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
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.
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
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
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
27. 28
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
28. 29
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.
34. 35
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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41. 45
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
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
48
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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