Purine and Pyrimidines : Structure, Synthesis and Metabolism

Purines and Pyrimidines Bases

Purines = 2 rings

  1. Adenine
  2. Guanine
  3. Hypoxanthine (Deaminated Adenine)
    • Adenine to Hypoxanthine deamination is mediated by Adenosine deaminase which is decreased in Autosomal recessive SCID. Accumulated dATP inhibit ribonucleotide reductase leading to deficient synthesis of other deoxyribonulceotide precursors for DNA synthesis.
  4. Xanthine (Deaminated Guanine)


Pure As Gold i.e. Purines are Adenine and Guanine.

How to identify purines?

1. First look for 2 rings. If 2 rings are present, then –

2. Look for location of NH2- (amino) group:

  • 12 o’ clock (A is the 1st letter): Adenine
  • 7 o’ clock (G is the 7th letter): Guanine
  • Non NH2- group: Hypoxanthine or Xanthine

3. If there is no NH2- group, look of O- group:

  • 1 O- group: Hypoxanthine (hypo means less)
  • 2 O- group: Xanthine

purines and pyrimidine bases

Pyrimidines = 1 ring

  1. Cytosine
  2. Uracil (Deaminated Cytosine)
  3. Thymine (Methylated Uracil)
    • Thymine requires 2 “T”s – Thymylate synthase and Tetrahydrofolate (THF).
    • Uracil to thymidine methylation is mediated by Thymidylate synthase which is inhibited by 5-FU. This reaction requires Tetrahydrofolate (THF) which is synthesized from Dihydrofolate (DHF) by DHF reductase i.e. inhibited by Methotrexate (eukaryotic), Trimethoprim (prokaryotic) and Pyrimethamine (protozoal).


Pyrimidines are CUT from Purines: Cytosine, Uracil and Thymine

How to identify pyrimidines?

1. Look for a single ring. If single ring is present:

2. Remember in sequence of CUT:

  • Cytosine has NH2- group.
  • Uracil in RNA (Deaminated cytosine) has no NH2- group.
  • Thymine in DNA (Methylated uracil) has CH3- group.

Complementary Purines and Pyrimidines

Adenine (A) pairs via 2 hydrogen bonds to Uracil (U) in RNA or Thymine (T) in DNA, i.e. A=U or T.

Guanine (G) pairs via 3 hydrogen bonds to Cytosine (C), i.e. G ≡ C.

Chargaff’s rule:

  • % purines = % pyrimidines
  • % A = % T (%U)
  • $G = % C

Nucleosides, Nucleotides and Nucleic acids

Nucleosides = Base + Pentose sugar (Ribose for RNA and Deoxyribose for DNA) e.g. (deoxy-)adenosine, (deoxy-)guanosine, (deoxy)-cytidine, (deoxy)-uridine, deoxythimidine

Nucleotides = Base + Pentose sugar + Phosphate group e.g. AMP, ADP, ATP, dAMP, dADP, dATP.

Ribonucleotide reductase: forms deoxyribonucleotides from ribonucleotides.

  • Inhibited by Hydroxyurea.
  • Inhibited by dATP (accumulated in ADA SCID).

Nucleic acid = Nucleotides linked by 3′,5′ phosphodiester bonds.

  • Phosphate group at 5′ position is connected to 3′ position of another nucleotide.
  • Base sequence is written in 5’→3′ direction (left to right) e.g. 5′-TCAG-3′ or TCAG.

phosphodiester bond


  • Histones are rich in: Arginine and Lysine, hence POSITIVE charged.
  • DNA have PO4³-, hence NEGATIVELY charged.
  • Histones (positive) is attracted to DNA (negative) and DNA is condensed.
  • Histone Acetylation by Histone Acetyltransferase (HAT) removes positive charge (from lysine) – Histones are repelled from DNA and DNA is relaxed and genomes are available for transcription, i.e. transcriptionally active: Euchromatin
    • Inhibited in Huntington’s disease.
  • Histone Deacetylation by Histone Deacetylase (HDA) reverses acetylation of histone – Histones condeses the DNA and genomes are not available for transcription, i.e. transcriptionally inactive: Heterchromatin.

histone acetylation deacetylation

Purine and Pyrimidine De-novo synthesis (Occurs in Liver)

PRPP (Phosphoribosyl pyrophosphate) is an important compound to note during Purine and Pyrimidine synthesis. PRPP synthetase transfers Pyrophosphate (PPi) from ATP to Ribose 5-Phosphate (product of HMP pathway) to form PRPP. This is the rate limiting step in synthesis of both purines and pyrimidines which is inhibited by nucleotides.

  1. Purine nucleotide synthesis: starts with sugar (ribose) and phosphate, i.e. PRPP.
  2. Pyrimidine nucleotide synthesis: starts with pyrimidine synthesis and sugar (ribose) and phosphate, i.e. PRPP is added later.

Pyrimidine synthesis:

pyrimidine base

Remember the pyrimidine ring – they have contribution from:

  • CO2 (from carbamoyl phosphate)
  • Glutamine (from carbamoyl phosphate)
  • Aspartate

Remember the mnemonic – COP for sequence of synthesis:

  1. Carbamoyl Phosphate (CO2 + Glutamine)
  2. Orotic acid (Add Aspartate)
  3. Pyrimidine nucleotide i.e. UMP (Add PRPP and use UMP synthase)

Carbamoyl Phosphate Synthetase-2 of Pyrimidine synthesis is present in cytoplasm, unlike CPS-1 of urea cycle which is mitochondrial. When carbamoyl phosphate accumulates in mitochondria (urea cycle) it can leak out into cytoplasm and participate in pyrimidine synthesis (Ornithine Transcarbamoylase or OTC deficiency). Hence, accumulation of orotic acid and orotic aciduria is seen in:

  1. OTC deficiency: Hyperammonemia (urea cycle block); No megaloblastic anemia (no block in DNA synthesis)
  2. UMP synthase deficiency: Megaloblastic anemia (DNA synthesis block); No hyperammonemia (no urea cycle block)
    • It comprises of 2 enzymes – orotate phosporibosyltransferase and orotidyldecarboxylase. Both enzymes are deficient in type I orotic aciduria and only the later one is deficient in type II orotic aciduria. Both are autosomal recessive condition.
    • Uridine administration relieves symptoms as it is salvaged to UMP which in turn feedback-inhibits CPS-2, preventing orotic acid synthesis.

purine pyridimidine denovo

Purine synthesis:

purine base

Remember the amide groups in purine as discussed earlier. Also remember, that purine nucleotide synthesis starts from sugar (PRPP).

1. NH2- (amide) group is added to PRPP by PRPP amido-transferase. This is inhibited by negative feedback from purine nucleotides and analogues likes:

  • Allopurinol
  • 6-Mercaptopurine and Azathioprine (which releases 6-Mercaptopurine).

2. Intermediate step: Nucleotide is formed from Glycine, i.e. Inosine Monophosphate (IMP) with Hypoxanthine as purine base (devoid of NH2- group). THF is carbon donor.

3. IMP is the precursor of both AMP and GMP. Based on NH2- group donation by different amino acids:

  • Amino from Aspartate: AMP
  • Amino from Glutamine: GMP

Remember a reciprocal relation: AMP synthesis requires GTP as energy source and GMP synthesis requires ATP as energy source. When there is sufficient ATP in cell, GMP is synthesized and when there is sufficient GTP in cell, AMP is synthesized.

Purine Metabolism (Occurs outside Liver)

First: Phosphate is lost from nucleotide and nucleoside formed (Nucleotide – Phosphate = Nucleoside)

Second: Sugar is lost from nucleoside and purine base is left (Nucleoside – Sugar = Purine base)

Third: Purine bases now have 2 options –

  1. Recycle through Salvage pathway with HGPRT (Hypoxanthine Guanyl Phosphoribosyl Transferase) that adds ribose-phsophate to purine base to form nucleotide again (IMP and GMP) – 90%.
    • Near-complete deficiency of HGPRT activity is seen in Lesch-Nyhan syndrome (X-linked recessive). Cells of basal ganglia normally have very high HGPRT activity.
    • Lesch-Nyhan syndrome presents with: Spastic cerebral palsy (basal ganglia involvement), mental retardation, self-mutilation of hands and lips, hyperuricemia (salvage pathway blocked leading to increased share of excretion pathway in which uric acid is formed) and early death.
    • Early sign of Lesch-Nyhan syndrome: Orange urine crystals in diaper
  2. Excreted in urine as uric acid mediated by Xanthine Oxidase10%.
    • Xanthine oxidase inhibitors: Purine analogue (Allopurinol – also inhibits PRPP amidotransferase in purine synthesis) and Non-purine analogue (Febuxostat – lesser adverse effects).
    • Lactate and urate compete for the same transport system in kidney: Hence, conditions leading to lactic acidosis cause hyperuricemia (Alcoholism, Von-Gierke’s disease i.e. Glucose 6-phosphatase deficiency).

fructose hyperuricemia

Phosphorylated sugar accumulation cause hyperuricemia:

1. Glucose-6-Phosphate (in Von-Gierke’s disease or Glucose 6-Phosphatase deficiency): Glucose 6-Phosphate accumulates which undergoes HMP shunt to generate excessive ribose-5-phosphate, the precursor of purines.

2. Phosphorylated sugars (Fructose 1-phosphate in Aldolase B deficiency i.e. hereditary fructose intolerance and Galactose 1-phosphate in G1PUT deficiency i.e. Classic galactosemia) accumulation leads to ATP depletion and Pi sequestration in sugar. Nucleotides and intracellular Pi must be in balance. When Pi decreases, liver AMP deaminase is activated leading to degradation of AMP into uric acid leading to hyperuricemia.

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