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 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.

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 hours.

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 limbs. 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 unknown

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 selfmutilating 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

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

Pyrimidine Salvage

Pyrimidine salvage defects have not been clinically documented