ID 112024
Author
Kato, Yusuke Tokyo University of Pharmacy and Life Sciences|Himeji Hinomoto College|Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Kihara, Hiroshi Himeji Hinomoto College
Kojima, Masaki Tokyo University of Pharmacy and Life Sciences
Keywords
Sirtuin
Metabolism
Homology modeling
Cancer
Docking
Ischemic heart disease
Content Type
Journal Article
Description
Sirtuin4 (Sirt4) is one of the mammalian homologues of Silent information regulator 2 (Sir2), which promotes the longevity of yeast, C. elegans, fruit flies and mice. Sirt4 is localized in the mitochondria, where it contributes to preventing the development of cancers and ischemic heart disease through regulating energy metabolism. The ADP-ribosylation of glutamate dehydrogenase (GDH), which is catalyzed by Sirt4, downregulates the TCA cycle. However, this reaction mechanism is obscure, because the structure of Sirt4 is unknown. We here constructed structural models of Sirt4 by homology modeling and threading, and docked nicotinamide adenine dinucleotide+ (NAD+) to Sirt4. In addition, a partial GDH structure was docked to the Sirt4-NAD+ complex model. In the ternary complex model of Sirt4-NAD+-GDH, the acetylated lysine 171 of GDH is located close to NAD+. This suggests a possible mechanism underlying the ADP-ribosylation at cysteine 172, which may occur through a transient intermediate with ADP-ribosylation at the acetylated lysine 171. These results may be useful in designing drugs for the treatment of cancers and ischemic heart disease.
Journal Title
Computational Biology and Chemistry
ISSN
14769271
NCID
AA11947228
AA11829786
Publisher
Elsevier
Volume
74
Start Page
94
End Page
104
Published Date
2018-03-10
Remark
論文本文は2020-03-10以降公開予定
Rights
© 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
language
eng
TextVersion
その他
departments
Institute of Advanced Medical Sciences