Purine metabolism | Anatomy2Medicine
Purine metabolism

Purine metabolism

Purine and pyrimidine metabolism

    • Purine synthesis
      • 5’-Phosphoribosyl-1’-pyrophosphate (PRPP) is the activated substrate in the synthesis of purine and pyrimidine synthesis.
      • The purine base is synthesized on the ribose moiety.

 

  • PRPP is formed from ATP and ribose.

 

          • The enzyme is PRPP synthetase.

 

  • PRPP provides the ribose moiety, reacting with glutamine to form phosphoribosylamine
  • This first step in purine biosynthesis produces N9 of the purine ring.

 

          • catalyzed by amidophosphoribosyl transferase (MCQ)
          • The enzyme is inhibited by AMP and GMP (MCQ)
        • A glycine molecule is added to the growing purine precursor.

 

  • C8 is donated by formyl tetrahydrofolate

 

          • N3 is donated by glutamine.
          • C6 is donated by CO2.
          • N1 is donated by aspartate.
          • Finally,C2 is donated by formyl tetrahydrofolate
        • Inosine monophosphate (IMP) is generated.
          • IMP contains the base hypoxanthine,
          • IMP can be converted in the liver to the free base, hypoxanthine, or to the nucleoside (by dephosphorylation).
          • Hypoxanthine, or inosine, travels to various tissues, where it is reconverted to the nucleotide.

 

  • IMP is the precursor of both AMP and GMP.

 

        • Formation of GMP,
          • IMP is converted first to xanthosine monophosphate
            • enzyme IMP dehydrogenase
          • IMP is finally converted to GMP
            • enzyme GMP synthetase.
        • Formation of AMP
          • IMP is converted first to adenylosuccinate
            • enzyme adenylosuccinate synthetase
          • IMP is finally converted to AMP
            • Enzyme:  adenylosuccinase.
        • By feedback inhibition, each product regulates its own synthesis from the IMP branch point and also inhibits the initial step in the pathway.
        • AMP and GMP can be phosphorylated to the triphosphate level.
        • ATP and GTP can be used for energy-requiring processes or for RNA synthesis.
      • Reduction of the ribose moiety to deoxyribose
        • occurs at the diphosphate level
        • catalyzed by ribonucleotide reductase, which requires the protein thioredoxin.
        • After the diphosphates are phosphorylated, deoxyadenosine triphosphate (dATP) and deoxyguanosine triphosphate (dGTP) can be used for DNA synthesis.
      • Purine bases can be salvaged by reacting with PRPP to re-form nucleotides
        • The purine-salvage enzymes
          • hypoxanthine-guanine phosphoribosyl transferase (HGPRT)
          • adenine phosphoribosyl transferase (APRT).
    • Purine degradation
      • In the degradation of the purine nucleotides

 

  • phosphate and ribose are removed first

 

      • then the nitrogenous base is oxidized.
    • Degradation of GMP
      • GMP is degraded to guanosine by the removal of the phosphate
        • Enzyme : 5’-nucleotidase
      • Guanosine is degraded to guanine and ribose 1-phosphate
        • Enzyme :purine nucleoside phosphorylase (PNP).
      • Guanine is then converted to xanthine.
    • Degradation of AMP
      • AMP is degraded to adenosine by the removal of the phosphate
        • Enzyme :  5’-nucleotidase.
      • Adenosine is converted to inosine
        • Enzyme : adenosine deaminase (ADA).
      • Degradation of inosine produces hypoxanthine and ribose 1-phosphate.
        • Enzyme : purine nucleoside phosphorylase (PNP)
      • Hypoxanthine is oxidized to xanthine
        • Enzyme : xanthine oxidase
        • this enzyme requires molybdenum.
      • Xanthine is oxidized to uric acid
        • Enzyme : xanthine oxidase.
      • Uric acid, which is not very water soluble, is excreted by the kidneys.
    • Applied aspects :
      • Occur due to lack of feedback inhibition
      • X-linked disorder
      • result in overproduction of nucleotides
      • Overactivity of PRPP synthetase

 

  • leads to increased degradation as well, resulting in hyperuricemia, gout, and kidney stones.

 

 

    • Mycophenolic acid
      • a powerful immunosuppressant
      • a reversible inhibitor of IMP dehydrogenase
      • The drug limits the formation of nucleic acids in activated and proliferating immune cells

 

  • used in treating autoimmune disease as well as to prevent transplant rejection.
  • hydroxyurea

 

      • antineoplastic agent
      • an inhibitor of ribonucleotide reductase.

 

  • used in the treatment of chronic myelogenous leukemia, polycythemia vera, and essential thrombocytosis.

 

    • Lesch-Nyhan syndrome
      • an X-linked recessive disorder

 

  • caused by a defective HGPRT

 

      • Purine bases cannot be salvaged (i.e., reconverted to nucleotides).
      • The purines are converted instead to uric acid, which increases in the blood.
      • Mental retardation and self-mutilation are characteristics of the disease.
    • Autosomal recessive mutations in APRT
      • result in the inability of cells to salvage the purine base adenine.

 

  • Patients develop nephrolithiasis with renal colic, hematuria, recurrent urinary tract infections, and dysuria.
  • Ineficiency of purine nucleoside phosphorylase (PNP)

 

      • results in accumulation of both dATP and dGTP in lymphoid tissue, which is toxic to immune cells.
      • Patients present with decreased numbers of T cells and lymphopenia. Neurologic symptoms, including mental retardation and muscle spasticity, and autoimmune disease are present.

 

  • ADA deficiency
  • leads to severe combined immunodeficiency (SCID)

 

      • As in PNP deficiency, both dATP and dGTP accumulate
      • ADA deficiency results in a T-, B-, and natural killer (NK)-cell deficiency with marked lymphopenia.
    • Allopurinol,

 

  • an inhibitor of xanthine oxidase

 

    • used in the treatment of gout.
  • Febuxostat
    • a novel nonpurine analog inhibitor of xanthine oxidase

. Pyrimidine synthesis

  • The pyrimidine base is synthesized before addition of the ribose moiety.
  • In the first reaction, glutamine reacts with CO2 and two ATP molecules to form carbamoyl phosphate.
    • catalyzed by carbamoyl phosphate synthetase II (MCQ)
    • inhibited by uridine triphosphate (UTP) (MCQ)
    • This reaction is analogous to the first reaction of the urea cycle.

 

  • However, for pyrimidine synthesis

 

      • glutamine provides the nitrogen
      • reaction occurs in the cytosol (MCQ)
    • An aspartate molecule adds to carbamoyl phosphate.
    • The molecule closes to yield a ring, which is oxidized, forming orotate.

 

  • Orotate reacts with PRPP, producing orotidine 5’-phosphate (OMP)

 

    • It is decarboxylated to form uridine monophosphate (UMP).
      • Both reactions are catalyzed by UMP synthase, which functions both as orotate phosphoribosyl transferase and OMP decarboxylase.
    • UMP is phosphorylated to UTP
      • UTP obtains an amino group from glutamine to form cytidine triphosphate (CTP). UTP and CTP are used for RNA synthesis.
      • The ribose moiety of cytidine diphosphate (CDP) is reduced to deoxyribose, forming deoxycytidine diphosphate (dCDP).
        • Enzyme : Ribonucleotide reductase

 

  • dCDP is dephosphorylated and deaminated to form deoxyuridine monophosphate (dUMP).

 

      • dUMP is converted to thymidine monophosphate (dTMP)
        • Enzyme : thymidylate synthase
        • requires methylene tetrahydrofolate.
      • Phosphorylations produce dCTP and deoxythymidine triphosphate (dTTP), which are precursors of DNA.
    • Pyrimidine degradation.
      • In pyrimidine degradation
        • carbons produce CO2 and a variety of water-soluble products
        • some nitrogens, released as ammonium ion, are used to produce urea.
    • Applied aspects

 

  • Hereditary orotic aciduria

 

        • orotic acid is excreted in the urine
        • UMP synthase is defective.
        • Pyrimidines cannot be synthesized
        • growth retardation occurs.
        • Oral administration of uridine bypasses the metabolic block and provides a source of pyrimidines.
      • 5-fluorouracil
        • antineoplastic agent
        • thymidylate synthase is inhibited by the 5-FU
        • 5-FU is converted by thymidylate synthase to 5-FdUMP, which remains bound to the enzyme, as a suicide inhibitor

 

  • 5-FU is used in the treatment of cancers such as breast an d colon cancer.