NUCLEOTIDE METABOLISM,DE NOVO SYNTHESIS OF PURINE, SALVAGE PATHWAY OF PURINE, DE-NOVO SYNTHESIS OF PYRIMIDINE, SALVAGE PATHWAY OF PYRIMIDINE, GOUT, HYPERURICEMIA, LESCH-NYAN SYNDROME, OROTIC ACIDURIA

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NUCLEOTIDE METABOLISM
AREEBAGHAYAS

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3. 3
Biochemical pathway where new nucleotides are
synthesized from simple precursor molecules.
The synthesis of nucleotide by recycling the pre-existing
free bases or nucleosides released from nucleic acid
breakdown.

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5. 5

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Tetrahydrofolate
THF
THF
THF
NITROGEN

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Formation of PRPP
Addition of N9(Glutamine)
PRPP synthetase
Glutamine PRPP
amidotransferase

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Addition of C8 (THF)
Addition of C4,C5 and N7
(Glycine)

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Addition of N3 (Glutamine)
Cyclisation (closure of ring) FGAM Cyclase

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Addition of C6 (Bicarbonate)
Addition of N1 (Aspartate )

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Addition of C2 (THF)
Removal of Fumarate

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Cyclisation (closure of ring)

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REGULATION OF
PURINE SYNTHESIS
IMP dehydrogenase
Adenylosuccinate
synthetase

16. • In purine salvage pathway free purine bases or nucleosides are converted to
nucleotides.
• No new nucleotides are synthesized from precursor.
• This pathway allows many tissues with low activity of De-Novo pathway of purine
synthesis to meet their nucleotide requirement, e.g. BRAIN, RBCs & NEUTROPHILS.
• HGPRTase is the “salvage enzyme” for purines.
 ADVANTAGE OF SALVAGE PATHWAY-
o This pathway requires much less energy and metabolic intermediates than the De-Novo
synthesis. 17

17. Adenine
Adenosine Monophosphate
PRPP PPi
This takes place in following two ways:-
1. CONVERSION OF FREE PURINES INTO NUCLEOTIDES -
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18. PPi
PRPP PPi
PRPP
Hypoxanthine
Guanine
Inosine Monophosphate
Guanosine Monophosphate19

19. Adenosine MonophosphateAdenosine
ATP ADP
2. CONVERSION OF NUCLEOSIDES INTO NUCLEOTIDES -
2’d CMP2’d Cytidine
ATP ADP2’d Guanosine
or
or
or
or
2’d Adenosine 2’d AMP
2’d GMP

20. End product of Purines (A&G) is URIC ACID.
• Degradation of purine nucleotides occurs by the action of Nucleotidase which yields
nucleosides (Adenosine & Guanosine).
• Adenosine is first converted to inosine by Adenosine deaminase.
• Inosine & Guanosine are respectively, converted to hypoxanthine & guanine (purine
bases) by Nucleoside Phosphorylase.
• Guanine undergoes deamination by Guanase to form Xanthine.
•Xanthine oxidase is an important enzyme that converts Hypoxanthine to Xanthine, &
Xanthine to Uric acid.
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CATABOLISM OF PURINE NUCLEOTIDES

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23. End product of purine metabolism is URIC ACID.
The normal concentration of serum uric acid is 4-7 mg / dl.
An elevated serum uric acid concentration is known as
HYPERURICEMIA.
 Excess formation & deposition of Uric acid & Sodium Urate
crystals in soft tissues and joints leads to GOUT.
DISORDERS OF PURINE METABOLISM

24. Classification of Gout-
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GOUT
Gout is a disease of joints caused by an elevated concentration of uric acid in
blood & tissues.
Increased serum uric acid is due to increased formation of uric acid or
decreased renal excretion.
1. Primary gout
2. Secondary gout

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Primary gout
Primary gout is an inborn error of metabolism due to overproduction of uric acid.
Increased level of uric acid lead to increased synthesis of purine nucleotides.
Causes defect in following enzymes of purine nucleotide biosynthesis :-
1. PRPP synthetase
2. Glutamine PRPP amidotransferase
3. HGPRTase

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Joints become inflamed, painful
& arthritic due to deposition of
sodium urate crystals (TOPHI)
Deposition of urate crystals in
kidney tubules & leads to
renal failure.
Symptoms of Primary Gout

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Secondary Gout
Secondary gout causes elevated destruction of cells or decreased elimination of
uric acid.
 Increased degradation of nucleic acid to uric acid occurs in Cancer, prolonged
starvation, alcohol etc.
 Decreased elimination occurs in chronic renal diseases.
 Glucose-6-phosphatase deficiency.

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LESCH-NYHAN SYMDROME
• Rare x-linked recessive disorder.
• Inborn error of purine metabolism.
• Deficiency of enzyme- HGPRTase
FEATURES-
1. Hyperuricemia
2. Gout
3. Urinary tract stones
4. Mental retardation
5. Spasticity
6. Self mutilation – biting of fingers and lips.

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Biosynthesis of Pyrimidine is simple than that of Purine.
The six-membered pyrimidine ring is made first (Orotate) and then attached to Ribose 5-P
which is donated by PRPP.
 Sources of CARBON & NITROGEN atoms
 N1,C6,C5 and C4 from Aspartate
 N3 from Glutamine
 C2 from Carbon dioxide
2

35.  This process require carbamoyl phosphate, which is also an intermediate in
the urea cycle.
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Formation of carbomyl
phosphate
Condensation

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Ring closure
Dehydrogenation

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Transfer of ribose
phosphate
Decarboxylation

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The end products of Pyrimidine nucleotides are highly water soluble.
These are-
1. CO2
2. NH3
3. β-alanine
4. β-aminoisobutyrate
CATABOLISM OF PYRIMIDINE NUCLEOTIDES

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TCA Cycle
Precursor of
Acetyl CoA
Succinyl CoA
TCA CycleExcreted in URINE
(marker of pyrimidine
degradation)

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44. It is an hereditary disease.
Results from absence of either one or both the enzymes;
 Orotatephosphoribosyltransferase (OPRTase)
 Orotidylate decarboxylase.
It is of 2 types:
1. Type I orotic aciduria:
• Due to deficiency of both orotate phosphoribosyltransferase (OPRTase) and
Orotidylate decarboxylase.
2. Type II orotic aciduria:
• Deficiency of Orotidylate decarboxylase.
OROTIC ACIDURIA
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45. Features:
■ Poor growth
■ Megaloblastic anaemia
■ Does not improve with vitamin B12 of folic acid
■ Excretion of large amount of orotate in urine
Treatment:
■ Can be successfully treated by feeding uridine.
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46. REYE’S SYNDROME:
• This is considered as a secondary orotic aciduria.
• Defect in ornithine trascarbamoylase leads to inability of severely
damages mitochondria to utilize carbamoyl phosphate in the
formation of urea.
• This is then diverted for cytosolic overproduction and excretion of
orotic acid.
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47. THANK YOU
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