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Disease and Nucleic Acid Metabolism


Excessive PRPP activity causes gout (deposition of uric acid crystals), along ... Gout. Elevated uric acid levels in the blood ... – PowerPoint PPT presentation

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Title: Disease and Nucleic Acid Metabolism

Disease and Nucleic Acid Metabolism
  • Nucleotide synthesis
  • Nucleotide Degradation
  • Nucleotide Salvage

Structures of purines and pyrimidines
Purine Synthesis
Purine Synthesis
  • Purine synthesis is critical to fetal
    development, therefore defects in enzymes will
    result in a nonviable fetus.
  • PRPP synthetase defects are known and have severe
    consequences (next slide)
  • PRPP synthetase superactivity has been
    documented, resulting in increased PRPP, elevated
    levels of nucleotides, and increased excretion of
    uric acid.

Phosphoribosyl Pyrophosphate (PRPP) Synthetase
  • PRPP deficiency results in convulsions, autistic
    behavior, anemia, and severe mental retardation.
  • Excessive PRPP activity causes gout (deposition
    of uric acid crystals), along with various
    neurological symptoms, such as deafness.

Pyrimidine Synthesis
Production of Uridine 5-monophosphate (UMP) from
orotate is catalyzed by the enzyme UMP synthase
Pyrimidine Synthesis
  • Pyrimidine Synthesis is critical to fetal
    development just as purine metabolism is
    critical. Therefore an absolute deficiency of an
    enzyme of pyrimidine synthesis would be fatal.
  • A very low level of the enzyme UMP synthase has
    been documented, resulting in the condition
    orotic aciduria.

Orotic Aciduria
  • Deficiency in UMP synthetase activity
  • Due to the demand for nucleotides in the process
    of red blood cell synthesis, patients develop the
    condition of megaloblastic anemia, a deficiency
    of red blood cells.
  • Pyrimidine synthesis is decreased and excess
    orotic acid is excreted in the urine (hence the
    name orotic aciduria)

Purine Degradation
  • Purine Nucleotides from ingested nucleic acids or
    turnover of cellular nucleic acids is excreted by
    humans as uric acid.
  • Humans excrete about 0.6 g uric acid every 24

Purine Degradation
The enzyme nucleotidase is also known as purine
nucleotide phosphorylase (PNP)
Adenosine Deaminase (ADA) and Purine Nucleoside
Phosphorylase (PNP) Deficiency.
  • A deficiency of either ADA or PNP causes a
    moderate to complete lack of immune function.
  • Affected children cannot survive outside a
    sterile environment.
  • They may also have moderate neurological
    problems, including partial paralysis of the
  • When a compatible donor can be found, bone marrow
    transplant is an effective treatment.

Pyrimidine Degradation
  • Pyrimidines are generally degraded to
    intermediates of carbon metabolism (for example,
    succinyl-CoA) and ammonia (NH4).
  • NH4 is packaged as urea through the urea cycle
    and excreted by humans
  • Defects in enzymes of pyrimidine degradation
    have been documented, resulting in increased
    levels of pyrimidines and neurological disorders.
  • No treatments are available and mechanisms are

Pyrimidine and Purine Salvage
  • Free Purine and Pyrimidine bases are constantly
    released in cells during the metabolic
    degradation of nucleotides.
  • Free Purine and Pyrimidine bases are in large
    part salvaged and reused to make nucleotides.
  • Salvage of free nucleotides consumes much less
    energy than de novo nucleotide synthesis and is
    the energetically preferred source of nucleotides
    for nucleic acid synthesis.

Purine Salvage
  • Salvage of the free purine bases guanine and
    hypoxanthine (the deamination product of adenine)
    often involves the enzyme hypoxanthine-guanine
    phosphoribosyltransferase (HGPRT)
  • Salvage of free adenine is accomplished by the
    enzyme adenine phosphoribosyltransferase (APRT),
    converting free adenine and PRPP to adenosine
    monophosphate (AMP)

Purine Salvage
Lesch-Nyhan Syndrome
  • Hypoxanthine Guanine Phosphoribosyltransferase
    (HGPRT) deficiency
  • X-linked genetic condition
  • Severe neurologic disease, characterized by
    self-mutilating behaviors such as lip and finger
    biting and/or head banging
  • Up to 20 times the uric acid in the urine than in
    normal individuals. Uric acid crystals form in
    the urine.
  • Untreated condition results in death within the
    first year due to kidney failure.
  • Treated with allopurinol, a competitive inhibitor
    of xanthine oxidase.

Allopurinol and Hypoxanthine
  • Elevated uric acid levels in the blood
  • Uric acid crystals will form in the extremities
    with a surrounding area of inflammation. This is
    called a tophus and is often described as an
    arthritic great toe.
  • Can be caused by a defect in an enzyme of purine
    metabolism or by reduced secretion of uric acid
    into the urinary tract.

Pyrimidine Salvage
Pyrimidine salvage defects have not been
clinically documented
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