de novo and salvage pathway of purines

DEPARTMENT OF FORENSIC BIOLOGYACADEMIC SEMINAR ON

‘DE NOVO AND SALVAGE PATHWAY OF PURINES’

PRESENTED BY-

JAYATI MISHRA

UNDER THE GUIDENCE OF:

PRADIP HIRAPUE

ASST PROF. FORENSIC BIOLOGY

Institute Of Forensic Science

JAYATI MISHRAROll No. 121

CONTENTS

� INTRODUCTION

� FUNCTION OF NUCLEOTIDES

� DE NOVO PATHWAY

� SALVAGE PATHWAY

REFERENCES


� REFERENCES

INTRODUCTION� Nucleotides are building blocks of nucleic acids.

� They are non-essential nutrients , because they can be synthesized in the body.

� Nucleic acids occur in the nucleoprotein.

� Nucleic acids are further digested in the small intestine to


� Nucleic acids are further digested in the small intestine to

generate nucleotides.

� Nucleotides are absorbed into intestinal mucosa cells , where they are degraded to three components : base , pentose , phosphate.

Pentose is absorbed but base is degraded and excreted

NITROGENEOUS BASE


Structure Of Nucleotide


Functions of Nucleotides1. They serve as building blocks of nucleic acids.

2. ATP plays an important role in energy transformation.

3. ATP , ADP, and AMP may function as allosteric regulatorsand participate in regulation of many metabolic path-ways. ATP involvesin covalentmodificationof enzymes.


ways. ATP involvesin covalentmodificationof enzymes.

4. CAMP and cGMP are second messengers.

Purine Nucleotide MetabolismAnabolism

� There are two pathways of synthesis of purine nucleotides :

1.the De Novo synthesis pathway and the

2.Salvage pathway.


� The former is the main synthesis pathway of nucleotides , the latter is important one in brain and bone marrow.

� The de novo synthesis of purine nucleotide means usingphosphoribose , amino acids , one carbon units and CO2as raw materials to synthesize purine nucleotide from the beginning.

De novo pathway


Contd.� The pathway can be divided into two stages.

� Stage one : formation of inosine monophosphate ( IMP )

� Stage two : conversion of IMP to either AMP or GMP


� Stage One

� PRPP synthetase� R5P + ATP---------------------------�PRPP + AMP

� amidotransferase� PRPP + Gln---------------------------�PRA + Glu

Contnd.Stage Two

� The conversion of IMP either to AMP or GMP requires

two reactions.


GTP,Mg++,adenylosuccinate synthase

� IMP + Asp-------------------------------�adenylosuccinate

adenylosuccinate lyase� Adenylosuccinate-----------------------�AMP + fumarate

Contd.

IMP dehydrogenase� IMP + H2O + NAD+---------------�XMP + NADH + H+

ATP, Mg++, GMP synthase� XMP + Gln------------------------------------�GMP + Glu


� Nucleoside triphosphates are the most common nucleotide used in metabolism.

� ATP is synthesized from ADP and Pi via oxidative.phosphorylation or substrate level phosphorylation.

Contd.� ADP is synthesized from AMP in a reaction catalyzed by

adenylate kinase.

AMP + ATP-------------------------� 2ADP

� Other NTPs are also synthesized in ATP-requiring reactions


� Other NTPs are also synthesized in ATP-requiring reactionscatalyzed by corresponding NMP kinases.

NMP + ATP-------------------------�NDP + ADP

� NDP kinase catalyzes the formation of NTP.

NDP + ATP-------------------------�NTP + ADP

Regulation of de novo Pathway� PRPP activates amidotransferase.

� IMP , AMP and GMP inhibit PRPP synthetase.

� AMP inhibits conversion of IMP to GMP and GMP inhibitsconversion of IMP to AMP.


conversion of IMP to AMP.

� ATP stimulates conversion of IMP to GMP and GTP stimulatesconversion of IMP to AMP.

� That ensures a balanced synthesis of both families of purine nucleotides.

Salvage Pathway of Purine Nucleotides� Many cells have mechanisms to retrieve purine bases and

purine nucleosides. They are used to synthesize purine nucleotides.

This is the salvage pathway.


Contd.� From Base to Nucleotides

APRT� A + PRPP--------------------------------�AMP + ppi


HGPRT� H + PRPP--------------------------------� IMP + ppi

HGPRT� G + PRPP--------------------------------�GMP + ppi

Contnd.� From Nucleoside to Nucleotide

AR kinase� AR + ATP--------------------------------�AMP + ADP

� In comparison to de novo pathway, salvage pathway


� In comparison to de novo pathway, salvage pathway is energy-saving.

� In brain and bone marrow tissues salvage pathway is theonly pathway of nucleotide synthesis.

� Deficiency of HGPRT causes Lesch Nyhan syndrome

Antimetabolites of Purine Nucleotides

� Antimetabolites of purine nucleotides are analogues of purine, amino acids or folic acid.

� They either act as competitive inhibitors of enzymes in


� They either act as competitive inhibitors of enzymes in purine nucleotides synthesis or can be incorporated into purine nucleotides.

� Thus they block purine nucleotides synthesis or interfere in nucleic acids synthesis.

Contd.

� 6-MP and 6-MG are purine analogues

.

� 6-MP nucleotide is structurally similar to IMP and inhibits

conversion of IMP to AMP and GMP.


conversion of IMP to AMP and GMP.

� It also blocks synthesis of PRA from PRPP ,, synthesis of GMP and IMP from G and H respectively.

Contd.

� Azaserine and diazonorleucine are amino acid analogues.

� They are analogues of Gln and interfere with Gln in


� They are analogues of Gln and interfere with Gln in purine nucleotide de novo synthesis.

�

Catabolism of Purine Nucleotide� AMP undergoes hydrolysis and deamination, the A residue

is converted to H. H is oxidized , yielding X and X is oxidized ,yielding uric acid.


� GMP is hydrolyzed and G is released. G is converted to X and X is oxidized yielding uric acid.

Contd.� In the human body the purine ring can not be degraded.

� Uric acid contains the purine ring and is less soluble in water.


water.

� Certain genetic defects in purine metabolism can cause high blood levels of uric acid and results in a diseaseknown as gout.

REFERENCES� Mc Curry, JE; Begley, TP (2005). The organic chemistry of biological pathways. Roberts & Company.

� Alberts B, Johnson A, Lewis J, Raff M, Roberts K & Wlater P (2002).Molecular Biology of the Cell (4th ed.). Garland Science

� David.L.Nelson,Michael.M.Cox …,, Lehninger Principles Of


� David.L.Nelson,Michael.M.Cox …,, Lehninger Principles Of Biochemistry.4th ed.

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