Inborn errors of pyrimidine degradation: Clinical, biochemical and molecular aspects

Gennip, Albert H.; Abeling, N. G. G. M.; Vreken, P.; Kuilenburg, André B. P.

doi:10.1023/a:1005356806329

Cited by 102 publications

(38 citation statements)

References 37 publications

(35 reference statements)

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“…␤-Alanine is also a building block of the dipeptidic anti-glycation agents carnosine and anserine, which have a putative role in protecting the central nervous system against diverse types of pathology (5)(6)(7). Disorders in pyrimidine degradation and ␤-alanine metabolism in humans are normally associated with neurological disorders (8,9). Yeasts require ␤-alanine as a precursor of pantothenate and coenzyme A biosynthesis, but generate it mostly via degradation of spermine (10).…”

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confidence: 99%

Crystal Structures of Yeast β-Alanine Synthase Complexes Reveal the Mode of Substrate Binding and Large Scale Domain Closure Movements

Lundgren

Andersen

Piškur

et al. 2007

Journal of Biological Chemistry

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␤-Alanine synthase is the final enzyme of the reductive pyrimidine catabolic pathway, which is responsible for the breakdown of uracil and thymine in higher organisms. The fold of the homodimeric enzyme from the yeast Saccharomyces kluyveri identifies it as a member of the AcyI/M20 family of metallopeptidases. Its subunit consists of a catalytic domain harboring a di-zinc center and a smaller dimerization domain. The present site-directed mutagenesis studies identify Glu 159 and Arg 322 as crucial for catalysis and His 262 and His 397 as functionally important but not essential. We determined the crystal structures of wild-type ␤-alanine synthase in complex with the reaction product ␤-alanine, and of the mutant E159A with the substrate N-carbamyl-␤-alanine, revealing the closed state of a dimeric AcyI/M20 metallopeptidase-like enzyme. Subunit closure is achieved by a ϳ30°rigid body domain rotation, which completes the active site by integration of substrate binding residues that belong to the dimerization domain of the same or the partner subunit. Substrate binding is achieved via a salt bridge, a number of hydrogen bonds, and coordination to one of the zinc ions of the di-metal center.

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confidence: 99%

Crystal Structures of Yeast β-Alanine Synthase Complexes Reveal the Mode of Substrate Binding and Large Scale Domain Closure Movements

Lundgren

Andersen

Piškur

et al. 2007

Journal of Biological Chemistry

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“…Generally, in disorders of the first and second steps of pyrimidine degradation, the symptomatology is variable. 2,3 Here, our detection of an asymptomatic case ofˇUPase deficiency suggests that a variety of clinical symptoms are also characteristic of disorders of the third step. The increases inˇUP andˇUIB were almost as great as those found in the original case.…”

Section: Discussionmentioning

confidence: 79%

Screening and diagnosis of β‐ureidopropionase deficiency by gas chromatographic/mass spectrometric analysis of urine

Ohse

Matsuo

Ishida³

et al. 2002

J. Mass Spectrom.

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Dihydropyrimidine dehydrogenase (DHPDase), dihydropyrimidinase (DHPase) and beta-ureidopropionase (betaUPase) are the enzymes that catalyze the first, second, and third steps of the degradation of pyrimidines, respectively. beta-Ureidopropionate (betaUP) and beta-ureidoisobutyrate (betaUIB) are increased in the urine of patients with betaUPase deficiency. The original case in which betaUPase deficiency was discovered by NMR spectroscopy was an 11-month-old patient who presented with hypotonia and dystonic movement. We detected a second but asymptomatic case during a pilot study of neonatal screening with filter-paper urine, urease pretreatment and gas chromatography/mass spectrometry (GC/MS). The urease pretreatment of urine without fractionation resulted in a high recovery of these polar ureide compounds and allowed the highly sensitive GC/MS detection and diagnosis of betaUPase deficiency. betaUP and betaUIB were identified using GC/MS techniques. In the urine of the neonate with betaUPase deficiency, betaUP and betaUIB were persistently increased. Thymine, 5,6-dihydrothymine and 5,6-dihydrouracil were increased only moderately but significantly. It is known that thymine and uracil increase markedly in DHPDase deficiency, and 5,6-dihydrothymine and 5,6-dihydrouracil increase in DHPase deficiency. Therefore, betaUPase deficiency can be differentially diagnosed from the first and second enzyme deficiencies. Application of this specific and sensitive diagnostic procedure will lead to an understanding of the clinical heterogeneity of betaUPase deficiency. Furthermore, the identification of patients with defects in pyrimidine metabolism will enable doctors to avoid cancer chemotherapy with pyrimidine analogues such as 5-fluorouracil, which could be dangerous for these patients.

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“…In general the clinical phenotypes of patients with defects of pyrimidine degradation pathways are highly variable, but often centred around neurological and developmental problems (Van Gennip et al 1997;Van Kuilenburg et al 1999). Regulation of pyrimidine pathways is also known to be disrupted in malignancies.…”

Section: Inborn Errors Of Pyrimidine Metabolismmentioning

confidence: 99%

Inborn errors of purine and pyrimidine metabolism

Jurecka

2009

J of Inher Metab Disea

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Genetic disorders of purine and pyrimidine (PP) metabolism are under-reported and infrequently mentioned in the general literature, as well as in reviews dedicated to other inborn errors of metabolism. Owing to limited awareness, relatively recent recognition, as well as considerable phenotypic variation, these disorders may often be misdiagnosed or remain undiagnosed. Disorders that arise as a result of dysfunction in PP metabolism represent some of the most challenging diagnostic problems in medicine. In addition to their low prevalence rates, they also present with extremely variable signs and symptoms. They may affect any system in a variety of manners, and often mimic other, more recognizable disorders. The diagnostic problem is compounded by the fact that some biochemically affected patients are symptom-free. Rapidly evolving laboratory techniques such as high-performance liquid chromatography coupled to tandem mass spectrometry are now well established as the preferred method for detection for these defects, but currently the most important step in diagnosis consists of suspecting the disorder. Diagnosis is vital because genetic counselling can be provided and, in some cases, specific treatment can be offered that may slow or even reverse clinical symptoms. If undiagnosed, these disorders can be devastating to patients and their families, resulting in early death or institutionalization for the rest of patient's life. This article describes the current state of knowledge about inborn errors of purine and pyrimidine metabolism, focusing on the varying clinical presentations, the laboratory findings and discusses indications for selective screening for these disorders.

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Inborn errors of pyrimidine degradation: Clinical, biochemical and molecular aspects

Cited by 102 publications

References 37 publications

Crystal Structures of Yeast β-Alanine Synthase Complexes Reveal the Mode of Substrate Binding and Large Scale Domain Closure Movements

Crystal Structures of Yeast β-Alanine Synthase Complexes Reveal the Mode of Substrate Binding and Large Scale Domain Closure Movements

Screening and diagnosis of β‐ureidopropionase deficiency by gas chromatographic/mass spectrometric analysis of urine

Inborn errors of purine and pyrimidine metabolism

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