2. 2
GLYCOLYSIS:
Two phases:
Aerobic Phase & Anaerobic Phase
Glycolysis occurs in three stages:
1. Priming stage ( Phosphorylation ).
2. Splitting stage ( converts into 2 molecules ).
3. Oxidoreduction-phosphorylation stage
( ATP formation in E.T.C ).
Oxidation of glucose or glycogen to pyruvate and lactate.
4. 4
Glucokinase
Hexokinase
1. Specific, can phosphorylase glucose
only.
2. Physiologically more labile.
3. Found only in liver.
4. Not inhibited by glucose-6-P.
5. Km is high, has low affinity for glucose
6. Increased by glucose meal or insulin.
1. Non specific, can phosphrylase any
hexose.
2. It is more stable enzyme.
3. Found almost in all tissues.
4. Allosteric inhibition by glucose-6-P
5. Km is low, has high affinity for glucose.
6. No change with glucose feeding/meal.
5. 5
Biomedical importance of glycolysis
1. This pathway is virtually meant for energy.
2. In sk. muscles, provides energy even in the absence of O2
3. Heart muscle has poor glycolytic activity in ischaemia.
4. In cancer cells, glycolysis is high, lactacidosis occurs which may be
favourable for cancer therapy.
5. Hexokinase & pyruvate kinase deficiency can produce hemolytic anemia.
6. 6
Energy yield per Glucose Molecule Oxidation
A. Aerobic phase of Glycolysis:
ATP production
Reaction catalyzed by
-1 ATP
-1 ATP
+6 ATP
+2 ATP
+2ATP
Stage I:
1. Hexokinase/Glucokinase reaction
2. Phosphofructoskinase-1 reaction
Stage II:
3. Glyceraldehyde-3-P
dehydrogenase
2NADH in ETC.
4. Phosphoglycerate kinase
substrate level
Stage III:
5. Pyruvate kinase ( substrate level
)
10-2=8 ATP
Net Gain
7. 7
B. Anaerobic phase of Glycolysis:
Pyruvate
LDH
Lactatic Acid
NAD
+
NADH+H+
4 - 2 = 2 ATP
8. 8
Regulation of Glycolysis
Depends upon the following factors:
1. Blood Glucose level.
2. Enzymatic change.
3. Hormonal control.
1. Glucose level:
• Can decrease the activity of enzymes.
• Can increase the activity of enzymes.
• Key enzymes are:
– Glucokinase.
– Phosphofructokinase-I.
– Pyruvate kinase.
9. 9
2. Enzyme changes:
• May be covalent modification by reversible
Phosphorylation, ↑ or ↓ glycolysis:
• Allosteric Modification:
• cAMP level
• Protein kinase level
Feedback control by:
• Inhibition of enzyme by citrate & ATP
• Activation of enzymes by AMP conc.
3. Hormonal control:
• Insulin: ↓ glucose level ( Hypoglycemic )
•Glucagon: ↑ glucose level ( hyperglycemic )
•Epinephrine: ↑ glucose level ( hyperglycemic )
•Glucorticoids: ↑ glucose by gluconeogenesis
14. 14
Biomedical importance of TCA cycle
1. Final common pathway for CHO, proteins & fats through
formation of 2- carbon unit acetyl – CoA.
2. Has catabolic role, energy rich cycle, acetyl CoA is
oxidized to CO2 & H2O producing energy.
3. It is amphibolic in nature, has anabolic role as well,
synthesis of FA, cholesterol, steroids, AA, heme, glucose
and ketone bodies is correlated with this cycle.
15. 15
Regulation of TCA Cycle
•Energy level through ECT/ Oxidative Phosphorylation
•Key Enzymes control:
- Citrate Synthetase
-Isocitrate dehydrogenase ( ICD )
-2-oxo- glutarate dehydrogenase
Their inhibition or activation depends upon ATP, ADP &
NAD,NADH.
16. 16
Glycogen Metabolism
• Glycogenesis
•Glycogenolysis
• Glycogen is the storage form of glucose.
• Why the glucose is not store itself in body?
Possible Reasons
1. Being insoluble it exerts no osmotic pressure.
2. Does not disturb the intracellular fluid (ICF) content.
3. Does not diffuse from its storage sites.
4. Has higher energy level than corresponding wt. of
glucose.
5. Readily broken under influence of hormones and
enzymes.
17. 17
Storage Capacity of Glycogen in
Normal Adult Man( 70kg )
Normal weight
of the organ
Amount
Organ
1800 gm
4-6%= 72-180
gm
Liver
35 kg
0.7%=245 gm
Sk. Muscles
Total volume=
10 literes
0.1% = 10 gm
EC Glucose
Total = 325-360
19. 19
Regulation of glycogenesis
• Glycogen synthase- key regulatory enzyme.
- Active from GS “ a “ ( GS-I ).
-Inactive from GS “ b “ (GS-D).
• cAMP dependant protein kinase.
• Glycogen conc. ( feedback control ).
20. 20
Stimulation of Glycogenesis
1. Insulin increases the pathway.
2. Glucocorticoids: 2-3 hrs after administration.
3. Glucose higher concentration ↑ synthesis.
Inhibition of Glycogenesis
1. Increase conc. of glycogen (feedback inhibition).
2. Increased conc. Of cAMP inhibition protein
phosphatase-I.
22. 22
Regulation of glycogenolysis
• cAMP dependant protein kinase.
• Phosphorylase – key regulatory enzyme.
• Hormones like Glucagon & Catecholamines.
• Calmodulin, Ca
++
dependant regulatory protein.
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23. 23
HEXOSE MONOPHOSPHATE (HMP) SHUNT
An alternate Pathway for oxidation of glucose
It is called by various names:
•Hexose Monophosphate Shunt or Pathway.
•Pentose - Phosphate Pathway (PP-Pathway).
•Pentose Oxidative Pathway (Pentose Cycle).
•Phosphogluconate Pathway (Dicken Pathway).
26. 26
Biomedical Importance of HMP Shunt
• Various tissues can utilize glucose readily by
this shunt when anaerobic glycolysis is
blocked by specific inhibitors as “ lodo-acetic
acid”
• Provides NADPH which is required for various
reductive synthesis in metabolic pathways i.e.
Fatty Acids, steroids & cholesterol.
• Provides pentoses required for nucleic acids
(RNA & DNA) synthesis.
• Deficiency of G6PD enzyme leads to hemolytic
anemia, which has great clinical importance.
• Not meant for energy, but multicyclic process
in which 3 molecules of Gl-6-P enter,
producing 3 moles of CO2 & 3 moles of 5-C
residues which rearrange to give 2 moles of
Fr.6.p & one mole of Glyceraldehyde -3-P.
27. 27
Difference of EM Pathway and HMP Shunt
HM Pathway
EM Pathway
1. Occurs in certain spec.
tissue
2. Multicyclic process
3. NADPH2 is produced
4. Not meant for energy
(ATP)
5. CO2 is produced
1. Occurs almost in all
tissues
2. Not a multicycle process
3. NADH2 is produced
4. ATP is required and
produced
5. CO2 is never formed
28. 28
GLUCONEOGENESIS
Formation of glucose or glycogen
from non carbohydrate sources.
Sources/substrates
•Glucogenic Amino Acids
•Lactate and Pyruvate
•Glycerol from lipolysis of fat
•Propionyl-CoA & Prop ionic
Acid
•Odd- Chain Fatly Acids.
Sites/tissues
i. Liver ii. Kidneys
iii. Heart iv. Intestine
No Gluconeogenesis in sk. muscles
31. 31
Biomedical importance
I. Gluconeogenesis meets the requirements of
glucose in body when Carbohydrates are not
sufficiently available.
Certain “basal level” of glucose is even
needed for specific uses:
• Source of energy for nervous tissues & RBCs
• For maintaining level of intermediates of TCA cycle
• Precursor of milk sugar (lactose) in lactating
mammary glands in females
• Source of glyceride-glycerol-P for adipose tissues
• Only fuel for sk. muscle in anaerobic conditions.
32. 32
2. Gluconeogenic mechanisms are required to
clear the products of metabolism of other
tissues from blood e.g.
•Lactic acid produced by muscles & RBCs
•Glycerol produced by fat lipolysis in adipose
33. 33
• Carbohydrate diet
• Insulin/Glucagon ratio
• Steroid Hormone (Cortisol)
• Fatty acid oxidation ↑ it
• Energy requirements of body
- pyruvate carboxylase (PC)
- PEPCK
- Fr. 1,6 bisphoshatase
- Gl-6-phosphatase
Regulation of Gluconeogenesis
• Key Enzymes are:
34. 34
GALACTOSE METABOLISM
1. Conversion to glucose
2. Conversion to lactose
3. Enters into glycolysis
4. Enters into HMP Shunt
5. Galactosemia disorder
35. 35
FRUCTOSE METABOLISM
1. Conversion to glucose
2. Conversion to sucrose
3. Enters into glycolysis
4. Conversion to fat (TAG)
5. Converts to sorbitol in
diabetes mellitus
6. Fructosuria can occur
36. 36
Biomedical importance
• Fructose is easily metabolized in body
• Fructose is good source of energy
• Sperms utilize fructose for energy
• Excess dietary fructose harmful ↑TAG
• In diabetics, through sorbitol pathway
causes development of cataract in eyes
• Heriditary fructose intolerance occurs in
deficiency of aldolase- B enzyme
38. 38
Biomedical Importance
• In this pathway energy is not produced
• Produces D- glucuronic acid which detoxifies
foreign chemicals & synthesizes MPS
• Inherited deficiency of enzyme in this pathway
produces “essential pentosuria”
• Pathway synthesizes vitamin C in birds, dogs
etc. but not in humans/primates & guinea pigs
40. 40
Inherited Disorders
GLYCOGEN STORAGE DISEASES
Clinical Features
Deficient
Enzyme
Name of
Disease
Type
Liver, kidney & intestine affected.
Hypoglycemia, ketosis, lactacidosis,
Uric acid↑, cholesterol↑,
hepatomegaly and growth stunted
(dwarfism).
GL.6.P
Phosphatase
Von Gierke’s
Disease
I
Liver, heart & smooth muscles
involved. Cardiomegaly, muscle
hypotonia, muscle weakness, No
hypoglycemia. Early death occurs.
Acid Maltase
(in lysosomes)
Pompe’s Disease
II
Liver, heart & muscles involved.
Hypoglycemia, acidosis, myopathy,
and hepatomegaly.
Debranching
Enzyme
Limit Dextrinosis
(Forbe’s Disease)
III
Liver, heart, muscle & R.E. system
involved. Hepatosplenomegaly, acites
and liver cirrhosis (hepatic failure).
Branching
Enzyme
Amylopectinosis
(Andersen’s
Disease)
IV
Sk.muscles involved. Muscle pains on
exercise. Weakness and stiffness of
muscles are also observed.
Muscle
phosphorylase
Mac Adle’s
Disease
V
Liver & leukocytes are involved.
Hypoglycemia, acidosis &
hepatomegaly have also been noted.
Liver
phosphorylase
Her’s Disease
VI
