1H NMR spectroscopy of body fluids in patients with inborn errors of purine and pyrimidine metabolism

Wevers, Ron A.; Engelke, Udo F. H.; Rotteveel, J.J.; Heerschap, Arend; Jong, J.G.N. de; Abeling, N. G. G. M.; Gennip, A. H. van; Abreu, Ronney A. De

doi:10.1023/a:1005313524869

Cited by 27 publications

(25 citation statements)

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“…It was possible to diagnose these deficiencies using in vitro NMR spectroscopy (5,14). Since the elevated concentrations of all metabolites that are relevant for diagnosing enzyme deficiencies in the pyrimidine breakdown are easily detectable with in vitro NMR spectroscopy, the technique can be used to discriminate between these three deficiencies.…”

Section: Discussionmentioning

confidence: 99%

“…NMR spectra of these samples have been published earlier (5,14). The concentrations of all relevant metabolites in urine samples of the different patients are shown in Table 2.…”

Section: Thementioning

confidence: 99%

“…Many reports on this topic have been published (1)(2)(3)(4)(5). Several inborn errors in the pyrimidine metabolism are known.…”

mentioning

confidence: 99%

“…Deficiencies of DHPDH and DHP in man have been reported previously (6 -13). They can be easily diagnosed by measuring urine samples using in vitro NMR spectroscopy (5,14). Recently, we diagnosed the first patient with a deficiency of the third enzyme in the catabolic pathway of uracil and thymine, i.e., UP deficiency (15).…”

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confidence: 99%

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β‐Ureidopropionase deficiency: A novel inborn error of metabolism discovered using NMR spectroscopy on urine

et al. 2001

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In this work, NMR investigations that led to the discovery of a new inborn error of metabolism, ␤-ureidopropionase (UP) deficiency, are reported. 1D 1 H-NMR experiments were performed using a patient's urine. 3-Ureidopropionic acid was observed in elevated concentrations in the urine spectrum. A 1D 1 H-1 H total correlation spectroscopy (TOCSY) and two heteronuclear 2D NMR techniques (heteronuclear multiple bond correlation (HMBC) and heteronuclear single-quantum correlation (HSQC)) were used to identify the molecular structure of the compound that caused an unknown doublet resonance at 1.13 ppm. Combining the information from the various NMR spectra, this resonance could be assigned to 3-ureidoisobutyric acid. These observations suggested a deficiency of UP. With 1D 1 H-NMR spectroscopy, UP deficiency can be easily diagnosed. The 1 H-NMR spectrum can also be used to diagnose patients suffering from other inborn errors of metabolism in the pyrimidine degradation pathway.

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Section: Discussionmentioning

confidence: 99%

“…NMR spectra of these samples have been published earlier (5,14). The concentrations of all relevant metabolites in urine samples of the different patients are shown in Table 2.…”

Section: Thementioning

confidence: 99%

“…Many reports on this topic have been published (1)(2)(3)(4)(5). Several inborn errors in the pyrimidine metabolism are known.…”

mentioning

confidence: 99%

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confidence: 99%

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β‐Ureidopropionase deficiency: A novel inborn error of metabolism discovered using NMR spectroscopy on urine

et al. 2001

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“…Although mass spectrometry is the more sensitive technique, NMR provides broad coverage of the metabolome by detecting all of the (hydrogencontaining) metabolites present in the biofluid simultaneously, with excellent reproducibility and only limited sample pretreatment. Thus, for example, many classic inborn errors of metabolism (IEM) can be diagnosed by the use of 1 H NMR spectroscopy of body fluids (15)(16)(17). Several of the IEM are associated with the accumulation of amino acids as metabolites in serum and urine.…”

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confidence: 99%

Class selection of amino acid metabolites in body fluids using chemical derivatization and their enhanced ¹³ C NMR

Shanaiah

DeSilva

Gowda

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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We report a chemical derivatization method that selects a class of metabolites from a complex mixture and enhances their detection by 13 C NMR. Acetylation of amines directly in aqueous medium with 1,1 -13 C2 acetic anhydride is a simple method that creates a high sensitivity and quantitative label in complex biofluids with minimal sample pretreatment. Detection using either 1D or 2D 13 C NMR experiments produces highly resolved spectra with improved sensitivity. Experiments to identify and compare amino acids and related metabolites in normal human urine and serum samples as well as in urine from patients with the inborn errors of metabolism tyrosinemia type II, argininosuccinic aciduria, homocystinuria, and phenylketonuria demonstrate the method. The use of metabolite derivatization and 13 C NMR spectroscopy produces data suitable for metabolite profiling analysis of biofluids on a time scale that allows routine use. Extension of this approach to enhance the NMR detection of other classes of metabolites has also been accomplished. The improved detection of low-concentration metabolites shown here creates opportunities to improve the understanding of the biological processes and develop improved disease detection methodologies.carbon-13 ͉ inborn errors of metabolism ͉ metabolite profiling ͉ metabolomics ͉ metabonomics T he metabolic profile in biofluids represents a snapshot of ongoing biological processes in the human body. The presence of a particular metabolite, panel of metabolites, or a certain ratio of metabolites can indicate normal homeostasis, a response to biological stress, or even a specific disease state. Conventional medical diagnostic methods are typically based on the selective detection of a single or a few biochemical parameters that are associated with a given disease. A major challenge in the present practice of clinical medicine is the lack of suitable biomarkers and bioanalytical technologies for earlier detection of numerous diseases. Metabolic profiling or metabolomics, defined as the analysis of multiple biofluid metabolites in parallel, holds the promise of earlier disease detection and improved understanding of systems biology (1-3). Early indications of this potential have been reported for the detection of several diseases, including inborn errors of metabolism, cardiovascular diseases, and cancer (4-7).NMR and mass spectrometry are the two most often used analytical methods for metabolite profiling because of their high resolution and rich data content (8)(9)(10)(11)(12)(13)(14). Although mass spectrometry is the more sensitive technique, NMR provides broad coverage of the metabolome by detecting all of the (hydrogencontaining) metabolites present in the biofluid simultaneously, with excellent reproducibility and only limited sample pretreatment. Thus, for example, many classic inborn errors of metabolism (IEM) can be diagnosed by the use of 1 H NMR spectroscopy of body fluids (15-17). Several of the IEM are associated with the accumulation of amino acids as metabolites in serum an...

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Capillary electrophoresis for detection of inherited disorders of purine and pyrimidine metabolism: A selective approach

2002

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We developed a capillary electrophoresis method as a diagnostic tool for purine and pyrimidine metabolic disorders. Optimal conditions allowed the separation of the major diagnostic metabolites in urine samples within an analysis time of 10 min and with a separation efficiency of about 350,000 theoretical plates/m. The diagnostically important metabolites (adenine, adenosine, 2-deoxyadenosine, 2-deoxyguanosine, 2,8-dihydroxyadenine, guanosine, hypoxanthine, orotidine, orotic acid, and creatinine) were detectable at concentrations of 1.0-5.7 micromol/L. The method gives a linear calibration curve for tested purine and pyrimidine derivatives within the range of 5-500 micromol/L (r > 0.996) The coefficients of variation for the within- and between-day imprecisions were less than 3.2 and 5.8%, respectively. Characteristic abnormalities were detected in the electropherograms of urine samples from patients with purine and pyrimidine enzyme deficiencies. We provide electrophoretic and spectral characteristics of intermediates in purine and pyrimidine metabolism and possible artifacts from medication and their UV-absorbing compounds. Our method allows the detection of the majority of inborn errors of purine and pyrimidine metabolism.

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1H NMR spectroscopy of body fluids in patients with inborn errors of purine and pyrimidine metabolism

Cited by 27 publications

References 7 publications

β‐Ureidopropionase deficiency: A novel inborn error of metabolism discovered using NMR spectroscopy on urine

β‐Ureidopropionase deficiency: A novel inborn error of metabolism discovered using NMR spectroscopy on urine

Class selection of amino acid metabolites in body fluids using chemical derivatization and their enhanced ¹³ C NMR

Capillary electrophoresis for detection of inherited disorders of purine and pyrimidine metabolism: A selective approach

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1H NMR spectroscopy of body fluids in patients with inborn errors of purine and pyrimidine metabolism

Cited by 27 publications

References 7 publications

β‐Ureidopropionase deficiency: A novel inborn error of metabolism discovered using NMR spectroscopy on urine

β‐Ureidopropionase deficiency: A novel inborn error of metabolism discovered using NMR spectroscopy on urine

Class selection of amino acid metabolites in body fluids using chemical derivatization and their enhanced 13 C NMR

Capillary electrophoresis for detection of inherited disorders of purine and pyrimidine metabolism: A selective approach

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Class selection of amino acid metabolites in body fluids using chemical derivatization and their enhanced ¹³ C NMR