Trends in Molecular Medicine
Volume 11, Issue 9, September 2005, Pages 430-437
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Pyrimidine pathways in health and disease

https://doi.org/10.1016/j.molmed.2005.07.003Get rights and content

Genetic defects involving enzymes essential for pyrimidine nucleotide metabolism have provided new insights into the vital physiological functions of these molecules in addition to nucleic acid synthesis. Such aberrations disrupt the haematological, nervous or mitochondrial systems and can cause adverse reactions to analogue therapy. Regulation of pyrimidine pathways is also known to be disrupted in malignancies. Nine genetic defects have now been identified but only one is currently treatable. Diagnosis is aided by the accumulation of specific metabolites. Recently, progress has been made in understanding the molecular mechanisms underlying inborn errors of pyrimidine metabolism, together with the key clinical issues and the implications for the future development of novel drugs and therapeutic strategies.

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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