Academic Thesis

Basic information

Name Koga Yuuichi
Belonging department
Occupation name
researchmap researcher code 5000076449
researchmap agency Okayama University of Science

Title

Structural and mechanistic insights into the kynurenine aminotransferase-mediated excretion of kynurenic acid.

Bibliography Type

 

Author

Ken Okada
Clement Angkawidjaja
Yuichi Koga
Shigenori Kanaya

Summary

Kynurenine aminotransferase (KAT) is a homodimeric pyridoxal protein that mediates the catalytic conversion of kynurenine (KYN) to kynurenic acid (KYA), an endogenous N-methyl-d-aspartate (NMDA) receptor antagonist. KAT is involved in the biosynthesis of glutamic and aspartic acid, functions as a neurotransmitter for the NMDA receptor in mammals, and is regulated by allosteric mechanisms. Its importance in various diseases such as schizophrenia makes KAT a highly attractive drug target. Here, we present the crystal structure of the Pyrococcus horikoshii KAT (PhKAT) in complex with pyridoxamine phosphates (PMP), KYN, and KYA. Surprisingly, the PMP was bound to the LYS-269 of phKAT by forming a covalent hydrazine bond. This crystal structure clearly shows that an amino group of KYN was transaminated to PLP, which forms a Schiff's base with the LYS-269 of the KYN. Thus, our structure confirms that the PMPs represent an intermediate state during the KAT reaction. Thus, PhKAT catalyzes the sequential conversion of KYN to KYA via the formation of an intermediate 4-(2-aminophenyl)-2,4-dioxobutanoate (4AD), which is spontaneously converted to KYA in the absence of an amino group acceptor. Furthermore, we identified the two entry and exit sites of the PhKAT homodimer for KYN and KYA, respectively. The structural data on PhKAT presented in this manuscript contributes to further the understanding of transaminase enzyme reaction mechanisms.

Magazine(name)

Journal of structural biology

Publisher

ACADEMIC PRESS INC ELSEVIER SCIENCE

Volume

185

Number Of Pages

3

StartingPage

257

EndingPage

66

Date of Issue

2014-03

Referee

Exist

Invited

Not exist

Language

English

Thesis Type

Research papers (academic journals)

ISSN

 

DOI

10.1016/j.jsb.2014.01.009

NAID

 

PMID

 

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arXiv ID

 

ORCID Put Code

 

DBLP ID