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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
Glycerol, for molecular biology, ≥99.0%
Sigma-Aldrich
Glycerol, ≥99.5%
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Glycerol, ACS reagent, ≥99.5%
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L-Tryptophan, reagent grade, ≥98% (HPLC)
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Glycerol, ReagentPlus®, ≥99.0% (GC)
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Glycerol, BioReagent, suitable for cell culture, suitable for insect cell culture, suitable for electrophoresis, ≥99% (GC)
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Glycerin, meets USP testing specifications
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3-Indoleacetic acid, suitable for plant cell culture, crystalline
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Glycerol, BioXtra, ≥99% (GC)
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3-Indoleacetic acid, 98%
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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)
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Glycerol solution, 83.5-89.5% (T)
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L-Tryptophan, BioUltra, ≥99.5% (NT)
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Glycerol, puriss., meets analytical specification of Ph. Eur., BP, USP, FCC, E422, anhydrous, 99.0-101.0% (alkalimetric)
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Glycerol, FCC, FG
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Glycerol, puriss. p.a., ACS reagent, anhydrous, dist., ≥99.5% (GC)
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Glycerol, tested according to Ph. Eur., anhydrous
Supelco
L-Tryptophan, certified reference material, TraceCERT®
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Indole-3-pyruvic acid, ≥97%
Supelco
3-Indoleacetic acid, PESTANAL®, analytical standard
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3-Indolepropionic acid, ReagentPlus®, 99%
Sigma-Aldrich
Indole-3-propionic acid, ≥99.0% (T)
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Glycerol solution, puriss., meets analytical specification of Ph. Eur., BP, 84-88%
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Indole-3-propionic acid, ≥97.0% (T)
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3-Indoleacrylic acid, BioReagent, ≥98% (HPLC)
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trans-3-Indoleacrylic acid, 98%
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3-Indoleacrylic acid, powder
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Glycerol solution, puriss. p.a., 86-89% (T)
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Anti-KYAT1 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution, Ab2

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