Nuclear magnetic resonance analysis and genetic metabolic disease

An accurate number of metabolites that play a role in human metabolism is unknown. The Human Metabolome Database (HMDB) (1) contains more than 7,900 metabolites present in human body fluids (concentration >1 µmol/L) (see Chapter 1), and the knowledge base Kyoto Encyclopedia of Genes and Genomes (KEGG) (2) contains 16,288 small molecules, biopolymers, and other chemical substances that are relevant to biological systems. Approximately 3,000 genes and 1,000,000 proteins are involved in human cellular metabolism and homeostasis. Inborn errors of metabolism (IEM) comprise a large class of genetic diseases involving disorders of metabolism. More than 500 IEM are known at the present time (3). Data suggest that many IEM remain as yet unknown. The analytical techniques that are used in routine diagnostics seem to be insufficient to detect a higher percentage of the estimated theoretical number of IEM. These techniques always rely on the detection of groups of metabolic intermediates with a special chemical group. Protons are available in almost any metabolite. Proton nuclear magnetic resonance (¹H NMR) spectroscopy may be able to identify and quantify simultaneously almost all metabolites in the micromolar and millimolar concentration range. For these reasons, NMR-based quantitative metabolomics is a powerful approach to study genetic metabolic diseases. NMR spectroscopy has been used as an analytical technique to detect metabolites, drugs, and toxic agents in body fluids, and several articles have reviewed NMR spectroscopy of body fluids. Two reviews described practical aspects relevant to metabolic analysis of body fluids and highlighted some of the strengths, limitations, and applications (4,5). Our group has reviewed body fluid NMR and IEM (6,7). These reviews show that more than 100 different IEM can be diagnosed by NMR spectroscopy. For most diseases, the Handbook of NMR Spectroscopy in Inborn Errors of Metabolism shows the characteristic parts of the NMR spectrum (8).