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.

Effect of slow-release β-alanine tablets on absorption kinetics and paresthesia

“…After deproteinization and filtration (Tan and Gajra 2006;Van Kuilenburg et al 2004), free amino acids from supernatants were separated by ion exchange chromatography, and bA was quantified using dual wavelength photometric detection following ninhydrin post column derivatization (Biochrom 30 Amino acid Analyzer, Biochrom Ltd, Cambridge, UK; PEEK Li columns, Laborservice Onken GmbH, D-Gründau). Repeatability of the assay was 3%, with a limit of quantitation of 15 lmol L -1 .…”

Analysis of Pyrimidine Catabolism inDrosophila melanogasterUsing Epistatic Interactions With Mutations of Pyrimidine Biosynthesis and β-Alanine Metabolism

“…DPD deficiency among patients is associated with toxic reactions to 5-fluorouracil (5-FU), one of the most commonly prescribed chemotherapeutic agents used to treat cancer (van Kuilenburg et al 2000;Gross et al 2003;Kubota 2003;van Kuilenburg 2004). Furthermore, deficiencies for DPD, DHP, or bAS have been reported among individuals exhibiting a variety of clinical presentations, including convulsive and other neurological disorders (Hamajima et al 1998;van Kuilenburg et al 1999van Kuilenburg et al , 2002van Kuilenburg et al , 2003van Kuilenburg et al , 2005. The metabolic mechanisms that underlie these abnormalities are poorly understood, however, and it is unclear whether they result from perturbed homeostasis of pyrimidines, b-alanine, or b-aminoisobutyrate (derived by catabolism of thymine by these same enzymes) .…”

Dihydropyrimidine Dehydrogenase Deficiency: Metabolic Disease or Biochemical Phenotype?

“…Therefore, it is an interesting observation that in DPD patients, plasma beta-aminoisobutyric acid (ß-AIB), a downstream metabolite in thymine catabolism, is significantly decreased (van Kuilenburg et al 2004a). The molecular structure of ß-AIB is very similar to gammaaminobutyric acid and glycine, two of the most important inhibitors of neuronal synaptic transmission.…”

“…Following this line of thought, low ß-AIB may contribute to the imbalance between excitatory and inhibitory agents and thus play a role in seizure aetiology in DPD. Since plasma concentrations of ß-AIB levels are very low in DPD patients this parameter may unfortunately not be useful to differentiate between mild and severely affected individuals (Van Kuilenburg et al 2004a).…”