6t8q

HKATII IN COMPLEX WITH LIGAND (2R)-N-benzyl-1-[6-methyl-5-(oxan-4-yl)-7-oxo-6H,7H-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamideHKATII IN COMPLEX WITH LIGAND (2R)-N-benzyl-1-[6-methyl-5-(oxan-4-yl)-7-oxo-6H,7H-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide

Structural highlights

6t8q is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.51Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

AADAT_HUMAN Transaminase with broad substrate specificity. Has transaminase activity towards aminoadipate, kynurenine, methionine and glutamate. Shows activity also towards tryptophan, aspartate and hydroxykynurenine. Accepts a variety of oxo-acids as amino-group acceptors, with a preference for 2-oxoglutarate, 2-oxocaproic acid, phenylpyruvate and alpha-oxo-gamma-methiol butyric acid. Can also use glyoxylate as amino-group acceptor (in vitro).^[1]

Publication Abstract from PubMed

Human kynurenine aminotransferase 2 (KAT2) inhibitors could be potentially used to treat the cognitive deficits associated with bipolar disease and schizophrenia. Although, there has been active drug research activity by several industrial and academic groups in developing KAT2 inhibitors over the years, no such compound has proceeded to the clinics. Here, we report two different chemical series of reversible KAT2 inhibitors with sub-micromolar activities. The first series was identified by a high-throughput screening of a diverse random library and the second one by structure-based virtual screening. Two novel crystal structures of KAT2 complexed with different reversible inhibitors were also deposited to the Protein databank which could be useful for future drug discovery efforts.

Discovery of sulfonamides and 9-oxo-2,8-diazaspiro[5,5]undecane-2-carboxamides as human kynurenine aminotransferase 2 (KAT2) inhibitors.,Kalliokoski T, Rummakko P, Rantanen M, Blaesse M, Augustin M, Ummenthala GR, Choudhary S, Venalainen J Bioorg Med Chem Lett. 2020 Feb 22:127060. doi: 10.1016/j.bmcl.2020.127060. PMID:32113843^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Han Q, Cai T, Tagle DA, Robinson H, Li J. Substrate specificity and structure of human aminoadipate aminotransferase/kynurenine aminotransferase II. Biosci Rep. 2008 Aug;28(4):205-15. PMID:18620547 doi:10.1042/BSR20080085
↑ Kalliokoski T, Rummakko P, Rantanen M, Blaesse M, Augustin M, Ummenthala GR, Choudhary S, Venalainen J. Discovery of sulfonamides and 9-oxo-2,8-diazaspiro[5,5]undecane-2-carboxamides as human kynurenine aminotransferase 2 (KAT2) inhibitors. Bioorg Med Chem Lett. 2020 Feb 22:127060. doi: 10.1016/j.bmcl.2020.127060. PMID:32113843 doi:http://dx.doi.org/10.1016/j.bmcl.2020.127060

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OCA

[1] Han Q, Cai T, Tagle DA, Robinson H, Li J. Substrate specificity and structure of human aminoadipate aminotransferase/kynurenine aminotransferase II. Biosci Rep. 2008 Aug;28(4):205-15. PMID:18620547 doi:10.1042/BSR20080085

[2] Kalliokoski T, Rummakko P, Rantanen M, Blaesse M, Augustin M, Ummenthala GR, Choudhary S, Venalainen J. Discovery of sulfonamides and 9-oxo-2,8-diazaspiro[5,5]undecane-2-carboxamides as human kynurenine aminotransferase 2 (KAT2) inhibitors. Bioorg Med Chem Lett. 2020 Feb 22:127060. doi: 10.1016/j.bmcl.2020.127060. PMID:32113843 doi:http://dx.doi.org/10.1016/j.bmcl.2020.127060

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