Deamidated Human Triosephosphate Isomerase is a Promising Druggable Target

Biomolecules
Sergio Enríquez-FloresGabriel López-Velázquez

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. Th...Continue Reading

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Citations

Feb 11, 2021·Antioxidants·Olga V KosmachevskayaAlexey F Topunov
May 31, 2021·Infection, Genetics and Evolution : Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases·Yusuf Oloruntoyin AyipoMohd Nizam Mordi

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Datasets Mentioned

BETA
M10036.1

Methods Mentioned

BETA
deamidation
electrophoresis
ELISA
X-ray

Software Mentioned

MOLEonline
GraphPad Prism
Chimera
Achilles Blind Docking Server
PBEQ Solver

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