Download MBBS Biochemistry PPT 55 Nucleoprotein Metabolism Lecture Notes

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Synopsis

Fates of dietary Nucleoproteins/Nucleic

Acids.

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De novo Biosynthesis of Purines and

Pyrimidines.

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Salvage of Purines and Pyrimidines
Catabolism of Purines and Pyrimidines
Disorders Associated To Nucleic Acid

Metabolism.

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Fates Of Dietary Nucleoproteins

Nucleoproteins are

conjugated Proteins.

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containing Nucleic acids

as a prosthetic group.
Nucleoproteins are

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constituents of each

and every living cell.

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Food substances of both plant and

animal origin contain

Nucleoproteins or Nucleic acids

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in them.
However Nucleoproteins and

Nucleic acids are non essential

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nutrients.

Since biosynthesized in the

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body.

Digestion and Absorption

Of

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Nucleoproteins
Dietary Nucleic acids

remain unchanged in

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mouth.

In Stomach gastric HCl

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denatures Dietary

Nucleoproteins.

Cleaves Hydrogen bonds

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of Nucleic acids.
Predominant and complete

digestion of Nucleic acids

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takes place in small intestine.

The specific Enzymes required

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for the digestion of DNA and

RNA are present in the

Pancreatic and Intestinal

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juice which specifically act and

break the bonds.
Nucleic acids are digested in the

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small intestine by

Deoxyribonuclease /

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Phosphodiesterase to generate

Nucleotides.

By the catalytic action of

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Nucleotidase and Nucleosidase.

Nucleotides and Nucleosides are,

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degraded to three components :

Nitrogen Base , Pentose and

Phosphate

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Degradation of Nucleoproteins

Nucleoprotein

In Stomach

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Gastric acid and

pepsin

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Nucleic acid

Protein

In small intestine

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Endonucleases: RNase and DNase

Nucleotide

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Nucleotidase

Phosphate

Nucleoside

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Nucleosidase

Base

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Ribose

End Products Of Nucleic Acid

Digestion

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Nitrogen Bases:

Purines and Pyrimidine

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Sugars:

Ribose and Deoxyribose

Phosphoric Acid

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Absorption

Dietary Purines and Pyrimidines

obtained through digestion of Nucleic

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acids are absorbed through intestinal

lumen.

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Some unabsorbed Purines are

metabolized by intestinal microbial

flora and excreted out through feces.

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The absorbed Nitrogen bases

are carried to Liver .

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These are degraded and

excreted out of the body.
Thus human body is not

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dependent upon the dietary

Nucleic acids for its use.

Ribose can be absorbed and

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catabolized to generate energy.
Nucleotides

Nucleotides are chemically composed of

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Nitrogen base: Purines and Pyrimidines
Sugar: Ribose / Deoxyribose
Phosphate group

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Functions of Nucleotides
v Precursors/Building blocks for

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DNA and RNA synthesis

v Essential carriers of chemical

energy, especially ATP (Energy

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transformation)

vComponents of the

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coenzymes NAD+, FAD, and

coenzyme A

vATP , ADP, and AMP may

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function as allosteric

regulators and participate in

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regulation of many metabolic

pathways.

vATP involved in covalent

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modification of enzymes.
vcAMP and cGMP, are also cellular

second messengers.

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v Formation of activated intermediates

such as UDP-Glucose and CDP-

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Diacylglycerol.

Can Cells Biosynthesize

Nucleotides?

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v Nearly all living organisms

biosynthesize Purine and

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Pyrimidine Nucleotides through

"De novo biosynthesis pathway"

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v Many organisms also "Salvage"

Purines and Pyrimidines from

diet and degradative pathways.

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Purine Nucleotide

Metabolism

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Anabolism
Purine Nucleotide Biosynthesis

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De Novo Biosynthesis

Of

Purine Nucleotides

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Purine Ring System

Purines And Pyrimidines

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Nucleoside and Nucleotide

Nucleoside =

Nitrogenous base Ribose

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Nucleotide =

Nitrogenous base Ribose Phosphate

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Nucleotides

are

Building blocks

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of

Nucleic acids

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Structure of Nucleotides

pyrimidine

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OR

purine

N-b-glycosyl

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bond

Ribose

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or

2-deoxyribose

There are two pathways

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leading to Biosynthesis of

Nucleotides
De Novo Biosynthesis:

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This is a main synthetic pathway.

The biosynthesis of

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nucleotides begins /very new
with the use of small metabolic
precursors as a raw material:

Amino acids, Ribose-5-phosphate,

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CO2, and One-carbon units.

Salvage pathways:

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The synthesis of nucleotide by

recycle of the free Nitrogen

bases or nucleosides released

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from nucleic acid breakdown.

This is important in Brain and Bone

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marrow
De Novo Biosynthesis

Of Purine Nucleotides

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Site Of

Purine Nucleotide

Biosynthesis:

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Predominantly In

cytosol of Liver,

To some extent in

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smal intestine and

Thymus.

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In humans, all

necessary enzymes for

Purine Nucleotide

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biosynthesis are found in

the cytoplasm of the cell.
Denovo biosynthesis occurs

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in most of the cells' cytosol

Except human Brain,

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Polymorphonuclear

leukocytes and

Erythrocytes.

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Requirements For

De Novo Biosynthesis

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Of

Purine Nucleotides
vPurines are syn thesized using

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5PhosphoRibose (R-5-P) as the

starting material step by step.

vPRPP (5-Phosphoribosyl-1-

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Pyrophosphate) is an active donor

of R-5-P.

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The Purine ring is synthesized by

a series of biochemical reactions
that add the carbon and nitrogen
atoms to a pre-formed Ribose-5-

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phosphate.


The Ribose-5-phosphate is

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synthesized as part of the

Hexose Mono Phosphate

pathway.

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HMP Shunt

Source For Ribose-5-Phosphate
Conversion of

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Ribose-5-Phosphate to PRPP

Phospho Ribosyl Pyro

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Phosphate (PRPP) is a starting

material for Purine Denovo

biosynthesis.

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PRPP is formed from Ribose-5

-Phophate.

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?The Pentose sugar is always a Ribose, which may

be reduced to Deoxyribose after nucleotide

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synthesis is complete.
?5-Phosphoribosyl-1-pyrophosphate (PRPP) is

also involved in synthesis of Pyrimidine

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nucleotides, NAD+, and Histidine biosynthesis.

?The De novo biosynthesis of Purine

nucleotide means a very new

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synthesis using raw materials as

?Phosphoribose

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?Amino acids : Gly , Gln and Asp

?One carbon units and

?CO2

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Nitrogen and Carbon Sources Of

Purine Ring Biosynthesis

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John Buchanan (1948) "traced" the

sources of all nine atoms of Purine ring

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N-1: Aspartic acid
N-3, N-9: Glutamine
C-2, C-8: N10-Formyl-THF- One carbon

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units

C-4, C-5, N-7: Glycine
C-6: CO2

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Element Sources For Purine bases

N10Formyltetrahydrofolate

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N10Formyltetrahydrofolate

FH4 (or THF)

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N10--CHO--FH4
The De Novo synthetic pathway can

be divided into two Stages:

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Stage one : Formation of Inosine

Mono Phosphate ( IMP )

Stage two : Conversion of IMP to

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either AMP or GMP

v IMP (Inosine-5'-Monophosphate) is

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first biosynthesized Purine

Nucleotide in this Denovo synthetic

pathway.

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vIMP is a nucleotide with

Hypoxanthine as Nitrogen base.

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vIMP is then converted to AMP and

GMP.
Biosynthesis of

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Inosine Mono Phosphate (IMP)

Basic pathway for De novo

biosynthesis of Purine

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Ribonucleotides

Starts from Ribose-5-phosphate(R-5-

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P)

Requires 11 steps overall

Occurs primarily in the Liver cytosol.

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Steps

Happenings

1

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Activation of PRPP

2 and 5

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Entry of Glutamine

3

Entry of Glycine

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4 and 10

Entry Of N10THF

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6

Ring Closure

7

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Entry Of CO2

8

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Entry of Aspartate

Steps

Happenings

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9

Removal of Fumarate

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11

Ring Closure
PRPP Synthetase

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Ribose 5Phosphate + ATP---------------------------PRPP +

AMP

Amidotransferase

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PRPP + Glutamine ---------------------------PRA + Glutamate

vOnce Phospho Ribosyl Amine

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(PRA) is formed , the building of the

Purine ring structure begins.

vIn nine successive reactions the first

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Purine nucleotide formed is IMP .

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Step 1:Activation of Ribose-5-phosphate

OH

Committed/Regulatory

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Step

1 ATP

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AMP

Ribose Phosphate Pyrophosphokinase/

PRPP Synthetase

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Step 2: Acquisition of Purine atom

2

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N9

Gln:PRPP

Amidotransferase

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?Steps 1 and 2 are tightly

regulated by feedback

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inhibition

5-PRA

Step 3: Acquisition of Purine atoms C4, C5, and N7

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3

Glycinamide Synthetase
?Step 4: Acquisition of Purine atom C8

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4

GAR transformylase

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Step 5: Acquisition of Purine atom N3

5

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?Step 6: Closing of the Imidazole ring

6

Step 7: Acquisition of C6

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7

AIR carboxylase

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Carboxyaminoimidazole
ribonucleotide (CAIR)
Step 8: Acquisition of N1

Carboxyaminoimidazole

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ribonucleotide (CAIR)

SAICAR synthetase

Step 9: Elimination of Fumarate

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Adenylosuccinate Lyase
Step 10: Acquisition of C2

AICAR Transformylase

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Step 11: Ring Closure to form IMP

? Once formed, IMP is rapidly

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converted to AMP and GMP (it does

not accumulate in cel s).

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IMP is a nucleotide of Nitrogen

base Hypoxanthine(6 OxyPurine).

IMP is the first Purine Nucleotide

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synthesized in Denovo Synthesis

mechanism.

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The De Novo pathway for Purine

biosynthesis.

Step 1: Ribose-5-phosphate

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pyrophosphokinase.

Step 2: Glutamine phosphoribosyl

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pyrophosphate

amidotransferase.

Step 3: Glycinamide ribonucleotide

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(GAR) synthetase.

Step 4: GAR transformylase.

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Step 5: FGAM synthetase (FGAR

amidotransferase).

Step 6: FGAM cyclase (AIR

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synthetase).

Step 7: AIR carboxylase.

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Step 8: SAICAR synthetase.

Step 9: adenylosuccinase.

Step 10: AICAR transformylase.

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Step 11: IMP synthase.


N10-CHOFH4

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N10-CHOFH4

6 ATPs are required in the

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Purine biosynthesis from

Ribose-5-phosphate to IMP.

Since in one step ATP is

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converted to AMP.

Hence this is really 7 ATP

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equivalents.
Conversion of IMP to AMP and GMP

Aspartate and GTP

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is used for

AMP synthesis.

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Glutamine and ATP

is used for

GMP synthesis.

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IMP is the precursor for both AMP and GMP.
ADP, ATP, GDP and GTP Biosynthesis

kinase

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kinase

AMP

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ADP

ATP

ATP

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ADP

ATP

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ADP

kinase

kinase

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GMP

GDP

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GTP

ATP

ADP

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ATP

ADP

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Regulation of

Purine Nucleotide Biosynthesis
Purine Nucleotide

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biosynthesis is well regulated

to meet the cellular demand.

Two enzymes are the

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key regulatory enzymes

for the Purine Nucleotide

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De novo biosynthesis.
PRPP Synthase synthesizing PRPP
(Phosphoribosyl Phosphate).

PRPP is "Feed-forward" activator

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PRPP Glutamyl Amidotransferase

The intracellular

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concentration of PRPP

regulates the Purine

biosynthesis to large extent.

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More availability of PRPP

increases more synthesis of Purine

nucleotides if the enzyme PRPP

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Synthetase is not inhibited by feed

back control.

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IMP, AMP and GMP

availability to sufficient

concentration inhibits the

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regulatory enzymes by.

feed back mechanism.
PRPP activates PRPP

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Glutamyl

Amidotransferase

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IMP , AMP and GMP inhibit

PRPP synthetase.

Sufficient AMP:

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Inhibits conversion of IMP to AMP

Sufficient GMP :

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Inhibits conversion of IMP to GMP.
Regulation of AMP

synthesis:

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Adenylosuccinate

synthetase is feedback-

inhibited by AMP

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Regulation of GMP

synthesis:

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IMP Dehydrogenase is

feedback-inhibited by

GMP

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ATP stimulates conversion of IMP to GMP
GTP stimulates conversion of IMP to AMP.

That ensures a balanced synthesis of both

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families of Purine nucleotides.

Significance of Regulation

Of Denovo Synthesis:

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v Meet the sufficient need of the

nucleotides to body function, without

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wasting.

vAMP and GMP control their respective

synthesis from IMP by a feedback

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mechanism, [GTP]=[ATP]


Purine Nucleotide biosynthesis is

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Regulated by Feedback inhibition
Antimetabolites /Inhibitors

of

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Purine Nucleotides

vNucleotide biosynthesis

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pathways are good targets for

anticancer/antibacterial

strategies.

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A ntimetabolites of Purine nucleotides are

structural analogs of

Purine,

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Amino acids and

Folic acid.

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They can interfere, inhibit or block

biosynthesis pathway of Purine

nucleotides and further block

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synthesis of DNA, RNA, and

proteins.

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Widely used to control

cancer(Chemotherapeutic

Agent).

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Purine Analogs

6-Mercaptopurine (6-MP) is a analog of

Hypoxanthine.

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6 Mercapta Purine

6 Mercapta Purine is an inhibitor of

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Enzymes:

Adenyl Succinase

IMP Dehydrgenase

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Decreases levels of AMP and GMP
6-MP nucleotide is a analog of IMP

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De novo synthesis

-

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amidotransferase

-

IMP

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6-MP

6-MP nucleotide

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-

AMP and GMP

-

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HGPRT

-

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salvage pathway

Amino acid Analogs

Azaserine (AS) is a analog of Gutamine.

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It inhibits 5th step of Purine biosynthesis.
Folate Analogs

Folate analogs Methotrexate and

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Sulfonamides block Purine biosynthesis
Sulfonamides structural analogs of

PABA inhibits Folate Synthesis in

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microbes.

It indirectly inhibit Purine

biosynthesis

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Since THFA is a carrier of one carbon

moiety N10FormylTHF.

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Folic acid Analogs

Aminopterin (AP) and Methotrexate (MTX)

MTX

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Methotrexate and Aminopterin

Folate analogs are inhibitors of

Folate Reductase which form THFA.

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Presence of these inhibitors affect

the reduction of Folate to THFA.

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THFA is not available for 1 Carbon

moiety transfer in Purine

biosynthesis.

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Methotrexate

NH

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CH3

2

6 methyl pterin

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p-amino benzoic acid

glutamate

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Tetrahydrofolate and

One-Carbon Units

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?Folic acid, a B vitamin found in

green plants, fresh fruits, yeast, and

liver, is named from folium, Latin for

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"leaf".

?Folates are acceptors and donors of

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one-carbon units for all oxidation

levels of carbon except CO2 (for

which biotin is the relevant carrier).

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?The active/coenzyme form is

Tetrahydrofolate.

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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

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relevant carrier).
Folate Analogs as Antimicrobial and

Anticancer Agents

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De novo Purine biosynthesis depends on folic acid

compounds at steps 4 and 10

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? For this reason, antagonists of folic acid

metabolism indirectly inhibit Purine

formation and, in turn, nucleic acid synthesis,

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cell growth, and cell development

? Rapidly growing cells, such as infective

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bacteria and fast-growing tumors, are more

susceptible to such agents

Sulfonamides are effective anti-

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bacterial agents

Methotrexate and Aminopterin are

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folic acid analogs that have been

used in cancer chemotherapy

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Precursors and analogs of Folic acid

employed as antimetabolites: sulfonamides ,

as well as methotrexate, aminopterin, and

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trimethoprim,

These compounds shown here bind to

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dihydrofolate reductase (DHFR) with about

1000-fold greater affinity than DHF and thus

act as virtually irreversible inhibitors.

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Anti Cancer Drugs: Methotrexate

Methotrexate, one of the earliest anti-

cancer drugs, inhibits folate

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metabolism

Folate provides methyl groups for

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biosynthetic reactions

It is essential for the conversion of

dUMP to TMP

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It provides carbon for the purine ring.

Methotrexate and Cancer

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? Affects rapidly growing cells

? Adverse events include anemia, scaly skin, GI

tract disturbances (diarrhea), and baldness

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? Resistance to MTX is caused by amplification of

dihydrofolate reductase gene
? The structural analogs of folic acid(e.g.

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MTX) are widely used to control

cancer (e.g. Leukemia).

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? Notice: These inhibitors also affect the

proliferation of normally growing cells.

This causes many side-effects

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including anemia, baldness, scaly skin

etc.
Formation of

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Deoxyribonucleotide

Formation of Deoxyribonucleotide

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involves the reduction of the sugar
moiety of Ribonucleoside
Diphosphates (ADP, GDP, CDP or
UDP).

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Deoxyribonucleotide synthesis occurs

at the nucleoside diphosphate(NDP)
level.

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Deoxyribonucleotide synthesis at the NDP level

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Summary of Purine biosynthesis

IMP
Biosynthesis Of Pyrimidines

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Nucleotides


Biosynthesis of Pyrimidine Nucleotides

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Pyrimidine Ring System

Pyrimidine Nucleotide

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Metabolism

There are also two synthesis

pathways of Pyrimidine

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nucleotides:

Denovo Synthesis and Salvage

--- Content provided by⁠ FirstRanker.com ---

pathway.


De Novo Synthesis Pathway

--- Content provided by​ FirstRanker.com ---

In De novo pathway the

Pyrimidine ring is assembled first

and then linked to Ribose

--- Content provided by​ FirstRanker.com ---

phosphate.

The carbon and nitrogen atoms

--- Content provided by​ FirstRanker.com ---

in the Pyrimidine ring are

derived from:

Bicarbonate

--- Content provided by⁠ FirstRanker.com ---

Aspartate
Glutamine

--- Content provided by FirstRanker.com ---

Shorter pathway than for Purine

Synthesis

Pyrimidine ring is made first,

--- Content provided by​ FirstRanker.com ---

then attached to ribose-P
(unlike Purine biosynthesis)

Pyrimidine Denovo synthesis

--- Content provided by‍ FirstRanker.com ---

requires 6 steps

(instead of 11 steps for

Purine)

--- Content provided by FirstRanker.com ---

The product is UMP (Uridine

Monophosphate)
Only 3 precursors are used for

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Pyrimidine Denovo synthesis.

These contribute to the 6-

--- Content provided by​ FirstRanker.com ---

membered ring

Aspartate

Glutamine

--- Content provided by‍ FirstRanker.com ---

HCO -

3

--- Content provided by‌ FirstRanker.com ---

Element Sources of Pyrimidine base
Pyrimidine

Biosynthesis involves 2

--- Content provided by‌ FirstRanker.com ---

ATPs

Steps

Happenings

--- Content provided by FirstRanker.com ---

1

Entry of CO2 and

--- Content provided by​ FirstRanker.com ---

Glutamine

2

Entry of Aspartate

--- Content provided by‍ FirstRanker.com ---

3

Ring Closure with

--- Content provided by​ FirstRanker.com ---

Dehydration

4

Oxidation of

--- Content provided by‍ FirstRanker.com ---

Di Hydro Orotate

5

--- Content provided by FirstRanker.com ---

Entry of PRPP

6

Decarboxylation To

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form UMP


Step 1:

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Synthesis of Carbamoyl Phosphate

? Carbamoyl phosphate

--- Content provided by‍ FirstRanker.com ---

synthetase(CPS) exists in 2 types:

? CPS-I, a mitochondrial enzyme,

is dedicated to the urea cycle and

--- Content provided by FirstRanker.com ---

arginine biosynthesis.

? CPS-II, a Cytosolic enzyme, used

--- Content provided by FirstRanker.com ---

here. It is the committed step in

animals.

--- Content provided by⁠ FirstRanker.com ---

Step 2:

Synthesis of Carbamoyl Aspartate

ATCase: Aspartate Transcarbamoylase

--- Content provided by FirstRanker.com ---

?Carbamoyl

phosphate is an

--- Content provided by⁠ FirstRanker.com ---

"activated"

compound, so no

energy input is

--- Content provided by FirstRanker.com ---

needed at this step.

Step 3:

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Ring closure to

form

DihydroOrotate

--- Content provided by​ FirstRanker.com ---

Step 4:

Oxidation of

--- Content provided by​ FirstRanker.com ---

DihydroOrotate

To

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CoQ

Orotate

QH2

--- Content provided by‍ FirstRanker.com ---

(a pyrimidine)

Step 5:

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Acquisition of Ribose Phosphate moiety


Step 6:

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Decarboxylation of OMP

OMP is decarboxylated to

UMP

--- Content provided by​ FirstRanker.com ---

Figure 26.15 The de novo pyrimidine biosynthetic pathway.


UMP Is Converted

--- Content provided by‌ FirstRanker.com ---

To

CMP and TMP
Conversion Of UMP to CMP

--- Content provided by‌ FirstRanker.com ---

UMP is converted to

CMP in presence of

--- Content provided by‍ FirstRanker.com ---

Glutamine and ATP

Formation of dTMP

The immediate precursor of thymidylate (dTMP) is dUMP.

--- Content provided by FirstRanker.com ---

The formation of dUMP either by deamination of dCMP or by

hydrolyzation of dUDP. The former is the main route.

UDP

--- Content provided by‌ FirstRanker.com ---

dUDP

dCMP

--- Content provided by​ FirstRanker.com ---

dCDP

dUMP

N5,N10-methylene-

--- Content provided by FirstRanker.com ---

tetrahydrofolic Acid

dTMP synthetase

--- Content provided by​ FirstRanker.com ---

dTMPATP

ATP

dTDP

--- Content provided by‍ FirstRanker.com ---

dTTP

ADP

--- Content provided by‍ FirstRanker.com ---

ADP
dTMP synthesis at the Nucleoside

Monophosphate level.

--- Content provided by‌ FirstRanker.com ---

Summary of pyrimidine biosynthesis

UMP
Antimetabolites of Pyrimidine

--- Content provided by‌ FirstRanker.com ---

Nucleotides

Antimetabolites of

Pyrimidine nucleotides are

--- Content provided by​ FirstRanker.com ---

similar with them of Purine

nucleotides.

--- Content provided by⁠ FirstRanker.com ---

Pyrimidine Analogs

5-fluorouracil (5-FU) is a

analog of Thymine.

--- Content provided by FirstRanker.com ---

Synthesis of dTMP from dUMP is

catalyzed by Thymidylate Synthase

? This enzyme methylates dUMP at the

--- Content provided by‌ FirstRanker.com ---

5-position to create dTMP
? The methyl donor is the one-carbon

folic acid derivative N5, N10-Methylene-

--- Content provided by‍ FirstRanker.com ---

THF

? The reaction is a reductive methylation; the

one-carbon unit is transferred at the

--- Content provided by‌ FirstRanker.com ---

methylene level of reduction and then

reduced to the methyl level

--- Content provided by‌ FirstRanker.com ---

? The THF cofactor is oxidized to yield DHF

? DHFR reduces DHF back to THF for serving

again

--- Content provided by⁠ FirstRanker.com ---

? dTMP synthesis has become a preferred

target for inhibitors designed to disrupt

--- Content provided by​ FirstRanker.com ---

DNA synthesis


? Fluoro-substituted

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analogs as

therapeutic agents

5-fluorouracil

--- Content provided by‌ FirstRanker.com ---

(5-FU) is used as a

chemotherapeutic

--- Content provided by‌ FirstRanker.com ---

agent in the

treatment of

cancers

--- Content provided by‌ FirstRanker.com ---

5-fluorocytosine is

used as an

--- Content provided by FirstRanker.com ---

antifungal drug

5-fluoroorotate is an

effective

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antimalarial drug


The 5-Fluoro substitution

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inhibits on the mechanism

of action of Thymidylate

--- Content provided by‌ FirstRanker.com ---

Synthase.

Which in turn affects

DNA synthesis.

--- Content provided by‍ FirstRanker.com ---

Figure 26.26 The thymidylate

synthase reaction.
Amino acid analogs

--- Content provided by​ FirstRanker.com ---

Azaserine (AS) inhibits the synthesis of CTP.

Folic acid Analogs

--- Content provided by‍ FirstRanker.com ---

Methotrexate (MTX) inhibits the synthesis of dTMP.

Nucleoside Analogs

Arabinosyl cytosine (Ara-c) inhibits the synthesis of

--- Content provided by⁠ FirstRanker.com ---

dCDP.
Salvage Pathway

Salvage Pathway is

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important in Brain and Bone

marrow

--- Content provided by⁠ FirstRanker.com ---

Where Denovo synthesis of

Purine and Pyrimidine

nucleotide do not occur.

--- Content provided by​ FirstRanker.com ---

Salvage Pathway of Purine

Nucleotides

Salvage pathway have

--- Content provided by‌ FirstRanker.com ---

mechanisms to retrieve

Purine bases and Purine

--- Content provided by​ FirstRanker.com ---

nucleosides. They are used

to synthesize Purine

nucleotides.

--- Content provided by FirstRanker.com ---

Purine bases created by degradation of

RNA or DNA and intermediate of purine

synthesis can be directly converted to the

--- Content provided by​ FirstRanker.com ---

corresponding nucleotides.

The significance of salvage pathway :

--- Content provided by FirstRanker.com ---

Save the fuel.
Some tissues and organs such as brain

and bone marrow are only capable of

--- Content provided by FirstRanker.com ---

synthesizing nucleotides by salvage

pathway.

Two Phosphoribosyl transferases

--- Content provided by​ FirstRanker.com ---

are involved:

APRTase

--- Content provided by⁠ FirstRanker.com ---

(Adenine phosphoribosyl

transferase) for Adenine.

HGPRTase

--- Content provided by‍ FirstRanker.com ---

(Hypoxanthine guanine

phosphoribosyl transferase) for

--- Content provided by FirstRanker.com ---

guanine or Hypoxanthine.


From Nitrogen Base to Nucleotides

--- Content provided by FirstRanker.com ---

APRTase

Adenine + PRPP--------------------------------AMP + ppi

HGPRTase

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Hypoxanthine + PRPP-------------------------------- IMP + ppi

HGPRTase

--- Content provided by‌ FirstRanker.com ---

Guanine + PRPP--------------------------------GMP + ppi

Purine Salvage Pathway
Absence of activity of

--- Content provided by FirstRanker.com ---

HGPRTase

leads to

Lesch-Nyhan Syndrome.

--- Content provided by FirstRanker.com ---

From Nucleoside to Nucleotide

AR kinase

--- Content provided by‌ FirstRanker.com ---

AdenineRibose + ATP--------------------------------AMP + ADP

In comparison to De novo pathway, salvage

pathway is energy-saving.

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In brain and bone marrow tissues salvage pathway

is the only pathway of nucleotide synthesis.
Pyrimidine Salvage pathway

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Salvage Pathway

Pyrimidine Phosphoribosyl Transferase

--- Content provided by​ FirstRanker.com ---

(PPRTase) catalyzes the following

Salvage reaction.

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Uracil + PRPP- --- UMP + ppi
In some organisms, free

Pyrimidines are salvaged and

--- Content provided by⁠ FirstRanker.com ---

recycled to form Pyrimidine

nucleotides

--- Content provided by‍ FirstRanker.com ---

In humans, Pyrimidines are

recycled from Nucleosides, but

free Pyrimidine bases are not

--- Content provided by​ FirstRanker.com ---

salvaged

Uridine Kinase catalyzes the

--- Content provided by​ FirstRanker.com ---

formation of UMP from Uridine

and ATP.

UR + ATP------- UMP + ADP

--- Content provided by⁠ FirstRanker.com ---

Formation of Deoxynucleotides

Deoxynucleotides are formed by reducing

Ribonucleotide Diphosphates.

--- Content provided by​ FirstRanker.com ---

Ribonucleotide Reductase
NDP + NADPH + H+-----------------dNDP + H2O

+ NADP+

--- Content provided by FirstRanker.com ---

. In the reaction of Ribonucleotide

Reductase Hydrogen atoms are not

--- Content provided by‌ FirstRanker.com ---

directly donated by NADPH.

Coenzyme Thioredoxin, a Protein

with two sulfhydryl groups mediates

--- Content provided by⁠ FirstRanker.com ---

the transfer of hydrogen atoms from

NADPH to Ribonucleotide Reductase.
Then the enzyme catalyzes the reduction of NDP, to form

--- Content provided by‍ FirstRanker.com ---

dNDP.

NDP reductase
NDP + Thioredoxin ( SH )2 -------- dNDP + Thioredoxin

--- Content provided by FirstRanker.com ---

(-S-S-)

The regeneration of reduced Thioredoxin is

--- Content provided by FirstRanker.com ---

catalyzed by Thioredoxin reductase.

Thioredoxin Reductase converts Oxidized

Thioredoxin to functional Reduced Thioredoxin.

--- Content provided by​ FirstRanker.com ---

Thioredoxin is NADPH+ H+ requiring enzyme

Thioredoxin (-S-S-) +NADPH +H+

--- Content provided by‍ FirstRanker.com ---

Thioredoxin ( SH )2+NADPH


NDP Reductase is an allosteric

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enzyme, Its activity is

controlled by various NTPs

and dNTPs.

--- Content provided by​ FirstRanker.com ---

Catabolism Of Purine Nucleotides

Degradation of Purine Nucleotides

--- Content provided by FirstRanker.com ---

Adenosine

Deaminase

(2,6,8-trioxypurine)

--- Content provided by‌ FirstRanker.com ---

The End product of Purine metabolism


Uric acid

--- Content provided by​ FirstRanker.com ---

Uric acid is a NPN, waste excreted end product

--- Content provided by‌ FirstRanker.com ---

of Purine catabolism.

The rate of uric acid excretion by the normal

adult human is about 0.6 g/24 h in urine, arising

--- Content provided by‍ FirstRanker.com ---

in part from ingested purines and in part from

the turnover of the purine nucleotides of nucleic

--- Content provided by⁠ FirstRanker.com ---

acids.

The normal concentration of uric acid in the

serum of adults is in the range of 3-7 mg/dl.

--- Content provided by FirstRanker.com ---

2, 6,8 Tri Oxy Purine
Catabolism Of Pyrimidines

--- Content provided by‍ FirstRanker.com ---

Degradation of Pyrimidine Nucleotides
How Are Pyrimidines

Degraded?

--- Content provided by⁠ FirstRanker.com ---

Catabolism of Pyrimidine Nitrogen

Bases Cytosine and Uracil yields :

-Alanine,

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Ammonium ions
CO2

-Alanine can be recycled into

--- Content provided by​ FirstRanker.com ---

the synthesis of coenzyme A
Catabolism of Thymine

yields:

--- Content provided by⁠ FirstRanker.com ---

-Aminoisobutyric acid
Ammonium ions
CO2

--- Content provided by​ FirstRanker.com ---

Highly soluble

--- Content provided by​ FirstRanker.com ---

Products
Principal differences

between metabolism of

--- Content provided by⁠ FirstRanker.com ---

Purines and Pyrimidines

Purines

Pyrimidines

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Character

De Novo

--- Content provided by​ FirstRanker.com ---

De Novo

Synthesis

Synthesis

--- Content provided by‌ FirstRanker.com ---

Number Of

--- Content provided by​ FirstRanker.com ---

Steps

Involved

--- Content provided by⁠ FirstRanker.com ---

11 Steps

6 Steps

--- Content provided by FirstRanker.com ---

Precursors Of Amino acids :Asp Gly Amino acids :Asp and Gln

Ring

and Gln

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CO2

N10FormylTHF

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CO2

Major Portion

Glycine

--- Content provided by‌ FirstRanker.com ---

Aspartate

Of Ring

--- Content provided by‌ FirstRanker.com ---

provided by
Purines

Pyrimidines

--- Content provided by‌ FirstRanker.com ---

Character

De Novo

De Novo

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Synthesis

Synthesis

--- Content provided by FirstRanker.com ---

Acquisition of

Ribose-

Phosphate

--- Content provided by FirstRanker.com ---

In Starting Steps

In End Steps

--- Content provided by‌ FirstRanker.com ---

Formation of In 1st step of their a heterocyclic ring is

N-Glycosidic biosynthesis

formed first, then it

--- Content provided by‌ FirstRanker.com ---

bond

(PRPP is the 1st Substrate) reacts with PRPP

--- Content provided by‍ FirstRanker.com ---

products of

Uric acid

CO2, NH3, -Amino

--- Content provided by‍ FirstRanker.com ---

degradation

(poor solubility in H2O) Isobutyrate and Ala

--- Content provided by‌ FirstRanker.com ---

NH

(soluble in H

3

--- Content provided by​ FirstRanker.com ---

2O)

Purines

--- Content provided by⁠ FirstRanker.com ---

Pyrimidines

Character

De Novo

--- Content provided by​ FirstRanker.com ---

De Novo

Synthesis

--- Content provided by‌ FirstRanker.com ---

Synthesis

Number Of

ATPs

--- Content provided by‌ FirstRanker.com ---

6 ATPs

2ATPs

--- Content provided by‌ FirstRanker.com ---

Involved

Nucleotide

Produced in

--- Content provided by‌ FirstRanker.com ---

IMP

UMP

--- Content provided by‌ FirstRanker.com ---

End

Ring Closure

--- Content provided by​ FirstRanker.com ---

At

6 and 11 steps

--- Content provided by‍ FirstRanker.com ---

3rd Step


Disorders Of

--- Content provided by​ FirstRanker.com ---

Nucleic Acid

Metabolism

Disorders of

--- Content provided by​ FirstRanker.com ---

Purine Nucleotides Metabolism
Gout

Gouty Arthritis

--- Content provided by‍ FirstRanker.com ---

Gout derived from Latin

Word: GUTTA

Meaning `A drop of

--- Content provided by FirstRanker.com ---

liquid'

Gout is a common metabolic

--- Content provided by​ FirstRanker.com ---

disorder of Purine

metabolism characterized by :

Persistent Hyperuricemia

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Hyperuricaciduria and
Joint pain


GOUT

--- Content provided by​ FirstRanker.com ---

Gout, is a disease of the joints, usually in males,

--- Content provided by FirstRanker.com ---

caused by an elevated concentration of uric

acid in the blood and tissues.

The joints become inflamed, painful, and

--- Content provided by‍ FirstRanker.com ---

arthritic, owing to the abnormal deposition of

crystals of sodium urate.

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The kidneys are also affected, because excess

uric acid is deposited in the kidney tubules.

Gout:"Disease of Kings"

--- Content provided by​ FirstRanker.com ---

?Rich foods have a

higher

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ORGAN MEATS

concentration of

WILD GAME

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Nucleoproteins.

SEAFOOD
? This could cause

--- Content provided by‍ FirstRanker.com ---

LENTILS

PEAS

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major problems for

ASPARAGUS

a person afflicted YEAST

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with Gout.

BEER
Types and Causes Of Gout

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Types Of Gout

Primary Gout (Genetic Cause)
Secondary Gout

--- Content provided by‍ FirstRanker.com ---

Basic Cause Of Gout

Hyperuricemia

Over Production Of Uric acid

--- Content provided by‍ FirstRanker.com ---

Under Excretion Of Uric acid

Primary Gout

Primary Gout is an

--- Content provided by‌ FirstRanker.com ---

inherited sex linked

recessive disorder.

--- Content provided by​ FirstRanker.com ---

Affecting more Males.
Causes Of Primary Gout

Basic cause of primary Gout is

--- Content provided by‍ FirstRanker.com ---

genetic cause.

It has Enzyme defects concerned with:

Over Production Of Purine Nucleotides

--- Content provided by​ FirstRanker.com ---

than the functional use.

Over catabolism of Purine Nucleotides
Results in Hyperuricemia

--- Content provided by‍ FirstRanker.com ---

5 Enzyme Defects

Causing Primary Gout
1. PRPP Synthetase

--- Content provided by‍ FirstRanker.com ---

(Increased Activity))
2. PRPP Glutamyl Amido Transferase
(Increased Activity)
3. HGPRTase
(Decreased Activity)

--- Content provided by​ FirstRanker.com ---

4. Glucose 6 Phosphatase
(Decreased Activity)
5. Glutathione Reductase
(Decreased Activity)

--- Content provided by⁠ FirstRanker.com ---

The defect of above 5 Enzymes

in primary Gout

Directly or indirectly increases

--- Content provided by‍ FirstRanker.com ---

the Denovo Biosynthesis of

Purine nucleotides.

--- Content provided by⁠ FirstRanker.com ---

There is overproduction of

Purine Nucleotides more than

--- Content provided by​ FirstRanker.com ---

their functional use

Which further catabolizes

them to produce increased

--- Content provided by⁠ FirstRanker.com ---

Uric acid levels

(Hyperuricemia)

--- Content provided by​ FirstRanker.com ---

Secondary Gout

It is an acquired cause:
In some pathological states where

--- Content provided by‍ FirstRanker.com ---

there is abnormal and excessive

breakdown of cells releases

Nucleic acids and Nucleotides.

--- Content provided by⁠ FirstRanker.com ---

Whose catabolism produces

increased Uric acid levels

--- Content provided by⁠ FirstRanker.com ---

(Hyperuricemia)
Conditions Of Secondary Gout

Leukemia
Lymphomas

--- Content provided by⁠ FirstRanker.com ---

Polycythemia
Treatment Of Large Tumors
Traumatic Conditions
Radiation Injury

--- Content provided by‌ FirstRanker.com ---

Renal Gout

Type of Gout caused due to

insufficiency of Renal System.

--- Content provided by‌ FirstRanker.com ---

Where there is reduced excretion

of Uric acid through Urine.

--- Content provided by FirstRanker.com ---

Retention of the Uric acid in blood

leading to Hyperuricemia.
Conditions Of Renal Gout

--- Content provided by⁠ FirstRanker.com ---

Renal Failure
Use of Thiazide diuretics
Metabolic Acidosis

Ketoacidosis and Lacticacidosis

--- Content provided by FirstRanker.com ---

affects the excretion of Uric acid

through Urine.

--- Content provided by​ FirstRanker.com ---

Incidence Of Gout

?Primary Gout accounts for 90% of

cases

--- Content provided by FirstRanker.com ---

?Affects primarily middle aged men
Risk Factors of Gout

Obesity (High BMI)

--- Content provided by‌ FirstRanker.com ---

Hypertension (HTN )
Use of Thiazide diuretics
Diet high in meat & seafood
Excess Alcohol use

--- Content provided by​ FirstRanker.com ---

o Highest with Beer

Diet high in Purines

may trigger an attack in

--- Content provided by⁠ FirstRanker.com ---

a susceptible persons.
RISK FACTORS OF GOUT

Male Gender

--- Content provided by‌ FirstRanker.com ---

Postmenopausal female
Older Persons
Pharmaceuticals:

Cyclosporine

--- Content provided by⁠ FirstRanker.com ---

Pathophysiology Of Gout
?Uric acid is NPN

compound

--- Content provided by FirstRanker.com ---

?Waste end product of

Purine metabolism

--- Content provided by‍ FirstRanker.com ---

?Excreted by the kidneys

through urine.

The Uric acid and the

--- Content provided by⁠ FirstRanker.com ---

Hypoxanthine

Gout

--- Content provided by‌ FirstRanker.com ---

Out of body

Xanthine

In urine

--- Content provided by‌ FirstRanker.com ---

Uric acid

Over 8mg/dl, in the

--- Content provided by​ FirstRanker.com ---

Diabetes

plasma

Nephrosis

--- Content provided by⁠ FirstRanker.com ---

Gout

Urate crystallization in

--- Content provided by​ FirstRanker.com ---

joints, soft tissue, cartilage

and kidney
The normal serum Uric

--- Content provided by‍ FirstRanker.com ---

acid level in adults is 2-7

mg%

--- Content provided by FirstRanker.com ---

0.5-1 g of uric acid is

formed daily in the

organism.

--- Content provided by⁠ FirstRanker.com ---

In Gout the serum Uric acid

levels rises above 8 mg%.

--- Content provided by‍ FirstRanker.com ---

Uric acid in miscible pool of

Gout patients is increased up

to 2000-4000 mg% (normally

--- Content provided by FirstRanker.com ---

1200mg%).


Uric acid is poorly soluble

--- Content provided by FirstRanker.com ---

in water.

The increased Uric acid

--- Content provided by‍ FirstRanker.com ---

levels

Decreases the solubility

of Uric acid and

--- Content provided by‌ FirstRanker.com ---

Get crystallized to form

Mono Sodium Urate

--- Content provided by FirstRanker.com ---

Crystals.
The Mono Sodium Urate

Crystals get deposited in the

--- Content provided by‌ FirstRanker.com ---

synovial spaces of joints

In periarticular ,articular and

extra articular tissues to form

--- Content provided by‍ FirstRanker.com ---

Tophi (Hard Mass/ Swelling)

Deposition of Urate crystals

--- Content provided by⁠ FirstRanker.com ---

in synovial spaces affects

the movements of joints.

Leads to pain ,

--- Content provided by​ FirstRanker.com ---

inflammation, stiffness

and redness of joints

--- Content provided by‌ FirstRanker.com ---

known as Gouty Arthritis.


?Deposits of sodium urate

--- Content provided by⁠ FirstRanker.com ---

crystals in articular,

periarticular, and subcutaneous

tissues in Gout

--- Content provided by⁠ FirstRanker.com ---

HYPERURICEMIA & GOUT

nHyperuricemia caused by

--- Content provided by⁠ FirstRanker.com ---

?Overproduction of Urate
?Under excretion of Urate

nNo Gout w/o crystal deposition
THE GOUT CASCADE

--- Content provided by‍ FirstRanker.com ---

Urate
Over production

Under excretion

--- Content provided by‍ FirstRanker.com ---

Hyperuricemia

________________________________________

--- Content provided by‍ FirstRanker.com ---

n Silent

Gout

Renal

--- Content provided by‌ FirstRanker.com ---

Associated

n Tissue

--- Content provided by‌ FirstRanker.com ---

Manifestations

CV events &

n Deposition

--- Content provided by‍ FirstRanker.com ---

mortality

Clinical Manifestations

--- Content provided by‌ FirstRanker.com ---

Of

Gouty Arthritis
?Onset of Gout is usually

--- Content provided by FirstRanker.com ---

nocturnal, with sudden swelling

and excruciating pain

?May have low grade fever

--- Content provided by​ FirstRanker.com ---

?Usually subsides within 2-10

days

--- Content provided by FirstRanker.com ---

?Joints are normal, with no

symptoms between attacks
?Gouty arthritis in one or more

--- Content provided by​ FirstRanker.com ---

joints (but less than four)

?Great /big toe joint

(Metatarsophalangeal) most

--- Content provided by‌ FirstRanker.com ---

common first manifestation

(Monoarticular)

--- Content provided by⁠ FirstRanker.com ---

Other joints may be

the foot, ankle, knee,

or wrist (Polyarticular)

--- Content provided by‍ FirstRanker.com ---

?Joints become tender

/stiff & cyanotic

?Recurrent attacks of pain

--- Content provided by⁠ FirstRanker.com ---

and swelling of the joints.

?Constant recurring

--- Content provided by FirstRanker.com ---

vermicular movements of

hands and feet.

?Involuntary and Jerky

--- Content provided by FirstRanker.com ---

movements

?Spasticity
?Mental Retardation

--- Content provided by‌ FirstRanker.com ---

Urate crystals trigger a local

immune-mediated inflammatory

reaction.

--- Content provided by⁠ FirstRanker.com ---

With one of the key proteins in the

inflammatory cascade being

--- Content provided by FirstRanker.com ---

interleukin 1.

Causing inflammation of the area.

Gouty Arthritis

--- Content provided by‌ FirstRanker.com ---

Main Symptoms

Joint Pain

--- Content provided by FirstRanker.com ---

Affects one or more joints : hip, knee,

ankle, foot, shoulder, elbow,wrist, hand,

or other joints

--- Content provided by⁠ FirstRanker.com ---

Great toe, ankle and knee are most

common

--- Content provided by FirstRanker.com ---

Swelling of Joint

Stiffness
Warm and red
Possible fever

--- Content provided by⁠ FirstRanker.com ---

Tophi/Skin Lump

which may drain chalky material
Gouty Arthritis may be

--- Content provided by‌ FirstRanker.com ---

precipitated by :

qTrauma
qSurgery

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qAlcohol ingestion
qInfection

Gouty Arthritis
Stages of Gout

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n Asymptomatic Hyperuricemia

n Acute Flares of Crystallization

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n Intervals between flares/Intercritical Stage

n Advanced/Chronic Gout

nComplications of Gout

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Stage 1

Asymptomatic Hyperuricemia.

Very initial stage of Gout

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When serum Urate concentration is

greater than 8 mg/dL,

Urate crystals may start to deposit

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in the joints.

No evidence that treatment is

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required.

ASYMPTOMATIC

A meaning without indicates

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that there are no symptoms

associated

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Patient will be unaware of

what is happening

Gout can only be determined

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with the help of a physician
Stage 2

Acute Gout

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If sufficient urate deposits around

joints, and if the local environment

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or some trauma triggers

The release of crystals into the joint

space, an inflammatory response

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occurs.

These flares can be self resolving but

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are likely to recur.

ACUTE GOUTY FLARES

nAbrupt onset of severe joint inflammation,

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often nocturnal

nWarmth, swelling, erythema, & pain;

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Possibly fever

nIf untreated get resolves in 3-10 days
n90% 1st attacks are monoarticular
n50% are podagra (Gout of big Toe)

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ACUTE GOUT

SITES OF ACUTE FLARES

n90% of gout

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patients

eventually have

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podagra : 1st

MTP joint
Stage 3

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Intercritical periods

These are the intervals between

attacks.

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During these periods, crystals

may still be present at a low

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level in the synovial tissue and

fluid, resulting in future

attacks.

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INTERCRITICAL

More

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concentration of

uric acid crystals

Typically no

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need for drug

intervention at

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the time.
FLARE INTERVALS

nSilent tissue

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deposition &

Hidden

Damage

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Stage 4

Advanced /Chronic Gout.

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If crystal deposits continue to

accumulate, patients may

develop chronically stiff,

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swollen joints and tophi.
This advanced stage of

Gout is relatively

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uncommon generally

avoidable with therapy..

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CHRONIC GOUT

Continuous or

persistent over a

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long period of

time

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Treatment

required

Not easily or

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quickly resolved
IN ADVANCED GOUT

Chronic Arthritis

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X-ray Changes noted

Tophi Developed

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Acute Flares continues

ADVANCED GOUT

Chronic

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Arthritis

Polyarticular

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acute flares with

upper

extremities

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more involved
Sites

nCan occur in

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other joints,

bursa & tendons

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Advanced Gout

Clinical y Apparent Tophi

1

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2

1

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3

1. Photos courtesy of Brian Mandell, MD, PhD, Cleveland Clinic.

2. Photo courtesy of N. Lawrence Edwards, MD, University of Florida.

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3. ACR Clinical Slide Col ection on the Rheumatic Diseases, 1998.

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Acute Intermittent Gout

Initial episode usually follows decades

of asymptomatic hyperuricemia

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Characterized by intense pain and

inflammation (warmth, swelling,

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erythema)

Usually begins as monoarticular

involvement with first MTP joint

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TOPHI

Solid urate

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deposits in

tissues
TOPHI

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Irregular &

destructive

Complications Of Gout

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?Joint deformity

?Osteoarthritis
?Tophi may produce draining

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sinuses that may become

infected.

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?Renal stones, pyelonephritis,

obstructive renal disease.

Assessment for Gout

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Complications

lFormation of kidney

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stones

lHypertriglyceridemia
lHypertension

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Gout: Kidney Stones

Diagnosis Of Gout

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?History taking & physical examination

?Family history of Gout

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?Clinicalsymptomsalonearesufficentto make

acuratediagnosiinmostcase

?Performing Diagnostic studies may help in

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knowing the stage and progression of Gout.

Gout Diagnosing Studies

--- Content provided by​ FirstRanker.com ---

Examination of joint

fluid (Arthrocentesis

extraction of joint

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fluid).

X-rays of joint
Blood Examination

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Diagnostic Profile

? Serum Uric acid levels usually

elevated.

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? 24 hour urine Uric acid levels

increased.

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?WBC Count elevated during acute

attacks.

? ESR (elevated)

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?Synovial fluid aspiration

contains Urate crystals

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? X-rays appear normal in

early stages; Tophi

appear as eroded areas of

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bone
SYNOVIAL FLUID ANALYSIS

(Polarized Light Microscopy)

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Considered as the Gold standard

Urate Crystals are intracellular during attacks

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Needle & rod shaped Urate crystals

With strong negative birefringence

SYNOVIAL FLUID

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Microcopy Of Urate Crystals

Treatment Of Gout
Pal iative Treatment

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Bed rest : No much

movements of joints.

Bed rest : With a position

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for comfort

Treatment and Nursing Care

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?Joint immobilization and protect

joint from pressure

?Local application of heat or cold

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around the joint area.
Restrict intake of diet rich in

Purine content.

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Restrict Alcohol

consumption

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Avoid dehydration
Drink lots of Water

Specific Treatment

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Allopurinol (Zyloprim) is a

drug of choice for

Treatment of Gouty

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arthritis.

Allopurinol is a structural

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analog of Hypoxanthine.
Allopurinol is a Competitive

inhibitor of Enzyme Xanthine

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Oxidase.

Prevents conversion of

Hypoxanthine and Xanthine to

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Uric acid.

Prevents accumulation of Uric

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acid and its crystallization and

deposition.

Hypoxanthine and

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Xanthine are more water

soluble form and readily

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excreted out.

Allopurinol is transformed

to Alloxanthine and excreted

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out.


Al opurinol ? a Suicide inhibitor used to treat Gout

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Xanthine oxidase

Xanthine oxidase

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Allopurinol Dosage:

Initial Stages
100-200 mg/day
For Maintenance

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200-600 mg/day
Administration of Uricosuric

drugs :

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Which decreases renal

reabsorption of Uric acid from

renal tubules

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Thereby increasing Uric acid

excretion.

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Example : Probenecid Salicylates.

Using Anti inflammatory

agents to arrest pain and

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inflammation in Gouty arthritis:

v Colchicine

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vNSAIDS : Diclofenac
vIbufren
vProxivan

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TREATMENT WITH

Colchicine- reduces pain,

swelling, and inflammation; of

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Gouty arthritis.

Pain subsides within 12 hrs and

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relief occurs after 48 hrs.

Col aborative Care

?Prevention of Acute Attacks

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lColchicine combined with:

Allopurinol (Zyloprim, Alloprim) ? blocks

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production of uric acid

Probenecid (Benemid), sulfinpyrazone

(Anturane) ? inhibit tubular reabsorption of

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uric acid

Febuxostat (Uloric) ? inhibits xanthine

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oxidase, recently shown to reduce serum

uric acid levels
Col aborative Care

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?Dietary measures

lWeight reduction
lAvoidance of Alcohol

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lAvoidance of Foods high in Purines

High Risk: Yeast , Sardines, Calms

Anchovies, Herring, Mussels, liver,

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kidney, goose, venison, meat soups,

sweetbreads, beer & wine

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Moderate Risk: Chicken, Salmon,

Crab, Veal, Lobster , mutton, bacon,

Pork, Turkey , beef, Ham

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Col aborative Care

?Prevention of Renal stones

lIncrease fluid intake to maintain

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adequate urine output

lAllopurinol
lACE inhibitor Losartin (Cozaar) ?

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promotes urate Diuresis

Prevent Drugs That Promote Gout

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Diuretics

Leads to increased uric acid reabsorption

Low-dose aspirin

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Over 6% increase in mean serum urate and 23%

decrease in uric acid clearance

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Pyrazinamide

Gout observed at higher incidence

Ethambutol

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Niacin
Factors Triggering Gouty Arthritis

vCool temperatures

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vRapid changes in uric acid level,
vAcidosis
v Articular hydration, and
vExtracellular Matrix Proteins,

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such as Proteoglycans, Collagens,

and Condroitin Sulfate

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Gout:

accumulation

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of Uric acid

salts in joints

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Gout:

Tophuses ?

accumulation

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of uric acid

salts in

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cartilages,

under skin.

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Lesch-Nyhan Syndrome

(LNS)

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Lesch-Nyhan Syndrome(LNS)

First described in

1964 by Michael

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Lesch and William L.

Nyhan.

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LNS is a genetic

disorder

Affects Salvage pathway

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of Purine Metabolism.
Caused due to defect or lack in the

HGPRTase an enzyme of Purine

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Salvage.

Severely affects the Brain growth

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and development.

LNS is a Sex-linked

genetic recessive disease

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that is linked to the X

chromosome.

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Affects only Males
Biochemical Defect

HGPRTase role in the body

--- Content provided by​ FirstRanker.com ---

Hypoxanthine-Guanine

Phosphoribosyl Transferase is a

Purine Salvage enzyme that

--- Content provided by‍ FirstRanker.com ---

Plays a key role in the recycling of the

Purine bases, Hypoxanthine, and

--- Content provided by⁠ FirstRanker.com ---

Guanine into Purine nucleotide pools

through Salvage pathway.
Purine Bases are Catabolized

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To Uric Acid

In LNS

In HGPRTase deficiency

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the free Purine bases are

not recycled through

--- Content provided by FirstRanker.com ---

Salvage pathway

Instead Purines are broken

down and excreted as Uric

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acid.
The rate of Purine

synthesis is increased

--- Content provided by FirstRanker.com ---

about 200-fold in LNS

Lack of HGPRTase activity in

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Lesch-Nyhan Syndrome

causes a buildup of PRPP.

This PRPP activates the De

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novo biosynthesis of Purine

nucleotides.
Loss of HGPRTase leads to

--- Content provided by⁠ FirstRanker.com ---

No use of PRPP in the Salvage

step

--- Content provided by FirstRanker.com ---

More availability of unused

PRPP

PRPP allosterically stimulates

--- Content provided by FirstRanker.com ---

PRPP Synthetase of De novo

Purine synthesis.

--- Content provided by​ FirstRanker.com ---

Purines synthesis is more

than its functional use.

Later these Purines are

--- Content provided by FirstRanker.com ---

catabolized to end high

Uric acid levels in blood

--- Content provided by FirstRanker.com ---

and body.


hypoxan hine-guanine

--- Content provided by​ FirstRanker.com ---

phosphoribosyl transferase

Guanine + PRPP

Guanylate + PPi

--- Content provided by FirstRanker.com ---

Hypoxanthine + PRPP

Inosinate + PPi

--- Content provided by⁠ FirstRanker.com ---

LNS Is A Cause For Primary Gout

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LNS is characterized with

hyperuricemia (Uric acid level rises)

and suffers from Gout.

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In addition there are mental

aberrations.

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LNS patients wil self-mutilate (self

harming) by biting lips and fingers off.
Hyperuricemia In LNS

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LNS is characterized with

Hyperuricemia (high

concentration of uric acid in the

--- Content provided by⁠ FirstRanker.com ---

blood).

A high concentration of uric acid,

--- Content provided by‌ FirstRanker.com ---

solidifies and deposits in the

tissues forming Gouty Tophi.

The deposits in the joints

--- Content provided by‌ FirstRanker.com ---

causes inflammation and

Gouty arthritis.

--- Content provided by​ FirstRanker.com ---

The kidneys excrete the extra

uric acid, which increases the

risk of forming Urate stones.

--- Content provided by⁠ FirstRanker.com ---

The urate stones may pass

as a sandy sludge or may

obstruct urine flow.

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This increases the risk for

hematuria and urinary tract

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infections.

Symptoms of LNS

All of the following

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symptoms of LNS are a

result of an overproduction

--- Content provided by​ FirstRanker.com ---

of Uric Acid
Swelling of the joints
Urate crystal formations,

which look like orange sand,

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are deposited in diapers of the

babies

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Kidney stones
Blood in the urine

? Basis of neurological

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aberrations in LNS

? May be due to defect in Brain

Salvage pathway.

--- Content provided by‌ FirstRanker.com ---

As in LNS there is defect in Salvage

Pathway primarily carried out in

Brain.

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This might affects the Brain

growth and development.

--- Content provided by⁠ FirstRanker.com ---

There by leading to Nervous

dysfunction and related

manifestations.

--- Content provided by​ FirstRanker.com ---

Athetosis (uncontrolled spastic

muscle movements of the arms

--- Content provided by​ FirstRanker.com ---

and legs)

Involuntary joint movements
Chorea (purposeless repetitive

--- Content provided by⁠ FirstRanker.com ---

movements)

Moderate mental retardation
Irritability
GIT disturbances are also noted

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LNS Behavioral Elements

- Cognitive dysfunction and

aggressive and impulsive

--- Content provided by‍ FirstRanker.com ---

behaviors
-Severe self injurious behavior

is common

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LNS and Cerebral Palsy

"Cerebral palsy is a group of

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movement disorders that result from

damage to the brain, either before,

during or shortly after birth."

--- Content provided by FirstRanker.com ---

Thus, LNS is often a cause for the

damage to the brain that triggers

--- Content provided by‌ FirstRanker.com ---

cerebral palsy.
LNS Treatment and Prognosis

--- Content provided by‍ FirstRanker.com ---

Treatment:

?Enzyme defect in LNS cannot be

treated.

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?Only the symptoms of LNS can be

treated.

--- Content provided by FirstRanker.com ---

?The drug Allopurinol may be used

to control excessive amounts of

uric acid.

--- Content provided by‌ FirstRanker.com ---

Treatment: Allopurinol ? Competitive

Inhibitor of Xanthine Oxidase

--- Content provided by⁠ FirstRanker.com ---

?Kidney stones can be treated

with lithotripsy

--- Content provided by‌ FirstRanker.com ---

?There are unfortunately no

treatments for the behavioral

and neurological effects of

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LNS


Prognosis:

--- Content provided by‌ FirstRanker.com ---

vThe prognosis for LNS is poor
vBecause there are no treatments for the

neurological effects of the syndrome as

--- Content provided by‍ FirstRanker.com ---

self-mutilation and may result in severe

retardation and death.

--- Content provided by‍ FirstRanker.com ---

vThe build-up of excessive uric acid in the

body causes painful episodes of joints.

Lesch-Nyhan Syndrome

--- Content provided by⁠ FirstRanker.com ---

?Build up of Hypoxanthine and Guanine

?Degradation of hypoxanthine and guanine results in

--- Content provided by‌ FirstRanker.com ---

increased uric acid

?Excess uric acid in urine often results in orange crystals

in the diaper of affected children

--- Content provided by‌ FirstRanker.com ---

?Severe mental retardation

?Self-mutilation

--- Content provided by​ FirstRanker.com ---

?Involuntary movements

?Gout

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Lesch-Nyhan Syndrome

Orotic Aciduria
Oroticaciduria is a rare inherited

--- Content provided by‍ FirstRanker.com ---

disorder of Pyrimidine synthesis.

Caused by a deficiency of the

enzyme

--- Content provided by‍ FirstRanker.com ---

Orotate Phospho Ribosyl

Transferase (OPRTase)

--- Content provided by‌ FirstRanker.com ---

OMP Decarboxylase.

Type I Oroticaciduria

Both OPRTase and OMP

--- Content provided by‌ FirstRanker.com ---

Decarboxylase Enzyme

deficient.

--- Content provided by​ FirstRanker.com ---

Bifunctional deficiency.
Type I Oroticaciduria

Only OMP

--- Content provided by‍ FirstRanker.com ---

Decarboxylase deficient.

Enzyme defects

accumulates Oroticacid in

--- Content provided by FirstRanker.com ---

blood

Increased excretion of

--- Content provided by⁠ FirstRanker.com ---

Orotic acid in urine

(Oroticaciduria : 1.0-1.5 g)
Symptoms

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Mental and Physical retarded

growth

Severe Megaloblastic Anemia

--- Content provided by⁠ FirstRanker.com ---

Treatment

Treat with feeding diet rich in

--- Content provided by‍ FirstRanker.com ---

Uridine /Cytidine

This provide Pyrimidine

nucleotides through Salvage

--- Content provided by FirstRanker.com ---

Pathway.

Promotes DNA and RNA

--- Content provided by⁠ FirstRanker.com ---

synthesis.
Also the introduced

Pyrimidine bases inhibits

--- Content provided by‌ FirstRanker.com ---

CPS II enzyme by feed

back mechanism and

block synthesis of

--- Content provided by⁠ FirstRanker.com ---

Oroticaciduria.

TREATMENT OF

--- Content provided by⁠ FirstRanker.com ---

OROTACIDURIA

Taking of

Cytidine and

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Uridine during

the whole life
Adenosine Deaminase (ADA)

--- Content provided by⁠ FirstRanker.com ---

defects

OR

--- Content provided by⁠ FirstRanker.com ---

Severe Combined Immuno

Deficiency

(SCID)

--- Content provided by​ FirstRanker.com ---

SCID

Induced by

--- Content provided by​ FirstRanker.com ---

Adenosine Deaminase

Defects
Adenosine Deaminase (ADA) is an

--- Content provided by‌ FirstRanker.com ---

Enzyme involved in Purine catabolism.

Deficiency of ADA enzyme leads to

Immunological disorder ?Severe

--- Content provided by‍ FirstRanker.com ---

Combined Immuno Deficiency

(SCID)

--- Content provided by‌ FirstRanker.com ---

The enzyme Adenosine

Deaminase is encoded by a

gene on chromosome 20.

--- Content provided by⁠ FirstRanker.com ---

ADA deficiency is inherited

in an Autosomal recessive

--- Content provided by‍ FirstRanker.com ---

manner.
Biochemical Defect

ADENOSINE DEAMINASE DEFICIENCY

--- Content provided by FirstRanker.com ---

IN PURINE DEGRADATION,

ENZYME Adenosine

Deaminase catalyzes the

--- Content provided by FirstRanker.com ---

conversion of:

ADENOSINE/AMP INOSINE/IMP

--- Content provided by⁠ FirstRanker.com ---

AMP

Deaminase

--- Content provided by⁠ FirstRanker.com ---

ADA Deficiency

Affects DNA Synthesis
ADA deficiency accumulates

--- Content provided by‍ FirstRanker.com ---

Adenosine/AMP later

transformed to dAMP and

dATP by enzyme Nucleoside

--- Content provided by​ FirstRanker.com ---

Kinases.

The formed dATP is an

--- Content provided by FirstRanker.com ---

inhibitor of enzyme

Ribonucleotide Reductase.

Ribonucleotide reductase

--- Content provided by‍ FirstRanker.com ---

is an enzyme which catalyzes

conversion of dNDPs to

--- Content provided by‌ FirstRanker.com ---

dNTPs.


Inhibited Ribonucleotide

--- Content provided by⁠ FirstRanker.com ---

Reductase thus unable

to produce dNTPs to

support DNA

--- Content provided by​ FirstRanker.com ---

biosynthesis.

Cause Of

--- Content provided by​ FirstRanker.com ---

Severe Combined Immunodeficiency Syndrome (SCID)
Thus Deficiency of ADA results in

accumulation of AMP and dATP

--- Content provided by​ FirstRanker.com ---

formed through Kinases.

dATP is an inhibitor of

Ribonucleotide reductase and

--- Content provided by⁠ FirstRanker.com ---

inhibit the biosynthesis of other

Deoxynucleotides like dCTP

--- Content provided by FirstRanker.com ---

ADA Deficiency Affects

The Growth and Multiplication

Of Rapidly Dividing Cells

--- Content provided by‌ FirstRanker.com ---

Low availability of dNTPs

affect the DNA

biosynthesis.

--- Content provided by‌ FirstRanker.com ---

This affects the rapidly

dividing cells of the body.

--- Content provided by⁠ FirstRanker.com ---

The low levels of dCTP affects DNA

replication.

Which further affects the growth of

--- Content provided by⁠ FirstRanker.com ---

rapidly dividing immune cells T

and B lymphocytes and other cells.
leading to IMMUNO DEFICIENCY.

--- Content provided by​ FirstRanker.com ---

ADA Deficiency

Leads To

Immuno Deficiency

--- Content provided by⁠ FirstRanker.com ---

? Defects in AMP Deaminase prevent

biodegradation of AMP

--- Content provided by‌ FirstRanker.com ---

? AMP is converted into dATP by Kinases
? dATP inhibits the synthesis of other

Deoxyribonucleotide by Ribonucleotide

--- Content provided by​ FirstRanker.com ---

reductase,

? Causing problems with the Immune

System (death of lymphocytes,

--- Content provided by‌ FirstRanker.com ---

immunodeficiency disease)
Decreased dATP,

dGTP levels inhibit

--- Content provided by FirstRanker.com ---

DNA replication

Function of Immune

--- Content provided by‍ FirstRanker.com ---

System depends upon

Lymphocyte Proliferation.

ADA deficiency inhibits

--- Content provided by⁠ FirstRanker.com ---

Ribonucleotide Reductase

and has Low dNTPs.
This inhibits DNA Synthesis of

--- Content provided by‍ FirstRanker.com ---

Lymphocytes and its

proliferation.

--- Content provided by​ FirstRanker.com ---

Immune System is

compromized due to non

functional T and B cells.

--- Content provided by FirstRanker.com ---

SCID

SCID is also known as

--- Content provided by‍ FirstRanker.com ---

Alymphocytosis
Glanzmann-Riniker Syndrome
Sever Mixed Immunodeficiency

Syndrome

--- Content provided by⁠ FirstRanker.com ---

Thymic Alymphoplasia
Incidence Of SCID

1 in 100 , 000 births.

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Some predict 1 in 50

,000 live births

SCID

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SELECTIVELY KILLS

LYMPHOCYTES

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Absence of Functional

BOTH B- and T-CELLS
Natural Killer Cells (NK)
SCID exhibits defective

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antibody response.

SCID sufferers are extremely

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susceptible to infectious

diseases(Bacterial , Viral

,Fungal).

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SCID Treatment

Bone Marrow transplant
Gene therapy

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Enzyme Replacement

Therapy - PEG-ADA
ADA DEFICIENCY

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ONE OF FIRST DISEASES TO BE TREATED

WITH GENE THERAPY

ADA GENE INSERTED INTO

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LYMPHOCYTES; THEN LYMPHOCYTES

RETURNED TO PATIENT

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PEG-ADA TREATMENTS

ACTIVITY LASTS 1-2 WEEKS

On September 14, 1990, the first

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gene therapy to combat this disease

was performed by Dr. William French

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Anderson

On a four year old girl, Ashanti

DeSilva, at the National Institutes

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of Health, Bethesda, Maryland,

U.S.A.

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SEVERE COMBINED IMMUNODEFICIENCY

(SCID)

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If ADA is deficient or absent,

Deoxyadenosine is not converted into

Deoxyinosine as normal.

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This elevates the levels of

Deoxyadenosine of Purine

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metabolism.

Deoxyadenosine is salvaged by a

Nucleoside Kinase, which converts it

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to dAMP, leading to accumulation of

dATP and
Inhibition of Deoxynucleotides

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synthesis through

Ribonucleotide reductase.

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Thus, DNA replication is ceased.
This affects the rapidly growing

cells.

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Points To Remember
Synthesis of Purine Nucleotides

De novo synthesis: Site,

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Characteristics, Element

sources of Purine bases

Salvage pathway: definition,

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significance, enzyme, Lesch-

Nyhan Syndrome

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Formation of

Deoxyribonucleotide: NDP

level

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Degradation of Purine Nucleotides

Uric acid, Gout

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Synthesis of Pyrimidine Nucleotides

De novo synthesis: Characteristics,

Element sources of Pyrimidine

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bases

Salvage pathway
Antimetabolites of Pyrimidine

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nucleotides

Catabolism of Pyrimidine Nucleotides
Related Disorders.

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Antimetabolites of Purine and

Pyrimidine Bases and

Nucleotides:

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Uses of Purine, Amino acid, and

Folic acid analogs.

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QUESTIONS

Long Essays.

1) Draw the Purine ring; write the sources

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of carbon and Nitrogen atoms of the ring.

OR

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Give the outline of Purine biosynthetic

pathway and a note on regulation and

inhibition of Purine nucleotide

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biosynthesis.
2) Describe metabolism of

Pyrimidine metabolism / synthesis

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and Degradation Pyrimidine

nucleotides.

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3) Catabolism of Purine nucleotides

/ formation of uric acid. Add a note

on Inborn Errors of Nucleotide

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metabolism.

Short Notes:

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1) Gout
2) Inter conversion of IMP to AMP

& GMP

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3) Salvage pathway.
4) Lesch Nyhan syndrome
5) PRPP
6) Digestion of Nucleic acids/

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Fate of Dietary Nucleic acid

7) Allopurinol /Treatment of

Gout

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8) Adenosine Deaminase

Deficiency/SCID

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9) Orotic aciduria.
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