Abstract
Classic galactosemia is an inborn error of metabolism associated with mutations that impair the activity and the stability of galactose-1-phosphate uridylyltransferase (GALT), catalyzing the third step in galactose metabolism. To date, no treatments (including dietary galactose deprivation) are able to prevent or alleviate the long-term complications affecting galactosemic patients. Evidence that arginine is able to improve the activity of the human enzyme expressed in a prokaryotic model of classic galactosemia has induced researchers to suppose that this amino acid could act as a pharmacochaperone, but no effects were detected in four galactosemic patients treated with this amino acid. Given that no molecular characterizations of the possible effects of arginine on GALT have been performed, and given that the samples of patients treated with arginine are extremely limited for drawing definitive conclusions at the clinical level, we performed computational simulations in order to predict the interactions (if any) between this amino acid and the enzyme. Our results do not support the possibility that arginine could function as a pharmacochaperone for GALT, but information obtained by this study could be useful for identifying, in the future, possible pharmacochaperones for this enzyme.
Highlights
Pharmacological chaperones are small molecules that, upon binding to specific target proteins, can stabilize their native conformation, or even correct misfolding in proteins affected by mutations, rescuing their original function [1]
Classic galactosemia (OMIM: #230400) is a rare disease affecting people carrying mutations in the gene coding for the enzyme galactose-1-phosphate uridylyltransferase (GALT) (Figure 1), catalyzing the third step in the Leloir pathway of galactose metabolism [4] (Scheme 1)
Targeting the active site of the enzyme could have an effect on the overall stability of the structure of GALT, given that the two active sites of the protein are at the interface between the two subunits forming the quaternary assembly and are formed by residues belonging to both monomeric chains; the mutant p.Gln188Arg shows a dominant negative effect due to the perturbation of the intersubunit interface caused by the mutation [13,20]
Summary
Pharmacological chaperones are small molecules that, upon binding to specific target proteins, can stabilize their native conformation, or even correct misfolding in proteins affected by mutations, rescuing their original function [1]. Several known pharmacochaperones act as reversible inhibitors, whereas others are able to bind to allosteric sites and stabilize or select more stable conformations of proteins. Computational approaches such as molecular dynamics (MD) simulations can shed light on the mechanisms of the interactions between the ligands and proteins, and play a crucial role in the discovery of suitable molecules [3]. Classic galactosemia (OMIM: #230400) is a rare disease affecting people carrying mutations in the gene coding for the enzyme galactose-1-phosphate uridylyltransferase (GALT) (Figure 1), catalyzing the third step in the Leloir pathway of galactose metabolism [4] (Scheme 1). Different forms of galactosemia derive from the impairment of each enzyme, as represented in the scheme
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