Cofactors and Metabolites as Protein Folding Helpers in Metabolic Diseases

Abstract

In the past few decades, improved early diagnosis methods, technological developments and an increasing crosstalk between clinicians and researchers has led to the identification of an increasing number of inborn metabolic diseases. In these disorders, missense mutations are the most frequent type of genetic defects, frequently resulting in defective protein folding. A better understanding at the molecular level of protein misfolding and its role in disease has prompted the emergence of therapies based in the use of small molecules that have the ability to correct protein folding defects. Well-known cases are reported for phenylketonuria and Gaucher's disease. Most of these compounds have a specific mechanism of action interacting directly with a particular protein, the so called pharmacological chaperones. Among such small molecules are protein ligands, either natural substrates or synthetic derivatives, cofactors, competitive inhibitors, and agonist/antagonists. In this review we will start by briefly overviewing the mechanisms through which such ligands exert a stabilizing action, and then move on to an extended discussion on therapeutic approaches and use of vitamins and substrates to correct protein misfolding in metabolic disorders. Examples of vitamins that have been successfully prescribed to rescue some cases of inborn errors of metabolism will be presented. In particular, the role of riboflavin supplementation in the treatment of fatty acid β-oxidation disorders will be thoroughly analyzed, focusing on recent reports that shed light on the molecular basis of vitamin responsiveness. Moreover, we will highlight the latest studies that point to a synergistic effect of cofactors and metabolites in the rescue of defective fatty acid β-oxidation enzymes. The synergism of multiple small molecules may underlie a promising general pharmacological strategy for the treatment of metabolic diseases in general.

FAD binding overcomes defects in activity and stability displayed by cancer-associated variants of human NQO1

“…Therefore, p.R139W may have and increased NQO1 activity [19]. Taken together, this suggests that di- involve FAD-dependent enzymes [67][68][69][70][71]. Furthermore, our results 552 predict that the levels of vitamin B2 required to rescue p.R139W will 553 be lower than those required for p.P187S (see Fig.…”

Stalled flavodoxin binds its cofactor while fully exposed outside the ribosome

“…Especially in eukaryotes, where protein synthesis is much slower than in prokaryotes (i.e., 3 instead of 20 amino acids per second [59]), such impediment of proteolysis could increase protein production efficiency. Indeed, for several flavoproteins involved in diseases, a beneficial effect has been observed when the respective flavin was supplemented [60].…”

Pharmacological chaperoning: A primer on mechanism and pharmacology

“…Reminiscent of pseudosubstrates and cofactors, which regulate the maturation and folding of their targets [148], evidence is accumulating that endogenous ligands act as “cognate ligand chaperones” to regulate the biogenesis of their target proteins. Coexpression of growth hormone and its receptor shows that growth hormone binds to nascent growth hormone receptors in the ER to facilitate receptor maturation, possibly by assisting dimerization [110].…”