Download MBBS Biochemistry PPT 55 Nucleoprotein Metabolism Lecture Notes

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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