title: New insights in dihydropyrimidine dehydrogenase deficiency: a pivotal role for beta-aminoisobutyric acid?
abstract: DPD (dihydropyrimidine dehydrogenase) constitutes the first step of the pyrimidine degradation pathway, in which the pyrimidine bases uracil and thymine are catabolized to beta-alanine and the R-enantiomer of beta-AIB (beta-aminoisobutyric acid) respectively. The S-enantiomer of beta-AIB is predominantly derived from the catabolism of valine. It has been suggested that an altered homoeostasis of beta-alanine underlies some of the clinical abnormalities encountered in patients with a DPD deficiency. In the present study, we demonstrated that only a slightly decreased concentration of beta-alanine was present in the urine and plasma, whereas normal levels of beta-alanine were present in the cerebrospinal fluid of patients with a DPD deficiency. Therefore the metabolism of beta-alanine-containing peptides, such as carnosine, may be an important factor involved in the homoeostasis of beta-alanine in patients with DPD deficiency. The mean concentration of beta-AIB was approx. 2-3-fold lower in cerebrospinal fluid and urine of patients with a DPD deficiency, when compared with controls. In contrast, strongly decreased levels (10-fold) of beta-AIB were present in the plasma of DPD patients. Our results demonstrate that, under pathological conditions, the catabolism of valine can result in the production of significant amounts of beta-AIB. Furthermore, the observation that the R-enantiomer of beta-AIB is abundantly present in the urine of DPD patients suggests that significant cross-over exists between the thymine and valine catabolic pathways.
authors.affiliation: Emma Children's Hospital and Department of Clinical Chemistry, Academic Medical Center, University of Amsterdam, The Netherlands. a.b.vanKuilenburg@amc.uva.nl
authors.forename: André B P
authors.initials: AB
authors.lastname: Van Kuilenburg
authors.forename: Alida E M
authors.initials: AE
authors.lastname: Stroomer
authors.forename: Henk
authors.initials: H
authors.lastname: Van Lenthe
authors.forename: Nico G G M
authors.initials: NG
authors.lastname: Abeling
authors.forename: Albert H
authors.initials: AH
authors.lastname: Van Gennip
mesh_terms: D000621:Aminoisobutyric Acids / Q000097:blood / Q000134:cerebrospinal fluid / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D020739:Brain Diseases, Metabolic, Inborn / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D054067:Dihydropyrimidine Dehydrogenase Deficiency; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics; D005472:Fluorouracil / Q000493:pharmacokinetics; D006706:Homeostasis; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D018377:Neurotransmitter Agents / Q000378:metabolism; D011686:Purine-Pyrimidine Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D013237:Stereoisomerism; D013941:Thymine / Q000378:metabolism*; D014498:Uracil / Q000378:metabolism; D014633:Valine / Q000378:metabolism*; D015091:beta-Alanine / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000652:urine
chemical_list: D000621:Aminoisobutyric Acids; D018377:Neurotransmitter Agents; D015091:beta-Alanine; D014498:Uracil; D042943:Dihydrouracil Dehydrogenase (NADP); D014633:Valine; D013941:Thymine; C033435:3-aminoisobutyric acid; D005472:Fluorouracil