3.

Digestion and absorption and

metabolism
Part of the human digestive (gastrointestinal) tract

3
 Cont…
Digestion: a physiological process by which
complex food particles are broken down to
simpler forms, suitable for absorption &
subsequent utilization.

Absorption: a physiological process by which

the end products of digestion and water,
electrolytes & vitamins pass through the
intestinal epithelium to enter the lymph &
blood stream.
 Sites of absorption
Site Nutrient
Jejunum Glucose & other monosaccharide’s, some
disaccharides, monoacyl glycerols, FA,
glycerol, cholesterol, AA, peptides,
electrolytes, iron, calcium, water.

Ileum Bile acids, vitamin B12, electrolytes, water

 DIGESTIVE JUICE WITH PH
DIGESTIVE SOURCE DAILY PH
JUICE SECRETION(L/day)
Saliva Salivary gland 1.5 6.8-7.0
Gastric juice Gastric glands 2.0-2.5 1.5-2.0
Pancreatic Pancreas 0.8-1.2 8.0-8.3
juice
Bile Liver 0.5-1.0 7.8
Succus Small intestinal 1.0-2.0 7.5
entericus mucosa
 Classification of digestive enzyme
1. Carbohydrate splitting enzyme – ptyalin,
pancreatic amylase, Sucrase, maltase, lactase
2. Proteolytic enzyme: pepsin,
trypsin,chymotrypsin.
3. Fat splitting enzyme: lingual lipase, gastric
lipase, pancreatic lipase.
•Zymogens: proteins that are secreted as inactive
form and activated at the site of action called
zymogene. Example- pepsinogen, trypsinogen,
chymotrypsinogen.
Composition of pancreatic juice
• Pancreatic juice consists of:
1)Water
2)Mineral salts
3)Enzymes
i)Amylase
ii)Lipase
4)Inactive enzyme precursors:
i)Trypsinogen
ii)Chymotrypsinogen
iii)Procarboxypeptidase.

The alkaline nature of Pancreatic juice is attributed to

presence of bicarbonate ions, which are alkaline in
solution.
 Functions of Pancreatic Juice
1)Digestion of Proteins: Enteropeptidase converts Trypsinogen
and chymotrypsinogen into the active proteolytic enzymes trypsin
and chymotrypsin. These activated enzymes convert polypeptides
to tripeptides, dipeptides and amino acids

2)Digestion of Carbohydrates: Pancreatic amylase helps in the

conversion of digestible polysaccharides (starch) not acted upon
by salivary amylase to disaccharides.

3)Digestion of lipids: lipase helps in conversion of fats to fatty

acids and glycerol. Bile salt decreases the size of the fat globules
by breakdown into smaller particle resulting in increased surface
area.
 Composition of bile

• Bile or gall is a bitter-tasting, dark green to

yellowish brown fluid, produced by the liver of
most vertebrates, that aids the process
of digestion of lipids in the small intestine.
• In many species, bile is stored in
the gallbladder and upon eating is discharged into
the duodenum.
• Bile is a composition of the following materials:
water (85%), bile salts (10%), mucus and
pigments (3%), fats (1%), inorganic salts (0.7%)
and cholesterol (0.3%).
 Physiological functions of bile
• Bile acts to some extent as a surfactant, helping
to emulsify the fats in the food.
• Bile salt anions have a hydrophilic side and
a hydrophobic side, and therefore tend to aggregate
around droplets of fat (triglycerides and phospholipids)
to form micelles, with the hydrophobic sides towards
the fat and hydrophilic towards the outside.
• The hydrophilic sides are positively charged due to
the lecithin and other phospholipids that compose bile,
and this charge prevents fat droplets coated with bile
from re-aggregating into larger fat particles.
• Ordinarily, the micelles in the duodenum have a
diameter of around 14-33 μm.
 Cont…
• The dispersion of food fat into micelles thus provide a
largely increased surface area for the action of the
enzyme pancreatic lipase, which actually digests the
triglycerides, and is able to reach the fatty core through
gaps between the bile salts.
• A triglyceride is broken down into two fatty acids and
a monoglyceride, which are absorbed by the villi on the
intestine walls.
• After being transferred across the intestinal
membrane, fatty acids are reformed into triglycerides,
then absorbed into the lymphatic system through
lacteals.
• Without bile salts, most of the lipids in the food would
be passed out in feces, undigested.
 Cont…
• Since bile increases the absorption of fats, it is an
important part of the absorption of the fat-soluble
substances, such as the vitamins D, E, K and A.
• Besides its digestive function, bile serves also as the
route of excretion for bilirubin, a byproduct of red
blood cells recycled by the liver. Bilirubin derives
from haemoglobin by glucuronidation.
• The alkaline bile also has the function of neutralizing
any excess stomach acid before it enters the ileum, the
final section of the small intestine. Bile salts also act
as bactericides, destroying many of the microbes that
may be present in the food.
 Bile (yellow material) in a liver biopsy in the setting of bile
stasis, i.e. cholestasis.
 Emulsification of Lipids by Bile
• Bile acts on lipids in a way similar to detergent
acting on greasy water:

large lipid droplet

bile

lipase
Action of bile salt
Enterohepatic circulation of bile
 Cont….
• Circulation of bile from liver to small intestine,
then small intestine to liver via portal vein is
called enter hepatic circulation of bile. About
95% secreted bile is recirculated in this way
and 5% excreted with stool.
• Liver Gall bladder

small intestine
 Micelle
• Bile salt anions have a hydrophilic side and
a hydrophobic side, and therefore tend to aggregate
around droplets of fat (triglycerides and
phospholipids) to form micelles, with the
hydrophobic sides towards the fat and hydrophilic
towards the outside.
• The hydrophilic sides are positively charged due to
the lecithin and other phospholipids that compose
bile, and this charge prevents fat droplets coated
with bile from re-aggregating into larger fat particles.
 Cont….
• Ordinarily, the micelles in the duodenum have
a diameter of around 14-33 μm.

• Function: ferrying action

1. Micelle transfer lipids from intestinal lumen to
intestinal brush border for absorption into
enterocyte.
2. Then it return into lumen and transfer lipids
again and again.
 Bile acids

1. Cholic acid
2. Chenodeoxycholic acid
3. Glycocholic acid
4. Deoxycholic acid
5. Taurocholic acid
6. Lithocholic acid
 The local hormones of GIT
• The gastrointestinal hormones (or gut hormones) constitute
a group of hormones secreted by enteroendocrine cells in
the stomach, pancreas, and small intestine that control
various functions of the digestive organs.
• Types of Gastrointestinal hormones: The gastrointestinal
hormones can be divided into three main groups based upon
their chemical structure.
1. Gastrin–cholecystokinin
family: gastrin and cholecystokinin
2. Secretin family: secretin, glucagon, vasoactive intestinal
peptide and gastric inhibitory peptide
3. Somatostatin family: Motilin family, Substance P.
 Digestion of carbohydrate
1. In mouth: starch: Salivary α-amylase converts starch to
maltose, maltotriose, α-limit dextrin
2. In stomach: HCL converts sucrose to glucose & fructose
3. In duodenum: Pancreatic α-amylase converts starch to
maltose, maltotriose & α- limit dextrin

4. In small intestine:
a) Maltose is converted to glucose by Maltase
b) Maltotriose is converted to glucose by Maltase
c) Lactose is converted to glucose by lactase
d) Sucrose is converted to glucose & fructose by sucrase
Digestion of carbohydrate
 Absorption of carbohydrate
End products Transport (lumen to Transport
enterocyte) (enterocyte to ECF)

Glucose/galactose Co-transport Facilated diffusion

(SGLT-1) (GLUT- 2)

Fructose Facilated diffusion Facilated diffusion

(GLUT-5) (GLUT-2)

Pentose Simple diffusion Simple diffusion

 2. Digestion of protein
1. In mouth: no digestion
2. In stomach: protein is converted to proteose,
peptone & PP by pepsin
3. In intestinal lumen:
a) Protein is converted to PP by Trypsin &
chymotrypsin.
b) PP is converted to AA by carboxypeptidase
c) Elastin is converted to PP & dipeptide by Elastase
d) In brush border of enterocyte: PP is converted to
dipeptide, tripeptide & AA by Aminopeptidase &
dipeptidase
e) In the cytosol of enterocyte: dipeptide & tripeptide
is converted to AA by intracellular peptidase.
Digestion of protein
 Absorption of protein
• Most of the proteins is absorbed as AA
1. For AA: 7 transporter system transport AA into
enterocyte. 5 of them require Na+ & transport (co-
transport) neutral AA, phenyl alanine, methionine &
imino acid. 2 of these are Na+ independent
(Facilated diffusion) & transport - neutral AA &
lipophilic AA.
2. For di & tri-peptides: transported into enterocyte
by a system that requires H+ instead of Na+.
3. From enterocyte to blood: 5 transport system. 2 of
these are Na+ dependent & 3 of these Na+
independent.
 Digestion of fat
1. In mouth: no digestion
2. In stomach: gastric lipase has little importance. Lingual
lipase is active in stomach & can digest 30% triglyceride
containing short chain FA.
3. In intestine:
a) At first, bile salt & lecithin emulsify fat globules into small
particles. Then pancreatic lipase breaks the 1 & 3 bonds of TAG
producing free FA & 2- monoacyl glycerol.
b) TAG is converted to free FA & 2- monoacyl glycerol by Pancreatic
lipase.
c) Cholesterol ester is converted to FA & Cholesterol by cholesterol
esterase
d) Phospholipid is converted to FA & lysophospholipid by
Phospholipase A2
e) 2- monoacyl glycerol is converted to glycerol & FA by Intestinal
lipase (in enterocyte)
Digestion of fat
 Absorption of fat
• Fat absorbed mainly as FA, glycerol, 1-
monoacyl glycerol, 2- monoacyl glycerol &
cholesterol.
1. Glycerol & FA containing < 10 C atom pass
through the enterocyte directly into portal
blood.
2. FA containing > 10-20 C atoms esterify 2-
monoacyl glycerol into TAG.
3. Cholesterol also esterified into Cholesterol ester.
 3. Bioenergetics
• Bioenergetics: bioenergetics deals with the study
of energy changes in biochemical reactions. The
reactions are broadly classified into –
1. Exergonic-release energy
2. Endergonic- consume energy
• Free energy: the energy available to do work is
called free energy.
• High energy compound: compounds that contain
phosphate with energy higher than ATP.
1. Examples-phosphoenolpyruvate, 1,3-
bisphosphoglycerate, acetyl Co-A, acyl Co-A.
2. These have standard free energy >10,000 cal/mol on
hydrolysis.
• Low energy compounds: compounds that contain
phosphate with energy lower than ATP.
 Examples: glucose 6 -phosphate, glycerol 3 –phosphate,
AMP.
 These have standard free energy <4,000 cal/mol on
hydrolysis.
• ATP: composed of adenine, ribose & three phosphates.
 Sources of ATP- oxidative Phosphorylation, glycolysis, TCA
cycle, beta oxidation.
 Energy value: 7, 3000 cal/mol.
• Functions of ATP:
1. Energy currency of cell
2. Allows the coupling of thermodynamically unfavorable
reactions to favorable ones
3. synthetic process
4. muscular contraction
5. nerve conduction
6. active transport etc.
• Oxidation: removal of electron, removal of
proton or addition of oxygen.
• Reduction: gaining of electron, gaining of
proton or removal of oxygen.
• Redox potential (Reduction- Oxidation):
redox potential (Eo) is constant that
describes the tendency of reactants to
donate or accept electron. It is expressed in
volts. It is directly related to to the change in
the free energy (G).
 Biological oxidation
• The oxidation that takes place in the biological system is
called biological oxidation. Many biological oxidations can
take place without the participation of molecular oxygen,
e.g. dehydrogenation. Oxidation either biological or
chemical is always accompanied by reduction.
• Enzymes in biological oxidation:
• Oxidases, dehydrogenases, hydroperoxydases, oxygenases.

• Characteristics of biological oxidation:

1. It is a stepwise degradation of metabolites for the
generation of energy
2. Final phase of oxidation is the utilization of oxygen &
production of CO2 in the tissue by the process of cellular
respiration.
3. Need enzyme, co- enzyme & cofactor.
 Respiratory chain
• Respiratory chain is a series of catalyst in the
inner mitochondrial membrane that are
involved in the transport of reducing
equivalents (H or electron) from the substrate
(NADH, FADH2) to the molecular oxygen to
form water with generation of ATP.
• Location: Components of ETC are found inner
mitochondrial membrane.
 Cont…
• Components of ETC: Components of
respiratory chain arranged in order of
increasing redox potential
1. Enzymes: oxygenase, dehydrogenase, oxydases
2. Coenzyme: NAD, FAD, FMN, coenzyme Q.
3. Iron-sulfur protein
4. Cytochrome (cyt a, a3, b, c1, c)
 Complexes of ETC
• Electrons flow through the respiratory chain through
a redox span of 1.1 V from NAD/NADH to O2/2H2O
passing through 3 large complexes:
1. Complex I(NADH-Q oxidoreductase)
2. Complex III(Q-Cytochrome c oxidoreductase)
3. complex IV(Cytochrome c oxidase)
4. Complex II(succinate Q reductase)
 Transfer of electron in respiratory chain

AH2 NAD+ FpH2 2Fe3+ H2O

Substrate flavoprotein cytochromes
A NADH Fp 2Fe2+ ½ O2
H+ H+ 2H+ 2H+
Electron transport chain(ETC)
ETC
Chemiosmotic theory of ATP production
 cont…
• Inhibitors of respiratory chain:
1. Cyanide, H2S & CO- inhibits cytochrome oxidase (aa3)
2. Barbiturates such as amobarbital- inhibit NAD linked
dehydrogenases by blocking transfer from FeS to Co Q.
• Importance of respiratory chain:
1. respiratory chain is responsible for the large proportion
of ATP production.
2. For example, out of total 40 moles of ATP produced from
oxidation of one mole of glucose, 34 moles of ATP
produced by oxidative phosphorylation from respiratory
chain.
 Oxidative Phosphorylation

• Oxidative phosphorylation is the process by

which the liberated free energy is trapped as
high energy phosphate. Production of ATP
associated with oxidation by Fp Cytochrome
system in respiratory chain is called oxidative
Phosphorylation.
• oxidative Phosphorylation is of 2 types-
1. Substrate level phosphorylation
2. Respiratory chain level phosphorylation
 Cont…
 Substrate level phosphorilation- phosphorilation of ADP to ATP at
substrate level without going into respiratory chain
• Example:

• Phosphoenolpyruvate + ADP
• Pyruvate + ATP

 Respiratory chain level phosphorilation: phosphorilation of

ADP to ATP as a result of transfer of electron through the
respiratory chain.
• Example:
• α-ketogluterate succinyl CoA

• NAD NADH + H+ respiratory chain 3 ATP

 Importance of oxidative Phosphorylation

• Oxidative Phosphorylation enables aerobic organism to

capture a far greater proportion of available free
energy of the respiratory substrates compared with
anaerobic organism. In basal condition 90% of oxygen
is consumed in mitochondria & 80% of those are used
for ATP synthesis.
• Oxidative Phosphorylation depends on:
1. Adequate ADP supply
2. Rapid utilization of ATP
3. Availability of metabolites to inner mitochondria- FA,
glucose, lactate etc.
4. Availability of O2
 Clinical aspects
• Fatal infantile mitochondrial myopathy & renal
dysfunction involves severe diminution or
absence of most oxidoreductases of
respiratory chain.
• MELAS(Mitochondrial encephalopathy, lactic
acidosis, & stroke) is an inherited condition
due to complex I or complex IV deficiency. It is
caused by mutation in mitochondrial DNA &
may be involved in Alzheimer disease & DM.
 Introduction to metabolism
• Metabolism: Entire spectrum of chemical reactions,
occurring in the living system, catalyzed by the
enzymes, coenzymes, cofactors regulated by hormones
& vitamins. Metabolism is divided into anabolism &
catabolism.
• Catabolism: the degradative processes concerned with
breakdown of complex molecules to simplest one, with
a concomitant release of energy, are called catabolism.
• Important catabolic pathways- glycolysis, HMP shunt
glycogenolysis, uronic acid pathway, beta oxidation,
deamination, catabolism of carbon skeleton of AA.
 Cont…
• Anabolism: biosynthetic reactions concerned with the
formation of complex molecule from simple precursors
with utilization of energy are called anabolism.
• Important anabolic pathways: glycogenesis, lipogenesis,
cholesterol synthesis, ketogenesis, protein synthesis, urea
synthesis.
• Amphibolic pathways: TCA cycle, transamination.
• Metabolic pathways that occurs within mitochondria:
oxidative Phosphorylation (resp. chain), TCA cycle, part of
gluconeogenesis, part of cori cycle, beta oxidation,
ketogenesis, part of urea cycle.
 Pathways of carbohydrate metabolism

• Anabolic pathway- glycogenesis, gluconeogenesis

• Catabolic pathway – glycolysis, glycogenolysis, HMP shunt,

uronic acid pathway

• Amphibolic pathway- citric acid cycle /Krebs cycle/TCA cycle

• Intermediary metabolism: the metabolic process involved in

the synthesis of cellular components between digestion of
food and excretion of waste products. It refers to the enter
range of catabolic & anabolic pathways.
 Pathways of lipid metabolism

• Anabolic pathway- FA synthesis, ketogenesis,

cholesterol synthesis, TAG synthesis,
phospholipids synthesis, lipoprotein synthesis,
steroid synthesis.

• Catabolic pathways- β- oxidation, lipolysis,

degradation of phospholipids, cholesterol &
lipoprotein.
 Pathways of protein metabolism
• Anabolic pathway- - synthesis of non EAA,
synthesis of protein, urea synthesis.

• Catabolic pathways – deamination,

breakdown of protein to AA, Catabolism of
carbon skeleton of AA

• Amphibolic pathway - transamination

Compartment of different metabolic pathways

• Only Cytosole- glycolysis, glycogenesis,

glycogenolysis, HMP shunt pathway, lipolysis,
transamination.

• Only Mitochondria-TCA cycle, βoxidation,

respiratory chain phosphorilation, ketogenesis,
deamination.

• Both- gluconeogenesis, cori cycle, urea cycle,

heam synthesis.
4. Carbohydrate metabolism
 Glycolysis (EM pathway)
• The oxidation of glucose (6C) or glycogen to 2 mole of pyruvate
(3C) in aerobic condition or lactate (3C) in anaerobic condition
with production of ATP called glycolysis.
• Substrate: glucose/glycogen
• Product: pyruvate or lactate
• Site: all cells
• Compartment: cytoplasm
• Rate limiting enzyme: phosphofructokinase
• Coenzyme: NAD
• ATP production: 8 in aerobic & 2 in anaerobic condition
• Unique specialty: occur in both in aerobic & anaerobic condition
• Regulation: stimulated by insulin, ADP, AMP & inhibited by
glucagon, ATP, citrate.
 Regulatory steps in glycolysis
 These reactions catalyzed by:
1. Hexokinase
2. Phosphofructokinase
3. Pyruvate kinase
 In RBC

1,3 bisphospho glycerate

2,3-bisphosphoglycerate

3-phosphoglycerate
 2,3-bisphosphoglycerate binds with Hb, decrease
its affinity for O2 & make O2 more readily available
for tissue.
 Enzyme deficiency & disease

1. Dietary deficiency of thiamine & in alcoholics

causes potentially fatal pyruvic & lactic acidosis.
2. Patient with inherited pyruvate dehydrogenase
deficiency commonly causes neurological
disturbance.
3. Inherited aldolase A deficiency & pyruvate kinase
deficiency in erythrocytes cause hemolytic anemia.
4. Muscle phosphofructokinase deficiency decrease
exercise capacity.
 Energy production in Glycolysis

Reaction catalyzed Method of ATP production Number of ATP

by production/mol

Glyceryldehyde 3 P Resp. chain oxidation of 2 NADH 6

dehydrogenase
Phosphoglycerate Phosphorylation at substrate level 2
kinase
Pyruvate kinase Phosphorylation at substrate level 2

Consumption of ATP hexokinase & phosphofructokinase -2

by reaction catalyzed

Total = 8 ATP
 Importance of glycolysis

1. Can produce ATP in anaerobic condition

2. Only pathway that occurs in all cells of the body
3. Only energy source of RBC
4. In strenuous exercise, anaerobic glycolysis is
major source of energy for muscle
5. In hypoxic state – liver, kidney, & lung meets
energy requirements from anaerobic glycolysis.
6. It is the preliminary step to complete oxidation
of glucose.
 Difference between glucokinase & hexokinase
Glucokinase Hexokinase
Active in liver & pancreas Active in other tissues
Active when glucose level is high Active when glucose level is low

Low affinity for glucose High affinity for glucose

Km is high Km is low
Vmax is high Vmax is low
Not inhibited by glucose 6 inhibited by glucose 6 phosphate
phosphate
Specific nonspecific
Affected & stimulated by insulin Not affected
 Oxidation of pyruvate to acetyl CoA

• Substrate: pyruvate
• Product: Acetyl CoA
• Site: all cells & tissue having mitochondria
• Compartment: mitochondria
• Nature: Catabolic
• Rate limiting enzyme: Pyruvate dehydrogenase complex
• ATP production: 6 ATP is produced from each mol of glucose.
• Significance: central step for linking glycolysis & TCA cycle
• Regulation: stimulated by insulin, NAD, ADP& inhibited by
ATP, NADH, acetyl COA.
 Cont…
CoA CO2
PDH
• Pyruvate Acetyl CoA
TPP
NAD NAD2H
• Pyruvate dehydrogenase complex:
1. Pyruvate dehydrogenase uses TPP
2. Dihydro lipoyl trans acetylase uses CoA, lipomide
3. Dihydro lipoyl dehydrogenase uses NAD, FAD

• Coenzymes of pyruvate dehydrogenase

complex: TPP, CoA, FAD, NAD, lipomide
 Sources & fates of acetyl CoA
• Sources:
1. Glycolysis
2. β- oxidation
3. Oxidation of AA
4. Ketone body degradation
5. Oxidation of ethanol
 Fates:
1. Oxidation in TCA cycle
2. Synthesis of FA
3. Synthesis of cholesterol
4. Synthesis of ketone bodies
5. Donation of acetyl group for acetylcholine synthesis
 TCA cycle/citric acid cycle/Krebs cycle
• It is a sequence of reaction in mitochondria that oxidize acetyl residues
& reduces coenzymes that upon re-oxidation is linked to the formation
of ATP. It is called TCA cycle because 1st step contain 3 coo- group.
• Substrate: acetyl CoA
• Products: Co2 H2O, ATP, reduced CoA
• Compartment: mitochondria
• Sites: almost all cells containing mitochondria
• Nature: amphibolic
• Rate limiting enzymes: citrate synthase, isocitreate dehydrogenase, &
α-ketogluterare dehydrogenase.
• Coenzyme needed: TPP, NAD, FAD, CoA, lipoic acid
• ATP production: 12 ATP for each molecule of acetyl CoA.
• Specialty: common metabolic pathway
• Regulation: stimulated by insulin, NAD, ADP& inhibited by ATP, NADH,
citrate.
TCA cycle is a common metabolic pathway
 Inhibitors of TCA cycle

Enzyme Inhibitor

Acotinase Fluoroacetate (non-competitive)

α-ketogluterate Arsenite (non-competitive)

dehydrogenase
Succinate dehydrogenase Malonate (competitive)
 Role of vitamin in TCA cycle
Enzyme Vitamin

Succinate dehydrogenase Niacin (FAD, NAD)

Isocitrate dehydrogenase, Thiamine (TDP)

α- keto gluterate dehydrogenase,
Malate dehydrogenase
α- keto gluterate dehydrogenase Pantothenic acid (CoA)
 TCA cycle plays a pivotal role in metabolism

• TCA cycle takes part in:

1. Transamination, deamination
2. Amino acid synthesis
3. Gluconeogenesis
4. Fatty acid synthesis
 Importance of TCA cycle

• Final common pathway for oxidation of

carbohydrate, protein & lipid

• Plays a major role in gluconeogenesis,

transamination, deamination, & lipogenesis

• It utilizes 2/3rd of total O2 consumed by the

body & generates about 2/3rd of ATP.
Energy output from 1 mole of glucose
 Energy production in Citric acid cycle
Enzyme Pathway ATP
Isocitrate dehydrogenase Resp. chain oxidation of 2 NADH 3

α-ketogluterate Resp. chain oxidation of 2 NADH 3

dehydrogenase
Succinate thiokinase Phosphorilation at substrate level 1
Succinate dehydrogenase Resp. chain oxidation of 2 FADH 2

Malate dehydrogenase Resp. chain oxidation of 2 NADH 3

• Total = 12 ATP.
• Per turn of TCA cycle produces 12 ATP.
 Total ATP production from complete oxidation of 1mol
of glucose

• Glycolysis: 8 ATP
• Conversion of pyruvate to Acetyl CoA: 3*2= 6 ATP
• TCA cycle:12*2= 24
• Grand total: 38 ATP
• Energy output in aerobic oxidation of 1 mole of glucose: 38 ATP
• Energy output in anaerobic oxidation of 1 mole of glucose: 2 ATP
• Per turn of TCA cycle produce: 12 ATP.
5. Glycogen metabolism
 Storage of carbohydrate in a 70 kg person

% of tissue Tissue wt. Body

wt. content (g)

Liver 5.0 1.8 Kg 90

glycogen

Muscle 0.7 35 Kg 245

glycogen

ECF glucose 0.1 10 L 10

 Glycogenesis
• The process of production of glycogen from glucose is called
glycogenesis.
• Substrate: glucose
• Product: glycogen
• Site: liver & skeletal muscle
• Compartment: cytoplasm
• Nature: Anabolic
• Rate limiting enzyme: Glycogen synthase
• ATP requirement: 3 ATP is required for each mol of glucose
production.
• Regulation: stimulated by insulin, glucose 6-p & inhibited by
glucagon, catecholamine.
 Glycogenolysis
• Breakdown of glycogen in liver to glucose & glucose 6 P in
muscle
• Substrate: glycogen
• Products: glucose in liver & glucose 6 P in muscle
• Compartment: cytoplasm
• Sites: liver, skeletal muscle
• Nature: Catabolic
• Rate limiting enzyme: Glycogen phosphorylase
• Co-enzyme needed: Pyridoxal phosphate
• Regulation: inhibited by insulin, ATP, glucose 6-p & stimulated
by glucagon, catecholamine, AMP.
 Difference between liver &muscle
glycogen
Traits Liver glycogen Muscle glycogen
Quantity 90 gm 245 gm
Sources CHO, protein, lipid, Blood glucose & muscle
muscle lactic acid lactic acid
Mobilization Fast Slow
Conversion to glucose Possible Impossible
Breakdown products Mostly glucose Pyruvic acid & lactic acid
Depletion During fasting Only after prolonged
vigorous exercise
Function Maintain blood glucose serve as fuel reserve
level between meals supply ATP during exercise &
muscle contraction
Glycogenesis & glycogenolysis
 Glycogen storage disease
• It is a genetic term to describe a group of
inherited disorders characterized by
accumulation of abnormal type or quantity of
glycogen in tissues due to enzyme defect,
either glycogen synthesis or degradation.
Glycogen storage disease
 Gluconeogenesis/ neoglucogenesis
• The process of converting non-carbohydrate precursors to glucose or glycogen
• Site:liver (90%) & kidney (10%)
• Up to 40% glucose is synthesized by kidney in fasting condition & more in
starvation.
• Compartment: mainly Cytoplasm & partly mitochondria
• Substrate: glucogenic amino acids, pyruvate, lactate, glycerol, propionate.
• Product: glucose.
• Nature: Anabolic
• Rate limiting enzymes: pyruvate carboxylase, phosphoenol pyruvate carboxy
kinase, fructose 1,6- bisphosphatase, glucose 6-phosphatase
• Co-enzyme needed: NADH
• ATP requirement: 6 ATP is needed for 1 glucose.
• Sources of ATP: oxidation of fatty acid.
 Importance of Gluconeogenesis
1. Gluconeogenesis provides glucose for body
during restricted carbohydrate diet.
2. Gluconeogenesis clears certain metabolites
(lactate, glycerol) from blood.
3. Brain, RBC, testes, renal medulla, muscle,
lenses of eye & cornea of eyes require a
continuous supply of glucose as a metabolic
fuel.
All cells are dependent on glucose.
the daily glucose requirement of the brain in a typical adult
human being is about 120 g
Red blood cells use only glucose as a fuel.

160 g of glucose needed daily by the whole body.

The amount of glucose present in body fluids is about 20 g, and that

readily available from glycogen is approximately 190 g.

During period of fasting glycogen in liver is mobilized but it only lasts 12 to

24 hours and this source of glucose may not fulfill metabolic need.
 Irreversible reactions in glycolysis
There are three irreversible reactions in glycolysis catalyzed by
hexokinase, phosphofructokinase, and pyruvate kinase.

1. Glucose + ATP  glucose-6-phosphate + ADP

(hexokinase)

(phosphofructokinase)
3. Fructose-6-phosphate + ATP  fructose-1,6-biphosphate + ADP
(pyruvate kinase)
10. Phosphoenolpyruvate + ADP  pyruvate + ATP

These three reactions must be bypassed in gluconeogenesis

 Bypassed Reactions in Gluconeogenesis
1. Phosphoenolpyruvate is formed from pyruvate by way of oxaloacetate
through the action of pyruvate carboxylase and phosphoenolpyruvate
carboxykinase.

Pyruvate + CO2 + ATP + H2O  oxaloacetate + ADP + Pi + 2H+

Oxaloacetate + GTP  phosphoenolpyruvate + GDP + CO2

2. Fructose 6-phosphate is formed from fructose 1,6-bisphosphate.

Enzyme - fructose 1,6-bisphosphatase.

Fructose 1,6-bisphosphate + H2O  fructose 6-phosphate + Pi

3. Glucose is formed by hydrolysis of glucose 6-phosphate in a reaction

catalyzed by glucose 6-phosphatase.

Glucose 6-phosphate + H2O  glucose + Pi

Gluconeogenesis
 Regulatory enzyme in carbohydrate metabolism
Glycolysis, glycogenolysis & pyruvate oxidation CHO feeding Fasting & DM

Glycogen synyhase Increase Decrease

Hexokinase Increase Decrease
Glucokinase Increase Decrease
Phosphofructokinase-1 Increase Decrease
Pyruvate kinase Increase Decrease
Pyruvate dehydrogenase Increase Decrease
Gulconeogenesis
Pyruvate carboxylase Decrease Increase
Phosphoenolpyruvate carboxykinase Decrease Increase
Glucose 6 phosphatase Decrease Increase
 Major glucose transporters
Tissue location Function
Facilitative bidirectional
transporter
GLUT 1 Brain, kidney, colon, Glucose uptake
placenta, erythrocytes
GLUT 2 Liver, β cell, , small Rapid Glucose uptake or
intestine, kidney. release
GLUT 3 Brain, kidney, placenta Glucose uptake
GLUT 4 Heart & sk. Muscle, Insulin stimulated glucose
adipose tissue uptake
GLUT 5 Small intestine Absorption of fructose
Sodium dependent
unidirectional transporter
GLUT1 Small intestine, kidney
 HMP Shunt

Hexose Mono Phosphate Shunt = Pentose

Phosphate Pathway = Complete Glucose
Oxidation
Function : Production of
 For NADPH
 Ribose 5P
Site :
 In the cytoplasm of all cells except muscle, and
nonlactating mammary gland (low activity)
 HMP shunt pathway
• It is an alternative pathway to glycolysis & TCA cycle for the
oxidation of glucose without generating or consumption of
any ATP.
• Substrate: glucose 6 phosphate, CO2, NADPH
• Product: ribose sugar, NADP2H
• Compartment: cytoplasm
• Sites: In the cytoplasm of all cells except muscle, and non-
lactating mammary gland (low activity)
• Nature: catabolic
• Rate limiting enzyme: glucose 6-P dehydrogenase
• Co-enzyme: NADP, TPP
• Steps: two phases-
1. Oxidative irreversible phase: generate NADPH
2. Non-oxidative reversible phase: generate ribose
precursors(Ribose 5P)
HMP shunt
pathway
 Importance of HMP shunt
1. Production of pentose sugars (mainly ribose 5 P) for nucleotide &
nucleic acid synthesis.
2. Production of NADPH for:
a) Reductive biosynthesis of FA, steroid, cholesterol, bile acids AA.
b) Detoxification of many drugs & foreign compounds in liver by
hydroxylation reaction.
c) Prevents hemolysis of RBC by detoxifying free radicals &
peroxides.
d) Support the production of free super oxide or free radicals in
phagocytes to kill bacteria and other pathogen after
phagocytosis.
e) Helps in reduction of H2O2.
f) Helps in synthesis of NO or EDRF.
3. It is an alternative pathway of glucose oxidation.
 Generation of NADPH
- mainly used for reductive syntheses of fatty
acids, steroids, amino acids via glutamate
dehydrogenase; and production of reduced
glutathione in erythrocytes and other cells.
- active in liver, adipose tissue, adrenal cortex,
thyroid, erythrocytes, testes, and lactating
mammary gland
- not active in non-lactating mammary gland
and has low activity in skeletal muscle.
 Production of ribose residues for nucleotide
and nucleic acid synthesis.
 NADPH for H2O2 elimination

• In the Erythrocytes, Pulmonary Cells, and Liver

Cells :
H2O2 + GSH  GS-SG + H2O (1)
GS-SG + 2 NADPH  2 GSH + 2 NADP (2)
Enzyme 1.Glutathione peroxidase
Enzyme 2.Glutathione reductase
 Glucose-6-phosphate dehydrogenase (G6PD)
deficiency causes hemolytic anemia

 Mutations present in some populations causes a deficiency in glucose

6-phosphate dehydrogenase, with consequent impairment of NADPH
production.
 Detoxification of H2O2 is inhibited, and cellular damage results - lipid
peroxidation leads to erythrocyte membrane breakdown and
hemolytic anemia.
 Most G6PD-deficient individuals are asymptomatic - only in
combination with certain environmental factors (sulfa antibiotics,
herbicides, antimalarials, *divicine) do clinical manifestations occur.
*toxic ingredient of fava beans
 Synthesis Ribose 5P in the muscle

G  G 6P  F 6P  F 1,6 BP

Glyceraldehyde 3P DHAP(Gld 3P)

Gld 3P + F 6P  Xylulose 5P + Erythrose 4P

Xylulose 5P  Riboluse5 P  Ribose 5P

 Other alternative pathways of carbohydrate
metabolism

• Glucose –Alanine cycle: in fasting, there is considerable

output of alanine from skeletal muscle which is far in
muscle protein that is being catabolized. Pyruvate is
converted to alanine by transamination with muscle AA &
exported to liver where it is again converted to pyruvate by
transamination and participate in gluconeogenesis.

• Uronic acid pathway: conversion of glucose to glucoronic

acid, ascorbic acid & pentose is referred to as uronic acid
pathway.

• Lactic acid cycle/Cori cycle

 Lactic acid cycle/Cori cycle

• The cycle involving synthesis of glucose in liver from

the skeletal muscle lactate & the reuse of glucose by
the tissues is called cori cycle.
• Substrate: lactate
• Product: glucose
• Importance:
1. Prevent lactic acid accumulation & lactic acidosis.
2. Helps in Gluconeogenesis.
3. Congenital absence of gluconeogenic enzymes
lead to lactic acidosis.
 Cori cycle
• Glucose Glucose Glucose

• Pyruvate Pyruvate
Cori cycle

• Lactate Lactate Lactate

liver blood muscle

Lactic acid cycle/Cori cycle
 6. Lipid profile

Lipid mg/dl

TAG <165

TC 150-200

LDL-C <180

HDL-C M->40
F->50
Synthesis of TAG/neutral fat
Glucose glycerol

glyceroldehyde
glycerol 3 p
3p

DHA-P
 Metabolism of eicosanoids
• Eicosanoids are chemical substances derived from 20 C (eicosa) FA,
the arachidonic acid.
• Membrane phospholipids
Phospholipase A2 (+) (-) steroid

Arachidonic acid
Lipoxygenase cycloxygenase (-) aspirin

(Leukotriens, lipoxins) (Prostaglandin, thromboxane)

 importance of Eicosanoids
• Eicosanoids physiologically considered as local
hormone
• PGI2 is the major prostaglandin causes dilatation
of coronary arteries & inhibit platelet
aggregation.
• Thromboxane causes vasoconstriction & platelet
aggregation.
• Leukotriens plays a major role in inflammatory
responses & chemotaxis
• Lipoxins have vasoactive & immunoregulatory
role.
 β-oxidation
• β- oxidation is the major pathway of catabolism
of saturated FA (also unsaturated FA) in
mitochondria, in which 2 carbon fragments are
successively removed from the carboxyl end of
fatty acyl CoA producing acetyl CoA, NADH,
FADH2. FA is broken between α (2) & β (3) carbon
atoms, hence, called β- oxidation.
• Substrate: FA
• Product: acetyl CoA, ATP
• Site: liver, skeletal muscle & cardiac muscle
• Compartment: mitochondria
Steps of β- oxidation

• Activation of FA (formation of acyl CoA)

1

• Entry of acyl CoA to into mitochondria through

inner mitochondrial membrane
2

• Breakdown, of acyl CoA to acetyl CoA

3
 Breakdown of
acyl CoA
Acyl CoA

Acyl CoA+ Trans-

Acetyl CoA Enoyl-CoA

Acetyl CoA
enters into TCA 3-ketoacyl 3-hydroxy
cycle
CoA acyl CoA
 Mechanism of entry of acyl CoA into
mitochondria
• Short chain FA can enter into mitochondria independently of
carnitine.
• Long chain FA cannot penetrate inner mitochondrial
membrane without the help of carnitine
acyl CoA carnitin carnitin acyl CoA
Inner

mitochondrial
membrane
carnitin acyl transferase I mito.
Inner carnitin acyl transferase II
mem.
CoA acyl carnitin acyl carnitin CoA

Carnitine shuttle
Carnitine shuttle
Carnitine
shuttle
 ATP generated by complete oxidation of a
molecule of palmitic acid
• ATP generated by complete oxidation of
palmitic(even number) acid:
• Complete oxidation of palmitic acid (16 C) by 7
times β- oxidation produces-
• 8 moles of acetyl CoA
• 7 moles of NADH and 7 moles of FADH2
• In 7 β- oxidation-
 7 NADH×3= 21 ATP
 7 FADH2×= 14 ATP
 8 acetyl CoA ×12= 96 ATP
 ATP used for FA activation= -2
 Net ATP produced=(21+14+96)-2=131 -2= 129 ATP
Oxidation of odd number fatty acid
• Oxidation of odd number fatty acid is same as
saturated fatty acid. But end product is acetyl
CoA and propionyl CoA. acetyl CoA enter into
TCA cycle. Propionyl CoA is converted into
succinyl CoA which also enter into TCA cycle
 Oxidation of odd no. FA

1 •Propionyl CoA

2 •Methyl malonyl CoA

3 •Succinyl CoA
 Ketogenesis
• Substrate: acetyl CoA
• Product: ketone bodies
• Compartment: mitochondria
• Site: liver only
• Normal level:
1. in blood-<3mg/dl
2. In urine-<1mg/day
 Synthesis of ketone bodies

Acyl CoA+ 2acetyl CoA

Acetoacetyl CoA +Acetyl CoA

HMG CoA

Acetoacetate

Acetone + (3) β-hydroxy butyrate

 Catabolism of ketone bodies
• liver cannot oxidize ketone bodies due to
absence of succinyl CoA acetoacetate
transferes(thiophorase) enzyme. Acetoacetate
& β-hydroxy butyrate are transported to
extrahepatic tissue via blood where they
reform acetyl CoA. This acetyl CoA is oxidized
in TCA cycle & produced energy. Acetone is
difficult to oxidized & excreted through lungs.
Production & utilization of ketone bodies
Production & utilization of ketone bodies
 KETOSIS
• Ketosis: simultaneous occurrence of
ketonemia & ketonuria.
• Ketoacidosis: acidosis due to excess kitone
body in blood.
MECHANISM OF DEVELOPMENT OF KITOSIS IN
UNCONTROLLED DM & STARVATION
DM (Starvation, vomiting, alcoholism)
Lack of insulin Hypoglycemia
Entry of glucose in cell Stimulation of HSL
OAA Excess FFA
(-) TCA cycle (+) β oxidation
Oxidation of acetyl CoA Acetyl CoA accumulation
(+) Ktogenesis
Ketosis & ketoacidosis
 7. Causes of fatty liver

1. Increased TAG synthesis – DM, starvation,

alcoholism, high fat diet.
2. Impaired synthesis of lipoproteins (VLDL)
3. Defect in phospholipids synthesis
4. Block in apoprotein formation
5. Failure in the formation/secretion of VLDL.
 Cont…
• Blood lipids • Lipid transport:
• TAG • Lipid transported in
• Phospholipids blood by lipoproteins.
• Cholesterol • Lipoproteins are-
• FFA. • Chylomicron
• VLDL
• LDL
• HDL
 Chylomicron metabolism
1. Assembly of chylomicron- Apo B-48 assembled with
dietary TG, cholesterol & cholesterol ester in
intestinal mucosal cells to form nascent Chylomicron.
2. Modification of nascent chylomicron particle-in
plasma, nascent chylomicron is modified by receiving
Apo E &C from HDL.
3. Degradation of TAG- lipoprotein lipase present in
capillary wall of most EHT is activated by Apo C-II &
degrades TG of chylomicron in FFA & glycerol.
4. Formation of chylomicron remnants-after
degradation, chylomicron decrease in size & increase
in density. Apo C is returned to HDL. chylomicron
which is taken up by liver. TG & cholesterol ester is
hydrolyzed to FA & free cholesterol.
Chylomicron metabolism
 HDL metabolism

1. Synthesis of HDL- occurs in liver & intestine

2. Uptake of free cholesterol by HDL-HDL takes up
free cholesterol from EHT.
3. Esterification of free cholesterol- once free
cholesterol is taken up by HDL, it is immediately
Esterified to cholesterol ester by LCAT(lecithin
cholesterol acyl transferase) which is activated
by Apo A-1. Discoid HDL becomes spherical.
4. Fate of HDL - spherical HDL is taken up by liver &
cholesterol esters are degraded to free
cholesterol.
 Overview of lipoprotein metabolism

• Peripheral tissue HDL

LDL liver

IDL IDL

Intestine CM CMR
 Cont…

Peripheral
CMR CM
tissue

HDL/LDL/IDL IDL Intestine

LIVER LDL
HDL metabolism
 VLDL metabolism

1. Synthesis of VLDL- occurs in liver. Nascent VLDL is

composed of mainly TG and Apo B-100 & A-1.
2. Modification of nascent VLDL- in plasma, nascent VLDL is
rapidly modified by receiving Apo E &C-II from HDL
3. Degradation of TAG- lipoprotein lipase present in capillary
wall of most EHT is activated by Apo C-II & degrades TG of
VLDL in FFA & glycerol. FFA is taken up by EHT.
4. Formation of LDL from VLDL in blood- after degradation,
VLDL decrease in size & increase in density. Apo C is
returned to HDL. The remaining particle is called VLDL
remnant or IDL. IDL has 2 fates- which is taken up by liver
or converted to LDL.
LDL & VLDL metabolism
 LDL metabolism
1. Synthesis of LDL- from VLDL. LDL contains apo B-
100, high conc. cholesterol, cholesterol ester &
less TG.
2. Uptake of LDL - by receptor mediated
endocytosis- in liver & EHT.
3. Degradation of LDL- about 70% LDL is degraded
in liver & 30% in EHT. LDL is degraded in
cholesterol, FA & AA. Fibroblasts, lymphocytes,
arterial smooth muscle & liver have specific LDL
receptor.
 Cholesterol metabolism

• Sources of cholesterol:
 Dietary source – foods of animal origin such as egg
yolk, meat, liver, & brain
 Endogenous source – synthesized in the body
virtually all tissues mainly liver, intestine, adrenal
cortex, & reproductive tissues including testis,
ovaries & placenta.
 Synthesis of cholesterol
• Substrate: acetyl CoA
• Product: cholesterol
• Compartment: cytoplasm
• Rate limiting enzyme: HMG(3-hydroxyl-3-methyl-glutaryl) CoA
reductase
1 • Synthesis of HMG COA & mevalonate (6C)

2 • Production of isoprenoid unit (5C)

3 • 6 isoprenoid units are condensed to form squalene (30C)

4. • Conversion of squqlene to lanosterol(30C)

5 • Formation of cholesterol (27C) from lanosterol

Change in atherosclerosis
Metabolism of TAG & phospholipids

Degradation of TAG- lipoprotein lipase present in

capillary wall of most extra hepatic tissue is
activated by Apo C-II & degrades TG in FFA &
glycerol

Phospholipids - is degraded to arachidonic acid &

subsequently to eicosanoids by phospholipase A2.
Examples of sphingolipidoses
 8. Protein metabolism
• Protein turnover: it is the key physiological process for the
contenuous degradation & resynthesis of all cellular proteins. Daily
300-400 gm of protein is degraded & re-synthesized.
• Amino acid pool: AA released by degradation of dietary or tissue
protein, synthesis de-novo & mixes with other FAA distributed
throughout the body and collectively constitutes the AA pool.
Amount 100gm.
• Composition: glutamate & glutamine – 50%, EAA – 10%, NEAA –
40%
• Sources:
1. Turnover of body protein
2. Breakdown of dietary protein
3. Synthesis of NEAA
Protein
metabolism
Overview of amino acid catabolism in mammals

166
Cont…
 Function/utilization of AA pool
1. Re-synthesis of body protein (300-400gm/day)
2. Synthesis of NPN compounds (30gm/day) –
porphyrine, purines, pyrimidines, creatine,
neurotransmitters.
3. Synthesis of glycogen & glucose
4. Synthesis of ketone bodies, FA & steroids
5. Oxidation for production of energy, H2O & Co2 in
TCA cycle.
 Nitrogen balance
• It is the balance between total nitrogen
intakes and total nitrogen output.
• Types:
1. Nitrogen equilibrium- intake & output is equal
e,g. healthy adult person
2. Positive nitrogen balance- intake is more than
output e,g. in childhood, pregnancy & lactation
3. Negative nitrogen balance- output is more than
intake e,g. trauma, burn, surgery, lack of EAA
intake
 Metabolic Fates of Amino Groups
• In the cytosol of
hepatocytes, amino groups
from most amino acids are
Transamination
transferred to a-
(cytosol) ketoglutarate to form
glutamate, which enters
mitochondria and gives up
its amino group to form
NH4+.
Deamination
(Mitochondria) • Excess ammonia generated
in most other tissues is
converted to the amide
nitrogen of glutamine,
which passes to the liver,
then into liver mitochondria.

170
 Deamination

• Removal of amino group of an AA as free NH3 with

simultaneous formation of corresponding keto acid
coupled with oxidation is called oxidative de-amination.
• Substrate: AA (mainly glutamate)
• Product: NH3, ketoacid (mainly α-ketogluterate)
• Compartment: mitochondria
• Nature: catabolic & reversible
• Site: liver & kidney • Glutamate + NAD
GDH
• Enzyme: GDH
• Coenzyme: NAD • α-ketogluterate+ NADH+NH3
 Importance of deamination

1. Formation of NH3 which serves as source of

nitrogen in urea synthesis
2. Formation of α-ketogluterate which can enter
into TCA cycle
 Trans-amination
• It is a chemical reaction that transfer
an amino group to a ketoacid to form
new amino acids, with simultaneous • α-
conversion of another keto acid to an ketogluter
AA is called trans-amination.
• Substrate: AA & ketoacid
• Product: corresponding ketoacid &
ALT ate +
glutamate
AA
• Possible sites: liver, sk. Muscle,
cardiac muscle, kidney.
• Compartment: cytoplasm
• Nature: amphibolic & reversible • Alanine +
• Enzyme: ALT/SGPT: pyruvate
• Coenzyme: pyridoxal phosphate
TRANSAMINATIN & DEAMINATION
TRANSAMINATIN & DEAMINATION
 Importance of transamination
• Funneling of amino group of most AA to make
it available for oxidative deamination
• Synthesis of NEAA
• Provide a linkage between carbohydrate &
protein metabolism
• Clinical importance of transaminases: AST &
ALT provide importance about liver & heart
disease.
• Fate of AA: AA is broken down to nitrogenous
part (NH3) & non-nitrogenous part (carbon
skeleton)
• Fate of carbon skeleton:
1. Glucogenic AA form glucose & glycogen by
Gluconeogenesis
2. Ketogenic AA form ketone bodies
3. Oxidation in TCA cycle for energy
4. Biosynthesis of NEAA
 Metabolic Fates of Amino Groups
1. Excretory forms of nitrogen: ammonia, urea, and uric acid
2. dietary protein is enzymatically degraded to amino acids
3. pyridoxal phosphate (PLP) participates in the transfer of a-
amino groups to a-ketoglutarate
4. glutamate releases its amino group as ammonia in the liver
5. glutamine transports ammonia in the bloodstream
6. alanine transports ammonia from skeletal muscles to the
liver
7. ammonia is toxic to animals

178
• Sources of ammonia: Amino acid, glutamine,
bacterial urase in intestine, amines, pyrimidine
• Disposal of ammonia:
1. Formation of urea
2. Ammonia is incorporated with glutamate to form non-
toxic glutamine in muscle.
3. Formation of ammonium salt- ammonia is incorporated
with glutamate to form non-toxic glutamine which is
transported to the kidney which further gives rise to
ammonium salt.
4. Synthesis of NEAA.
5. Synthesis of non-protein nitrogenous substances-
Purine, Pyrimidine, creatine
6. Synthesis of amino sugar asparagines.
 Ammonia intoxication
 Elevated conc. of ammonia in blood produces toxic effects
known as ammonia intoxication.
 Normal serum concentration: 5-50 µmol/L.
 Cause:
1. Acquired: hepatitis, alcoholism, liver cirrhosis.
2. Genetic: defect in enzyme in urea synthesis resulting in
accumulation of ammonia.
 Pathogenesis:
 Symptoms:
1. Slurring of speech
2. Blurring of vision
3. Tremor
4. Coma & death
 Alanine Transports Ammonia from Skeletal Muscles to the Liver --
Glucose-alanine cycle
• Alanine serves as a carrier of
ammonia and of the carbon skeleton
of pyruvate from skeletal muscle to
Cori cycle liver. The ammonia is excreted and
Glucose-alanine the pyruvate is used to produce
Pyruvate cycle glucose, which is returned to the
muscle.
• Vigorously contracting skeletal
muscles operate anaerobically,
Lactate producing pyruvate and lactate from
glycolysis as well as ammonia from
protein breakdown.
• Ammonia (use glucose-alanine cycle) ,
Pyruvate pyruvate and lactate (use Cori cycle)
Gluconeogenesis  liver (gluconeosis glucose;
Needs O2 for
ATP ammonia urea)

181
 Biochemical basis of ammonia intoxication

1. High level of ammonia is combined with α-ketogluterate to

form glutamine, as a result there is decreased level of α-
keto gluterate which hamper TCA cycle. Production of less
ATP and s/s of ammonia intoxication.
2. High levels of NH4+ lead to increased levels of glutamine,
which acts as an osmotically active solute (osmolyte) in brain
astrocytes, star-shaped cells of the nervous system that
provide nutrients, support, and insulation for neurons. High
levels of NH4+ triggers an uptake of water into the astrocytes
to maintain osmotic balance, leading to swelling and the
symptoms of ammonia intoxication.
Blood urea nitrogen (BUN)

• Human:15 -50 mg/dL

• Dogs: 8-25 mg/dL
• Cats: 15-35 mg/dL
• Horses: 10-27 mg/dL
• Cattle: 5-23 mg/dL
Normal values may vary among laboratories
 Urea cycle
• Urea biosynthesis occur in 4 steps-
1. Transamination
2. Deamination
3. Ammonia transport
4. Urea cycle proper
 Urea cycle proper
• one nitrogen atom comes from ammonia &
another comes from aspartate.
• Substrate: ammonia, CO2, aspartate
• Product: urea
• Site: liver
• Compartment: cytosol & mitochondria
 Steps of urea cycle proper

1. Synthesis of carbamyl phosphate

2. Formation of citruline
3. Formation of arginosuccinate
4. Cleavage of arginosuccinate
5. Formation of urea
Reactions that feed amino groups into urea cycle

187
 Importance of urea cycle

1. Conversion of toxic ammonia to non toxic

urea
2. Formation of fumarate which is oxidized in
TCA cycle & used in Gluconeogenesis.
3. Formation of arginine which is used in
protein synthesis
4. Metabolic defect in enzymes of urea cycle
leads to ammonia intoxication
 Uraemia
• Excessive accumulation of metabolic end
products of protein like urea & creatinine in
blood produce clinical syndrome called uremia.
• S/S: lethargy, anorexia, nausea, vomiting, mental
retardation, confusion, convulsion, coma &
death.
• Biochemical findings: increased BUN & creatinine
level.
• Treatment: hemodialysis/renal transplantation
 Creatinine
• Human: 0.6 – 1.2 mg/dL
• Dogs: 0.3-1.2 mg/dL
• Cats: 0.8-1.8 mg/dL
• Horses: 1.0-1.8 mg/dL
• Cattle: 0.6-1.5 mg/dL

Normal values may vary among laboratories

 Production of creatinine
• Non-enzymatic
breakdown product of
phosphocreatine in
muscle
• Produced at a relatively
constant rate based on
age, gender, and
muscle mass
• Not affected by diet
Distribution and excretion of creatinine

• Freely permeable and distributed

throughout total body water
• Renal excretion most important
– Filtered by glomeruli
– Not reabsorbed by renal tubules
– Not secreted by renal tubules
• Excreted at a relatively constant rate
Abnormal serum creatinine concentration

• Non-renal factors (usually transient)

• Renal factors
– Pre-renal (e.g. dehydration, heart failure, shock)
– Renal (e.g. parenchymal renal disease)
– Post-renal (e.g. urethral obstruction, ruptured
bladder)
 Implication of azotemia
• In a “steady state” and when non-renal factors
have been eliminated from consideration, an
increase of BUN or creatinine above normal
implies that at least 75% of the nephrons are
not functioning
 9. Integration of metabolism
• It is the hormonal regulation of major metabolic
pathways with the objective to store energy when
food is available in abundance or to make stored
energy available for use during survival crises like
starvation, famine, and severe injury, fight or
flight situations.
• It is primarily regulated by: Insulin, glucagon,
catecholamine, cortisol, and growth hormone.
Among these hormones insulin & glucagon plays
pivotal role; catecholamine, cortisol plays
important role in stressful condition.
 Blood glucose homeostasis
• Factors regulating & maintaining normal blood
glucose level-
1. Metabolic factors- role of liver, muscle& kidney
2. Hormonal factors- insulin, glucagon,
epinephrine, thyroxin, glucocorticoids, GH &
ACTH.
3. Nervous factor- sensation of hunger & satiety
Integration of metabolism
 Glucostatic function of liver
• Maintenance of normal blood glucose level by
liver during the tendency of hypoglycemia or
hyperglycemia is known as glucostatic
function of liver.
• These are:
1. Glycogenolysis,
2. Gluconeogenesis,
3. Glycogenesis
4. Lipogenesis
Role of liver in absorptive state
Role of liver in starvation
 Metabolic Adjustment

• In Feeding- by glycogen synthesis, TAG

synthesis, & protein synthesis.
• in Fasting(4th -24th hrs after meal) &
starvation (>24 hrs after meal)-
glycogenolysis, lipolysis & proteolysis.
 Plasma concentrations of metabolic fuels (mmol/L) in
the feed & fasting state

Feed 40 h fasting 7 days

starvation
Glucose 5.5 3.6 3.5

Nonesterified 0.30 1.15 1.19

FA
Ketone bodies Negligible 2.9 4.5
Inborn errors of metabolism
• Heterogeneous group of disorders with an
underlying genetic etiology affecting one or
many of the metabolic pathways.
• Classification-
1. Disorders of carbohydrate metabolism- GSD, LSD,
lactose intolerance.
2. Disorders of AA metabolism- phenylketonuria,
hyperhomocyeteinemia, albinism, alkaptonuria,
maple syrup urine disease, defect in urea cycle.
 Cont….
3. Disorders of lipid metabolism- Gaucher,s disease,
niemann pick disease, FA oxidation defect.
4. Disorders of nucleotide metabolism-
hyperuricemia , gout.
5. Disorders of trace elements metabolism- Wilson's
disease, haemochromatosis.
5. Miscellaneous- porphyrias