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

Agnieszka B. Wegrzyn, Sarah Stolle, Rienk A. Rienksma, Vítor A.P. Martins dos Santos, Barbara M. Bakker, Maria Suarez-Diez

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

Abstract

Flavin 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 metabolic impact of multiple-acyl-CoA-dehydrogenase deficiency as well as of systemic flavin-depletion. Moreover, simulations with the new model allowed us to identify a larger number of biomarkers in flavoproteome-related diseases, without loss of accuracy. We conclude that adequate inclusion of cofactors in constraint-based modelling contributes to higher precision in computational predictions.

LanguageEnglish
Pages360-370
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1865
Issue number2
DOIs
Publication statusPublished - 1 Feb 2019

Fingerprint

Flavoproteins
Biomarkers
Genome
Multiple Acyl Coenzyme A Dehydrogenase Deficiency
Flavins
Flavin Mononucleotide
Preventive Medicine
Flavin-Adenine Dinucleotide
Poisons
Enzymes
Oxidation-Reduction
Newborn Infant
Phenotype
Mutation
Research
Proteins
4,6-dinitro-o-cresol
Therapeutics

Keywords

  • Constraint-based modelling
  • FAD
  • Flavoprotein
  • FMN
  • Human genome-scale reconstruction
  • Inborn errors of metabolism

Cite this

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title = "Cofactors revisited – Predicting the impact of flavoprotein-related diseases on a genome scale",
abstract = "Flavin 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 metabolic impact of multiple-acyl-CoA-dehydrogenase deficiency as well as of systemic flavin-depletion. Moreover, simulations with the new model allowed us to identify a larger number of biomarkers in flavoproteome-related diseases, without loss of accuracy. We conclude that adequate inclusion of cofactors in constraint-based modelling contributes to higher precision in computational predictions.",
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Cofactors revisited – Predicting the impact of flavoprotein-related diseases on a genome scale. / Wegrzyn, Agnieszka B.; Stolle, Sarah; Rienksma, Rienk A.; Martins dos Santos, Vítor A.P.; Bakker, Barbara M.; Suarez-Diez, Maria.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1865, No. 2, 01.02.2019, p. 360-370.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - Wegrzyn, Agnieszka B.

AU - Stolle, Sarah

AU - Rienksma, Rienk A.

AU - Martins dos Santos, Vítor A.P.

AU - Bakker, Barbara M.

AU - Suarez-Diez, Maria

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AB - Flavin 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 metabolic impact of multiple-acyl-CoA-dehydrogenase deficiency as well as of systemic flavin-depletion. Moreover, simulations with the new model allowed us to identify a larger number of biomarkers in flavoproteome-related diseases, without loss of accuracy. We conclude that adequate inclusion of cofactors in constraint-based modelling contributes to higher precision in computational predictions.

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KW - Human genome-scale reconstruction

KW - Inborn errors of metabolism

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T2 - Biochimica et Biophysica Acta. Molecular Basis of Disease

JF - Biochimica et Biophysica Acta. Molecular Basis of Disease

SN - 0925-4439

IS - 2

ER -