Trends in Molecular Medicine
Pyrimidine pathways in health and disease
Section snippets
The importance of pyrimidines
New insights into the importance of pyrimidine biosynthesis and metabolism in humans followed the recognition of the first genetic defect, hereditary orotic aciduria 1, 2. The pivotal role of uridine monophosphate (UMP), the tissue- and species specificity of particular pathways [3] and their roles in healthy humans became evident from the differing clinical manifestations when seven further disorders were diagnosed [1]. The accumulation of specific metabolites in these disorders has aided
Pyrimidine metabolism in healthy humans
Pyrimidines are heterocyclic, six-membered, nitrogen-containing carbon ring structures, with uracil, cytosine and thymine being the basal structures of ribose-containing nucleosides (uridine, cytidine and thymidine respectively), or deoxyribose-containing deoxynucleosides, and their corresponding ribonucleotides or deoxyribonucleotides [2]. Pyrimidines serve essential functions in human metabolism as ribonucleotide bases in RNA (uracil and cytosine), and as deoxyribonucleotide bases in DNA
Pharmacological inhibition of pyrimidine metabolism
The importance of intact pyrimidine pathways in human physiology, and their upregulation in malignancy [20], makes them ideal targets for pharmacological intervention. The first inhibitors targeted CAD (Figure 1). N-phosphonoacetyl-L-aspartate, an ATCase inhibitor in prokaryotes, gave disappointing results in humans because gene amplification, leading to CAD overproduction, caused resistance in cancer cells. This effect of N-phosphonoacetyl-L-aspartate formed the basis for clinical trials of
Pyrimidine pathway enzymes and adverse responses to therapy
Pyrimidine disorders can be the unsuspected cause of adverse reactions during analogue therapy. This problem possibly derives from using animals in drug testing which have a different complement or distribution of some pyrimidine pathway enzymes (e.g. phosphorylases and kinases) compared with humans 1, 3, 12. Asymptomatic carriers of dihydropyrimidine dehydrogenase (DPD) deficiency, and completely deficient patients, suffer severe haematological or gastrointestinal toxicity during treatment
Clinical and biochemical consequences of genetic pyrimidine disorders
Since the serious clinical consequences of genetic disorders disrupting step(s) in the integrated network of pyrimidine metabolism first came to light 1, 26, nine defects have been identified, the latest being reported recently [37] (Table 1). None yet involve uridine salvage, which suggests that such defects might be incompatible with life. Recognition can be difficult because of heterogeneity in clinical expression, in and between families. Diagnosis is aided by the identification of the
Phenotypic heterogeneity makes diagnosis difficult
Neonatal fitting, epilepsy, microcephaly, dysmorphic features and mental retardation should lead clinicians to suspect that pyrimidine disorders might be present. All genetic disorders of pyrimidine, or deoxypyrimidine, metabolism are autosomal recessive and can be investigated as follows.
The first suspicion of pyrimidine disorders has often stemmed from an abnormal profile in a metabolic laboratory screening for more common genetic disorders by gas chromatography-mass spectrometry. Abnormally
Concluding remarks
The broad spectrum of clinical presentation and the accumulation of specific metabolites in the nine genetic disorders of pyrimidine nucleotide metabolism provide valuable new insights into the vital roles of pyrimidines and their deoxyanalogues in every aspect of human metabolism. Pinpointing the relationship between such specific metabolites and the enzyme involved is essential to aid research into understanding, and eventually treating, the associated pathologies. No defect in uridine
Acknowledgements
We are indebted to all the patients and families whose collaboration made these studies possible, to our many colleagues for helpful discussions, and to the organizers and sponsors of ICAP2004 for their generous support.
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