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  • Structural insight into the inhibition of human kynurenine aminotransferase I/glutamine transaminase K.

Structural insight into the inhibition of human kynurenine aminotransferase I/glutamine transaminase K.

Journal of medicinal chemistry (2009-04-03)
Qian Han, Howard Robinson, Tao Cai, Danilo A Tagle, Jianyong Li
ABSTRACT

Human kynurenine aminotransferase I (hKAT I) catalyzes the formation of kynurenic acid, a neuroactive compound. Here, we report three high-resolution crystal structures (1.50-1.55 A) of hKAT I that are in complex with glycerol and each of two inhibitors of hKAT I: indole-3-acetic acid (IAC) and Tris. Because Tris is able to occupy the substrate binding position, we speculate that this may be the basis for hKAT I inhibition. Furthermore, the hKAT/IAC complex structure reveals that the binding moieties of the inhibitor are its indole ring and a carboxyl group. Six chemicals with both binding moieties were tested for their ability to inhibit hKAT I activity; 3-indolepropionic acid and DL-indole-3-lactic acid demonstrated the highest level of inhibition, and as they cannot be considered as substrates of the enzyme, these two inhibitors are promising candidates for future study. Perhaps even more significantly, we report the discovery of two different ligands located simultaneously in the hKAT I active center for the first time.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
trans-3-Indoleacrylic acid, 98%
Sigma-Aldrich
Glycerol solution, puriss., meets analytical specification of Ph. Eur., BP, 84-88%
Sigma-Aldrich
Indole-3-pyruvic acid, ≥97%
Sigma-Aldrich
3-Indoleacetic acid, suitable for plant cell culture, crystalline
Sigma-Aldrich
Indole-3-propionic acid, ≥99.0% (T)
Sigma-Aldrich
Indole-3-propionic acid, ≥97.0% (T)
Supelco
3-Indoleacetic acid, PESTANAL®, analytical standard
Sigma-Aldrich
Glycerol solution, 83.5-89.5% (T)
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3-Indoleacetic acid, 98%
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L-Tryptophan, reagent grade, ≥98% (HPLC)
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L-Tryptophan, from non-animal source, meets EP, JP, USP testing specifications, suitable for cell culture, 99.0-101.0%
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Glycerol, BioUltra, for molecular biology, anhydrous, ≥99.5% (GC)
Sigma-Aldrich
Glycerol, tested according to Ph. Eur., anhydrous
Sigma-Aldrich
Glycerol, for molecular biology, ≥99.0%
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Glycerol, ≥99.5%
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Glycerin, meets USP testing specifications
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Glycerol, BioXtra, ≥99% (GC)
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Glycerol, BioReagent, suitable for cell culture, suitable for insect cell culture, suitable for electrophoresis, ≥99% (GC)
Sigma-Aldrich
3-Indolepropionic acid, ReagentPlus®, 99%
Sigma-Aldrich
Glycerol, FCC, FG
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Glycerol, puriss. p.a., ACS reagent, anhydrous, dist., ≥99.5% (GC)
Sigma-Aldrich
Glycerol, ReagentPlus®, ≥99.0% (GC)
Sigma-Aldrich
Glycerol, ACS reagent, ≥99.5%
Sigma-Aldrich
3-Indoleacrylic acid, powder
Sigma-Aldrich
Glycerol, puriss., anhydrous, 99.0-101.0% (alkalimetric)