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Understanding the role of vitamin B2 in lipid metabolism diseases

ITQB researchers look into mitochondrial protein folding
Understanding the role of vitamin B2 in lipid metabolism diseases

Vitamin B2 and mitochondrial ETF protein folding

Oeiras, 16.04.09

Vitamin B2 is used therapeutically in patients suffering from Glutaric Aciduria type II, a lipid metabolism disease with a vast range of clinical features, but the mechanism of action of this compound was only recently elicited by the Laboratory of Protein Biochemistry, Folding & Stability and co-workers. The results are published on the February issue of the Journal of Biological Chemistry.

Many genetic metabolic diseases result from defects in protein folding and conformation. In Glutaric Aciduria type II, point mutations affect the mitochondrial ETF protein and lead to a deficient fatty acid metabolism. While the severity of the disease depends on the gene variant, in milder clinical forms, the residual activity of ETF is also modulated by the cell environment, such as temperature or the presence of cofactors. It is precisely here that vitamin B2 plays a role. In the cell, vitamin B2 is converted into flavin adenine dinucleotide (FAD), the cofactor present in ETF.

By combining biophysical, spectroscopic, and biochemical methodologies, the work now published on JBC shows how the presence of FAD improves the conformational stability, biological activity and lifetime of a clinical mutant variant of ETF in vitro. In vivo, the increased FAD concentrations resulting from vitamin B2 supplementation may enhance the conformational quality of the affected ETF protein by a similar mechanism.

The protective role of FAD (and presumably of vitamin B2) is present even when mimicking a cellular stress, like fever – a condition known to aggravate the symptoms of patients with mild fatty acid metabolism disorders. The findings now reported open new avenues concerning the development and use of small molecules to act as correctors of protein folding defects, the so-called pharmacological chaperones, in order to ameliorate disease symptoms.


Original paper:

J. Biol. Chem, 284:   42... 

Henriques, B.J., Rodrigues, J.V., Olsen, R., Bross, P., Gomes, C.M.

Role of flavinylation in a mild variant of multiple acyl-CoA dehydrogenation deficiency: a molecular rationale for the effects of riboflavin supplementation



The Journal of Biological Chemistry publishes papers based on original research that are judged, after editorial review, to make a novel and important contribution to the understanding of any area of biochemistry and molecular biology

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