Structure of the PLP-Form of the Human Kynurenine Aminotransferase II in a Novel Spacegroup at 1.83 Å Resolution.

Alireza Nematollahi,Jane Hanrahan,Guanchen Sun,Stephen Harrop,W Church

doi:10.3390/ijms17040446

Alireza Nematollahi, Jane Hanrahan + Show 3 more

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https://doi.org/10.3390/ijms17040446

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Abstract

Kynurenine aminotransferase II (KAT-II) is a 47 kDa pyridoxal phosphate (PLP)-dependent enzyme, active as a homodimer, which catalyses the transamination of the amino acids kynurenine (KYN) and 3-hydroxykynurenine (3-HK) in the tryptophan pathway, and is responsible for producing metabolites that lead to kynurenic acid (KYNA), which is implicated in several neurological diseases such as schizophrenia. In order to fully describe the role of KAT-II in the pathobiology of schizophrenia and other brain disorders, the crystal structure of full-length PLP-form hKAT-II was determined at 1.83 Å resolution, the highest available. The electron density of the active site reveals an aldimine linkage between PLP and Lys263, as well as the active site residues, which characterize the fold-type I PLP-dependent enzymes.

Highlights

Kynurenic acid (KYNA), with several specific biological activities, is known to antagonize all ionotropic glutamate receptors
In this paper we describe the three-dimensional (3D) crystal structure of the pyridoxal phosphate (PLP) form of hKAT-II (PDB entry: 5EUN) in the novel space group P43212, at 1.83 Å resolution, which is the highest available for the hKAT-II structure
The activity assay results were consistent with previous reports of recombinant hKAT-II activity with α-ketoglutarate as co-substrate (Figure 1) [31,32]

Summary

Introduction

Kynurenic acid (KYNA), with several specific biological activities, is known to antagonize all ionotropic glutamate receptors. The physiological role described for KYNA which prevents glutamate receptors from becoming excessively excited establishes it as crucial for brain stability under normal physiological conditions [5]. It is clear that increased KYNA levels protects neurons against ischemic brain damage, and anti-seizure activity is known [6,7]. Studies revealed that α7-nicotinic acetylcholine receptors (α7-nAChRs) are inhibited by KYNA, and this results in a decreased release of glutamate, which balances levels of extracellular dopamine [8]. As inflammation (resulting from viral and bacterial infections) can activate the tryptophan catabolic pathway [10,11], the ensuing tryptophan catabolism decreases plasma levels of tryptophan and increases KYNA plasma levels [12,13]. KYNA exhibits antioxidant activity due to its capability of scavenging free radical agents [14,15] which is independent of its pharmacological actions at receptors

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