Fibroblast-specific genome-scale modelling predicts an imbalance in amino acid metabolism in Refsum disease.

Agnieszka B Wegrzyn,Katharina Herzog,Justina C Wolters,Alida E M Van Lint,Marcel Kwiatkowski,Amalia M Dolga,Ronald J A Wanders,Barbara M Bakker,Hans R Waterham,Albert Gerding

doi:10.1111/febs.15292

Abstract

Refsum disease (RD) is an inborn error of metabolism that is characterised by a defect in peroxisomal α‐oxidation of the branched‐chain fatty acid phytanic acid. The disorder presents with late‐onset progressive retinitis pigmentosa and polyneuropathy and can be diagnosed biochemically by elevated levels of phytanate in plasma and tissues of patients. To date, no cure exists for RD, but phytanate levels in patients can be reduced by plasmapheresis and a strict diet. In this study, we reconstructed a fibroblast‐specific genome‐scale model based on the recently published, FAD‐curated model, based on Recon3D reconstruction. We used transcriptomics (available via GEO database with identifier GSE138379), metabolomics and proteomics (available via ProteomeXchange with identifier PXD015518) data, which we obtained from healthy controls and RD patient fibroblasts incubated with phytol, a precursor of phytanic acid. Our model correctly represents the metabolism of phytanate and displays fibroblast‐specific metabolic functions. Using this model, we investigated the metabolic phenotype of RD at the genome scale, and we studied the effect of phytanate on cell metabolism. We identified 53 metabolites that were predicted to discriminate between healthy and RD patients, several of which with a link to amino acid metabolism. Ultimately, these insights in metabolic changes may provide leads for pathophysiology and therapy.DatabasesTranscriptomics data are available via GEO database with identifier GSE138379, and proteomics data are available via ProteomeXchange with identifier PXD015518.

Highlights

Peroxisomes are organelles that, among other functions, are crucial for cellular lipid metabolism
We used an updated version of the Recon3D model in which flavoprotein-related metabolism was curated [20]. This addition was essential for this study because many enzymes in fatty acid metabolism are flavoproteins, which carry FAD as a cofactor
We present a fibroblast-specific metabolic model for Refsum disease (RD)

Summary

Introduction

Peroxisomes are organelles that, among other functions, are crucial for cellular lipid metabolism. They perform both anabolic and catabolic processes, including the a- and b-oxidation of very-long-chain fatty acids, dicarboxylic acids and methyl-branched-chain fatty acids [1]. The end product of x-oxidation of phytanate is 3-methyladipic acid (3-MAA), and x-oxidation has been described to be upregulated in patients with RD [5]. Phytanate solely derives from the diet, and patients with RD are mostly diagnosed in late childhood [3,5]. Patient management focuses on the reduction of phytanate levels by plasmapheresis and a strict diet to reduce the intake of dairy-derived fat [6]

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