Deamidated Human Triosephosphate Isomerase is a Promising Druggable Target.

Sergio Enríquez-Flores,Pedro Gutiérrez-Castrellón,Gabriel López-Velázquez,Luis Antonio Flores-López,Ignacio De La Mora-De La Mora,Itzhel García-Torres,Yoalli Martínez-Pérez,Nallely Cabrera

doi:10.3390/biom10071050

Abstract

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 tim 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.

Highlights

Deamidation of asparagine (Asn) residues is a commonly occurring posttranslational modification in proteins
These results indicate that the incorporation of de novo negative charges in N16D HsTIM leads to important structural alterations in the interatomic network of contacts at the interface of the enzyme
By using antitumor agents, doxorubicin and paclitaxel, Thornalley et al demonstrated that the effect of these drugs is linked to increased glucose metabolism and related increased formation of MGO

Summary

Introduction

Deamidation of asparagine (Asn) residues is a commonly occurring posttranslational modification in proteins. Deamidation causes de novo negative charges into the protein structure by changing Asn to aspartic acid (Asp) or isoaspartic acid (isoAsp) in a nonenzymatic reaction. In mammals, such reactions can be directed by N-terminal asparagine amidohydrolase 1 (NTAN1) [1]. This modification is believed to be a major pathway to protein turnover but may induce structural changes that can lead to new functions [2]. Deamidation at internal Asn residues in proteins occurs near neutral pH through an intramolecular arrangement of two steps. In some proteins, this ratio can change, resulting in a higher yield of Asp [7]

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