Deamidated Human Triosephosphate Isomerase is a Promising Druggable Target

• Main Authors: Sergio Enríquez-Flores, Luis Antonio Flores-López, Itzhel García-Torres, Ignacio de la Mora-de la Mora, Nallely Cabrera, Pedro Gutiérrez-Castrellón, Yoalli Martínez-Pérez, Gabriel López-Velázquez
• Format: Article
• Language: English
• Published: MDPI AG 2020-07-01
• Series: Biomolecules
• Subjects: protein structure; triosephosphate isomerase; Glycolysis; AGEs; SARS-CoV-2; omeprazole
• Online Access: https://www.mdpi.com/2218-273X/10/7/1050

Therapeutic strategies for the treatment of any severe disease are based on the discovery and validation of druggable targets. The human genome encodes only 600–1500 targets for small-molecule drugs, but posttranslational modifications lead to a considerably larger druggable proteome. The spontaneous conversion of asparagine (Asn) residues to aspartic acid or isoaspartic acid is a frequent modification in proteins as part of the process called deamidation. Triosephosphate isomerase (TIM) is a glycolytic enzyme whose deamidation has been thoroughly studied, but the prospects of exploiting this phenomenon for drug design remain poorly understood. The purpose of this study is to demonstrate the properties of deamidated human TIM (HsTIM) as a selective molecular target. Using in silico prediction, in vitro analyses, and a bacterial model lacking the <i>tim</i> gene, this study analyzed the structural and functional differences between deamidated and nondeamidated HsTIM, which account for the efficacy of this protein as a druggable target. The highly increased permeability and loss of noncovalent interactions of deamidated TIM were found to play a central role in the process of selective enzyme inactivation and methylglyoxal production. This study elucidates the properties of deamidated HsTIM regarding its selective inhibition by thiol-reactive drugs and how these drugs can contribute to the development of cell-specific therapeutic strategies for a variety of diseases, such as COVID-19 and cancer.