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

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.

Biochemical Competition Makes Fatty-Acid β-Oxidation Vulnerable to Substrate Overload

“…The reactions correspond to the mitochondrial β-oxidation module in the updated human metabolic reconstruction [14], with the difference that we tailored them to rat liver. Thus, we added the long-chain acyl-CoA dehydrogenase (LCAD), which is involved in rodent β-oxidation [15]–[18].…”

Downregulation of the acetyl-CoA metabolic network in adipose tissue of obese diabetic individuals and recovery after weight loss

“…These genes all participate in the immediate vicinity of acetyl-CoA metabolism and are known hotspots of human metabolism, with ACAT1, ALDH6A1 and ACACA recorded among inborn errors of metabolism (IEM) (Online Mendelian Inheritance in Man [OMIM]: 203750, 614105 and 613933, respectively). IEMs are congenital metabolic defects arising from single or multiple enzyme deficiencies [26]. Recently, IEMs have been mapped onto a mathematical reconstruction of human metabolism [27].…”

Systems biology of stored blood cells: Can it help to extend the expiration date?

“…This translation results in a genome scale metabolic reconstruction, which represents a biochemical, genetic and genomic (BIGG) knowledge base [11] for a target organism. These reconstructions may then be used to investigate fundamental biological questions, guide industrial strain design, and provide a systems perspective for analysis of the expanding ocean of omics data [12][13][14].…”