DIGESTION, ABSORPTION AND METABOLISM OF LIPIDS.docx
1. Basic Notes For Medical & Allied Health Science Students
Dr. SANTHOSH KUMAR / ASSOCIATE PROFESSOR
DIGESTION, ABSORPTION AND METABOLISM OF LIPIDS
Dietary lipids consist of triglycerides, phospholipids & cholesterol esters and cholesterol. Most
of the fat in the human diet is in the form of triacylglycerol (TAG). In the digestive tract, TAG is
hydrolyzed by the enzyme lipase, to release free fatty acids and mono acyl glycerides.
Digestion in mouth
Digestion of dietary lipids starts in the mouth.
Lingual lipase is secreted by sublingual glands. They act on triglycerides containing short
chain fatty acids.
Digestion in stomach
Very small amounts of lipase are present in gastric juice.
Digestion of fat is negligible
Digestion in small intestine
• it occurs in two process a) Emulsification of lipids by bile salts
b) Enzymatic degradation of lipids
Degradation of Triacylglycerols (fats)
Pancreatic lipase is the major enzyme that digests dietary fats.
Pancreatic lipase catalyzes hydrolysis of ester bonds present at 1st
& 3rd
position of TG to
gives 2-mono glycerides.
Further 2-mono glycerides undergo isomerizationto 1-MAG, Then 1-MAG is hydrolysed by
pancreatic lipase. Products of lipase are 2-monoglycerides, 1–monoglycerides, Glycerol &
FFAs.
Glycerol directly enters the portal blood.
2. Basic Notes For Medical & Allied Health Science Students
Dr. SANTHOSH KUMAR / ASSOCIATE PROFESSOR
Degradation of cholesterol esters:
Cholesteryl esterases hydrolyses of ester bonds present at 3rd
Carbon of cholesteryl esters to
gives cholesterol.
Degradation of Phospholipids
Pancreatic juice is rich in Phospholipase A2 isresponsible for the hydrolysis of
phospholipids, which cleaves the fatty acid at the 2nd
position of phospholipids. The
products of phospholipase are FFAs & Lysophospholipids.
The major digestible products (2-mono acylglycerol, FFA, cholesterol & lyso-
phospholipids) now ready for absorption in the intestinal lumen by passive process.
ABSORPTION OF LIPIDS
Products combine with bile salts to form micelles. Micelles are absorbed into the
intestinal mucosal cells.
Micelles serve as the major vehicles for the transport of lipids from the intestinal lumen
to intestinal mucosa.
In intestinal mucosal cells, TGs are resynthesized from absorbed FFA & mono acyl
glycerol.
The resynthesized TGs cannot pass in to portal blood, but it enters the lymphatic vessels
as a chylomicrons.
The lymphatic duct then discharges the chylomicrons into bloodstream through thoracic
duct & left sub clavian vein, reached to heart, then to peripheral tissues & finally to liver.
Chylomicrons are hydrolyzed in adipose tissues by lipoprotein lipase to yield FFA &
glycerol.
In adipose tissues, the FFAs are re esterified with glycerol-3-P to synthesize TGs, which
are stored as fuel reserve and provides the energy to skeletal muscle, cardiac muscle &
liver.
3. Basic Notes For Medical & Allied Health Science Students
Dr. SANTHOSH KUMAR / ASSOCIATE PROFESSOR
METABOLISM OF TRIGLYCEROL
LIPOGENESIS
• Synthesis of TGs from fatty acyl CoA
(from acetyl CoA) glycerol-3-P in
adipose tissues.
• Glycerol 3-P when it combined with
two molecules of fatty acyl CoA to
form lysophosphatidic acid first then
phosphatidic acid by the enzymes acyl
transferases.
• Phosphatidic acid looses phosphate
group and binds with third molecule of
acyl CoA to form Triacylglycerides by
acyl transferase.
LIPOLYSIS:
• Adipose tissue is a specialized connective tissue designed for synthesis, storage, hydrolysis
of TGs.
• Most of the body TGs stored as lipid droplets in cytoplasm of adipocyte whenever need of
metabolic energy, the TGs undergo lipolysis.
• Lipase catalyzes hydrolysis of ester bonds present at 1st
, 3rd
than 2nd
position of TG to gives
Di, mono glycerides & finally glycerol & FFAs.
UTILIZATION OF FATTY ACIDS FOR PRODUCTION OF ENERGY
Fatty acids in the circulation are taken up by cells and used for energy production, primarily
in mitochondria, in a process integrated with energy generation from other sources.
Utilization of fatty acids for energy production varies from tissue to tissues, depends on
metabolic status, that is, fed or fasted.
Oxidation of fatty acids:
CoA esters of fatty acids are the substrates for oxidation.
They are mainly
o β-oxidation of fatty acid
o α-Oxidation of fatty acid and ώ- oxidation of fatty acid
Glycerol -3-Phoshate
Lysophosphatidic acid
Phosphatidic acid
Di Acylglycerol
Acyl Transferase
FA- CoA
CoA
Acyl Transferase
Phosphatase
Acyl Transferase
Triacylglycerol
Reactions of Lipogenesis
FA- CoA
CoA
FA- CoA
CoA
Pi
4. Basic Notes For Medical & Allied Health Science Students
Dr. SANTHOSH KUMAR / ASSOCIATE PROFESSOR
BETA (β) OXIDATION OF FATTY ACIDS
Fatty acid oxidation occurs through the sequential removal of 2-carbon units by oxidation at
the β-carbon position of the fatty acyl-CoA molecule.
β - Oxidation of fatty acids takes place in the mitochondrial matrix.
β - Oxidation of fatty acids involves in three stages
I) Activation of Fatty Acids in cytosol
II) Transport of fatty acyl CoA into mitochondria
III) β – Oxidation reactions
5. Basic Notes For Medical & Allied Health Science Students
Dr. SANTHOSH KUMAR / ASSOCIATE PROFESSOR
I. Activation of Fatty Acidsin cytosol
In the presence of ATP and coenzyme A, the enzyme acyl CoA synthetase catalyses the
conversion of a free fatty acid to fatty acyl CoA (active form fatty acids).
II. Transport of fatty acyl CoA into the mitochondrion
Long-chain fatty acids cannot directly cross the inner mitochondrial membrane to
mitochondrial matrix, so carnitine carrier system helps to transport the long chain fatty acids
from cytosol to mitochondrial matrix. But Short-chain fatty acids are transported through the
membrane freely.
III. Steps of β-Oxidation:
First reaction is the dehydrogenation. It is catalyzed by Acyl-CoA dehydrogenase to form
∆2
Trans enoyl-CoA from fatty acyl CoA. FAD converted to FADH2
Second reaction: water is added across the new double bond to make -β -hydroxy acyl-CoA
from ∆2
trans-enoyl-CoA by enoyl-CoA hydratase.
Third reaction: oxidation of the hydroxyl group at the β- position which forms a β -
ketoacyl-CoA. This is the 2nd
oxidation step catalyzed by β –OH-acyl-CoA dehydrogenase.
NAD converted to NADH+H+
Final reaction: Thiolase catalyzed reaction, cleaves the β - ketoacyl-CoA using CoASH to
produce acetyl-CoA and a fatty acyl CoA that has been shortened by two carbons from
original FA-CoA.
This sequence of four steps is repeated until the fatty acyl chain is completely degraded to
acetyl CoA.
OXIDATION OF PALMITOYL CoA:
Beta oxidation of Palmitoyl CoA undergoes 7 cycles to yield 8 acetyl CoAs.
I. In the β- oxidation - (7 cycles)
Acyl-CoA dehydrogenase [1 FADH2] 1.5 ATPs
β -OH-acyl-CoA Dehydrogenase [1NADH+H+
] 2.5 ATP
One cycle of β –oxidation produces 4 ATPs
Total 7 β- oxidation cycles produces 7×4 = 28 ATPs
Initial activation step use - 2 ATPs
Total ATPs Produced 26 ATPs
6. Basic Notes For Medical & Allied Health Science Students
Dr. SANTHOSH KUMAR / ASSOCIATE PROFESSOR
II. from Acetyl CoA:
One acetyl CoA can enter the TCA cycle & get completely oxidized to produce CO2 & H2O and
produced 10 ATPs. Total 8 Acetyl CoA produced (8x 10 ATPs) = 80ATPs
From one molecule of palmitoyl CoA completely oxidized to produce 106ATPs
Beta oxidation 26 ATPs
NET ATPs : 106 ATPs
TCA cycle 80 ATPs
METABOLISM OF KETONE BODIES
Ketone bodies are Acetoacetic acid, β-OH butyric acid & acetone.
Ketone bodies are formed from acetyl CoA resulting from β oxidation of fatty acids.
KETOGENESIS:
Ketogenesis is the process of formation of ketone bodies from acetyl CoA in the liver
mitochondria.
Two molecules of acetyl CoA react with each other to form acetoacetyl CoA.
Acetyl CoA
Acetoacetyl CoA
HMG –CoA
(β-Hydroxy –β-Methyl-Glutaryl CoA)
Acetyl CoA
Acetyl CoA
CoA-SH
Acetyl CoA
Thiolase
HMG-CoA Synthase
HMG-CoA Lyase
H2O
CoASH + H+
Acetoacetate
Acetone
β- Hydroxybutyrate
NADH+ H+
NAD+
H+
CO2
β- OH butyrate
dehydrogenase
Non- Enzymatic
reaction
Reactions of Ketogenesis
7. Basic Notes For Medical & Allied Health Science Students
Dr. SANTHOSH KUMAR / ASSOCIATE PROFESSOR
HMG CoA (β hydroxyl- β methyl glutaryl CoA) formed from the condensation of
acetoacetyl CoA with acetyl CoA catalyzed by HMG CoA synthetase.
HMG-CoA lyase enzyme catalyzes the cleavage of HMG-CoA to acetoacetate and acetyl
CoA
Acetoacetate produces β-hydroxybutyrate in a reaction catalyzed by β-hydroxybutyrate
dehydrogenase in the present NADH.
Both acetoacetate and β-hydroxybutyrate can be transported across the mitochondrial
membrane then enter to the blood stream to be used as a fuel by other cells of the body.
Small amounts of acetoacetate are spontaneously (non- enzymatically) decarboxylated to
form acetone. While under normal conditions, acetone formation is negligible.
Regulation:
HMG CoA synthase is the regulatory enzyme of ketogenesis
Ketogenesis induced by increased fatty acids in the blood.
It is inhibited by high level of CoASH
Inhibited by insulin and stimulated by glucagon
KETOLYSIS / UTILYZATION OF KETONE BODIES
Acetoacetyl CoA
Acetyl CoA Acetyl CoA
Acetoacetate
β- Hydroxybutyrate
NADH+H+
β- OH butyrate
Dehydrogenase
Acetoacetyl-CoA
Thiolase
CoA-SH
NAD+
CoASH + ATP
AMP + PPi
Thiophorase
Thiokinase
Succinyl CoA
Succinate
8. Basic Notes For Medical & Allied Health Science Students
Dr. SANTHOSH KUMAR / ASSOCIATE PROFESSOR
Ketolysis is the complete oxidation of ketone bodies in mitochondria of extrahepatic
tissues, but not in the liver because of thiokinase and thiophorase enzymes deficiency.
β-hydroxy butyrate is dehydrogenated to form acetoacetate, the reaction is catalyzed by
β-hydroxy butyrate dehydrogenase.
Activation of acetoacetate to acetoacetyl-CoA occurs by one of two pathways:
a) One mechanism involves the activation of acetoacetate with ATP in presence of
CoASH catalyzed by thiokinase.
b) Other mechanism involves Succinyl CoAand the enzyme Thiophorase.
Acetoacetyl CoA is split to acetyl CoA by thiolase and oxidized via citric acid cycle to
CO2 and H2O
CLINICAL SIGNIFICATION:
Normal levels of ketone bodies in blood is less than 1 mg/dl and in urine 1mg/day
KETOSIS:
It is a condition, increase of the ketone bodies in the blood (Ketonemia), their
appearance in the urine (ketonuria) and together with acetone odor in the breath is
called ketosis.
Causes:
Uncontrolled diabetes mellitus, starvation & excessive alcohol consumption
Unbalanced diet i.e. high fat, low carbohydrate diet.
KETOACIDOSIS
Ketoacidosis is a metabolic state associated with high conc. of ketone bodies and
uncontrolled ketosis.
In ketoacidosis, the body fails to adequately regulate ketone bodies production, so it leads to
decreased the blood pH & acidosis
In Diabetic ketoacidosis (DKA)
It is mainly seen in patients with uncontrolled diabetes mellitus.
Characterized by hyperglycemia causes severe osmotic dieresis leads to dehydration &
loss of electrolytes.
9. Basic Notes For Medical & Allied Health Science Students
Dr. SANTHOSH KUMAR / ASSOCIATE PROFESSOR
Accumulation of acidic ketone bodies in blood leads to decreases pH, resulting in
metabolic acidosis (ketoacidosis). Since it is seen due to insulin deficiency.
Patients of DKA will show a deep gasping breathing pattern (referred to as "Kussmaul
respiration") due to compensatory hyperventilation.
Patient exhales acetone - Ketotic" (fruity) odor is present.
Management:
Administration of insulin
Restoration of water & electrolyte balance
Diagnosed by
For ketone bodies - Urine dipstick test &Rothera’s test
METABOLISM OF CHOLESTEROL
The enzymes involved in cholesterol biosynthesis are present in cytosol
The process of cholesterol synthesis:
Squalene
Squalene-2, 3-Oxide
Squalene Mono
oxygenase
Lanosterol
Cholesterol
Isopentenyl Pyrophosphate (IPP)
NADPH +H+
O2+NADPH+ H+
H2O+ NADP
NADP +PPi
5 IPPs
Squalene
Synthase
Acetyl CoA + Acetyl CoA
Acetoacetyl CoA
HMG-CoA
Thiolase
CoASH
H2O
HMG CoA
Synthase
Mevalonate
HMG-CoA
Reductase
Isopentenyl Pyrophosphate (IPP)
2NADPH +2H+
3ATP
Acetyl CoA
CoASH + H+
2NADP+CoASH
3ADP+ Pi+CO2
3 Phosphorylations &
one Decarboxylation
reactions
Cholesterol Synthesis
10. Basic Notes For Medical & Allied Health Science Students
Dr. SANTHOSH KUMAR / ASSOCIATE PROFESSOR
1) Cholesterol is synthesized from cytosolic acetyl CoA. It starts by the condensation of
three molecules of acetyl CoA to forming acetoacetyl CoA and finally HMG CoA by
thiolase & HMG-CoA synthase.
2) HMG-CoA is converted to mevalonate (C6), catalyzed by HMG-CoA reductase. It
consumes two NADPH. This reaction is the rate limiting step of cholesterol
biosynthesis.
3) Mevalonate is then activated by three phosphorylated and decarboxylated reactions,
catalyzed by kinase, ATP-dependent decarboxylase yields isopentenyl pyrophosphate
(IPP). IPP is involved in isomerisation reaction to form dimethylallyl pyrophosphate
(DMPP).
4) Four molecules of isopentenyl pyrophosphate condense with DMPP to generate
squalene by squalene synthase (NADPH-dependent enzyme).
5) Squalene undergoes cyclization to yield lanosterol, catalyzed by squalene mono
oxygenase. Then finally it forms cholesterol by a multi step process, resulting in the
shortening of the carbon chain from 30C to 27C.
Regulation of cholesterol synthesis:
HMG CoA reductase, is a rate-limiting enzyme,
It is the major control point for cholesterol biosynthesis, and is subject to different kinds
of metabolic control like by covalent modifications, hormonal regulation, some drugs.
COMPOUNDS DERIVED FROM CHOLESTEROL:
Vitamin-D
Bile Acids Bile Salts
Steroid Hormones
Derivatives of Cholesterol
Vit -D3 (Cholecalciferol) formed from cholesterol.Vit-D3 enhancing intestinal
absorption of Ca+
and helps in bone formation.
Cholesterol involved in the synthesis of steroid hormones like glucocorticoids,
mineralocorticoids & sex hormones (estrogen and progesterone), help control
CHOLESTEROL
11. Basic Notes For Medical & Allied Health Science Students
Dr. SANTHOSH KUMAR / ASSOCIATE PROFESSOR
metabolisms, inflammation, immune functions, water and electrolyte balance,
development of sexual characteristics.
Cholesterol is required for the synthesis of bile salts that are important in lipid
digestion &absorption.
DISORDERS OF LIPID METABOLISM
HYPERCHOLESTEROLEMIA:
High levels of cholesterol in the blood.
It is a combination of "hyperlipidemia" (elevated levels of lipids in the blood) &
"hyperlipoproteinemia" (elevated levels of lipoproteins in the blood).
Causes
• Environmental factors - Dietary choices.
• Genetic factors - due to a single gene defect such as in the case of familial
hypercholesterolemia.
Secondary causes:
o High consumption alcohol, smoking
o Obesity
o Type 2 Diabetes mellitus
o Nephrotic syndrome
o Obstructive jaundice and
o Hypothyroidism
ATHEROSCLEROSIS:
Thickening or hardening of arteries due to the accumulation
of lipids & cholesterol in the inner arterial wall.
• Hypercholesterolemia leads to formation of
atheromatous plaques in the arteries (atherosclerosis)
and progressive stenosis (narrowing) or even completes
occlusion (blockage) of the involved arteries.
• Finally to obstruct blood flow (low oxygen supply) in coronary artery, results in a myocardial
infarction or heart attack.
Primary causes:
o Environmental factors: Dietary choices.
Deposition of lipids (TG,
Cholesterol& other lipids) in the
inner arterial wall.
↓
Formation of plaque
↓
Endothelial damage
↓
Narrowing of the arterial lumen
12. Basic Notes For Medical & Allied Health Science Students
Dr. SANTHOSH KUMAR / ASSOCIATE PROFESSOR
o Genetic factors: additive effects of multiple genes & single gene defect (case of familial
hypercholesterolemia).
Secondary causes:
o Obesity, high consumption alcohol & smoking, Diabetes mellitus, nephrotic syndrome,
obstructive jaundice, hypothyroidism & Cushing’s syndrome
o It can reduced by
Consumption of PUFA with low cholesterol diet
Dietary fibers
Avoiding high carbohydrate diet &
Taking statin drugs (lovastatin, simvastatin & atorvastatin)
Treatment:
o Eat low fat diet & exercise
o Moderate consumption of alcohol,
o Drugs therapy e.g., statin drugs.
o Natural antioxidants such as Vit- E, C or β-carotene (protecting LDL against oxidation)
OBESITY
Anyone who is more than 20% above the standard weight for the same age, sex, and race,
generally is considered to be overweight.
Causes:
Physiological: Overeating than caloric requirement, use of oral contraceptives for prolonged
period & post menopausal women, genetic influences.
Metabolically: Diabetes mellitus & Hyperlipidemia states
Hormonal: Hypothyroidism, Hypogonadism, Hypopituitarism & cushing’s syndrome
Obesity leads to hypertension, cardio vascular diseases, stroke, diabetes & atherosclerosis
Metabolic changes in Obesity:
o Serum triglyceride & Cholesterol levels are raised.
o Mobilization of free fatty acid is reduced.
o Promotes lipogenesis and inhibits lipolysis
o BMR is normal.
LIPOPROTEINEMIAS
13. Basic Notes For Medical & Allied Health Science Students
Dr. SANTHOSH KUMAR / ASSOCIATE PROFESSOR
Lipoproteinemias are high conc. of plasma lipoproteins.
o Primary: genetic disorder
o Secondary: underlying disease (thyroid, liver, renal diseases)
HYPO LIPOPROTEINEMIAS (Decreased lipoproteins)
Lipoproteinemias Defect Decreased levels
A beta lipoproteinemias Absence of LDL Low plasma cholesterol, chylomicrons
because of low VLDL & TG
Familial α-lipoprotein
deficiency (Tangier’s disease)
Deficiency of HDL Plasma HDL completely absent & also
Apo A-I & II
HYPER LIPOPROTEINEMIAS:
FREDERICK SON CLASSIFICATION OF LIPOPROTEINEMIAS
Lipoproteinemias Defect Increased levels
Type-I: Familial
lipoproteinemias
Lipoprotein lipase
enzyme & Apo C-II
TG, chylomicrons, LDL, VLDL &
HDL
Type –II: Familial hyper
cholesterolaemia
LDL receptors LDL, Cholesterol &TG
Type –III: Familial Dys-Beta
lipoproteinemias (broad beta
disease)
Defect in remnant
metabolism
LDL, VLDL, cholesterol, TG, Apo-E
& Apo-B
Type-IV: Familiar Hyper
triglyceridaemia:
VLDL, endogenous TG.
Decreased HDL, LDL.
Type-V : Combined hyper
Lipidaemias
Increased chylomicrons & VLDL &
TG.Decreased con.c of HDL & LDL
HYPOCHOLESTEROLEMIA:
Decreased cholesterol below the normal levels in plasma
Causes:
o Hyper thyroidism,
o Liver necrosis,
o Malabsorption syndrome,
14. Basic Notes For Medical & Allied Health Science Students
Dr. SANTHOSH KUMAR / ASSOCIATE PROFESSOR
o Pernicious anemia & Haemolytic jaundice
CHAPTER-17
DIGESTION AND ABSORPTION OF PROTEINS
Digestion and absorption takes place in GI tract at different levels with proteolytic enzymes
aided by gastro intestinal hormones
Digestion in stomach
Hydrochloric acid secreted by parietal cells of stomach denatures proteins and makes it
susceptible to hydrolysis by protease enzymes.
Pepsin:
It is secreted as inactive zymogen –pepsinogens by chief cells of stomach
Pepsinogens is converted to pepsin by HCl
HCl
Pepsinogens Pepsin
Later, pepsin itself causes activation of pepsinogens to pepsinogens to pepsin (auto
catalysis).
Pepsin
Pepsinogens Pepsin
It is an endopeptidase with an optimum pH of 1 of 2.
Its end products are proteases and peptones.
It hydrolysis peptide bonds of phenyl alanine, tyrosine, tryptophan, glutamate
Digestion in duodenum
Proteolytic enzymes of pancreatic juice carry on further digestion
Pancreatic enzymes secreted trypsinogen, chymotrypsinogen, procarboxypeptidase, proelastes
and collagenase. These are zymogens released from pancrease mediated by the secretion of
cholecystokinin and secretin ( two polypeptide hormones of digestive tract)
Trypsin
It is secreted as inactive trypsinogen. The activation is brought about by an enzyme
enterokinase of intestinal juice.
It is an endopeptidase, hydrolyses peptide bonds formed by basic amino acids arginine,
histidine and lysine
15. Basic Notes For Medical & Allied Health Science Students
Dr. SANTHOSH KUMAR / ASSOCIATE PROFESSOR
It acts on proteins, proteoses, peptones converting them to polypeptides.
Optimum pH is 8 to 9.
Enterokinase
Trypsinogen Trypsin
Chymotrypsin
It is secreted as inactive chymotrypsinogen.
It is an endopeptidase specific for peptide bonds of aromatic amino acids (Phenyl alanine,
tyrosine and tryptophan).
Optimum pH is 7 to 8
Trypsin
Chymotrypsinogen Chymotrypsin
Proelastase:
It is an endopeptidase.
Hydrolyses peptide bonds next to small amino acid residues such as glycine, alanine and
serine
Trypsin
Proelastase Elastase
Carboxypeptidase:
It is an exopeptidase. It hydrolyses peptide bonds adjacent to carboxyl terminal, liberating
amino acids
Trypsin
Procarboxypeptidase Carboxypeptidase
Proteins
↓
Proteoses
↓
Peptones
↓
Amino acids
16. Basic Notes For Medical & Allied Health Science Students
Dr. SANTHOSH KUMAR / ASSOCIATE PROFESSOR
In small intestine:
Amino peptidase
Present in intestinal juice, it is an exopeptidase.
It hydrolyses peptide bonds adjacent to amino terminal, liberating amino acids.
Dipeptidase:
Present in intestinal juice
It hydrolyses dipeptides to liberate amino acids
Dipeptide Amino acid + Amino acid
End products of protein digestion is amino acids
ABSORPTION
Amino acids are absorbed in small intestine by active transport, which is sodium dependent
system
These are six different carrier proteins for different groups of amino acids.
L-amino acids are preferentially absorbed compared to D- amino acids.
Amino acids are carried to liver and further metabolized
Gamma glutamyl cycle (Meisters cycle)
It takes place in kidney tubules and brain.
Amino acids enter into the cell with help of glutathione.
Meisters cycle
Digestion of proteins
17. Basic Notes For Medical & Allied Health Science Students
Dr. SANTHOSH KUMAR / ASSOCIATE PROFESSOR
Tripeptide glutathione (GSH) reacts with the neutral amino acids to form gamma
glutamyl amino acid .This is catalyzed by gamma glutamyl transferase
The glutamyl amino acid is then cleaved to give the free amino acid inside the membrane.
The net result is the transfer of an amino acid across the membrane.
The transport of one molecule of amino acid and regeneration of GSH requires 3
molecules of ATP The transport of one amino acid with regeneration of glutathione
required three molecules of ATP
OVERVIEW OF DIGESTION OF PROTEINS
S/
No
Proteolytic
Enzyme
Zymogen
Form
Activation Substrate Products Optimum
pH
Specifications
01 Pepsin
Stomach
Gastric
Juice
Pepsinoge
n
By Gastric
HCL
Protein
Proteoses
Peptone
Poly
peptides
1-2
Low pH
It is a endopeptidase
specifically hydrolysis on
interior peptide bond where
the- NH2 group is coming
from aromatic amino acid.
Like phenyl alanine or
tyrosine.
02 Trypsin
Intestine
Pancreatic
Juice
Trypsinog
en
Entero
kinase
(In
intestine)
Protein
Proteoses
Peptone
Poly
peptides
7-8 It is endopeptidase specifically
hydrolyzing the interior
peptide bond where the -NH2
group is coming from basic
amino acid like arginine,
histidine, and lysine etc
03 Chymotry
psin
Pancreatic
Juice
Chymotrip
sinogen
Trypsin
pancreas
Protein
Proteoses
Peptone
Poly
peptides
7-8 It is endopeptidase specifically
hydrolyzing the interior
peptide bond where the –
COOH group coming from
aromatic amino acid, like
phenyl alanine or tyrosine.
04 Carboxy
peptidase
Pancreas
Pancreatic
Juice
Procarbox
y
peptidase
Trypsin
Pancreas
Polypepti
des
Tri
peptides
&
Di
peptides
7-8 It is an exopeptidase acts from
carboxylic end of polypeptide
cleaving one or 2 or 3 amino
acids at a time producing
tripeptides, dipeptides &
amino acids.
05 Amino
peptidase
Intestinal
mucosal
- - Polypepti
des
Tri
Peptides
&
Di
7-8 It is an exopeptidase acts from
amino end of polypeptide
cleaving 2 or 3 amino acids at
a time producing tripeptides,
18. Basic Notes For Medical & Allied Health Science Students
Dr. SANTHOSH KUMAR / ASSOCIATE PROFESSOR
cells peptides dipeptides.
06 Tri
peptidase
Intestinal
juice
- - Tri
peptides
Di
peptides
&
Amino
acids
7-8 It is an exopeptidase acts from
amino end of polypeptide
cleaving one or 2 or 3 amino
acids at a time producing tri-
peptides, dipeptides & free a a.
07 Di
peptidase
Intestinal
juice
- - Di
peptides
Amino
acids
7-8 It is an exopeptidase acts from
amino end of polypeptide
cleaving one or 2 or 3 a.a s at
a time producing tripeptides,
dipeptides & free a.a’s
Note: Di & Tripeptidases also help in completion of protein digestion, final products are free
amino acids.
CHAPTER-18
GENERAL REACTIONS OF AMINO ACID
The amount of free amino acids distributed throughout the body is called amino acid pool.
Plasma level for most amino acids varies widely throughout the day. It ranges between 4 –8
mg/dl.
It tends to increase in the fed state and tends to decrease in the post absorptive state.
19. Basic Notes For Medical & Allied Health Science Students
Dr. SANTHOSH KUMAR / ASSOCIATE PROFESSOR
All the catabolic pathway of amino acids involves decarboxylation, transamination, and
deamination reactions to form α-keto acid.
During the catabolism of amino acids, the α-keto acids that remain after removal of
carboxylic group as carbon dioxide and amino group as ammonia from amino acids are
called the carbon skeleton. Further carbon skeleton either enters carbohydrate
(glucogenic) or lipid metabolisms (ketogenic)
Ammonia is converted into urea in the liver.
a) Decarboxylation reactions:
Decarboxylation means removal of CO2 from amino acid with formation of
corresponding amines.
It is catalyzed by decarboxylase enzyme.
Examples of decarboxylation reaction include:
o Decarboxylation of histidine to form
histamine.
o Decarboxylation of tyrosine to form Tyramine
o Glutamate to form gamma amino glutamic acid (GABA)
b) Transamination reactions:
Transamination means transfer of amino group from α-amino acid to α-keto acid with
formation of a new α-amino acid and a new α-keto acid. It occurs in liver.
Biosynthesis of
nonessential amino
acids
Dietary protein
Breakdown of tissue
proteins
Amino acids
pool
Sources of amino acid
Fate of amino acids
Formation of Structural protein
(eg: tissue proteins)
Biosynthesis of peptide hormones,
haemoglobin, myoglobin & enzymes)
Synthesis of biological important
peptides (eg: Glutathione)
Biosynthesis of NPN substances (eg:
Urea, uric acid, creatine, creatinine)
20. Basic Notes For Medical & Allied Health Science Students
Dr. SANTHOSH KUMAR / ASSOCIATE PROFESSOR
All amino acids can be transaminated except lysine, threonine, proline and hydroxy proline.
All transamination reactions are reversible.
α- Amino acid New α- Keto acid
+ Transaminase / Amino transferase & PLP
+
α- Keto acid New α- Amino acid
It is catalyzed by aminotransferases (transaminases).
It needs pyridoxal phosphate as a coenzyme.
Pyridoxal phosphate accepts the amino group from amino acid to form pyridoxamine
phosphate, which in turn gives the amino group to α-keto acid.
Examples of transaminases:
Serum glutamate oxaloacetate transaminase (SGOT) /Aspartate amino transferase
(AST) is specific for the cardiac lesions & also acute liver diseases, Hemolytic anemia.
Serum glutamate pyruvate transaminase (SGPT) / Alanine amino transferase (ALT) is
specific for liver diseases and also increases in acute hepatitis, hepatic Jaundice
DEAMINATION REACTIONS:
Deamination means the removal of amino group from α-amino acid in the form of
ammonia with formation of α-keto acid in liver and kidney.
Deamination occurs in two ways: A. Oxidative deamination.
B. Non oxidative deamination.
A. Oxidative deamination:
It is catalyzed by enzymes L & D-amino acid oxidase and Glutamate dehydrogenase.
Removal of ammonia from the amino acids with the link of oxidation process
L- Alanine Pyruvate
Alanine amino transferase (ALT)
PLP
+
α- ketoglutarate
+
L-Glutamate
L- Aspartate Oxaloacetate
Aspartate amino transferase (AST)
PLP
+
α- ketoglutarate L-Glutamate
+
21. Basic Notes For Medical & Allied Health Science Students
Dr. SANTHOSH KUMAR / ASSOCIATE PROFESSOR
B. Non-oxidative deamination:
Removal of ammonia from the amino acids without link of oxidation process
Dehydratase enzyme deaminates amino acids containing hydroxyl group & it needs
pyridoxal phosphate as coenzyme.
METABOLISM OF AMMONIA:
The transport of ammonia mostly occurs in the form of glutamine or alanine and not as
free ammonia.
Alanine is important for NH3 transport from muscle to liver by glucose – alanine cycle
(in starvation).
The ammonia is absorbed from the intestine into the portal venous blood.
Liver promptly removes the ammonia from the portal blood.
DISPOSAL OF AMMONIA:
Ammonia has been disposed as Urea
From amino acids via
Transamination &
deamination
Degradation of
biogenic amines AMMONIA
Formation and Metabolic fate of ammonia in the body
Converted to urea (urea cycle)
Synthesis of non essential amino acids
Formation of Purines & Pyrimidines
Maintains the acid base balance via
NH4
+
ions
From the amino group of
purines and Pyrimidines
acids
By the action of intestinal
bacteria (urease) on urea
acids
Synthesis of Glutamine
Formation of amino sugars
Serine + H2O Pyruvate + NH4
+
Serine dehydratase
Threonine dehydratase
Threonine α- ketoglutarate + NH4
+
Glutamic acid + H2O α- Ketoglutarate + NH4
+
Glutamate dehydratase
NADH+H+
NAD+
22. Basic Notes For Medical & Allied Health Science Students
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UREA
Urea is the end product of protein catabolism.
It is synthesized in liver & transported to kidneys for excretion in urine.
The nitrogen of amino acids converted to ammonia first, it is toxic to the body. Then
immediately it converted to urea by detoxification process (non toxic product).
About 80-90% of N2 in the urine is in the form of urea.
Structure of urea:
Urea molecule has two —NH2 groups joined by a carbonyl (C=O) functional group.
In this two —NH2 groups derived from one from ammonia & the other from aspartate.
Carbonyl (C=O) group is supplied by CO2
UREA CYCLE (FORMATION OF UREA)
The urea cycle takes place partly in the cytosol and partly in the mitochondria.
Carbamyl phosphate synthetase 1 [CPS1]: This mitochondrial enzyme converts the
ammonia into carbamyl phosphate, which is an unstable high energy compound. It requires
two molecules of AMP +
PPi to drive its synthesis.
Ornithine
transcarbamylase: The
next reaction also takes
place in the liver,
mitochondrial matrix space,
where ornithine is
converted into citrulline.
The remainder of the urea
cycle takes place in the
cytosol.
Arginino-succinate
synthetase: Once in the
cytosol, citrulline
Urea formation (Urea cycle)
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Dr. SANTHOSH KUMAR / ASSOCIATE PROFESSOR
condenses with aspartate and the reaction is driven by ATP. In this way aspartate contributes
the second nitrogen atom to urea, the first having come from ammonia. [Production of
arginino-succinate is an energetically expensive process, since the ATP is split to AMP and
pyrophosphate. The pyrophosphate is then cleaved to inorganic phosphate using
pyrophosphatase, so the overall reaction costs two equivalents of high energy phosphate per
mole].
Arginino-succinate lyase: Elimination of fumarate from arginino-succinate then yields
arginine. [Fumarate is formed as a by-product. Fumarate is not transported by
mitochondria, so this requires the presence of cytosolic fumarase to form malate].
Arginase: Cleavage of arginine by arginase to produce urea regenerates ornithine, which is
then available for another round of the cycle.
Regulation of urea cycle:
Carbamyl phosphate synthetase-I is rate limiting step.
CPS-1 is strongly activated by N-acetyl glutamate (NAG), which controls the overall rate of
urea production
More intake of protein rich meal it leads to increasing NAG in liver. Then leads to increased
urea synthesis.
Inherited disorders of urea cycle:
Inherited disorders Clinical features
Hyper ammonemia
type-I
Carbamyl phosphate synthetase -1 (CRP-1) enzyme defect.
Ammonia toxicity is occurs.
Ornithinemia (or)
Hyper ammonemia
type-II
Ornithine transcarbamylase enzyme defect
Increased levels of glutamine, NH3& ornithine seen in blood.
Citrullinemia Arginino succinate synthetase enzyme defect.
Mental retardation occurs in this case.
Increased levels of NH3& citrulline are seen in blood.
Argininosuccinic
acidurias
It is inherited disorder in fatal (before 2year of age).
Arginino succinase enzyme defect.
24. Basic Notes For Medical & Allied Health Science Students
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Mental retardation.
Increased levels of Arginino-succinate are seen in blood & urine.
Hyper argininemia Arginase enzyme defect.
Hyper ammonemia is occurs.
Increased excretion of lysine, cystine, ornithine & arginine in urine.
CLINICAL ASPECT OF AMMONIA:
The concentration of ammonia in blood from 40 to 70 μ gm/100ml,
AMMONIA TOXICITY:
A marginal elevation of NH3 in blood is found to be toxic to the body.
Hyper ammonemia:
1) Acquired hyper ammonemia is usually the result of cirrhosis of the liver with the
development of a collateral circulation, which shunts the portal blood around the organ,
there by severely reducing the synthesis of urea.
2) Inherited hyper ammonemia results from genetic defects in the urea cycle enzymes.
Ammonia intoxication is characterized by:
o A peculiar flapping tremor.
o Slurring of speech.
o Blurring of vision.
o And in severe cases coma and death due to increased NH3 concentration in blood and
brain.
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METABOLISM OF NON PROTEIN NITROGENOUS (NPN)
SUBSTANCES
Definition:
The nitrogen containing substances other than protein are called non-protein nitrogenous
substances.
The important NPN substances are
o Urea
o Uric acid and
o Creatinine
Urea formations see in above page no:
Clinical significance of urea:
Normal levels: Blood urea conc is 15 to 45 mg/dl
Hyper Uremia :
Increased urea levels in blood more than 45mg/dl
Hyper uremia mainly occurs in three conditions
Pre Renal Conditions Renal Conditions Post Renal Conditions
Dehydration, shock,
severe burn, major
surgeries &
Hemorrhage
Acute & chronic
glomerulonephritis and
Hydronephrosis (obstruction of the
free flow of urine from the kidney)
Enlargement of prostate,
Stones in urinary tract and
Tumors of bladder
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Hypo Uremia:
o Decreased urea levels seen in Severe liver diseases like liver hepatitis, Decreased
protein intake And Protein malnutrition
II) URIC ACID
Uric acid is an end product of purine nucleotide catabolism
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen,
and hydrogen with the formula C5H4N4O3.
Biomedical Importance of Uric acid
It is a strong reducing agent.
It plays as a potent antioxidant
Act as a free radical scavenging molecule acting together with thiol groups of
proteins.
Removes both hydroxyl & peroxyl radicals.
Formation of uric acid:
Catabolism of the purine nucleotides leads to the production of uric acid.
The enzyme xanthine oxidase makes uric acid from xanthine and hypoxanthine, which in
turn are produced from purines.
CLINICAL SIGNIFICANCE:
Normal levels of Uric acids:
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o In serum/ plasma: 3.0 - 7.0 mg/dl
o In urine: 0.5 to 0.7gm/day
HYPER URICAEMIA:
- Increased uric acid levels in serum & decreased excretion by the kidney
- Ethanol, increases the turnover of ATP & uric acid production
A) GOUT:
- It is a very painful arthritic condition. It may affect men between the ages of 40 to 50 years
Gout is associated with either
– Increased formation of uric acid
- Decreased renal excretion
Needle shaped urate crystals that get deposited in & around the joints of the extremities and
cause inflammation (painful reddish swelling) called gouty tophi (clusters of urate crystals).
Gout, apart from joints, may affect, kidneys and gall bladder in long standing untreated cases,
associated with diabetes and obesity
Classification of gout:
Primary gout Secondary gout
An inborn error of metabolism due to
overproduction of uric acid.
Due to the defective enzymes of purine
biosynthesis
Symptoms like painful arthritis & renal
failure
It results from a variety of diseases
Increased production of uric acid leads to
increased destruction or turnover of cells
(Leukemia, Polycythemia & psoriasis)
Hyper catabolic states (starvation,
trauma)
Treatment
o Reduce dietary purine intake & restrict alcohol
o Taking uricosuric drugs (Increase renal excretion & decrease
the reabsorption of uric acid )
o Allopurinol is used mainly for Gout
Allopurinol is an analog of hypoxanthine
Competitive inhibitor of xanthine oxidase
Decreasing the formation of uric acid
Allopurinol
28. Basic Notes For Medical & Allied Health Science Students
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B) LESCH-NYHAN SYNDROME
It is X- linked inherited disorder,
That affects only males
Mainly caused by a complete deficiency of an enzyme HGPRT (Hypoxanthine guanine
phosphoribosyl transferase)
It leads to decreased rate of salvage pathway, resulting in accumulation of PRPP
(phosphoribosyl pyrophosphate)
PRPP stimulates purine biosynthesis leads to increases production of uric acid
Symptoms:
o Self mutilation (destructive biting of fingers & lips)
o Hyperuricemia,
o Primary Gout,
o Urinary tract stones and nephrolithiasis,
o Neurological symptoms like mental retardation
Allopurinol is used in treatment but does not alleviate the neurologic symptoms
III) CREATINE / CREATININE:
o Creatine is a nitrogenous organic acid that occurs naturally in vertebrates.
o Helps to supply energy to all cells in the body, primarily muscle.
Formation of Creatine and Creatine Phosphate
The primary locations of creatine synthesis in the body mainly liver and kidneys.
Three amino acids L-arginine, glycine, and L-methionine are involved in creatine
formation.
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The glycine and arginine react to produce two compounds ornithine and guanidinoacetate,
catalyzed by a mitochondrial enzyme transamidinase in kidneys. This reaction is first rate-
limiting step of creatine biosynthesis.
S-adenosylmethionine (SAM) to donate the methyl group from methionine to
guanidinoacetate thus producing creatine by guanidinoacetate N-methyl transferase in
liver.
Creatine reversible process catalyzed by creatine kinase, with the help of ATP to form
phosphocreatine or creatine phosphate, then stored in skeletal muscles (95%), liver &
kidneys (5%).
Phospho creatine is a key component in energy metabolism in muscles. The creatine
kinase is a key protein that is able to regenerate ATP for muscle exercise.
FORMATION OF CREATININE
The metabolism of creatinine is a spontaneous, non-enzymatic process.
Creatinine is formed from dehydrate creatine and from dephosphorylated creatine
phosphate,
Creatinine is endogenous non-protein nitrogenous product formed in muscle from the
high-energy compound creatine phosphate. The amount of creatinine produced is fairly
constant & is primarily a function of muscle mass.
Creatinine is removed from plasma by glomerular filtration & then excreted in urine.
Methyl Transferase
(In Liver)
Guanidoacetate
CREATINE
Creatine Phosphate
S-adenosylmethionine (SAM)
ATP
Glycine
Transamidinase (In kidney)
Ornithine
Formation of Creatine and Creatinine
Arginine
S-adenosylhomocysteine
(SAH)
Creatine Kinase
(In skeletal muscle)
ADP
CREATININE
H2O
Pi
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Clinical significance:
Elevated levels of creatinine in serum are associated with various renal diseases.
Elevated levels of serum creatinine & is the half mark of chronic renal failure & may be
observed in extensive muscle destruction also.
Normal levels:
Serum creatinine – 0.6 to 1.5 mg/100ml
Daily excretion of creatinine in urine is 1 to 2 gms/day.
Increased levels Decreased levels
- Muscle dystrophy
- Impaired renal
functions
- Reduced renal blood
flow
- Congenital heart
failure.
- Diuretics, such as coffee and tea, cause more
frequent urination, thus potently decreasing
creatinine levels.
- A decrease in muscle mass will also cause a lower
creatinine, as will pregnancy.
- Vegetarians have been shown to have lower
creatinine levels.
Difference between creatine and creatinine
Creatine Creatinine
It is a muscle protein, present as creatine
phosphate
It is an anhydrous form of creatine
It formed from glycine, arginine and
methionine
It formed in muscle from creatine phosphate
It helps to supply energy to all muscle
cells in the body.
In the early stage of renal disease, creatinine
clearance test is sensitive index of impaired
renal function
CHAPTER-19
METABOLISM OF INDIVIDUAL AMINO ACIDS
METABOLISM OF GLYCINE
Glycine is a simple, neutral, nutritionally non essential, glycogenic, optically inactive but
metabolically very active amino acid.
Formation:
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Glycine synthesized from serine catalyzed by Serine OH methyl transferase
SERINE GLYCINE
THF Methylene THF
Catabolism:
Serine and glycine both enters anabolic and catabolic process. Serine undergoes non
oxidative deamination by dehydratase with PLP to pyruvate and NH3, so glycine is
glucogenic in nature.
Glycine forms glyoxylate to oxalate on transamination reaction.
Glycine + Pyruvate Glyoxylate +Alanine
Oxalate also formed on deamination of Glycine.
Glycine undergoes oxidative deamination to form NH3, CO2 and one carbon unit
methylene -THFA, further ammonia converted to urea.
Metabolic role of glycine:
It is essential for protein synthesis.
Heme is mainly synthesized by glycine and succinyl CoA.
Glycine + Succinyl CoA γ ALA Heme
It required for the formation of tissue protein like collagen (every 3rd
amino acid was
glycine)
Glycine reacts with γ-glutamyl cysteine to form glutathione
It helps in protects membranes of RBC from oxidation
Play on important role in detoxifying H2O2 and lipids, peroxides and other
harmful by products).
Benzoic acid detoxified by glycine to form hippuric acid by conjugation in liver
Hippuric acid (Detoxification)
GLYCINE
Amino acetone
Glycocholic acid (Bile acid)
Purines (C4, C5 & N7)
Glyoxylate
Glucose (gluconeogenesis)
N5, N10 methylene FH4
Tissue protein synthesis
Synthesis of Glutathione
Formation of Creatine
Heme synthesis
Formation of serine
32. Basic Notes For Medical & Allied Health Science Students
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Glycine involved in the transport of amino acids through Meister cycle.
Formation of creatine: glycine along with arginine and methionine to form creatine, than
creatine stored as a form of high energy phosphate -creatine phosphate in muscle.
Whole glycine molecule is incorporated into purine (C4, C5 and N7 of purine).
Glycine involved in bile acids synthesis (Glycocholic acid) from cholesterol to help in
emulsification process in digestion & absorption of lipids.
Under starvation, glycine it gives glucose to the body.
Glycine is present in brain stem and spinal cord; it opens chloride channels and acts as
neurotransmitter.
Glycine metabolic disorders:
Primary Hyperoxaluria
It is an autosomal recessive trait.
Increased transamination of glycine forms more glyoxylate to form oxalates. Increased
excretion of oxalates leads to oxaluria.
Normal urine 50mg/day, but in this condition it leads to 600mg/day
o More oxalates with calcium, deposits as crystals to results in stones in urinary tract,
kidneys etc.,
o Recurrent urinary tract infections in infancy
o Death in early life from renal failure / hypertension
Treatment:
Increases oxalate excretion by increased water intake, washed & minimized
Oxalate free diet (restricting tea, cocoa, beetroot, spinach, sesame seeds and leafy
vegetables).
Glycinuria:
It is inborn error of glycine metabolism.
Characterized by glycine excreted in urine, due to defect in renal reabsorption of glycine.
METABOLISM OF AROMATIC AMINO ACIDS:
Aromatic amino acids are phenylalanine, tyrosine and tryptophan
Phenylalanine (benzene group), tyrosine (indole group) are essential amino acids & non
polar amino acids.
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Tyrosine is a non essential amino acid, polar amino acid and contains phenol group.
Conversion of Phenylalanine to Tyrosine
• Phenylalanine is hydroxylated at para-position by phenylalanine hydroxylase to produce
tyrosine (p-OH phenylalanine).
• This is an irreversible reaction and requires a specific coenzyme biopterin.
• The enzyme phenylalanine hydroxylase is present in the liver
Formation of Tyrosine
Catabolism of tyrosine:
Reactions:
Tyrosine on transamination to forms para hydroxy phenyl pyruvate by tyrosine
transaminase enzyme.
On oxidation p-OH phenyl pyruvate to forms homogentisic acid
Aromatic ring of homogentisic acid opens by oxidase to converts 4-maleyl acetoacetate
4-maleylacetoacetate isomerizes to form 4-Fumaryl acetoacetate
4-Fumarylacetoacetate hydrolyses to Fumarate to inters into TCA cycle & Acetoacetate
enters to fat metabolism, so phenylalanine, tyrosine is glucogenic & ketogenic amino
acid
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Catabolism of Tyrosine
(How Tyrosine is a Glucogenic and Ketogenic amino acid showed on above reaction)
FATE OF TYROSINE:
Dopamine and norepinephrine serves as neurotransmitters in the brain and autonomic
nervous system.
Norepinephrine and epinephrine stimulate the degradation of triglycerides & glycogen.
They cause an increase in the blood pressure.
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Tyrosine is the precursor for melanin (pigment of skin, hair and eye) occurs in
melanosomes present in melanocytes.
T3 hormone synthesized from the tyrosine residues of the protein - thyroglobulin and
activated by iodine.
Derivatives derived from Tyrosine
Iodination of tyrosine ring occurs to produce mono-and diiodotyrosine from which
triiodothyronine (T3) and thyroxine (T4) are synthesized. The protein thyroglobulin
undergoes proteolytic breakdown to release the free hormones, T3 and T4.
DISORDERS OF PHENYLALANINE &TYROSINE
Phenylketonuria
Phenylketonuria (PKU) is the most common metabolic disorder in amino acid
metabolism. The incidence of PKU is 1 in 10,000 births.
It is due to the deficiency of the hepatic enzyme, phenylalanine hydroxylase.
Causes:
The accumulation of phenylalanine in tissues and blood, and results in its increased
excretion in urine.
Excessive production of phenyl-pyruvate, phenyl-acetate, phenyl-lactate and phenyl-
glutamine excreted in urine in high concentration.
Effects on CNS system -Mental and growth retardation, failure to walk or talk & seizures
and tremor
Effect on pigmentation - Inhibits tyrosinase and impairs melanin formation. It result is
hypo pigmentation that causes light skin colour, fair hair, etc.
TYROSINE
Dopamine DOPA
Norepinephrine
Thyroid Hormones
(T3 & T4)
Epinephrine
Melanin
(Color pigment)
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Phenyl acetate presents in this patient’s urine and gives the urine mousy odor.
This is usually assayed by Guthrie test, which is a bacterial (Bacillus subtilis) bioassay
for phenylalanine and phenylpyruvate in urine can be detected by ferric chloride test (a
green colour is obtained).
Tyrosinemia type II:
Due to a defect in the enzyme Tyrosine transaminase.
Accumulation and excretion of tyrosine and its metabolites – (p-OH phenyl pyruvate, p-
OH phenyl lactate, p-OH phenyl acetate, N-acetyl tyrosine and tyramine).
Neonatal tyrosinemia
The absence of the enzyme p-hydroxyphenyl pyruvate dioxygenase causes neonatal
tyrosinemia.
This is mostly a temporary condition and usually responds to ascorbic acid.
Alkaptonuria
It is a autosomal recessive disorder, due to the defective enzyme homogentisate oxidase
in tyrosine metabolism.
Homogentisate accumulates in tissues and blood, and is excreted into urine.
Homogentisate, on standing, gets oxidized to the corresponding quinones, which
polymerize to give black or brown coloured alkaptones. For this reason, the urine of
alkaptonuric patients resembles DARK BROWN in colour.
In diagnosis, change in colour of the urine on standing to brown or dark .The urine
gives a positive test with ferric chloride and silver nitrate.
Tyrosinosis or tyrosinemia type - I
This is due to the deficiency of the enzymes fumaryl acetoacetate hydroxylase and /or
maleyl -acetoacetate isomerase.
Causes:
o Liver failure, Rickets,
o Renal tubular dysfunction and polyneuropathy, diarrhea, Vomiting and
o ‘Cabbage-like’ odor.
ALBINISM
Albinism is an inborn error, due to the lack of synthesis of the pigment melanin.
37. Basic Notes For Medical & Allied Health Science Students
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Biochemical basis:
Deficiency or lack of the enzyme is tyrosinase.
Decrease in melanosomes of melanocytes.
Impairment in melanin polymerization
Lack or protein matrix in melanosomes.
Limitation of substrate (tyrosine) availability.
Lack of melanin in albinos makes them sensitive to sunlight.
Increased susceptibility to skin cancer (carcinoma) is observed.
Photophobia (intolerance to light) is associated with lack of pigment in the eyes.
METABOLISM OF BRANCHED CHAIN AMINO ACIDS
Valine, leucine and isoleucine are the branched chain and essential amino acids.
Valine is glycogenic amino acid, leucine is ketogenic amino acid and isoleucine was
glycogenic & ketogenic amino acid.
Reaction:
All the three amino acids undergo same sequence of reactions initially and later diverge to form
different end products.
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Common reaction:
Transamination – valine, leucine and isoleucine undergo transamination to form their
respective keto acids
Decarboxylation – alpha keto acid dehydrogenase complex converts alpha keto acids to
the corresponding α,β unsaturated acyl CoA thioesters.
Dehydrogenation – acyl CoA dehydrogenase catalyses to form corresponding acyl CoA.
Separate steps:
Valine finally to form propionyl CoA
Leucine is catabolized to acetyl CoA & acetoacetate.
Isoleucine is degraded to form Propionyl CoA & acetyl CoA. Based on the end products
obtained, the branched chain amino acids are either glycogenic & ketogenic.
Disorders:
Maple syrup urine disease:
It is a rare genetic defect due to the defect of enzyme branched chain -keto acid
dehydrogenase.
The urine of the affected individuals smells like maple syrup or burnt sugar.
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Causes:
Blockade in the conversion of -keto acids to the respective acyl CoA thioesters.
The plasma and urine conc of BCAAs and their keto acids are highly elevated.
Complications and symptoms
Accumulation of branched chain amino acids causes impairment in transport and function
of other amino acids.
Protein biosynthesis is reduced.
Branched chain amino acids competitively inhibit glutamate dehydrogenase.
It results in acidosis, lethargy, convulsions, mental retardation, coma and finally death
within one year after birth.
Diagnosis- FeCl3 test, DNPH test , Rothera's test
Treatment: Low diet of branched chain amino acid