A compendium of inborn errors of metabolism mapped onto the human metabolic network.
Inborn errors of metabolism (IEMs) are hereditary metabolic defects, which are encountered in almost all major metabolic pathways occurring in man. Many IEMs are screened for in neonates through metabolomic analysis of dried blood spot samples. To enable the mapping of these metabolomic data onto the published human metabolic reconstruction, we added missing reactions and pathways involved in acylcarnitine (AC) and fatty acid oxidation (FAO) metabolism. Using literary data, we reconstructed an AC/FAO module consisting of 352 reactions and 139 metabolites. When this module was combined with the human metabolic reconstruction, the synthesis of 39 acylcarnitines and 22 amino acids, which are routinely measured, was captured and 235 distinct IEMs could be mapped. We collected phenotypic and clinical features for each IEM enabling comprehensive classification. We found that carbohydrate, amino acid, and lipid metabolism were most affected by the IEMs, while the brain was the most commonly affected organ. Furthermore, we analyzed the IEMs in the context of metabolic network topology to gain insight into common features between metabolically connected IEMs. While many known examples were identified, we discovered some surprising IEM pairs that shared reactions as well as clinical features but not necessarily causal genes. Moreover, we could also re-confirm that acetyl-CoA acts as a central metabolite. This network based analysis leads to further insight of hot spots in human metabolism with respect to IEMs. The presented comprehensive knowledge base of IEMs will provide a valuable tool in studying metabolic changes involved in inherited metabolic diseases.
Center for Systems Biology, University of Iceland, Iceland.
Swagatika
S
Sahoo
Leifur
L
Franzson
Jon J
JJ
Jonsson
Ines
I
Thiele
D000105:Acetyl Coenzyme A / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D050260:Carbohydrate Metabolism; D002331:Carnitine / Q000031:analogs & derivatives* / Q000378:metabolism; D059788:Dried Blood Spot Testing; D005227:Fatty Acids / Q000378:metabolism*; D015894:Genome, Human; D006801:Humans; D007231:Infant, Newborn; D050356:Lipid Metabolism; D053858:Metabolic Networks and Pathways; D008661:Metabolism, Inborn Errors / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D055432:Metabolomics / Q000379:methods*; D010084:Oxidation-Reduction; D053719:Tandem Mass Spectrometry
D000596:Amino Acids; D005227:Fatty Acids; C116917:acylcarnitine; D000105:Acetyl Coenzyme A; D002331:Carnitine