The Clinical Aspects of Inherited Defects in Pyrimidine Degradation

Abstract

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 1.3.1.2.), 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 3.5.2.2) followed by degradation of ureidopropionate and ureidoisobutyrate to from (β-alanine and (β-aminoisobutyrate, respectively, by the enzyme uriedopropionase (UP; EC 3.5.1.6). The latter two enzymes are expressed exclusively in liver. The (β-alanine and (β-aminoisobutyrate are then further metabolized to carbon dioxide and ammonia.