3-Hydroxykynurenine as a Potential Ligand for Hsp70 Proteins and Its Effects on Drosophila Memory After Heat Shock

Aleksandr V Zhuravlev,Boris F Shchegolev,Polina N Ivanova,Ekaterina A Nikitina,Gennadii A Zakharov,Elena V Savvateeva-Popova

doi:10.1007/s12035-021-02704-3

Aleksandr V Zhuravlev, Boris F Shchegolev + Show 4 more

Open Access

https://doi.org/10.1007/s12035-021-02704-3

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Abstract

Kynurenine products of tryptophan metabolism are modifiers of the nervous activity and oxidative processes in mammals and invertebrates. 3-Hydroxykynurenine (3HOK) in moderate concentrations is a lipid peroxidation inhibitor. However, its accumulation and oxidative auto-dimerization lead to oxidative stress development manifested in age-related neurodegenerative diseases (NDD) and neurological disorders provoked by acute stress. Different forms of stress, the mostly studied being heat shock response, rely on functioning of heat shock proteins of the Hsp70 superfamily. Since kynurenines are called "kids of stress," we performed computational estimation of affinity of 3HOK and other kynurenines binding to predicted ATP site of Drosophila melanogaster Hsp cognate 71 protein (Dhsp71) using AutoDock Vina. The binding energy of 3HOK dimer is - 9.4kcal/mol; its orientation within the active site is close to that of ATP. This might be a new mechanism of producing a competitive inhibitor of Hsp70 chaperones that decreases organism ability to adapt to heat shock. We also showed that the Drosophila cardinal (cd1) mutant with 3HOK excess, serving as a model for Huntington's disease (HD), manifests severe defects of short-term memory after heat shock applied either in adults or at the prepupal stage.

Highlights

Kynurenine pathway (KP) is a main route of tryptophan catabolism in different animal species and phyla
We showed that the Drosophila melanogaster cardinal mutant with 3HOK excess, serving as a model for Huntington's disease (HD), manifests severe defects of short-term memory after heat shock applied either in adults, or at the prepupal stage
The mutant flies without hsp70 genes showed a 4-fold lower 3 h learning and memory scores than control CS flies. This clearly pinpointed the involvement of Hsp70 in the learning process, namely in the formation of short-term memory (STM)

Summary

Introduction

Kynurenine pathway (KP) is a main route of tryptophan catabolism in different animal species and phyla. The major prerequisite to NDDs development is the concentration ratio of different kynurenines. Lkynurenine (KYN), 3-hydroxykynurenine (3HOK) and quinolinic acid (QUIN) exert either neuroprotective, or neurodegenerative effects. As to 3HOK, its high concentration is a critical factor for development of many NDDs. In moderate concentrations, 3HOK and 3-hydroxyanthranilic acid (3HAA) are inhibitors of lipid peroxidation that can ameliorate the toxic action of reactive oxygen species (ROS) [5, 6]. Kynurenic acid (KYNA) is an endogenous protector against neurotoxicity [11, 12]

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