A compendium of inborn errors of metabolism mapped onto the human metabolic network (original) (raw)

* Corresponding authors

a Center for Systems Biology, University of Iceland, Iceland
E-mail: ines.thiele@gmail.com

b Department of Biochemistry & Molecular Biology, Faculty of Medicine, University of Iceland, Iceland

c Department of Genetics and Molecular Medicine, Landspitali, National University Hospital of Iceland, Iceland

d Faculty of Industrial Engineering, Mechanical Engineering & Computer Science, University of Iceland, Iceland

Abstract

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.

Graphical abstract: A compendium of inborn errors of metabolism mapped onto the human metabolic network

This article is part of the themed collection:Molecular BioSystems Emerging Investigators 2012

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Article information

DOI

https://doi.org/10.1039/C2MB25075F

Article type

Paper

Submitted

06 Mar 2012

Accepted

27 Apr 2012

First published

02 May 2012

Download Citation

Mol. BioSyst., 2012,8, 2545-2558

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