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Metabolism
Anabolism Catabolism
Building up. Break down.
Needs energy Releases energy
(endergonic) (exergonic)
Bioenergetics
It is the study of the energy changes accompanying
biochemical reactions.
Energy is considered the capacity of the organism to do
work. Two types of energy are considered in our body:
o Heat energy: It maintains the body temperature.
o Free energy: It is available for the performance of
work
a) Bioenergetic system needs:
o A source of energy.
o A mechanism for the degradation of the food stuffs to
release energy.
1
o A mechanism for the collection and storage of the
free energy liberated in the form of high energy
phosphate bonds.
a) Sources of energy:
Oxidation of food stuffs mainly carbohydrates.
b) Degradation of food stuffs:
Some free energy is obtained from the breakdown of small
molecules as glucose, glycerol, amino acids and fatty acids to
acetyl Co-A, which via Krebs’ cycle forms free energy, CO 2
and water.
Energy level of hydrolizable bonds:
Energy bonds are divided into 2 groups:
Energy Bonds
I- Low energy bonds:
Give 2000 – 3000 cal/bond.
Designed as ordinary dash (-).
e.g. glucose-6-phosphate.
II- High energy bonds:
Give 10,000-16,000 cal/bond.
Designed as (~).
e.g.: ATP, ADP, creatine phosphate.
2
Pyruvatekinase
Phosphoenol Pyruvate Enol-pyruvate + ATP
+ ADP
Reduced substrate
FP
ATP ATP ATP
Reduced NAD FP Q Cyt b Cyt C 1 Cyt C Cyt a Cyt a3 O
substrate
Respiratory Chain
3
Carbohydrate Metabolism
I-Digestion
In The mouth:
Starch Salivary Amylase Maltose
In the stomach:
Disaccharides (maltose, sucrose and lactose) HCl
monosaccharides
II- Absorption
It occurs mainly in the small intestine.
Polysaccharides and oligosaccharides are not absorbable.
Monosaccharides are absorbed from the jejunum.
Absorption of sugars occurs by:
1- Passive diffusion:
This depends on the concentration gradient of the sugar
between the intestinal lumen, mucosal cells and blood
plasma.
2- Active transport:
There are 2 active transport systems, one for glucose and
galactose and the other for other hexoses.
The first system needs simultaneous absorption of Na + by
a common carrier present in the brush border of the
mucosal cells in the presence of ATP.
4
Absorption increases by T4 and corticosteroids but insulin
has no effect.
It decreases in case of diarrhea.
Core of villus
ATP ADP+Pi
Lumen Na+ Na+
ATPase
Na+ carrier
Glucose Glucose
Glucose
Brush Basal
Border border
2- Uptake by tissues:
This occurs by facilitated diffusion, i.e. requires a carrier
protein.
5
4-Storage:
Excess glucose is stored as glycogen in liver and muscles and
as triglycerides in adipose tissues.
5- Excretion in urine:
Excess blood glucose excreted by the kidney in the
urine if the blood level exceeds the normal renal
threshold (180 mg %)
Normally, no detectable glucose in urine.
Comment on glycolysis:
6
Regulation:
1- Glycolysis is regulated by factors which control the
activity of the 3 irreversible reactions.
2- Insulin induces the synthesis of GK, PFK, PK, while
glucagons and adrenaline inhibit this synthesis.
3- Carbohydrate feeding increases insulin secretion, thus
increasing the synthesis of the 3 irreversible enzymes in
the liver. So, glycolysis will be increased in the liver.
4- During starvation, there is decreased secretion of insulin
and increased secretion of anti-insulin hormones. This
decreases the synthesis of GK, PFK and PK. This inhibits
glycolysis in the liver.
Importance of glycolysis:
1- Glycolysis provides the mitochondria with pyruvate, an
important source of oxaloacetate which is the primer of
Krebs’ cycle.
2- It provides dihydroxyacetone phosphate, which is
convertible to glycerol for lipogenesis.
3- It liberates a little amount of energy from glucose. This is
very important during muscular exercise and also
provides most of the energy required by RBCs.
4- Energy yield in the absence of O2:
- 2 ATP in step 1 and 3 (glucokinase)
+2 ATP in step 7 (phosphoglycerate kinase).
+2 ATP in step 10 (pyruvate kinase).
+ 2 ATP
7
8
B- Aerobic Oxidation
In the presence of oxygen, pyruvate enters the
mitochondria to be oxidized to CO2 and H2O. The process
starts by oxidative decarboxylation of pyruvate to acetyl-
CoA.
1- Oxidative decarboxylation
It is an irreversible reaction that requires a multienzyme
complex: the pyruvate dehydrogenase complex, which is
composed of 3 enzymes. It requires Mg++ , TPP, FAD,
NAD+, CoASH and lipoic acid.
O
II CO 2
CH3-C-COOH Pyruvate-DH-complex CH3-CO~SCoA
NAD+ NADH + H+
Malic enzyme
Oxidative
Decarboxylation Malate
Oxaloacetate
Acetyl~Co A
Citrate
Krebs’ cycle
9
Citric Acid Cycle
(Krebs' Cycle)
3-Specific inhibitors:
a- Malonate inhibits succinate dehydrogenase.
b- Fluoro- citrate inhibits aconitase.
10
- 9 ATP from oxidation of NADH+H+ (isocitrate DH, α-
ketoglutarate DH and malate DH).
Net = 12 ATP.
+ 3 ATP from oxidative decarboxylation of pyruvate.
15 ATP
So, oxidation of one mole of glucose gives:
15 X 2 = 30 ATP
+ 8 ATP from glycolysis.
_______
38 ATP
6- CO2 fixation:
CO2 liberated in Krebs’ cycle is utilized in various
reactions, such as:
1- Pyruvate + CO2 Oxaloacetate.
2- Acetyl- CoA + CO2 Malonyl CoA.
3- Pyruvate + CO2 Malic Acid.
4-CO2 + NH3 Urea
5-CO2 + NH3 Pyrimidine
11
12
Minor Pathways of Glucose Oxidation
Glucose-6-P-dehydrogenase
Glucose-6-phosphate Ribose-5-phosphate
Significance of HMP:
1- Production of ribose 5-phosphate for nucleotides and
nucleic acid synthesis. Ribose of diet is excreted in
urine as there is no pentokinase for phosphorylation.
2- NADPH produced through the HMP is important
for:
a. Fatty acid synthesis: which is important for
lipogenesis . So, HMP is very active in the
liver, adipose tissue and lactating mammary
gland.
b. Steroid synthesis: HMP is active in the adrenal
cortex, testis, ovaries and placenta.
c. NADPH is important for retinal reductase
enzyme which is necessary for the
transformation of retinal into retinol in the eye.
That is why HMP is active in the eye.
13
d. Keep iron of hemoglobin in the reduced form,
thus preserving its capacity to carry oxygen.
Favism: It is a congenital disease resulting from glucose-6-
phosphate dehydrogenase deficiency. Normally, NADPH
produced from HMP is important to keep glutathione in the
reduced form. Reduced glutathione is important to get rid of
H2O2 produced from metabolism. When a person suffering from
glucose-6-P-dehydrogenase deficiency eats Fava Beans or takes
drugs such as Aspirin, H2O2 production increases. This will
destroy the wall of RBCs leading to hemolysis.
Comment:
14
Glycogen Metabolism
1-Glycogenesis:
Formation of glycogen from excessive glucose or other
hexoses.
Site of formation:
Liver and muscles and to a lesser extent in other tissues.
Steps:
15
Regulation of glycogenesis:
1. glycogen synthase is the key enzyme of glycogenesis, it
exists in 2 forms:
a. Active form: Synthase I (dephosphorylated)
b. Inactive form: Synthase D (phosphorylated)
2. Protein kinase converts the active form to the inactive
form. It can only work in the presence of cyclic-AMP
(cAMP) which is formed from ATP by adenyl cyclase
enzyme which is activated by thyroxin, adrenaline and
glucagons. Thus, these hormones decrease
glycogenesis.
Glycogen
Glycogen Synthase I Protein Kinase Synthase D
Synthase Phosphatase
Pi H2O
3. Nutritional state:
In normal person, glycogenesis occurs after a
carbohydrate meal to store excess glucose.
During fasting, secretion of adrenaline and glucagon
inhibits glycogenesis.
2- Glycogenolysis:
16
It is the break down of glycogen in the liver into blood
glucose and in muscle to lactate.
Site:
1-In the liver to maintain the level of blood glucose during
fasting.
2-In muscles, to supply energy during muscular exercise.
Mechanism:
Phosphorylase enzyme acts on the α 1,4-glucosidic linkage
of glycogen, producing glucose-1-phosphate, until each
branch reaches 4 glucose units. Then transferring enzyme
transfers 3 glucose units from the end of one branch to the
end of the other branch.
Debranching enzyme hydrolyses the α 1,6-glucosidic
linkage and then the process is repeated.
Regulation of glycogenolysis:
Glycogen phosphorylase is the key enzyme. It is present in
2 forms, the active form (a) which is phosphorylated and
the inactive form (b) which is dephosphorylated.
The activation of (b) to (a) is catalyzed by phosphorylase
kinase which is present in 2 forms:
1- Active phosphorylase -kinase (a) (phosphorylated).
2- Inactive phosphorylase-kinase (b)
(dephosphorylated).
The main regulator of glycogenolysis is cAMP which
catalyzes the conversion of inactive protein-kinase to the
active form which catalyzes the conversion of inactive
phosphorylase (b) kinase to the active form (a).
Active phosphorylase-kinase (a) stimulates the conversion
of phosphorylase (b) to the active form.
17
2-Glucagon, in liver, and adrenaline, in liver and muscles,
stimulate glycogenolysis by increasing cAMP level which
activates protein kinase and phosphorylase kinase, so stimulate
glycogenolysis.
+
Phosphorylase Kinase (b) Phosphorylase
(Inactive) Kinase (a) (Active)
ATP Mg2+ ADP
18
Muscle Glycogen and blood glucose:
Muscle glycogen can be converted into blood glucose via
indirect pathway known as Cori's cycle during muscle
exercise or by glucose-alanine cycle during starvation as
follows:
Glycogen Glycogen
Pyruvate Pyruvate
LDH LDH
Lactate Lactate Lactate
19
Gluconeogenesis
Definition:
Gluconeogenesis is the synthesis of glucose or glycogen from
non-carbohydrate sources, such as glucogenic amino acids,
lactate, glycerol and odd chain fatty acids (propionyl CoA).
Importance:
It maintains the blood glucose level during starvation and in low
carbohydrate diet.
Site:
Mainly in the cytosol of the liver cells and to a lesser extent in
kidneys, not in adipose tissues or muscles.
Mitochondria Cytosol
H2O Pi
3-Glucokinase reaction is reversed by glucose-6-phosphatase.
H2O Pi
20
Gluconeogenic Precursors:
1-Lactate:
It is released from skeletal muscles during exercise. Then, via
Cori's cycle, it is transferred to the liver to form pyruvate then
glucose.
2-Glycerol:
Produced from the digestion of fats and from lipolysis:
ATP ADP
Dehydrogenase
Glucose Dihydroxy-acetone-phosphate
Glycolysis
21
Lipogenesis
It is the formation of triglycerides from carbohydrates.
This process takes place in liver and adipose tissue and is
stimulated by insulin. The following is a summary for the
process:
Pyruvic
Dihydroxy acetone-P
Oxid.
Decarboxylation
NADPH
α-glycerol-P Triglycerides
Fatty acids
22
Blood Glucose and Its Regulation
Sources of blood glucose:
1. Dietary carbohydrates.
2. glycogenolysis.
3. gluconeogenesis.
23
a. Oxidation of glucose via the major and minor
pathways.
b. Glycogenesis.
c. Lipogenesis.
2. If the blood glucose level decreases, it will increase it
through:
a. Glycogenolysis.
b. Gluconeogenesis.
c. Interconversion of different hexoses as fructose and
galactose into glucose.
[III] Kidney:
[IV] Hormones:
24
Hyperglycemic factor secreted by alpha cells of pancreas.
It stimulates glycogenolysis.
5. Insulin: (Hypoglycemic hormone):
It is a protein hormone secreted by beta-cells of islets of
Langerhans of the pancreas.
Chemistry of insulin:
Insulin contains 51 amino acids arranged in 2 chains, A-chain
containing 21 amino acids, and B-chain containing 30 amino
acids. The two chains are linked together through disulphide
linkages-S-S.
Mechanism of action:
Insulin is the only hypoglycemic hormone. It decreases the
blood glucose level by the following mechanisms:
1-It stimulates the transfer of glucose to the intracellular
compartment.
2- It stimulates the oxidation of glucose as it exerts a
suppressive effect on the synthesis of enzymes responsible for
reversal of glycolysis.
3- It stimulates glycogenesis as it enhances glycogen synthetase
activity.
4- It inhibits glycogenolysis by inhibiting phosphorylase
through cAMP.
5- It inhibits gluconeogenesis by promoting synthesis of proteins
from amino acids.
6- It stimulates lipogenesis by oxidation of glucose which
supplies active acetate, α-glycerol-P, NADPH and ATP.
25
Catabolism of Insulin:
Insulin is inactivated mainly in the liver, but also in the kidney
and muscles by the enzyme insulinase which causes reductive
cleavage of S-S bonds.
Glucose Tolerance
26
increases to a maximum of about 120-150mg/100ml in one hour
due to absorption of glucose.
%Mg
160
Utilization Diabetic
120 Insulin
Absorption
80
Normal
1
F /2 1 11/2 2 Time
Oral Glucose Tolerance Curve
27
Diabetes Mellitus
Metabolic disturbances:
A- Carbohydrate disturbances:
1. Hyperglycemia due to decreased ability of the peripheral
tissues to take up glucose.
2. Glucosuria.
3. Excessive gluconeogenesis.
B- Fat disturbances
1. Increased lipolysis.
2. Ketosis: FA is oxidized in the liver into acetyl-CoA which
exceeds the capacity of the Krebs’cycle. Condensation of
acetyl-CoA ketone bodies which increase in
blood (Ketonemia) and urine (Ketonuria).
C-Protein disturbances:
1. Negative N2 balance.
2. N2 in urine increases.
3. Protein synthesis decreased.
28
Degree of diabetes:
1. Mild diabetes: Fasting blood glucose 120-150 mg/100ml.
2. Moderate diabetes: Fasting blood glucose 150-180
mg/100ml.
3. Severe diabetes: Fasting blood glucose more than 180
mg/100ml.
Glucosuria
Causes:
1. Diabetes mellitus glucosuria: discussed before
2. Adrenaline glucosuria: (emotional glucosuria ).
Stress,fear and anxiety stimulate adrenaline secretion
hyperglycemia, if it rises above the adrenal threshold
glucosuria.
3. Renal glucosuria: Due to abnormally decreased renal
threshold, which is a pathological condition.
4. Alimentary glucosuria: Due to ingestion of large
amounts of carbohydrates after deprivation.
29
5. Pregnancy glucosuria: occurs in 20% of pregnancies. It
is partly due to decreased renal threshold and partly due to
decreased glucose tolerance.
6. Phlorrhizin glucosuria: Phlorrhizin inhibits
phosphorylation of glucose in the kidney glucosuria.
Detection of glucosuria:
1. Reduction of Fehling and Benedict solutions by
glucose in the urine. Benedict is more sensitive than
Benedict as Benedict, being less alkaline, will not be
reduced by other reducing substances in urine, e.g. Vit.
C, uric acid or creatinine.
2. Glucose strips.
30
Lipid Metabolism
Dietary Lipids:
1. Triglycerides: present mainly in meat, liver &butter.
2. Phospholipids: in liver, brain & meat.
3. Cholesterol: in egg yolk & liver.
4. Fat soluble vitamins: (A, D, E, K).
Digestion
A-Triglycerides: (TG)
1. In the mouth: No digestion due to absence of the
lipolytic enzymes.
2. In the stomach: By gastric lipase only in infants as
the pH is suitable.
3. In the intestine:
Lipase Lipase
TG 1,2 –Diacylglycerol 2- monoacylglycerol
H2O R3 H2O R1
Isomerase
Lipase
Glycerol 1-Monoacylglycerol
R2 H2O
B-Cholesterol:
Pancreatic
Cholesteryl ester Cholesterol + fatty acids
Sterol esterase
31
C-Phospholipids:
Pancreatic Phospholipase
Phospholipids Lysophospholipids +FA
H2O
Absorption
The digested lipids undergoing absorption from the small
intestine consist of a mixture of monoglycerides and fatty
acids, with much smaller amount of di- and triglycerides.
This mixture, in combination with bile salts, becomes highly
emulsified forming very fine absorbable particles called
"micelles".
Glycerol is absorbed by diffusion, short chain fatty acids go to
the portal vein. Long chain fatty acids are activated as follows:
Thiokinase
R-COOH + CoASH R-Co~SCoA
(acyl-CoA)
Cholesterolmonoglycerides
Chylomicrons TG
Phospholipids diglycerides
+ Proteins
Glycerol-P
Intestinal Phosphatidic (from glycolysis)
lymphatics acid
32
2- Deficiency of bile salts as in obstruction of bile duct and
also in hepatitis.
3- Diseased epithelial wall (malabsorption syndromes).
Plasma lipids
(400-700 mg %)
Liver, kidney
2-Utilization by tissues:
a- Oxidation of fatty acids.
b- Conversion to glucose.
33
c- Formation of tissue fat.
3-Storage: in the form of depot fat.
4- Excretion: by sebaceous glands in sebum or by lactating
mammary glands into milk.
Comments:
1. Fatty acids oxidation is a major source of energy during
starvation.
2. Energy yield: Oxidation of one mole of palmitic acid
(16 C) results in the production of 8 acetyl- CoA by
passing through (7) β-oxidation cycles. Each β-
oxidation cycle yields one molecule of FADH2 and one
NADH+H+, the hydrogens of which are oxidized via the
respiratory chain forming 5 ATP. Thus we get 5X 7 = 35
ATP from oxidation of palmitic acid to acetyl- CoA. 8
moles of acetyl- CoA, by oxidation in Krebs’ cycle
yield 12 X 8 = 96 ATP.
Thus the total gain is 35 + 96 = 131 ATP. Since 2 ATPs were lost
in the activation of FA into acetyl-CoA , therefore the net is 131-
2=129 ATP.
34
35
Origin of acetyl-CoA (active acetate):
1- From carbohydrates:
glycolysis oxidative
Glucose pyruvic acid
decarboxylation
Acetyl-CoA
2- From fats:
glycolysis
TG Glycerol Pyruvic acid
β - oxidation
FA acetyl- CoA.
2- From proteins:
Ketogenic amino acids acetyl-CoA.
Glucogenic amino acids pyruvic acid.
Acetyl-CoA:
Fatty Acids TG
Ketone bodies
Cholesterol
36
Lipogenesis
It is the fat stored in fat cells of adipose tissue. Its amount varies
according to the nutritional state of the individual and so it is
called the variable element.
a) Origin of depot fat:
1. Excess fat in diet.
2. Lipogenesis.
37
Lipolysis
It is the hydrolysis of TG from the adipose tissues to glycerol
and fatty acids, then via blood to the liver
Regulation of lipolysis:
Lipolysis is controlled by the hormone sensitive lipase which is
present in 2 forms
1. Phosphorylated form(active).
2. Dephosphorylated form (inactive).
Hormone Sensitive
Hormone Sensitive Protein Kinase Lipase (Inactive)
Lipase (Inactive)
ATP Mg2+ ADP
Synthase Phosphatase
Pi H2O
38
Tissue fat (constant element)
It is the fats present in every cell, its amount is not affected
by nutritional state (constant).
1. Composition: mainly phospholipids and cholesterol, fatty
acids are mainly unsaturated.
2. Importance:
a. In plasma membrane, it regulates its permeability.
b. In mitochondria, it is an important component of
respiratory chain enzymes.
c. In myelin sheath acts as insulator to nerve impulses.
Differences between depot fat and tissue fat:
Depot fat Tissue fat
1-Variable -Constant.
2-Present in certain tissues as -Present in every cell.
adipose tissue.
3-Composition:
A-Mainly neutral fat. -Mainly cholesterol,
phospholipids and glycolipids.
B-Fatty acids present are mainly -Unsaturated fatty acids mainly.
saturated fatty acids.
4-Imprtance: -Regulates permeability of
A-Storage of energy. plasma membrane.
B-Heat insulator -Important component of
respiratory chain enzymes in
mitochondria .
-Insulator to nerve impulses in
myelin sheath.
39
Ketone Body Metabolism
Types:
1- Acetoacetic acid CH3-CO- CH2-COOH
2- β-hydroxybuteric acid CH3-CHOH- CH2-COOH
3- Acetone CH3-CO- CH3
1- Ketogenesis:
It is the synthesis of ketone bodies in the mitochondria of the
liver from acetyl-CoA.
Thiolase
Acetyl-CoA Acetoacetyl-CoA
H2O
Acetyl-CoA CoASH
Acetyl-CoA
HMG-CoA-
Synthase
CoASH
HMG-CoA Lyase
Acetyl-CoA
NAD+
β-hydroxybuteric acid
40
Regulation of ketogenesis:
- Ketogenesis increases during starvation, high fat meal and low
carbohydrate in diet.
- It decreases after carbohydrate and protein feeding.
2- Ketolysis:
It is the complete oxidation of ketone bodies to CO2, H2O and
energy. This occurs mainly in the mitochondria of extrahepatic
tissues due to high activity of thiophorase and acetoacetate
thiokinase.
β-hydroxybuteric acid
NAD+
Dehydrogenases
NADH + H+
Thiopherase Acetacetate-
thiokinase
Acetoacetyl-CoA AMP+PPi
Succinic acid
CoASH Thiolase
2 Acetyl-CoA
Oxaloacetate CO2+H2O+Energy
Krebs’ Cycle
Regulation of ketolysis:
Ketolysis increases by insulin which increases oxidation of
glucose by tissues and decreases gluconeogenesis from
oxaloacetate.
Ketolysis decreases by anti-insulin hormones.
Importance:
It completes the oxidation of FA and it is a major source of
energy to extrahepatic tissues during starvation.
41
Ketosis:
It is a condition characterized by increased ketone bodies in the
blood (ketonemia) and in urine (ketonuria).
Causes:
This is due to excess production of ketone bodies in the liver
rather than due to deficiency in the utilization by extrahepatic
tissues.
It occurs in the following conditions:
1-Diabetes mellitus.
2- Starvation.
3- Excess fat in diet and low carbohydrate in diet.
42
Cholesterol Metabolism
Sources:
1. From diet as egg yolk, liver and brain.
2. Synthesized in the body from acetyl-CoA.
43
5. Nephrosis.
b) Hypocholesterolemia: decrease in the level of cholesterol due
to:
1. Starvation.
2. Low carbohydrate and fat in diet.
3. Liver disease.
4. Hyperthyroidism.
Metabolism of Phospholipids
Sources:
1. Exogenous in diet such as eggs, brain and liver.
2. Endogenous: in all cells. Liver is responsible for plasma
phospholipid synthesis and degradation.
Level: the total plasma phospholipids are 200 mg/100ml : 60%
lecithin, 25% cephalins and 15% sphingomyelin.
Importance of phospholipids:
1. They enter in the structure of cell membrane and thus
affecting its permeability.
2. Intermediates in triglycerides absorption from
gastrointestinal tract as well as their biosynthesis in liver
and adipose tissue.
3. Sphingomyelin acts as electric insulator, so play a role in
nerve impulse conduction.
4. In blood clotting; factor III and IV are phospholipids in
nature.
5. Important for some enzymatic actionm e.g. cytochromes.
Degradation: by phospholipases.
Fatty liver
44
condition is prolonged, the liver cells die and become replaced
with fibrous tissue leading to liver cirrhosis and impaired liver
functions.
4. Decreased oxidation
1. Over feeding of Of fatty acids as in
Carbohydrates. ++ -- Deficiency of carnitine and
pantothenic acid (CoA).
2. Over feeding of 5. Decreased mobilization of
Fat. ++ fat from liver to blood as
e.g. in:
3. Over mobilization LIVER Deficiency of essential
-- amino acids.
Of fat from depot
Toxic factors as CCl4
liver. ++
cloroform, phosphorus
arcenic.
Abetalipoproteinemia.
6. Decreased phospholipids
-- synthesis e.g. in:
Deficiency of essential
fatty acids.
Deficiency of choline.
Deficiency of inositol
45