Biosynthesis of Purine

Biosynthesis of Purine



       At the end of this lecture, student will be able to

       Explain biosynthesis of purine nucleotides

       Explain salvage pathway

       Describe degradation of purine nucleotides 

       Discuss consequences of defective purine metabolism

Biosynthesis of purine nucleotides

       Two major routes for purine nucleotide biosynthesis


       Many compounds contribute to purine ring of nucleotides

       N1 of purine is derived from Aspartate

       C2 & C8 arise from N10-Formyl THF

       N3 &N9 from glutamine

       C4, C5 & C7 from glycine

       C6 directly comes from CO2

       Major site of purine synthesis is in the liver

       Purines are actually synthesised as ribonucleotides

       Synthesis of the purine nucleotides begins with PRPP and leads to the first fully formed nucleotide, IMP

       The purine base without the attached ribose moiety is hypoxanthine

        The purine base is built upon the ribose by several amidotransferase and transformylation reactions

       Synthesis of IMP requires five moles of ATP, two moles of glutamine, one mole of glycine, one mole of CO2, one mole of aspartate and two moles of formate

  1. Liver is the major organ for purine nucleotide synthesis
  2. Ribose 5P obtained by carbohydrate metabolism is the precursor for synthesis of purine nucleotides. It react with ATP to form Phosphoribosyl pyrophosphate (PRPP) in presence of PRPP synthetase
  3. Glutamine transfers its amide to PRPP to replace pyrophosphate & produce β-5-phosphoribosyl amine
  4. Phosphoribosyl amine react with glycine in presence of ATP to form glycin amide ribosy-5-phosphate  
  5. N10 formyl THF donate the formyl group & produce formyl glycin amide ribosyl -5- phosphate
  6. Glutamine transfer the second amide group to form formyl glycin amide ribosyl -5- phosphate
  7. The imidazole ring is closed in an ATP dependent reaction to yield 5-amino-imidazole ribosyl -5- phosphate
  8. Incorporation of Co2 occurs to yield amino imidazole carboxylate ribosyl -5- phosphate
  9. Aspartate  condenses to form amino imidazole-4- succinyl carboxamide ribosyl -5- phosphate
  10. Adenosuccinatelyase cleaves of fumarate and only the amino group of aspartate is retained to yield amino imidazole -4- carboxamide ribosyl -5- phosphate
  1. N10-Formyl THF donate a one carbon moiety to produce 5 formyl amino imidazole -4- carboxamide ribosyl-5- posphate . With this reaction all the carbon & nitrogen atoms of purines ring are obtained
  2. Formyl amino imidazole -4-carboxamide ribosyl-5- phosphate catalysed by cyclohydrolase and leads to close ring with elimination of H2O molecule to form Inosine monophosphate
  3. IMP is the immediate precursor for formation of GMP & AMP
  4. Aspartate condenses with IMP in presence of GTP to produce Adenyl succinate which cleavage to form AMP
  5. IMP undergoes NAD dependent dehydrogenation to form AMP and glutamine then combines with XMP and forms GMP.

       IMP (parent nucleotide) does not accumulate in cells but is rapidly converted to other purine nucleoside monophosphates AMP (adenosine monophosphate) & GMP (guanosine monophosphate)

       IMP represents a branch point for purine biosynthesis, because it can be converted into either AMP or GMP through two distinct reaction pathways

       The pathway leading to AMP requires energy in the form of GTP; that leading to GMP requires energy in the form of ATP

Salvage pathway

Phosphoribosyl transferases involved in salvage pathway convert free bases to nucleotides

Purines can be directly converted to the corresponding nucleotides

       Regulation of purine biosynthesis is based on the availability of intracellular concentration of PRPP, PRPP synthase and ribose -5- Phosphate

Catabolism of Purine nucleotides


Disorders of defective purine metabolism

1. Hyperuricemia:

uric acid is the end product of purine metabolism

Normal concentration in serum is 2.5 -7mg / dl in men & 1.5-6mg/dl in women

Elevation in serum level referred as hyperuricemia

2. Gout:

       Metabolic diseases associated with over production of uric acid, where crystals of sodium urate gets deposited in soft tissue like joints. Such deposit is known as tophi and leads to gouty arthritis

       More common in men than in women

       Two types of gout:

       Primary gout: In born error of metabolism due to over production of uric acid (treatment by Allopurinol etc)

       Hyperuricemia of primary gout is due to excessive production of purines and to renal retention of uric acid

       Excessive purine synthesis is due to deficiency of hypoxanthine-guanine phosphoribosyl transferase

       Secondary Gout: Due to various diseases which causes increased synthesis or decreased excretion of uric acid

       Increased degradation of nucleic acids (hence more uric acid formation) is observed in various cancers (leukemias, polycythemia, lymphomas, etc.) psoriasis and increased tissue breakdown (trauma, starvation etc.)

       Disorders associated with impairment in renal function cause accumulation of uric acid which may lead to gout


       Two major sources of nucleotides are salvage pathway and de novo biosynthesis

       Purine nucleotides are biodegraded by nucleotidases, nucleotide phosphorylases, deaminases & xanthine oxidase

       Uric acid is the final product of purine biodegradation in mammals

       Defective purine metabolism leads to clinical disease

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