline)
❖Insulin
• Insulin has an antagonistic effect to adrenaline.
❖Calcium ions
• Calcium ions or cyclic AMP (cAMP) act as
secondary messengers.
• This is an example of negative control. The calcium ions
activate phosphorylase kinase. This activates glycogen
phosphorylase and inhibits glycogen synthase.
Control and regulations

13. Regulation
• Glycogenolysis is regulated
hormonally in response to
blood sugar levels by glucagon
and insulin, and stimulated by
epinephrine during the fight-
or-flight response.
• In myocytes, glycogen
degradation may also be
stimulated by neural signals.
FUNCTIONS OF LIVER AND MUSCLE GLYCOGEN

14. DEGRADATION OF GLYCOGEN

15. ALLOSTERIC REGULATION
OF GLYCOGEN SYNTHESIS AND
DEGRADATION

16. ⦿ The synthesis of glucose from non-
carbohydrate compounds is known as
gluconeogenesis.
⦿ The major substrates/precursors for
gluconeogenesis:
⦿ Lactate, pyruvate, glucogenic amino acids,
propianate and glycerol.

17. ⦿ Site:
⦿ Gluconeogenesis occurs mainly in the liver,
and to a lesser extent in the renal cortex.
⦿ The pathway is partly mitochondrial
&partly cytoplasmic.
⦿ About 1kg glucose synthesized everyday

18. ⦿ Brain & CNS, erythrocytes, testes & kidney
medulla are dependent on glucose for
continuous supply for energy.
⦿ Human brain alone requires about 120g of
glucose per day, out of about 160g needed by
the entire body.
⦿ Glucose is the only source that supplies to the
skeletal muscle, anaerobic conditions.

19. ⦿ During starvation gluconeogenesis
maintains the blood glucose level.
⦿ The stored glycogen is depleted within the
first 12-18hours of fasting.
⦿ On prolonged starvation, the
gluconeogenesis is speeded up & protein
catabolism provides the substrates, namely
glucogenic amino acids.

20. ⦿ Gluconeogeenesis closely resembles the
reversed pathway of glycolysis.
⦿ The 3irreversible steps of glycolysis are
catalysed by the 3enzymes.
⦿ Hexokinase
⦿ PFK
⦿ Pyruvate kinase

21. ⦿ These three stages bypassed by alternate
enzymes specific to gluconeogenesis.
⦿ These are:
⦿ Pyruvate carboxylase
⦿ Phosphoenol pyruvate carboxy kinase
⦿ Fructose-1-6-bisphosphatase
⦿ Glucose-6-phosphatase

22. ⦿ Takes place in two steps pyruvate
carboxylase is a biotin dependent
mitochondrial enzyme that converts
pyruvate to oxaloacetate in presence of ATP
& CO2
⦿ This enzyme regulates gluconeogenesis &
requires acetyl CoA for its activity.

23. ⦿ Oxaloacetate is synthesized in the
mitochondrial matrix.
⦿ It has to be transported to the cytosol.
⦿ Due to membrane impermeability,
oxaloacetate cannot diffuse out of the
mitochondria.
⦿ It is converted to malate & transported to
cytosol.
⦿ In the cytosol, oxaloacetate is regenerated.

24. ⦿ The reversible conversion of oxaloacetate to
malate is catalysed by MDH, present in
mitochondria & cytosol
⦿ In the cytosol, phosphoenolpyruvate
carboxykinase converts oxaloacetate to
phosphoenol pyruvate.
⦿ GTP or ITP (not ATP) is used in this reaction
and the CO2 is liberated.
⦿ For the conversion of pyruvate to
phosphoenol pyruvate, 2ATP equivalents are
utilized.

25. ⦿ Phosphoenolpyruvate undergoes the reversal
of glycolysis until Fructose 1,6-bisphosphate is
produced.
⦿ The enzyme Fructose 1,6-bisphosphatase
converts Fructose 1,6-bisphosphate to Fructose
6-phosphate & it requires Mg2+ ions.
⦿ This is also a regulatory enzyme.

26. ⦿ Glucose 6-phosphatase catalyses the
conversion of glucose 6-phosphate to glucose.
⦿ It is present in liver &kidney but absent in
muscle, brain and adipose tissue.
⦿ Liver can replenish blood sugar through
gluconeogenesis, glucose 6- phosphatase is
present mainly in liver.

30. Regulation of gluconeogenesis

31. ⦿ The carbon skeleton of glucogenic amino
acids (all except leucine & lysine) results in
the formation of pyruvate or the
intermediates of citric acid cycle.
⦿ Which, ultimately, result in the synthesis of
glucose.

32. Glucose-Alanine Cycle

33. ⦿ Glycerol is liberated in the adipose tissue by
the hydrolysis of fats (triacylglycerols).
⦿ The enzyme glycerokinase (found in liver &
kidney, absent in adipose tissue) activates
glycerol to glycerol 3- phosphate.
⦿ It is converted to DHAP by glycerol 3-
phosphate dehydrogenase.
⦿ DHAP is an intermediate in glycolysis.

35. ⦿ Oxidation of odd chain fatty acids & the
breakdown of some amino acids (methionine,
isoleucine) yields a three carbon propionyl CoA.
⦿ Propionyl CoA carboxylase acts on this in the
presence of ATP & biotin & converts to methyl
melonyl CoA

36. ⦿ Which is then converted to succinyl CoA in the
presence of B12.
⦿ Succinyl CoA formed from propionyl CoA
enters gluconeogenesis.

37. ⦿ Definition:
⦿ It is a process in which glucose is converted to
Lactate in the muscle and in the liver this lactate
is re-converted to glucose.
⦿ In an actively contracting muscle, pyruvate is
reduced to lactic acid which may tend to
accumulate in the muscle.
⦿ To prevent lactate accumulation, body utilizes
cori cycle.

38. ⦿ Thislactic acid from muscle diffuses into the
blood.
⦿ Lactate then reaches liver, where it is
oxidised to pyruvate.
⦿ It is entered into gluconeogenesis.
⦿ Regenerated glucose can enter into blood
and then to muscle.
⦿ This cycle is called cori cycle.

39. Cori Cycle

40. ⦿ Gluconeogenesis & glycolysis are reciprocally
regulated
⦿ One pathway is relatively inactive when the
other is active.
⦿ Regulatory enzymes:
⦿ Pyruvate Carboxylase.
⦿ Fructose-1,6-bisphosphatase.
⦿ ATP.
⦿ Hormonal Regulation of Gluconeogenesis.

41. ⦿ It is an allosteric enzyme.
⦿ Acetyl CoA is an activator of pyruvate
carboxylase so that generation of
oxaloacetate is favored when acetyl CoA
level is high.

42. ⦿ Citrate is an activator.
⦿ Fructose-2,6-bisphosphate & AMP are
inhibitors.
⦿ All these three effectors have an exactly
opposite effect on the phosphofructokinase
(PFK).
⦿ ATP:
⦿ Gluconeogenesis is enhanced by ATP.

43. ⦿ Glucagon & glucocorticoids increase
gluconeogenesis
⦿ Glucocorticoids induce the synthesis of
hepatic amino transferases & provides
substrate for gluconeogenesis.

44. ⦿ The high glucagon-insulin ratio favors
induction of synthesis of gluconeogenic
enzymes (PEPCK, Fructose-1,6-bisphosphatase
& glucose-6-phosphatase).
⦿ At the same time, synthesis of glycolytic
enzymes HK, PFK & PK are depressed.

46. Hormones Involved in
Regulation of blood glucose

47. Hormones Involved in
Regulation of blood glucose
• DECRESE Blood
Glucose
• Insulin
• Somatostatin
• INCREASE Blood
Glucose
• Glucagon
• Epinephrine
• Cortisol
• ACTH
• Growth Hormone
• Thyroxine

48. Hormones from pancreas
➢GLUCAGON
➢INSULIN
➢SOMATOSTATIN

49. ➢Alpha (α)cells secrete glucagon, which elevates the level of glucose in
the blood.
➢Beta (β)cells secrete insulin, which decrease the level of glucose.
➢Delta (δ)cells secrete somatostatin, which regulates the αand βcells.
➢F cells secretes a polypeptide that inhibits the digestive enzymes
produced in the pancreas.
HORMONES SECRETED IN PANCREAS

50. ➢Insulin is a peptide hormone produced by beta cells in the pancreas.
➢It regulates the metabolism of carbohydrates and fats by promoting the
absorption of glucose from the blood to skeletal muscles and fat tissue and by
causing fat to be stored rather than used for energy.
Tissue of Origin
Pancreatic βCells
➢Metabolic Effect
✓Enhances entry of glucose into cells;
✓Enhances storage of glucose as glycogen, or conversion to fatty acids;
✓ Enhances synthesis of fatty acids and proteins;
✓Suppresses breakdown of proteins into amino acids, of adipose tissue into free
fatty acids.
Effect on Blood Glucose- Lowers
INSULIN

51. ACTION OF INSULIN

52. ➢Somatostatin (also known as growth hormone-inhibiting hormone (GHIH)
or somatotropin release-inhibiting factor(SRIF)) or somatotropin release-inhibiting
hormone
➢It is a peptide hormone that regulates the endocrine system and affects
neurotransmission and cell proliferation via interaction with G protein-coupled
somatostatin receptors
➢Inhibition of the release of numerous secondary hormones.
➢Somatostatin inhibits insulin and glucagon secretion.
Tissue of Origin
Pancreatic δCells
➢Metabolic Effect
Suppresses glucagon release from αcells (acts locally);
Suppresses release of Insulin, Pituitary tropic hormones, gastrin and secretin.
Effect on Blood Glucose- Lowers
SOMATOSTATIN

53. ACTION OF SOMATOSTATIN
Somatostatin DECREASE glucagon secretion & Lowers the blood glucose level

54. ➢Glucagon is a peptide hormone, produced by alpha cells of the pancreas, that
raises the concentration of glucose in the bloodstream.
➢Its effect is opposite that of insulin, which lowers the glucose concentration.]
➢The pancreas releases glucagon when the concentration of glucose in the
bloodstream falls too low. Glucagon causes the liver to convert stored glycogen
into glucose, which is released into the bloodstream.
Tissue of Origin
Pancreatic αCells
➢Metabolic Effect
✓Enhances release of glucose from glycogen;
✓Enhances synthesis of glucose from amino acids or fatty acids.
Effect on Blood Glucose- Raises
GLUCAGON

55. ACTION OF GLUCAGON

56. ACTION OF GLUCAGON & INSULIN

57. Hormones from adrenal glands
➢Adrenal
medulla
Epinephrine
➢Adrenal cortex
Cortisol

58. . Tissue of Origin
Adrenal medulla
➢Metabolic Effect
✓Enhances release of glucose
from glycogen;
✓Enhances release of fatty
acids from adipose tissue
Effect on Blood
Glucose- Raises
EPINEPHRINE

59. Tissue of Origin
Adrenal cortex
➢Metabolic
Effect
✓Enhances
gluconeogenesis;
✓Antagonizes
Insulin.
Effect on Blood
Glucose- Raises
CORTISOL

60. Hormones from anterior pituitary
gland
ACTH
Growth Hormone

61. Tissue of Origin
Anterior pituitary
➢Metabolic Effect
✓Enhances release of cortisol;
✓Enhances release of fatty acids from adipose tissue.
Effect on Blood Glucose- Raises
ACTH

62. ACTION OF ACTH

63. Tissue of Origin
Anterior pituitary
➢Metabolic Effect
✓Antagonizes Insulin
Effect on Blood Glucose- Raises
GROWTH HORMONE

64. ➢Reduction in the blood glucose level also promotes secretion of ACTH and the growth
hormone from the pituitary gland through the hypothalamus.
➢ACTH acts on the adrenal cortex to promote glucocorticoid secretion (cortisol in humans).
➢Hyperglycemic hormones such as glucagon, adrenalin, cortisol, and the growth
hormone act on the muscles and liver to promote glycogen decomposition and
also inhibit glucose infiltration into the heart and muscles, which
are organs that consume glucose.
ACTION OF GROWTH HORMONE

65. HORMONE FROM THYROID
GLAND
➢THYROXIN
E

66. Tissue of Origin
Thyroid
➢Metabolic Effect
✓Enhances release of glucose from glycogen;
✓Enhances absorption of sugars from intestine
Effect on Blood Glucose- Raises
THYROXINE

67. ACTION OF THYROXINE