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Eric Niederhoffer, Ph.D. SIU-SOM

Pyrimidines and Purines. Eric Niederhoffer, Ph.D. SIU-SOM. Pyrimidine and purine synthesis Pyrimidine and purine salvage/degradation Pathway disorders. Outline. Pyrimidine and Purine Synthesis. HCO 3 - + Gln. R5P. CPSII. RPK. CP. Asp. PRPP. Oro. Gln. UMPS. Gly. UMP.

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Eric Niederhoffer, Ph.D. SIU-SOM

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  1. Pyrimidines and Purines Eric Niederhoffer, Ph.D. SIU-SOM

  2. Pyrimidine and purine synthesis Pyrimidine and purine salvage/degradation Pathway disorders Outline

  3. Pyrimidine and Purine Synthesis HCO3- + Gln R5P CPSII RPK CP Asp PRPP Oro Gln UMPS Gly UMP N10fTHF CO2 UTP Asp CDP dCDP IMP dUMP GDP ADP N5,N10-mTHF TS RR dTMP dGTP dATP RNA DNA

  4. Pyrimidine and Purine Salvage UTP CDP dCDP IMP dUMP N5,N10-mTHF TS GDP ADP RR dTMP RR dGTP dATP UMP TMP RNA DNA UTPT PRPP U T adenosine ADA HGPT inosine PNP A G PRPP HX XO APT urate X XO

  5. Pathway Disorders Rare autosomal recessive disorders • UMP synthase – deficiency in either orotatephosphoribosyltransferaseor OMP decarboxylase leads to hereditary oroticaciduria, megaloblastic anemia appearing weeks to months after birth that does not respond to cobalamin, folic acid, or iron,oroticcrystalluria and nephropathy, cardiac malformations, strabismus, and recurrent infection. Urine orotic acid overexcretion. Enzyme assay of RBC. Treatment with oral uridine. • Adenosine deaminase– (Severe combined immunodeficiency disorder) variety of clinical phenotypes, history of infections, diarrhea, dermatitis, and failure to thrive,ribs and vertebrae abnormalities (defects in cartilaginous structures). Lymphopenia, B and T cell production affected. Enzyme assay of RBC/WBC. Treatment by bone marrow/stem cell transplantation or enzyme replacement. • Purine nucleotide phosphorylase– (Immunodeficiency)lymphopenia, thymic deficiency, recurrent infections, and hypouricemia, developmental delay, ataxia, or spasticity. T cell production affected. Enzyme assay of RBC, lymphocytes, fibroblasts. Treatment by bone marrow/stem cell transplantation. • Adenine phosphoribosyltransferase– frequent infections, renal colic, renal failure. Elevated urine levels of 2,8-dihydroxyadenine, 8-hyroxyadenine, and adenine; serum uric acid normal. Enzyme assay. Treated with dietary purine restriction, high fluid intake, and avoidance of urine alkalinization, Allopurinol to prevent oxidation of adenine.

  6. Pathway Disorders X-linked recessive disorder • Hypoxanthine-guanine phosphoribosyltransferase– (Lesch-Nyhansyndrome) usually presents at 3 to 12 months with orange sandy urine precipitate, dystonia, intellectual disability, self-mutilation (lips, tongue, fingers), and gout. Elevated serum and urine uric acid levels. Enzyme assay on RBC, lymphocytes, fibroblasts. Molecular genetics of gene. Treated supportively with low-purine diet, allopurinol, and plenty of hydration.

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