Disease and Nucleic Acid Metabolism

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DiseaseandNucleic Acid Metabolism

• Nucleotide synthesis
• Nucleotide Degradation
• Nucleotide Salvage

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Structures of purines and pyrimidines
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Purine Synthesis
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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.

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Phosphoribosyl Pyrophosphate (PRPP) Synthetase
Defects

• 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.

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Pyrimidine Synthesis
Production of Uridine 5-monophosphate (UMP) from
orotate is catalyzed by the enzyme UMP synthase
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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.

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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)

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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
  hours.

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Purine Degradation
The enzyme nucleotidase is also known as purine
nucleotide phosphorylase (PNP)
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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
  limbs.
• When a compatible donor can be found, bone marrow
  transplant is an effective treatment.

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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
  havebeen documented, resulting in increased
  levels of pyrimidines and neurological disorders.
• No treatments are available and mechanisms are
  unknown

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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.

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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)

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Purine Salvage
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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.

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Allopurinol and Hypoxanthine
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Gout

• 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.

tophus
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Pyrimidine Salvage
Pyrimidine salvage defects have not been
clinically documented