The Clinical Aspects of Inherited Defects in Pyrimidine Degradation
Degradation pathways of pyrimidine bases are common to uracil, thymine, and the halogenated analogues of uracil and involve the same enzymes (Fig. 1). Cytosine nucleotides undergo deamination to form uracil nucleotides before entering the pyrimidine degradation pathway. Degradation of uracil and thymine occurs mainly in the liver although other tissues are also involved in this metabolic process (Levine et al. 1974; Naguib et al. 1985). The first degradative enzyme of this pathway is dihydropyrimidine dehydrogenase (DPD; EC 18.104.22.168.), an NADPH-dependent enzyme that reversibly reduces uracil and thymine forming dihydrouracil (DHU) and dihydrothymine (DHT), respectively. DPD enzymatic activity, which is considered rate limiting, is highest in the liver; however, it can be measured in most other tissues including white blood cells and cultured skin fibroblasts. The next degradative step involves enzymatic cleavage of the dihydropyrimidine ring by dihydropyrimidine amidohydrolase (DHPH; EC 22.214.171.124) followed by degradation of ureidopropionate and ureidoisobutyrate to from (β-alanine and (β-aminoisobutyrate, respectively, by the enzyme uriedopropionase (UP; EC 126.96.36.199). The latter two enzymes are expressed exclusively in liver. The (β-alanine and (β-aminoisobutyrate are then further metabolized to carbon dioxide and ammonia.
KeywordsToxicity NADPH Pyrimidine Hypoglycemia Purine
Unable to display preview. Download preview PDF.
- Bakkeren JAJM, de Abreu RA, Sengers RCA, Gabreels FJM, Maas JM, Renier WO (1984) Elevated urine, blood and cerebrospinal fluid levels of uracil and thymine in a child with dihydrothymine dehydrogenase deficiency. Clin Chim Acta 140: 247–256Google Scholar
- Chaudhuri NK, Mukherjee KL, Heidelberger C (1958) Studies on fluorinated pyrimidines. VII — the degradative pathway. Biochem Pharm 1: 328–341Google Scholar
- Duran M, Rover P, de Bree PK, Schreuder CH, Beukenhorst H, Dorland L, Berger R (1991) Dihydropyrimidinuria: a new inborn error of pyrimidine metabolism. J Inher Metab Dis 14: 367–370Google Scholar
- Levine RL, Hoogenraad NJ, Kretchmer N (1974) A review: Biological and clinical aspects of pyrimidine metabolism, Pediatr Res 8: 724–734Google Scholar
- Wadman SK, Beemer FA, de Bree PK, Duran M, van Gennip AH, Ketting D, van Sprang FJ (1984) New defects of pyrimidine metabolism. Adv Ezp med Biol 165A: 109–114Google Scholar
- Wadman SK, Berger R, Duran M, de Brce PK, Stoker-de Vries SA, Beemer FA, Weits Binnerts JJ, Penders TJ, van der Woude JK (1985) Dihydropyrimidine dehydrogenase deficiency leading to thymineuraciluria. An inborn error of pyrimidine metabolism. J Inher Metal, Dis 8 (suppl2): 113–114Google Scholar
- Wilcken B, Hammond J (1985) Dihydropyrimidine dehydrogenase deficiency - a further case. J Inher Metal, Dis 8 (Suppl 2): 115–116Google Scholar