Biosynthesis of Purine

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Biosynthesis
of Purine

Objective

•       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

 Summary:

•       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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