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 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