Download MBBS (Bachelor of Medicine, Bachelor of Surgery) 1st year (First Year) Biochemistry ppt lectures Topic 55 Nucleoprotein Metabolism Notes. - biochemistry notes pdf, biochemistry mbbs 1st year notes pdf, biochemistry mbbs notes pdf, biochemistry lecture notes, paramedical biochemistry notes, medical biochemistry pdf, biochemistry lecture notes 2022 ppt, biochemistry pdf.
Nucleoprotein
Metabolism
Synopsis
Fates of dietary Nucleoproteins/Nucleic
Acids.
De novo Biosynthesis of Purines and
Pyrimidines.
Salvage of Purines and Pyrimidines
Catabolism of Purines and Pyrimidines
Disorders Associated To Nucleic Acid
Metabolism.
Fates Of Dietary Nucleoproteins
Nucleoproteins are
conjugated Proteins.
containing Nucleic acids
as a prosthetic group.
Nucleoproteins are
constituents of each
and every living cell.
Food substances of both plant and
animal origin contain
Nucleoproteins or Nucleic acids
in them.
However Nucleoproteins and
Nucleic acids are non essential
nutrients.
Since biosynthesized in the
body.
Digestion and Absorption
Of
Nucleoproteins
Dietary Nucleic acids
remain unchanged in
mouth.
In Stomach gastric HCl
denatures Dietary
Nucleoproteins.
Cleaves Hydrogen bonds
of Nucleic acids.
Predominant and complete
digestion of Nucleic acids
takes place in small intestine.
The specific Enzymes required
for the digestion of DNA and
RNA are present in the
Pancreatic and Intestinal
juice which specifically act and
break the bonds.
Nucleic acids are digested in the
small intestine by
Deoxyribonuclease /
Phosphodiesterase to generate
Nucleotides.
By the catalytic action of
Nucleotidase and Nucleosidase.
Nucleotides and Nucleosides are,
degraded to three components :
Nitrogen Base , Pentose and
Phosphate
Degradation of Nucleoproteins
Nucleoprotein
In Stomach
Gastric acid and
pepsin
Nucleic acid
Protein
In small intestine
Endonucleases: RNase and DNase
Nucleotide
Nucleotidase
Phosphate
Nucleoside
Nucleosidase
Base
Ribose
End Products Of Nucleic Acid
Digestion
Nitrogen Bases:
Purines and Pyrimidine
Sugars:
Ribose and Deoxyribose
Phosphoric Acid
Absorption
Dietary Purines and Pyrimidines
obtained through digestion of Nucleic
acids are absorbed through intestinal
lumen.
Some unabsorbed Purines are
metabolized by intestinal microbial
flora and excreted out through feces.
The absorbed Nitrogen bases
are carried to Liver .
These are degraded and
excreted out of the body.
Thus human body is not
dependent upon the dietary
Nucleic acids for its use.
Ribose can be absorbed and
catabolized to generate energy.
Nucleotides
Nucleotides are chemically composed of
Nitrogen base: Purines and Pyrimidines
Sugar: Ribose / Deoxyribose
Phosphate group
Functions of Nucleotides
v Precursors/Building blocks for
DNA and RNA synthesis
v Essential carriers of chemical
energy, especially ATP (Energy
transformation)
vComponents of the
coenzymes NAD+, FAD, and
coenzyme A
vATP , ADP, and AMP may
function as allosteric
regulators and participate in
regulation of many metabolic
pathways.
vATP involved in covalent
modification of enzymes.
vcAMP and cGMP, are also cellular
second messengers.
v Formation of activated intermediates
such as UDP-Glucose and CDP-
Diacylglycerol.
Can Cells Biosynthesize
Nucleotides?
v Nearly all living organisms
biosynthesize Purine and
Pyrimidine Nucleotides through
"De novo biosynthesis pathway"
v Many organisms also "Salvage"
Purines and Pyrimidines from
diet and degradative pathways.
Purine Nucleotide
Metabolism
Anabolism
Purine Nucleotide Biosynthesis
De Novo Biosynthesis
Of
Purine Nucleotides
Purine Ring System
Purines And Pyrimidines
Nucleoside and Nucleotide
Nucleoside =
Nitrogenous base Ribose
Nucleotide =
Nitrogenous base Ribose Phosphate
Nucleotides
are
Building blocks
of
Nucleic acids
Structure of Nucleotides
pyrimidine
OR
purine
N-b-glycosyl
bond
Ribose
or
2-deoxyribose
There are two pathways
leading to Biosynthesis of
Nucleotides
De Novo Biosynthesis:
This is a main synthetic pathway.
The biosynthesis of
nucleotides begins /very new
with the use of small metabolic
precursors as a raw material:
Amino acids, Ribose-5-phosphate,
CO2, and One-carbon units.
Salvage pathways:
The synthesis of nucleotide by
recycle of the free Nitrogen
bases or nucleosides released
from nucleic acid breakdown.
This is important in Brain and Bone
marrow
De Novo Biosynthesis
Of Purine Nucleotides
Site Of
Purine Nucleotide
Biosynthesis:
Predominantly In
cytosol of Liver,
To some extent in
smal intestine and
Thymus.
In humans, all
necessary enzymes for
Purine Nucleotide
biosynthesis are found in
the cytoplasm of the cell.
Denovo biosynthesis occurs
in most of the cells' cytosol
Except human Brain,
Polymorphonuclear
leukocytes and
Erythrocytes.
Requirements For
De Novo Biosynthesis
Of
Purine Nucleotides
vPurines are syn thesized using
5PhosphoRibose (R-5-P) as the
starting material step by step.
vPRPP (5-Phosphoribosyl-1-
Pyrophosphate) is an active donor
of R-5-P.
The Purine ring is synthesized by
a series of biochemical reactions
that add the carbon and nitrogen
atoms to a pre-formed Ribose-5-
phosphate.
The Ribose-5-phosphate is
synthesized as part of the
Hexose Mono Phosphate
pathway.
HMP Shunt
Source For Ribose-5-Phosphate
Conversion of
Ribose-5-Phosphate to PRPP
Phospho Ribosyl Pyro
Phosphate (PRPP) is a starting
material for Purine Denovo
biosynthesis.
PRPP is formed from Ribose-5
-Phophate.
?The Pentose sugar is always a Ribose, which may
be reduced to Deoxyribose after nucleotide
synthesis is complete.
?5-Phosphoribosyl-1-pyrophosphate (PRPP) is
also involved in synthesis of Pyrimidine
nucleotides, NAD+, and Histidine biosynthesis.
?The De novo biosynthesis of Purine
nucleotide means a very new
synthesis using raw materials as
?Phosphoribose
?Amino acids : Gly , Gln and Asp
?One carbon units and
?CO2
Nitrogen and Carbon Sources Of
Purine Ring Biosynthesis
John Buchanan (1948) "traced" the
sources of all nine atoms of Purine ring
N-1: Aspartic acid
N-3, N-9: Glutamine
C-2, C-8: N10-Formyl-THF- One carbon
units
C-4, C-5, N-7: Glycine
C-6: CO2
Element Sources For Purine bases
N10Formyltetrahydrofolate
N10Formyltetrahydrofolate
FH4 (or THF)
N10--CHO--FH4
The De Novo synthetic pathway can
be divided into two Stages:
Stage one : Formation of Inosine
Mono Phosphate ( IMP )
Stage two : Conversion of IMP to
either AMP or GMP
v IMP (Inosine-5'-Monophosphate) is
first biosynthesized Purine
Nucleotide in this Denovo synthetic
pathway.
vIMP is a nucleotide with
Hypoxanthine as Nitrogen base.
vIMP is then converted to AMP and
GMP.
Biosynthesis of
Inosine Mono Phosphate (IMP)
Basic pathway for De novo
biosynthesis of Purine
Ribonucleotides
Starts from Ribose-5-phosphate(R-5-
P)
Requires 11 steps overall
Occurs primarily in the Liver cytosol.
Steps
Happenings
1
Activation of PRPP
2 and 5
Entry of Glutamine
3
Entry of Glycine
4 and 10
Entry Of N10THF
6
Ring Closure
7
Entry Of CO2
8
Entry of Aspartate
Steps
Happenings
9
Removal of Fumarate
11
Ring Closure
PRPP Synthetase
Ribose 5Phosphate + ATP---------------------------PRPP +
AMP
Amidotransferase
PRPP + Glutamine ---------------------------PRA + Glutamate
vOnce Phospho Ribosyl Amine
(PRA) is formed , the building of the
Purine ring structure begins.
vIn nine successive reactions the first
Purine nucleotide formed is IMP .
Step 1:Activation of Ribose-5-phosphate
OH
Committed/Regulatory
Step
1 ATP
AMP
Ribose Phosphate Pyrophosphokinase/
PRPP Synthetase
Step 2: Acquisition of Purine atom
2
N9
Gln:PRPP
Amidotransferase
?Steps 1 and 2 are tightly
regulated by feedback
inhibition
5-PRA
Step 3: Acquisition of Purine atoms C4, C5, and N7
3
Glycinamide Synthetase
?Step 4: Acquisition of Purine atom C8
4
GAR transformylase
Step 5: Acquisition of Purine atom N3
5
?Step 6: Closing of the Imidazole ring
6
Step 7: Acquisition of C6
7
AIR carboxylase
Carboxyaminoimidazole
ribonucleotide (CAIR)
Step 8: Acquisition of N1
Carboxyaminoimidazole
ribonucleotide (CAIR)
SAICAR synthetase
Step 9: Elimination of Fumarate
Adenylosuccinate Lyase
Step 10: Acquisition of C2
AICAR Transformylase
Step 11: Ring Closure to form IMP
? Once formed, IMP is rapidly
converted to AMP and GMP (it does
not accumulate in cel s).
IMP is a nucleotide of Nitrogen
base Hypoxanthine(6 OxyPurine).
IMP is the first Purine Nucleotide
synthesized in Denovo Synthesis
mechanism.
The De Novo pathway for Purine
biosynthesis.
Step 1: Ribose-5-phosphate
pyrophosphokinase.
Step 2: Glutamine phosphoribosyl
pyrophosphate
amidotransferase.
Step 3: Glycinamide ribonucleotide
(GAR) synthetase.
Step 4: GAR transformylase.
Step 5: FGAM synthetase (FGAR
amidotransferase).
Step 6: FGAM cyclase (AIR
synthetase).
Step 7: AIR carboxylase.
Step 8: SAICAR synthetase.
Step 9: adenylosuccinase.
Step 10: AICAR transformylase.
Step 11: IMP synthase.
N10-CHOFH4
N10-CHOFH4
6 ATPs are required in the
Purine biosynthesis from
Ribose-5-phosphate to IMP.
Since in one step ATP is
converted to AMP.
Hence this is really 7 ATP
equivalents.
Conversion of IMP to AMP and GMP
Aspartate and GTP
is used for
AMP synthesis.
Glutamine and ATP
is used for
GMP synthesis.
IMP is the precursor for both AMP and GMP.
ADP, ATP, GDP and GTP Biosynthesis
kinase
kinase
AMP
ADP
ATP
ATP
ADP
ATP
ADP
kinase
kinase
GMP
GDP
GTP
ATP
ADP
ATP
ADP
Regulation of
Purine Nucleotide Biosynthesis
Purine Nucleotide
biosynthesis is well regulated
to meet the cellular demand.
Two enzymes are the
key regulatory enzymes
for the Purine Nucleotide
De novo biosynthesis.
PRPP Synthase synthesizing PRPP
(Phosphoribosyl Phosphate).
PRPP is "Feed-forward" activator
PRPP Glutamyl Amidotransferase
The intracellular
concentration of PRPP
regulates the Purine
biosynthesis to large extent.
More availability of PRPP
increases more synthesis of Purine
nucleotides if the enzyme PRPP
Synthetase is not inhibited by feed
back control.
IMP, AMP and GMP
availability to sufficient
concentration inhibits the
regulatory enzymes by.
feed back mechanism.
PRPP activates PRPP
Glutamyl
Amidotransferase
IMP , AMP and GMP inhibit
PRPP synthetase.
Sufficient AMP:
Inhibits conversion of IMP to AMP
Sufficient GMP :
Inhibits conversion of IMP to GMP.
Regulation of AMP
synthesis:
Adenylosuccinate
synthetase is feedback-
inhibited by AMP
Regulation of GMP
synthesis:
IMP Dehydrogenase is
feedback-inhibited by
GMP
ATP stimulates conversion of IMP to GMP
GTP stimulates conversion of IMP to AMP.
That ensures a balanced synthesis of both
families of Purine nucleotides.
Significance of Regulation
Of Denovo Synthesis:
v Meet the sufficient need of the
nucleotides to body function, without
wasting.
vAMP and GMP control their respective
synthesis from IMP by a feedback
mechanism, [GTP]=[ATP]
Purine Nucleotide biosynthesis is
Regulated by Feedback inhibition
Antimetabolites /Inhibitors
of
Purine Nucleotides
vNucleotide biosynthesis
pathways are good targets for
anticancer/antibacterial
strategies.
A ntimetabolites of Purine nucleotides are
structural analogs of
Purine,
Amino acids and
Folic acid.
They can interfere, inhibit or block
biosynthesis pathway of Purine
nucleotides and further block
synthesis of DNA, RNA, and
proteins.
Widely used to control
cancer(Chemotherapeutic
Agent).
Purine Analogs
6-Mercaptopurine (6-MP) is a analog of
Hypoxanthine.
6 Mercapta Purine
6 Mercapta Purine is an inhibitor of
Enzymes:
Adenyl Succinase
IMP Dehydrgenase
Decreases levels of AMP and GMP
6-MP nucleotide is a analog of IMP
De novo synthesis
-
amidotransferase
-
IMP
6-MP
6-MP nucleotide
-
AMP and GMP
-
HGPRT
-
salvage pathway
Amino acid Analogs
Azaserine (AS) is a analog of Gutamine.
It inhibits 5th step of Purine biosynthesis.
Folate Analogs
Folate analogs Methotrexate and
Sulfonamides block Purine biosynthesis
Sulfonamides structural analogs of
PABA inhibits Folate Synthesis in
microbes.
It indirectly inhibit Purine
biosynthesis
Since THFA is a carrier of one carbon
moiety N10FormylTHF.
Folic acid Analogs
Aminopterin (AP) and Methotrexate (MTX)
MTX
Methotrexate and Aminopterin
Folate analogs are inhibitors of
Folate Reductase which form THFA.
Presence of these inhibitors affect
the reduction of Folate to THFA.
THFA is not available for 1 Carbon
moiety transfer in Purine
biosynthesis.
Methotrexate
NH
CH3
2
6 methyl pterin
p-amino benzoic acid
glutamate
Tetrahydrofolate and
One-Carbon Units
?Folic acid, a B vitamin found in
green plants, fresh fruits, yeast, and
liver, is named from folium, Latin for
"leaf".
?Folates are acceptors and donors of
one-carbon units for all oxidation
levels of carbon except CO2 (for
which biotin is the relevant carrier).
?The active/coenzyme form is
Tetrahydrofolate.
Tetrahydrofolate and One-Carbon Units
Folates are acceptors and donors of one-carbon units for all
oxidation levels of carbon except CO2 (for which biotin is the
relevant carrier).
Folate Analogs as Antimicrobial and
Anticancer Agents
De novo Purine biosynthesis depends on folic acid
compounds at steps 4 and 10
? For this reason, antagonists of folic acid
metabolism indirectly inhibit Purine
formation and, in turn, nucleic acid synthesis,
cell growth, and cell development
? Rapidly growing cells, such as infective
bacteria and fast-growing tumors, are more
susceptible to such agents
Sulfonamides are effective anti-
bacterial agents
Methotrexate and Aminopterin are
folic acid analogs that have been
used in cancer chemotherapy
Precursors and analogs of Folic acid
employed as antimetabolites: sulfonamides ,
as well as methotrexate, aminopterin, and
trimethoprim,
These compounds shown here bind to
dihydrofolate reductase (DHFR) with about
1000-fold greater affinity than DHF and thus
act as virtually irreversible inhibitors.
Anti Cancer Drugs: Methotrexate
Methotrexate, one of the earliest anti-
cancer drugs, inhibits folate
metabolism
Folate provides methyl groups for
biosynthetic reactions
It is essential for the conversion of
dUMP to TMP
It provides carbon for the purine ring.
Methotrexate and Cancer
? Affects rapidly growing cells
? Adverse events include anemia, scaly skin, GI
tract disturbances (diarrhea), and baldness
? Resistance to MTX is caused by amplification of
dihydrofolate reductase gene
? The structural analogs of folic acid(e.g.
MTX) are widely used to control
cancer (e.g. Leukemia).
? Notice: These inhibitors also affect the
proliferation of normally growing cells.
This causes many side-effects
including anemia, baldness, scaly skin
etc.
Formation of
Deoxyribonucleotide
Formation of Deoxyribonucleotide
involves the reduction of the sugar
moiety of Ribonucleoside
Diphosphates (ADP, GDP, CDP or
UDP).
Deoxyribonucleotide synthesis occurs
at the nucleoside diphosphate(NDP)
level.
Deoxyribonucleotide synthesis at the NDP level
Summary of Purine biosynthesis
IMP
Biosynthesis Of Pyrimidines
Nucleotides
Biosynthesis of Pyrimidine Nucleotides
Pyrimidine Ring System
Pyrimidine Nucleotide
Metabolism
There are also two synthesis
pathways of Pyrimidine
nucleotides:
Denovo Synthesis and Salvage
pathway.
De Novo Synthesis Pathway
In De novo pathway the
Pyrimidine ring is assembled first
and then linked to Ribose
phosphate.
The carbon and nitrogen atoms
in the Pyrimidine ring are
derived from:
Bicarbonate
Aspartate
Glutamine
Shorter pathway than for Purine
Synthesis
Pyrimidine ring is made first,
then attached to ribose-P
(unlike Purine biosynthesis)
Pyrimidine Denovo synthesis
requires 6 steps
(instead of 11 steps for
Purine)
The product is UMP (Uridine
Monophosphate)
Only 3 precursors are used for
Pyrimidine Denovo synthesis.
These contribute to the 6-
membered ring
Aspartate
Glutamine
HCO -
3
Element Sources of Pyrimidine base
Pyrimidine
Biosynthesis involves 2
ATPs
Steps
Happenings
1
Entry of CO2 and
Glutamine
2
Entry of Aspartate
3
Ring Closure with
Dehydration
4
Oxidation of
Di Hydro Orotate
5
Entry of PRPP
6
Decarboxylation To
form UMP
Step 1:
Synthesis of Carbamoyl Phosphate
? Carbamoyl phosphate
synthetase(CPS) exists in 2 types:
? CPS-I, a mitochondrial enzyme,
is dedicated to the urea cycle and
arginine biosynthesis.
? CPS-II, a Cytosolic enzyme, used
here. It is the committed step in
animals.
Step 2:
Synthesis of Carbamoyl Aspartate
ATCase: Aspartate Transcarbamoylase
?Carbamoyl
phosphate is an
"activated"
compound, so no
energy input is
needed at this step.
Step 3:
Ring closure to
form
DihydroOrotate
Step 4:
Oxidation of
DihydroOrotate
To
CoQ
Orotate
QH2
(a pyrimidine)
Step 5:
Acquisition of Ribose Phosphate moiety
Step 6:
Decarboxylation of OMP
OMP is decarboxylated to
UMP
Figure 26.15 The de novo pyrimidine biosynthetic pathway.
UMP Is Converted
To
CMP and TMP
Conversion Of UMP to CMP
UMP is converted to
CMP in presence of
Glutamine and ATP
Formation of dTMP
The immediate precursor of thymidylate (dTMP) is dUMP.
The formation of dUMP either by deamination of dCMP or by
hydrolyzation of dUDP. The former is the main route.
UDP
dUDP
dCMP
dCDP
dUMP
N5,N10-methylene-
tetrahydrofolic Acid
dTMP synthetase
dTMPATP
ATP
dTDP
dTTP
ADP
ADP
dTMP synthesis at the Nucleoside
Monophosphate level.
Summary of pyrimidine biosynthesis
UMP
Antimetabolites of Pyrimidine
Nucleotides
Antimetabolites of
Pyrimidine nucleotides are
similar with them of Purine
nucleotides.
Pyrimidine Analogs
5-fluorouracil (5-FU) is a
analog of Thymine.
Synthesis of dTMP from dUMP is
catalyzed by Thymidylate Synthase
? This enzyme methylates dUMP at the
5-position to create dTMP
? The methyl donor is the one-carbon
folic acid derivative N5, N10-Methylene-
THF
? The reaction is a reductive methylation; the
one-carbon unit is transferred at the
methylene level of reduction and then
reduced to the methyl level
? The THF cofactor is oxidized to yield DHF
? DHFR reduces DHF back to THF for serving
again
? dTMP synthesis has become a preferred
target for inhibitors designed to disrupt
DNA synthesis
? Fluoro-substituted
analogs as
therapeutic agents
5-fluorouracil
(5-FU) is used as a
chemotherapeutic
agent in the
treatment of
cancers
5-fluorocytosine is
used as an
antifungal drug
5-fluoroorotate is an
effective
antimalarial drug
The 5-Fluoro substitution
inhibits on the mechanism
of action of Thymidylate
Synthase.
Which in turn affects
DNA synthesis.
Figure 26.26 The thymidylate
synthase reaction.
Amino acid analogs
Azaserine (AS) inhibits the synthesis of CTP.
Folic acid Analogs
Methotrexate (MTX) inhibits the synthesis of dTMP.
Nucleoside Analogs
Arabinosyl cytosine (Ara-c) inhibits the synthesis of
dCDP.
Salvage Pathway
Salvage Pathway is
important in Brain and Bone
marrow
Where Denovo synthesis of
Purine and Pyrimidine
nucleotide do not occur.
Salvage Pathway of Purine
Nucleotides
Salvage pathway have
mechanisms to retrieve
Purine bases and Purine
nucleosides. They are used
to synthesize Purine
nucleotides.
Purine bases created by degradation of
RNA or DNA and intermediate of purine
synthesis can be directly converted to the
corresponding nucleotides.
The significance of salvage pathway :
Save the fuel.
Some tissues and organs such as brain
and bone marrow are only capable of
synthesizing nucleotides by salvage
pathway.
Two Phosphoribosyl transferases
are involved:
APRTase
(Adenine phosphoribosyl
transferase) for Adenine.
HGPRTase
(Hypoxanthine guanine
phosphoribosyl transferase) for
guanine or Hypoxanthine.
From Nitrogen Base to Nucleotides
APRTase
Adenine + PRPP--------------------------------AMP + ppi
HGPRTase
Hypoxanthine + PRPP-------------------------------- IMP + ppi
HGPRTase
Guanine + PRPP--------------------------------GMP + ppi
Purine Salvage Pathway
Absence of activity of
HGPRTase
leads to
Lesch-Nyhan Syndrome.
From Nucleoside to Nucleotide
AR kinase
AdenineRibose + ATP--------------------------------AMP + ADP
In comparison to De novo pathway, salvage
pathway is energy-saving.
In brain and bone marrow tissues salvage pathway
is the only pathway of nucleotide synthesis.
Pyrimidine Salvage pathway
Salvage Pathway
Pyrimidine Phosphoribosyl Transferase
(PPRTase) catalyzes the following
Salvage reaction.
Uracil + PRPP- --- UMP + ppi
In some organisms, free
Pyrimidines are salvaged and
recycled to form Pyrimidine
nucleotides
In humans, Pyrimidines are
recycled from Nucleosides, but
free Pyrimidine bases are not
salvaged
Uridine Kinase catalyzes the
formation of UMP from Uridine
and ATP.
UR + ATP------- UMP + ADP
Formation of Deoxynucleotides
Deoxynucleotides are formed by reducing
Ribonucleotide Diphosphates.
Ribonucleotide Reductase
NDP + NADPH + H+-----------------dNDP + H2O
+ NADP+
. In the reaction of Ribonucleotide
Reductase Hydrogen atoms are not
directly donated by NADPH.
Coenzyme Thioredoxin, a Protein
with two sulfhydryl groups mediates
the transfer of hydrogen atoms from
NADPH to Ribonucleotide Reductase.
Then the enzyme catalyzes the reduction of NDP, to form
dNDP.
NDP reductase
NDP + Thioredoxin ( SH )2 -------- dNDP + Thioredoxin
(-S-S-)
The regeneration of reduced Thioredoxin is
catalyzed by Thioredoxin reductase.
Thioredoxin Reductase converts Oxidized
Thioredoxin to functional Reduced Thioredoxin.
Thioredoxin is NADPH+ H+ requiring enzyme
Thioredoxin (-S-S-) +NADPH +H+
Thioredoxin ( SH )2+NADPH
NDP Reductase is an allosteric
enzyme, Its activity is
controlled by various NTPs
and dNTPs.
Catabolism Of Purine Nucleotides
Degradation of Purine Nucleotides
Adenosine
Deaminase
(2,6,8-trioxypurine)
The End product of Purine metabolism
Uric acid
Uric acid is a NPN, waste excreted end product
of Purine catabolism.
The rate of uric acid excretion by the normal
adult human is about 0.6 g/24 h in urine, arising
in part from ingested purines and in part from
the turnover of the purine nucleotides of nucleic
acids.
The normal concentration of uric acid in the
serum of adults is in the range of 3-7 mg/dl.
2, 6,8 Tri Oxy Purine
Catabolism Of Pyrimidines
Degradation of Pyrimidine Nucleotides
How Are Pyrimidines
Degraded?
Catabolism of Pyrimidine Nitrogen
Bases Cytosine and Uracil yields :
-Alanine,
Ammonium ions
CO2
-Alanine can be recycled into
the synthesis of coenzyme A
Catabolism of Thymine
yields:
-Aminoisobutyric acid
Ammonium ions
CO2
Highly soluble
Products
Principal differences
between metabolism of
Purines and Pyrimidines
Purines
Pyrimidines
Character
De Novo
De Novo
Synthesis
Synthesis
Number Of
Steps
Involved
11 Steps
6 Steps
Precursors Of Amino acids :Asp Gly Amino acids :Asp and Gln
Ring
and Gln
CO2
N10FormylTHF
CO2
Major Portion
Glycine
Aspartate
Of Ring
provided by
Purines
Pyrimidines
Character
De Novo
De Novo
Synthesis
Synthesis
Acquisition of
Ribose-
Phosphate
In Starting Steps
In End Steps
Formation of In 1st step of their a heterocyclic ring is
N-Glycosidic biosynthesis
formed first, then it
bond
(PRPP is the 1st Substrate) reacts with PRPP
products of
Uric acid
CO2, NH3, -Amino
degradation
(poor solubility in H2O) Isobutyrate and Ala
NH
(soluble in H
3
2O)
Purines
Pyrimidines
Character
De Novo
De Novo
Synthesis
Synthesis
Number Of
ATPs
6 ATPs
2ATPs
Involved
Nucleotide
Produced in
IMP
UMP
End
Ring Closure
At
6 and 11 steps
3rd Step
Disorders Of
Nucleic Acid
Metabolism
Disorders of
Purine Nucleotides Metabolism
Gout
Gouty Arthritis
Gout derived from Latin
Word: GUTTA
Meaning `A drop of
liquid'
Gout is a common metabolic
disorder of Purine
metabolism characterized by :
Persistent Hyperuricemia
Hyperuricaciduria and
Joint pain
GOUT
Gout, is a disease of the joints, usually in males,
caused by an elevated concentration of uric
acid in the blood and tissues.
The joints become inflamed, painful, and
arthritic, owing to the abnormal deposition of
crystals of sodium urate.
The kidneys are also affected, because excess
uric acid is deposited in the kidney tubules.
Gout:"Disease of Kings"
?Rich foods have a
higher
ORGAN MEATS
concentration of
WILD GAME
Nucleoproteins.
SEAFOOD
? This could cause
LENTILS
PEAS
major problems for
ASPARAGUS
a person afflicted YEAST
with Gout.
BEER
Types and Causes Of Gout
Types Of Gout
Primary Gout (Genetic Cause)
Secondary Gout
Basic Cause Of Gout
Hyperuricemia
Over Production Of Uric acid
Under Excretion Of Uric acid
Primary Gout
Primary Gout is an
inherited sex linked
recessive disorder.
Affecting more Males.
Causes Of Primary Gout
Basic cause of primary Gout is
genetic cause.
It has Enzyme defects concerned with:
Over Production Of Purine Nucleotides
than the functional use.
Over catabolism of Purine Nucleotides
Results in Hyperuricemia
5 Enzyme Defects
Causing Primary Gout
1. PRPP Synthetase
(Increased Activity))
2. PRPP Glutamyl Amido Transferase
(Increased Activity)
3. HGPRTase
(Decreased Activity)
4. Glucose 6 Phosphatase
(Decreased Activity)
5. Glutathione Reductase
(Decreased Activity)
The defect of above 5 Enzymes
in primary Gout
Directly or indirectly increases
the Denovo Biosynthesis of
Purine nucleotides.
There is overproduction of
Purine Nucleotides more than
their functional use
Which further catabolizes
them to produce increased
Uric acid levels
(Hyperuricemia)
Secondary Gout
It is an acquired cause:
In some pathological states where
there is abnormal and excessive
breakdown of cells releases
Nucleic acids and Nucleotides.
Whose catabolism produces
increased Uric acid levels
(Hyperuricemia)
Conditions Of Secondary Gout
Leukemia
Lymphomas
Polycythemia
Treatment Of Large Tumors
Traumatic Conditions
Radiation Injury
Renal Gout
Type of Gout caused due to
insufficiency of Renal System.
Where there is reduced excretion
of Uric acid through Urine.
Retention of the Uric acid in blood
leading to Hyperuricemia.
Conditions Of Renal Gout
Renal Failure
Use of Thiazide diuretics
Metabolic Acidosis
Ketoacidosis and Lacticacidosis
affects the excretion of Uric acid
through Urine.
Incidence Of Gout
?Primary Gout accounts for 90% of
cases
?Affects primarily middle aged men
Risk Factors of Gout
Obesity (High BMI)
Hypertension (HTN )
Use of Thiazide diuretics
Diet high in meat & seafood
Excess Alcohol use
o Highest with Beer
Diet high in Purines
may trigger an attack in
a susceptible persons.
RISK FACTORS OF GOUT
Male Gender
Postmenopausal female
Older Persons
Pharmaceuticals:
Cyclosporine
Pathophysiology Of Gout
?Uric acid is NPN
compound
?Waste end product of
Purine metabolism
?Excreted by the kidneys
through urine.
The Uric acid and the
Hypoxanthine
Gout
Out of body
Xanthine
In urine
Uric acid
Over 8mg/dl, in the
Diabetes
plasma
Nephrosis
Gout
Urate crystallization in
joints, soft tissue, cartilage
and kidney
The normal serum Uric
acid level in adults is 2-7
mg%
0.5-1 g of uric acid is
formed daily in the
organism.
In Gout the serum Uric acid
levels rises above 8 mg%.
Uric acid in miscible pool of
Gout patients is increased up
to 2000-4000 mg% (normally
1200mg%).
Uric acid is poorly soluble
in water.
The increased Uric acid
levels
Decreases the solubility
of Uric acid and
Get crystallized to form
Mono Sodium Urate
Crystals.
The Mono Sodium Urate
Crystals get deposited in the
synovial spaces of joints
In periarticular ,articular and
extra articular tissues to form
Tophi (Hard Mass/ Swelling)
Deposition of Urate crystals
in synovial spaces affects
the movements of joints.
Leads to pain ,
inflammation, stiffness
and redness of joints
known as Gouty Arthritis.
?Deposits of sodium urate
crystals in articular,
periarticular, and subcutaneous
tissues in Gout
HYPERURICEMIA & GOUT
nHyperuricemia caused by
?Overproduction of Urate
?Under excretion of Urate
nNo Gout w/o crystal deposition
THE GOUT CASCADE
Urate
Over production
Under excretion
Hyperuricemia
________________________________________
n Silent
Gout
Renal
Associated
n Tissue
Manifestations
CV events &
n Deposition
mortality
Clinical Manifestations
Of
Gouty Arthritis
?Onset of Gout is usually
nocturnal, with sudden swelling
and excruciating pain
?May have low grade fever
?Usually subsides within 2-10
days
?Joints are normal, with no
symptoms between attacks
?Gouty arthritis in one or more
joints (but less than four)
?Great /big toe joint
(Metatarsophalangeal) most
common first manifestation
(Monoarticular)
Other joints may be
the foot, ankle, knee,
or wrist (Polyarticular)
?Joints become tender
/stiff & cyanotic
?Recurrent attacks of pain
and swelling of the joints.
?Constant recurring
vermicular movements of
hands and feet.
?Involuntary and Jerky
movements
?Spasticity
?Mental Retardation
Urate crystals trigger a local
immune-mediated inflammatory
reaction.
With one of the key proteins in the
inflammatory cascade being
interleukin 1.
Causing inflammation of the area.
Gouty Arthritis
Main Symptoms
Joint Pain
Affects one or more joints : hip, knee,
ankle, foot, shoulder, elbow,wrist, hand,
or other joints
Great toe, ankle and knee are most
common
Swelling of Joint
Stiffness
Warm and red
Possible fever
Tophi/Skin Lump
which may drain chalky material
Gouty Arthritis may be
precipitated by :
qTrauma
qSurgery
qAlcohol ingestion
qInfection
Gouty Arthritis
Stages of Gout
n Asymptomatic Hyperuricemia
n Acute Flares of Crystallization
n Intervals between flares/Intercritical Stage
n Advanced/Chronic Gout
nComplications of Gout
Stage 1
Asymptomatic Hyperuricemia.
Very initial stage of Gout
When serum Urate concentration is
greater than 8 mg/dL,
Urate crystals may start to deposit
in the joints.
No evidence that treatment is
required.
ASYMPTOMATIC
A meaning without indicates
that there are no symptoms
associated
Patient will be unaware of
what is happening
Gout can only be determined
with the help of a physician
Stage 2
Acute Gout
If sufficient urate deposits around
joints, and if the local environment
or some trauma triggers
The release of crystals into the joint
space, an inflammatory response
occurs.
These flares can be self resolving but
are likely to recur.
ACUTE GOUTY FLARES
nAbrupt onset of severe joint inflammation,
often nocturnal
nWarmth, swelling, erythema, & pain;
Possibly fever
nIf untreated get resolves in 3-10 days
n90% 1st attacks are monoarticular
n50% are podagra (Gout of big Toe)
ACUTE GOUT
SITES OF ACUTE FLARES
n90% of gout
patients
eventually have
podagra : 1st
MTP joint
Stage 3
Intercritical periods
These are the intervals between
attacks.
During these periods, crystals
may still be present at a low
level in the synovial tissue and
fluid, resulting in future
attacks.
INTERCRITICAL
More
concentration of
uric acid crystals
Typically no
need for drug
intervention at
the time.
FLARE INTERVALS
nSilent tissue
deposition &
Hidden
Damage
Stage 4
Advanced /Chronic Gout.
If crystal deposits continue to
accumulate, patients may
develop chronically stiff,
swollen joints and tophi.
This advanced stage of
Gout is relatively
uncommon generally
avoidable with therapy..
CHRONIC GOUT
Continuous or
persistent over a
long period of
time
Treatment
required
Not easily or
quickly resolved
IN ADVANCED GOUT
Chronic Arthritis
X-ray Changes noted
Tophi Developed
Acute Flares continues
ADVANCED GOUT
Chronic
Arthritis
Polyarticular
acute flares with
upper
extremities
more involved
Sites
nCan occur in
other joints,
bursa & tendons
Advanced Gout
Clinical y Apparent Tophi
1
2
1
3
1. Photos courtesy of Brian Mandell, MD, PhD, Cleveland Clinic.
2. Photo courtesy of N. Lawrence Edwards, MD, University of Florida.
3. ACR Clinical Slide Col ection on the Rheumatic Diseases, 1998.
Acute Intermittent Gout
Initial episode usually follows decades
of asymptomatic hyperuricemia
Characterized by intense pain and
inflammation (warmth, swelling,
erythema)
Usually begins as monoarticular
involvement with first MTP joint
TOPHI
Solid urate
deposits in
tissues
TOPHI
Irregular &
destructive
Complications Of Gout
?Joint deformity
?Osteoarthritis
?Tophi may produce draining
sinuses that may become
infected.
?Renal stones, pyelonephritis,
obstructive renal disease.
Assessment for Gout
Complications
lFormation of kidney
stones
lHypertriglyceridemia
lHypertension
Gout: Kidney Stones
Diagnosis Of Gout
?History taking & physical examination
?Family history of Gout
?Clinicalsymptomsalonearesufficentto make
acuratediagnosiinmostcase
?Performing Diagnostic studies may help in
knowing the stage and progression of Gout.
Gout Diagnosing Studies
Examination of joint
fluid (Arthrocentesis
extraction of joint
fluid).
X-rays of joint
Blood Examination
Diagnostic Profile
? Serum Uric acid levels usually
elevated.
? 24 hour urine Uric acid levels
increased.
?WBC Count elevated during acute
attacks.
? ESR (elevated)
?Synovial fluid aspiration
contains Urate crystals
? X-rays appear normal in
early stages; Tophi
appear as eroded areas of
bone
SYNOVIAL FLUID ANALYSIS
(Polarized Light Microscopy)
Considered as the Gold standard
Urate Crystals are intracellular during attacks
Needle & rod shaped Urate crystals
With strong negative birefringence
SYNOVIAL FLUID
Microcopy Of Urate Crystals
Treatment Of Gout
Pal iative Treatment
Bed rest : No much
movements of joints.
Bed rest : With a position
for comfort
Treatment and Nursing Care
?Joint immobilization and protect
joint from pressure
?Local application of heat or cold
around the joint area.
Restrict intake of diet rich in
Purine content.
Restrict Alcohol
consumption
Avoid dehydration
Drink lots of Water
Specific Treatment
Allopurinol (Zyloprim) is a
drug of choice for
Treatment of Gouty
arthritis.
Allopurinol is a structural
analog of Hypoxanthine.
Allopurinol is a Competitive
inhibitor of Enzyme Xanthine
Oxidase.
Prevents conversion of
Hypoxanthine and Xanthine to
Uric acid.
Prevents accumulation of Uric
acid and its crystallization and
deposition.
Hypoxanthine and
Xanthine are more water
soluble form and readily
excreted out.
Allopurinol is transformed
to Alloxanthine and excreted
out.
Al opurinol ? a Suicide inhibitor used to treat Gout
Xanthine oxidase
Xanthine oxidase
Allopurinol Dosage:
Initial Stages
100-200 mg/day
For Maintenance
200-600 mg/day
Administration of Uricosuric
drugs :
Which decreases renal
reabsorption of Uric acid from
renal tubules
Thereby increasing Uric acid
excretion.
Example : Probenecid Salicylates.
Using Anti inflammatory
agents to arrest pain and
inflammation in Gouty arthritis:
v Colchicine
vNSAIDS : Diclofenac
vIbufren
vProxivan
TREATMENT WITH
Colchicine- reduces pain,
swelling, and inflammation; of
Gouty arthritis.
Pain subsides within 12 hrs and
relief occurs after 48 hrs.
Col aborative Care
?Prevention of Acute Attacks
lColchicine combined with:
Allopurinol (Zyloprim, Alloprim) ? blocks
production of uric acid
Probenecid (Benemid), sulfinpyrazone
(Anturane) ? inhibit tubular reabsorption of
uric acid
Febuxostat (Uloric) ? inhibits xanthine
oxidase, recently shown to reduce serum
uric acid levels
Col aborative Care
?Dietary measures
lWeight reduction
lAvoidance of Alcohol
lAvoidance of Foods high in Purines
High Risk: Yeast , Sardines, Calms
Anchovies, Herring, Mussels, liver,
kidney, goose, venison, meat soups,
sweetbreads, beer & wine
Moderate Risk: Chicken, Salmon,
Crab, Veal, Lobster , mutton, bacon,
Pork, Turkey , beef, Ham
Col aborative Care
?Prevention of Renal stones
lIncrease fluid intake to maintain
adequate urine output
lAllopurinol
lACE inhibitor Losartin (Cozaar) ?
promotes urate Diuresis
Prevent Drugs That Promote Gout
Diuretics
Leads to increased uric acid reabsorption
Low-dose aspirin
Over 6% increase in mean serum urate and 23%
decrease in uric acid clearance
Pyrazinamide
Gout observed at higher incidence
Ethambutol
Niacin
Factors Triggering Gouty Arthritis
vCool temperatures
vRapid changes in uric acid level,
vAcidosis
v Articular hydration, and
vExtracellular Matrix Proteins,
such as Proteoglycans, Collagens,
and Condroitin Sulfate
Gout:
accumulation
of Uric acid
salts in joints
Gout:
Tophuses ?
accumulation
of uric acid
salts in
cartilages,
under skin.
Lesch-Nyhan Syndrome
(LNS)
Lesch-Nyhan Syndrome(LNS)
First described in
1964 by Michael
Lesch and William L.
Nyhan.
LNS is a genetic
disorder
Affects Salvage pathway
of Purine Metabolism.
Caused due to defect or lack in the
HGPRTase an enzyme of Purine
Salvage.
Severely affects the Brain growth
and development.
LNS is a Sex-linked
genetic recessive disease
that is linked to the X
chromosome.
Affects only Males
Biochemical Defect
HGPRTase role in the body
Hypoxanthine-Guanine
Phosphoribosyl Transferase is a
Purine Salvage enzyme that
Plays a key role in the recycling of the
Purine bases, Hypoxanthine, and
Guanine into Purine nucleotide pools
through Salvage pathway.
Purine Bases are Catabolized
To Uric Acid
In LNS
In HGPRTase deficiency
the free Purine bases are
not recycled through
Salvage pathway
Instead Purines are broken
down and excreted as Uric
acid.
The rate of Purine
synthesis is increased
about 200-fold in LNS
Lack of HGPRTase activity in
Lesch-Nyhan Syndrome
causes a buildup of PRPP.
This PRPP activates the De
novo biosynthesis of Purine
nucleotides.
Loss of HGPRTase leads to
No use of PRPP in the Salvage
step
More availability of unused
PRPP
PRPP allosterically stimulates
PRPP Synthetase of De novo
Purine synthesis.
Purines synthesis is more
than its functional use.
Later these Purines are
catabolized to end high
Uric acid levels in blood
and body.
hypoxan hine-guanine
phosphoribosyl transferase
Guanine + PRPP
Guanylate + PPi
Hypoxanthine + PRPP
Inosinate + PPi
LNS Is A Cause For Primary Gout
LNS is characterized with
hyperuricemia (Uric acid level rises)
and suffers from Gout.
In addition there are mental
aberrations.
LNS patients wil self-mutilate (self
harming) by biting lips and fingers off.
Hyperuricemia In LNS
LNS is characterized with
Hyperuricemia (high
concentration of uric acid in the
blood).
A high concentration of uric acid,
solidifies and deposits in the
tissues forming Gouty Tophi.
The deposits in the joints
causes inflammation and
Gouty arthritis.
The kidneys excrete the extra
uric acid, which increases the
risk of forming Urate stones.
The urate stones may pass
as a sandy sludge or may
obstruct urine flow.
This increases the risk for
hematuria and urinary tract
infections.
Symptoms of LNS
All of the following
symptoms of LNS are a
result of an overproduction
of Uric Acid
Swelling of the joints
Urate crystal formations,
which look like orange sand,
are deposited in diapers of the
babies
Kidney stones
Blood in the urine
? Basis of neurological
aberrations in LNS
? May be due to defect in Brain
Salvage pathway.
As in LNS there is defect in Salvage
Pathway primarily carried out in
Brain.
This might affects the Brain
growth and development.
There by leading to Nervous
dysfunction and related
manifestations.
Athetosis (uncontrolled spastic
muscle movements of the arms
and legs)
Involuntary joint movements
Chorea (purposeless repetitive
movements)
Moderate mental retardation
Irritability
GIT disturbances are also noted
LNS Behavioral Elements
- Cognitive dysfunction and
aggressive and impulsive
behaviors
-Severe self injurious behavior
is common
LNS and Cerebral Palsy
"Cerebral palsy is a group of
movement disorders that result from
damage to the brain, either before,
during or shortly after birth."
Thus, LNS is often a cause for the
damage to the brain that triggers
cerebral palsy.
LNS Treatment and Prognosis
Treatment:
?Enzyme defect in LNS cannot be
treated.
?Only the symptoms of LNS can be
treated.
?The drug Allopurinol may be used
to control excessive amounts of
uric acid.
Treatment: Allopurinol ? Competitive
Inhibitor of Xanthine Oxidase
?Kidney stones can be treated
with lithotripsy
?There are unfortunately no
treatments for the behavioral
and neurological effects of
LNS
Prognosis:
vThe prognosis for LNS is poor
vBecause there are no treatments for the
neurological effects of the syndrome as
self-mutilation and may result in severe
retardation and death.
vThe build-up of excessive uric acid in the
body causes painful episodes of joints.
Lesch-Nyhan Syndrome
?Build up of Hypoxanthine and Guanine
?Degradation of hypoxanthine and guanine results in
increased uric acid
?Excess uric acid in urine often results in orange crystals
in the diaper of affected children
?Severe mental retardation
?Self-mutilation
?Involuntary movements
?Gout
Lesch-Nyhan Syndrome
Orotic Aciduria
Oroticaciduria is a rare inherited
disorder of Pyrimidine synthesis.
Caused by a deficiency of the
enzyme
Orotate Phospho Ribosyl
Transferase (OPRTase)
OMP Decarboxylase.
Type I Oroticaciduria
Both OPRTase and OMP
Decarboxylase Enzyme
deficient.
Bifunctional deficiency.
Type I Oroticaciduria
Only OMP
Decarboxylase deficient.
Enzyme defects
accumulates Oroticacid in
blood
Increased excretion of
Orotic acid in urine
(Oroticaciduria : 1.0-1.5 g)
Symptoms
Mental and Physical retarded
growth
Severe Megaloblastic Anemia
Treatment
Treat with feeding diet rich in
Uridine /Cytidine
This provide Pyrimidine
nucleotides through Salvage
Pathway.
Promotes DNA and RNA
synthesis.
Also the introduced
Pyrimidine bases inhibits
CPS II enzyme by feed
back mechanism and
block synthesis of
Oroticaciduria.
TREATMENT OF
OROTACIDURIA
Taking of
Cytidine and
Uridine during
the whole life
Adenosine Deaminase (ADA)
defects
OR
Severe Combined Immuno
Deficiency
(SCID)
SCID
Induced by
Adenosine Deaminase
Defects
Adenosine Deaminase (ADA) is an
Enzyme involved in Purine catabolism.
Deficiency of ADA enzyme leads to
Immunological disorder ?Severe
Combined Immuno Deficiency
(SCID)
The enzyme Adenosine
Deaminase is encoded by a
gene on chromosome 20.
ADA deficiency is inherited
in an Autosomal recessive
manner.
Biochemical Defect
ADENOSINE DEAMINASE DEFICIENCY
IN PURINE DEGRADATION,
ENZYME Adenosine
Deaminase catalyzes the
conversion of:
ADENOSINE/AMP INOSINE/IMP
AMP
Deaminase
ADA Deficiency
Affects DNA Synthesis
ADA deficiency accumulates
Adenosine/AMP later
transformed to dAMP and
dATP by enzyme Nucleoside
Kinases.
The formed dATP is an
inhibitor of enzyme
Ribonucleotide Reductase.
Ribonucleotide reductase
is an enzyme which catalyzes
conversion of dNDPs to
dNTPs.
Inhibited Ribonucleotide
Reductase thus unable
to produce dNTPs to
support DNA
biosynthesis.
Cause Of
Severe Combined Immunodeficiency Syndrome (SCID)
Thus Deficiency of ADA results in
accumulation of AMP and dATP
formed through Kinases.
dATP is an inhibitor of
Ribonucleotide reductase and
inhibit the biosynthesis of other
Deoxynucleotides like dCTP
ADA Deficiency Affects
The Growth and Multiplication
Of Rapidly Dividing Cells
Low availability of dNTPs
affect the DNA
biosynthesis.
This affects the rapidly
dividing cells of the body.
The low levels of dCTP affects DNA
replication.
Which further affects the growth of
rapidly dividing immune cells T
and B lymphocytes and other cells.
leading to IMMUNO DEFICIENCY.
ADA Deficiency
Leads To
Immuno Deficiency
? Defects in AMP Deaminase prevent
biodegradation of AMP
? AMP is converted into dATP by Kinases
? dATP inhibits the synthesis of other
Deoxyribonucleotide by Ribonucleotide
reductase,
? Causing problems with the Immune
System (death of lymphocytes,
immunodeficiency disease)
Decreased dATP,
dGTP levels inhibit
DNA replication
Function of Immune
System depends upon
Lymphocyte Proliferation.
ADA deficiency inhibits
Ribonucleotide Reductase
and has Low dNTPs.
This inhibits DNA Synthesis of
Lymphocytes and its
proliferation.
Immune System is
compromized due to non
functional T and B cells.
SCID
SCID is also known as
Alymphocytosis
Glanzmann-Riniker Syndrome
Sever Mixed Immunodeficiency
Syndrome
Thymic Alymphoplasia
Incidence Of SCID
1 in 100 , 000 births.
Some predict 1 in 50
,000 live births
SCID
SELECTIVELY KILLS
LYMPHOCYTES
Absence of Functional
BOTH B- and T-CELLS
Natural Killer Cells (NK)
SCID exhibits defective
antibody response.
SCID sufferers are extremely
susceptible to infectious
diseases(Bacterial , Viral
,Fungal).
SCID Treatment
Bone Marrow transplant
Gene therapy
Enzyme Replacement
Therapy - PEG-ADA
ADA DEFICIENCY
ONE OF FIRST DISEASES TO BE TREATED
WITH GENE THERAPY
ADA GENE INSERTED INTO
LYMPHOCYTES; THEN LYMPHOCYTES
RETURNED TO PATIENT
PEG-ADA TREATMENTS
ACTIVITY LASTS 1-2 WEEKS
On September 14, 1990, the first
gene therapy to combat this disease
was performed by Dr. William French
Anderson
On a four year old girl, Ashanti
DeSilva, at the National Institutes
of Health, Bethesda, Maryland,
U.S.A.
SEVERE COMBINED IMMUNODEFICIENCY
(SCID)
If ADA is deficient or absent,
Deoxyadenosine is not converted into
Deoxyinosine as normal.
This elevates the levels of
Deoxyadenosine of Purine
metabolism.
Deoxyadenosine is salvaged by a
Nucleoside Kinase, which converts it
to dAMP, leading to accumulation of
dATP and
Inhibition of Deoxynucleotides
synthesis through
Ribonucleotide reductase.
Thus, DNA replication is ceased.
This affects the rapidly growing
cells.
Points To Remember
Synthesis of Purine Nucleotides
De novo synthesis: Site,
Characteristics, Element
sources of Purine bases
Salvage pathway: definition,
significance, enzyme, Lesch-
Nyhan Syndrome
Formation of
Deoxyribonucleotide: NDP
level
Degradation of Purine Nucleotides
Uric acid, Gout
Synthesis of Pyrimidine Nucleotides
De novo synthesis: Characteristics,
Element sources of Pyrimidine
bases
Salvage pathway
Antimetabolites of Pyrimidine
nucleotides
Catabolism of Pyrimidine Nucleotides
Related Disorders.
Antimetabolites of Purine and
Pyrimidine Bases and
Nucleotides:
Uses of Purine, Amino acid, and
Folic acid analogs.
QUESTIONS
Long Essays.
1) Draw the Purine ring; write the sources
of carbon and Nitrogen atoms of the ring.
OR
Give the outline of Purine biosynthetic
pathway and a note on regulation and
inhibition of Purine nucleotide
biosynthesis.
2) Describe metabolism of
Pyrimidine metabolism / synthesis
and Degradation Pyrimidine
nucleotides.
3) Catabolism of Purine nucleotides
/ formation of uric acid. Add a note
on Inborn Errors of Nucleotide
metabolism.
Short Notes:
1) Gout
2) Inter conversion of IMP to AMP
& GMP
3) Salvage pathway.
4) Lesch Nyhan syndrome
5) PRPP
6) Digestion of Nucleic acids/
Fate of Dietary Nucleic acid
7) Allopurinol /Treatment of
Gout
8) Adenosine Deaminase
Deficiency/SCID
9) Orotic aciduria.
THANK YOU
This post was last modified on 05 April 2022