Cofactors revisited – Predicting the impact of flavoprotein-related diseases on a genome scale

Publication date: Available online 29 October 2018Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of DiseaseAuthor(s): Agnieszka B. Wegrzyn, Sarah Stolle, Rienk A. Rienksma, Vítor A.P. Martins dos Santos, Barbara M. Bakker, Maria Suarez-DiezAbstractFlavin adenine dinucleotide (FAD) and its precursor flavin mononucleotide (FMN) are redox cofactors that are required for the activity of more than hundred human enzymes. Mutations in the genes encoding these proteins cause severe phenotypes, including a lack of energy supply and accumulation of toxic intermediates. Ideally, patients should be diagnosed before they show symptoms so that treatment and/or preventive care can start immediately. This can be achieved by standardized newborn screening tests. However, many of the flavin-related diseases lack appropriate biomarker profiles. Genome-scale metabolic models can aid in biomarker research by predicting altered profiles of potential biomarkers. Unfortunately, current models, including the most recent human metabolic reconstructions Recon and HMR, typically treat enzyme-bound flavins incorrectly as free metabolites. This in turn leads to artificial degrees of freedom in pathways that are strictly coupled. Here, we present a reconstruction of human metabolism with a curated and extended flavoproteome. To illustrate the functional consequences, we show that simulations with the curated model – unlike simulations with earlier Recon versions - correctly predict the me...

Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - October 30, 2018 Category: Molecular Biology Source Type: research