Disease relevance of UPB1

• Heterologous expression of the mutant enzyme in Escherichia coli showed that the A85E mutation resulted in a mutant beta-ureidopropionase enzyme without residual activity [1].
• During the pilot study for newborn screening, we found neonates with diseases at a rate of 1 per 1,400 including propionic acidemia, methylmalonic acidemia, orotic aciduria, beta-ureidopropionase deficiency, lactic aciduria and neuroblastoma [2].
• Beta-ureidopropionase deficiency presenting with febrile status epilepticus [3].

High impact information on UPB1

• beta-Ureidopropionase deficiency: an inborn error of pyrimidine degradation associated with neurological abnormalities [1].
• Furthermore, an altered homeostasis of beta-aminoisobutyric acid and/or increased oxidative stress might contribute to some of the clinical abnormalities encountered in patients with a beta-ureidopropionase deficiency [1].
• Analysis of the beta-ureidopropionase gene (UPB1) of these patients revealed the presence of two splice-site mutations (IVS1-2A>G and IVS8-1G>A) and one missense mutation (A85E) [1].
• In this study, we report the elucidation of the genetic basis underlying a beta-ureidopropionase deficiency in four patients presenting with neurological abnormalities and strongly elevated levels of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid in plasma, cerebrospinal fluid and urine [1].
• Beta-ureidopropionase is the third enzyme in the catabolic pathway of uracil and thymine [3].

Biological context of UPB1

• A cDNA encoding beta-ureidopropionase (BUP) was isolated from a human liver cDNA library, expressed in E. coli, and purified from the culture extract [4].
• Using computer methods for database search and multiple alignment, statistically significant sequence similarities were identified between several nitrilases with distinct substrate specificity, cyanide hydratases, aliphatic amidases, beta-alanine synthase, and a few other proteins with unknown molecular function [5].
• A radiochemical assay for beta-ureidopropionase using radiolabeled N-carbamyl-beta-alanine obtained via hydrolysis of [2-(14)C]5, 6-dihydrouracil [6].
• Human beta-ureidopropionase obeyed Michaelis-Menten kinetics with an apparent Km for N-carbamyl-beta-alanine of 15.5 +/- 1.9 microM [6].
• RT-PCR analysis of the complete beta-ureidopropionase cDNA suggested that both splice-site mutations lead to a variety of alternative splice variants, with deletions of a single or several exons [7].

Associations of UPB1 with chemical compounds

• The complex regulatory function and the negative cooperative mechanism of BUP by beta-alanine have been observed in rats [4].
• The diagnosis of IEM of purine and pyrimidine such as deficiencies of hypoxanthine-guanine phosphoribosyl transferase, adenine phosphoribosyl transferase, dihydropyrimidine dehydrogenase, dihydropyrimidinase and beta-ureidopropionase are described [2].
• N-Carbamoyl-beta-alanine, the natural substrate of beta-ureidopropionase, does not interfere with the described assay system [8].
• A sensitive assay for beta-ureidopropionase based on derivatization of the reaction product beta-alanine with phenylisothiocyanate has been developed [8].
• Beta-alanine synthase, an enzyme involved in catabolism of uracil and thymine [9].

Other interactions of UPB1

• It has been suggested that D-amino acid production from DL-5-substituted hydantoin involves the action of a series of enzymes involved in pyrimidine degradation, namely amide-ring opening enzyme, dihydropyrimidinase, and N-carbamoylamide hydrolyzing enzyme, beta-ureidopropionase [10].
• No activity of beta-ureidopropionase could be detected in a liver biopsy of the patient, while a normal activity of dihydropyrimidine dehydrogenase and dihydropyrimidinase was present [11].

Analytical, diagnostic and therapeutic context of UPB1

• Assay for beta-ureidopropionase by high-performance liquid chromatography [8].
• A radiochemical assay was developed to measure the activity of beta-ureidopropionase in human liver homogenates which is based on the detection of the reaction product (14)CO(2) by liquid scintillation counting [6].

References