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Article

Functional Recovery of a GCDH Variant Associated to Severe Deflavinylation—Molecular Insights into Potential Beneficial Effects of Riboflavin Supplementation in Glutaric Aciduria-Type I Patients

1
Biosystems and Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
2
Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(19), 7063; https://doi.org/10.3390/ijms21197063
Received: 11 August 2020 / Revised: 21 September 2020 / Accepted: 22 September 2020 / Published: 25 September 2020
(This article belongs to the Special Issue Flavin Adenine Dinucleotide (FAD): Biosynthesis and Function)
Riboflavin is the biological precursor of two important flavin cofactors—flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN)—that are critical prosthetic groups in several redox enzymes. While dietary supplementation with riboflavin is a recognized support therapy in several inborn errors of metabolism, it has yet unproven benefits in several other pathologies affecting flavoproteins. This is the case for glutaric aciduria type I (GA-I), a rare neurometabolic disorder associated with mutations in the GCDH gene, which encodes for glutaryl-coenzyme A (CoA) dehydrogenase (GCDH). Although there are a few reported clinical cases that have responded to riboflavin intake, there is still not enough molecular evidence supporting therapeutic recommendation. Hence, it is necessary to elucidate the molecular basis in favor of riboflavin supplementation in GA-I patients. Here, using a combination of biochemical and biophysical methodologies, we investigate the clinical variant GCDH-p.Val400Met as a model for a phenotype associated with severe deflavinylation. Through a systematic analysis, we establish that recombinant human GCDH-p.Val400Met is expressed in a nonfunctional apo form, which is mainly monomeric rather than tetrameric. However, we show that exogenous FAD is a driver for structural reorganization of the mutant enzyme with concomitant functional recovery, improved thermolability, and resistance to trypsin digestion. Overall, these results establish proof of principle for the beneficial effects of riboflavin supplementation in GA-I patients. View Full-Text
Keywords: riboflavin; FAD; flavoenzymes; flavinylation; protein folding; spectroscopies; glutaric aciduria type I; neurometabolic disorder; inborn errors of metabolism riboflavin; FAD; flavoenzymes; flavinylation; protein folding; spectroscopies; glutaric aciduria type I; neurometabolic disorder; inborn errors of metabolism
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MDPI and ACS Style

Ribeiro, J.V.; Gomes, C.M.; Henriques, B.J. Functional Recovery of a GCDH Variant Associated to Severe Deflavinylation—Molecular Insights into Potential Beneficial Effects of Riboflavin Supplementation in Glutaric Aciduria-Type I Patients. Int. J. Mol. Sci. 2020, 21, 7063. https://doi.org/10.3390/ijms21197063

AMA Style

Ribeiro JV, Gomes CM, Henriques BJ. Functional Recovery of a GCDH Variant Associated to Severe Deflavinylation—Molecular Insights into Potential Beneficial Effects of Riboflavin Supplementation in Glutaric Aciduria-Type I Patients. International Journal of Molecular Sciences. 2020; 21(19):7063. https://doi.org/10.3390/ijms21197063

Chicago/Turabian Style

Ribeiro, Joana V.; Gomes, Cláudio M.; Henriques, Bárbara J. 2020. "Functional Recovery of a GCDH Variant Associated to Severe Deflavinylation—Molecular Insights into Potential Beneficial Effects of Riboflavin Supplementation in Glutaric Aciduria-Type I Patients" Int. J. Mol. Sci. 21, no. 19: 7063. https://doi.org/10.3390/ijms21197063

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