Molecular Mechanisms, Genotype–Phenotype Correlations and Patient-Specific Treatments in Inherited Metabolic Diseases

Advances in DNA sequencing technologies are revealing a vast genetic heterogeneity in human population, which may predispose to metabolic alterations if the activity of metabolic enzymes is affected [1,2,3,4]. Mutations and polymorphism may affect several protein functions simultaneously, such as catalysis, regulation, ligand binding, intracellular folding, degradation, aggregation and transport [5,6,7,8,9,10,11,12]. This is a consequence of the propagation of local stability effects across the protein structure [11,13,14,15,16,17,18] (Figure 1). In this Special Issue, we focus on three critical aspects currently under development regarding metabolic diseases with a genetic origin, namely the high-throughput computation of genotype–phenotype correlations [19], their treatment using natural or pharmacological chaperones [20,21] and the inhibition of altered metabolic routes to prevent the accumulation of toxic intermediates [22].

Most human proteins are oligomeric. Human alanine:glyoxylate aminotransferase (AGT) is responsible for glyoxylate detoxification in human liver peroxisomes, and inherited mutations lead to a life-threatening metabolic disease called primary hyperoxaluria type I (PH1), characterized by oxalate accumulation and liver and kidney failure [11,23]. Dindo and coworkers describe in this Special Issue the importance of the dimerization of human alanine:glyoxylate amino transferase (AGT) for the proper folding of the enzyme in cells and its import to peroxisomes, where the enzyme is metabolically useful, as well as the chaperone role of the protein cofactor pyridoxal 5′-phosphate (PLP) for dimerization and function [24]. More recently, the same group have described the successful development of pharmacological chaperones that partially restore the normal AGT activity of PH1-causing mutations [25]. Moya-Garzón and coworkers present in this Special Issue an alternative for the treatment of PH1 based on inhibitors of oxalate formation that is currently under further development by using tools from medicinal chemistry [22,26]. Human galactose 1-phosphate uridylyltransferase (GALT) is also a dimeric protein involved in the metabolism of galactose, and whose deficiency due to inherited mutations leads to galactosemia type I (GT1) [27]. The recently reported structure for GALT has allowed us to rationalize the effect of many disease-causing mutations, although many aspects of GT1 pathophysiology remain unclear [27]. The pathological mechanisms as well as novel therapies (mechanism- or phenomenological-based) and disease models are extensively discussed for GT1 in this Special Issue by Banford and coworkers [28] and Delnoy and coworkers [29].

Another example of oligomeric protein with a very complex regulation (through product inhibition and several phosphorylation events at the N-terminal domain), for which structural information has been recently provided is Tyrosine hydroxylase (TH) [30], the rate-limiting enzyme in catecholamine biosynthesis. The recently available high-resolution structural information for TH will likely improve our capacity to predict functional or folding effects of inherited mutations in the TH associated with Dopa-responsive dystonia (DRD), DA deficiency and Parkinsonisms [30]. In this Special Issue, Nygaard and coworkers deeply discussed multiple aspects of DRD, including genotype–phenotype correlations based on structural and experimental evidence as well as different therapeutic approaches such as pharmacological chaperones, gene- and enzyme-replacement therapies [31].

Pharmacophores found in high-throughput screening campaigns are promising as pharmacological chaperones for the treatment of inherited metabolic disease, although they often show drawbacks regarding solubility, bioavailability and side-effects [21,32,33]. In this Special Issue, Bernardo-Seisdedos and coworkers described the improvement of Ciclopirox as a repurposed drug for the treatment Congenital Erythropoietic Porphyria (CEP), a disease caused by a deficiency in the UROIIIS protein [7,33,34]. This type of optimization is fundamental to bringing basic studies to the clinical realm.

Overall, this Special Issue addresses several fundamental questions on the prediction of phenotypes and novel therapies for Personalized Medicine in Inborn Errors of Metabolism. It is important to highlight that all the groups that have contributed to this Special Issue are currently working on the improvement of the different mechanistic and therapeutic approaches presented. The exception is Prof. David J. Timson, who sadly passed away last summer. We hope that we will update all these studies in 2023.