Structural Basis for Inhibitor-Induced Hydrogen Peroxide Production by Kynurenine 3-Monooxygenase
DC Field | Value | Language |
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dc.contributor.author | Kim, Hyun Tae | - |
dc.contributor.author | Na, Byeong Kwan | - |
dc.contributor.author | Chung, Jiwoung | - |
dc.contributor.author | Kim, Sulhee | - |
dc.contributor.author | Kwon, Sool Ki | - |
dc.contributor.author | Cha, Hyunju | - |
dc.contributor.author | Son, Jonghyeon | - |
dc.contributor.author | Cho, Joong Myung | - |
dc.contributor.author | Hwang, Kwang Yeon | - |
dc.date.accessioned | 2021-09-02T12:38:51Z | - |
dc.date.available | 2021-09-02T12:38:51Z | - |
dc.date.created | 2021-06-16 | - |
dc.date.issued | 2018-04-19 | - |
dc.identifier.issn | 2451-9448 | - |
dc.identifier.uri | https://scholar.korea.ac.kr/handle/2021.sw.korea/76115 | - |
dc.description.abstract | Kynurenine 3-monooxygenase (KMO) inhibitors have been developed for the treatment of neurodegenerative disorders. The mechanisms of flavin reduction and hydrogen peroxide production by KMO inhibitors are unknown. Herein, we report the structure of human KMO and crystal structures of Saccharomyces cerevisiae (sc) and Pseudomonas fluorescens (pf) KMO with Ro 61-8048. Proton transfer in the hydrogen bond network triggers flavin reduction in p-hydroxybenzoate hydroxylase, but the mechanism triggering flavin reduction in KMO is different. Conformational changes via pi-pi interactions between the loop above the flavin and substrate or non-substrate effectors lead to disorder of the C-terminal alpha helix in scKMO and shifts of domain III in pfKMO, stimulating flavin reduction. Interestingly, Ro 61-8048 has two different binding modes. It acts as a competitive inhibitor in scKMO and as a non-substrate effector in pfKMO. These findings provide understanding of the catalytic cycle of KMO and insight for structure-based drug design of KMO inhibitors. | - |
dc.language | English | - |
dc.language.iso | en | - |
dc.publisher | CELL PRESS | - |
dc.subject | P-HYDROXYBENZOATE HYDROXYLASE | - |
dc.subject | FLAVOPROTEIN HYDROXYLASES | - |
dc.subject | RECEPTOR EXPRESSION | - |
dc.subject | CELL-DEATH | - |
dc.subject | WILD-TYPE | - |
dc.subject | ACID | - |
dc.subject | FLAVIN | - |
dc.subject | BRAIN | - |
dc.subject | MONOOXYGENASE | - |
dc.subject | MECHANISM | - |
dc.title | Structural Basis for Inhibitor-Induced Hydrogen Peroxide Production by Kynurenine 3-Monooxygenase | - |
dc.type | Article | - |
dc.contributor.affiliatedAuthor | Kim, Sulhee | - |
dc.contributor.affiliatedAuthor | Hwang, Kwang Yeon | - |
dc.identifier.doi | 10.1016/j.chembiol.2018.01.008 | - |
dc.identifier.scopusid | 2-s2.0-85041687575 | - |
dc.identifier.wosid | 000430679100009 | - |
dc.identifier.bibliographicCitation | CELL CHEMICAL BIOLOGY, v.25, no.4, pp.426 - + | - |
dc.relation.isPartOf | CELL CHEMICAL BIOLOGY | - |
dc.citation.title | CELL CHEMICAL BIOLOGY | - |
dc.citation.volume | 25 | - |
dc.citation.number | 4 | - |
dc.citation.startPage | 426 | - |
dc.citation.endPage | + | - |
dc.type.rims | ART | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Biochemistry & Molecular Biology | - |
dc.relation.journalWebOfScienceCategory | Biochemistry & Molecular Biology | - |
dc.subject.keywordPlus | P-HYDROXYBENZOATE HYDROXYLASE | - |
dc.subject.keywordPlus | FLAVOPROTEIN HYDROXYLASES | - |
dc.subject.keywordPlus | RECEPTOR EXPRESSION | - |
dc.subject.keywordPlus | CELL-DEATH | - |
dc.subject.keywordPlus | WILD-TYPE | - |
dc.subject.keywordPlus | ACID | - |
dc.subject.keywordPlus | FLAVIN | - |
dc.subject.keywordPlus | BRAIN | - |
dc.subject.keywordPlus | MONOOXYGENASE | - |
dc.subject.keywordPlus | MECHANISM | - |
dc.subject.keywordAuthor | drug design | - |
dc.subject.keywordAuthor | flavin reduction | - |
dc.subject.keywordAuthor | hydrogen peroxide | - |
dc.subject.keywordAuthor | KMO inhibitor | - |
dc.subject.keywordAuthor | kynurenine 3-monooxygenase | - |
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